High intake of lycopene has been associated with a lower risk of a variety of cancers including lung cancer. We recently showed that lycopene can be converted to apo-10'-lycopenoids [Hu et al. (2006). J. Biol. Chem., 281, 19327-19338] in mammalian tissues both in vitro and in vivo, raising the question of whether apo-10'-lycopenoids have biological activities against lung carcinogenesis. In the present study, we report that apo-10'-lycopenoic acid inhibited the growth of NHBE normal human bronchial epithelial cells, BEAS-2B-immortalized normal bronchial epithelial cells and A549 non-small cell lung cancer cells. This inhibitory effect of apo-10'-lycopenoic acid was associated with decreased cyclin E, inhibition of cell cycle progression from G(1) to S phase and increased cell cycle regulators p21 and p27 protein levels. In addition, apo-10'-lycopenoic acid transactivated the retinoic acid receptor beta (RARbeta) promoter and induced the expression of RARbeta. We further examined the effect of apo-10'-lycopenoic acid treatment on 4-(N-methyl-N-nitrosamino)-1-(3-pyridal)-1-butanone (NNK)-induced lung tumorigenesis in the A/J mouse model. We found that the lung tumor multiplicity was decreased dose dependently from an average of 16 tumors per mouse in the NNK injection alone group, to an average of 10, 7 and 5 tumors per mouse in groups injected with NNK and supplemented with 10, 40 and 120 mg/kg diet of apo-10'-lycopenoic acid, respectively. These observations demonstrate that apo-10'-lycopenoic acid is a biological active metabolite of lycopene and suggest that apo-10'-lycopenoic acid is a potential chemopreventive agent against lung tumorigenesis.

While early studies focused on the potential roles in health and disease of provitamin A carotenoids, such as beta-carotene, research over the past decade has provided a framework for our understanding of the functions of non-provitamin A carotenoids such as lycopene, especially in regards to its association with a reduced risk of a number of chronic diseases, including cancer. Recent data suggests that lycopene metabolites may possess specific biological activities on several important cellular signaling pathways and molecular targets. Carotenoid metabolites may have more important biological roles than their parent compounds in human health and disease. This notion has been reinforced by the observation of both beneficial and detrimental effects of carotenoid metabolites in cancer prevention.

Lycopene can be cleaved by carotene 9 0 ,10 0 -oxygenase at its 9 0 ,10 0 double bond to form apo-10 0 -lycopenoids, including apo-10 0 -lycopenal, -lycopenol and -lycopenoic acid. The latter has been recently shown to inhibit lung carcinogenesis both in vivo and in vitro, however, the mechanism(s) underlying this protection is not well defined. In the present study, we report that treatment with apo-10 0 -lycopenoic acid, in a time-and dose-dependent manner, results in the nuclear accumulation of transcription factor Nrf2 (nuclear factor E 2 -related factor 2) protein in BEAS-2B human bronchial epithelial cells. The activation of Nrf2 by apo-10 0 -lycopenoic acid is associated with the induction of phase II detoxifying/antioxidant enzymes including heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1, glutathione S-transferases, and glutamate-cysteine ligases in BEAS-2B cells. Furthermore, apo-10 0 -lycopenoic acid treatment increased total intracellular glutathione levels and suppressed both endogenous reactive oxygen species generation and H 2 O 2 -induced oxidative damage in BEAS-2B cells. In addition, both apo-10 0 -lycopenol and apo-10 0 -lycopenal induced heme oxygenase-1 gene expression in BEAS-2B cells. These data strongly suggest that the anti-carcinogenic and antioxidant functions of lycopene may be mediated by apo-10 0 -lycopenoids via activating Nrf2 and inducing phase II detoxifying/ antioxidant enzymes. ' 2008 Wiley-Liss, Inc.Key words: lycopene; apo-10 0 -lycopenoic acid; phase II enzymes; Nrf2; GSH; oxidative damageThe chemopreventive effect of lycopene, a carotenoid rich in tomato and tomato-based products, against cancers has been suggested in many epidemiological and animal studies. [1][2][3][4][5][6] One of explanations for the protective effect of lycopene is its ability to induce phase II detoxifying/antioxidant enzymes found in both in vitro and in vivo studies. [7][8][9] The induction of phase II detoxifying/antioxidant enzymes, such as heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferases (GSTs), glutathione reductase (GSR), glutamate-cysteine ligase (catalytic subunit, GCLC; and modifier subunit, GCLM), microsomal epoxide hydrolase 1 (mEH) and UDP glucuronosyltransferase 1 family, polypeptide A6 (UGT1A6), results in the detoxification of carcinogens and the inactivation of reactive oxygen species (ROS), contributing to the protective effect of chemopreventive agents. 10 Many of these enzymes are primarily regulated by the nuclear factor-E2 related factor 2 (Nrf2), a transcription factor that binds to the antioxidant response element (ARE) in the 5 0 -flanking region of target genes. 10 Under normal conditions, the majority of the Nrf2 is sequestered in the cytoplasm by Kelch-like erythroid Cap'n'Collar homologue-associated protein 1 (Keap 1), while only residual nuclear Nrf2 binds to the ARE, driving basal activities. Exposure to certain chemopreventive agents leads to the dissociation of the Nrf2-Keap1 complex in the cytoplasm and the translocatio...

Background: Vitamin D deficiency has been associated with markers for allergy and asthma severity in children with asthma. However, its association with Chinese adult asthmatics has not been studied. Objective: To examine whether vitamin D status is associated with lung function and total serum IgE in Chinese adults with newly diagnosed asthma. Methods: We conducted a cross-sectional study including 435 Chinese patients aged >18 years with newly diagnosed asthma. Vitamin D status was assessed by measuring serum 25 hydroxyvitamin D (25OHD) concentrations. The primary outcomes included airflow limitation, as measured by the forced expiratory volume in 1 s (FEV₁), FEV₁ % predicted, and FEV₁/forced vital capacity (FVC), and serum total IgE concentration. Results: Vitamin D deficiency was prevalent in Chinese adults with asthma, with 88.9% of the subjects having 25OHD <50 nmol/l. Serum 25OHD concentration was positively correlated with FEV₁ % predicted (p = 0.02, r = 0.12). After adjusting for age, sex, body mass index, smoking, month of blood collection, and symptom duration, we found significant positive associations between 25OHD concentrations and FEV₁ (in liters), FEV₁ % predicted, and FEV₁/FVC (p for trend < 0.05 for all). The adjusted odds ratios for the highest versus the lowest 25OHD quartile were 0.50 (0.26–0.96) for FEV₁ <75% predicted and 0.44 (0.20–0.95) for FEV₁/FVC% <0.75. There was no significant association between 25OHD concentrations and total IgE. Conclusions: Vitamin D deficiency was highly prevalent in Chinese asthma patients, and vitamin D status was associated with lung function.

Lycopene has been shown to be beneficial in protecting against high-fat diet-induced fatty liver. The recent demonstration that lycopene can be converted by carotene 9',10'-oxygenase into a biologically active metabolite, ALA, led us to propose that the function of lycopene can be mediated by ALA. In the present study, male ob/ob mice were fed a liquid high-fat diet (60% energy from fat) with ALA supplementation (ALA group, 240 μg · kg body weight(-1) · d(-1)) or without ALA supplementation as the control (C group) for 16 wk. Steatosis, SIRT1 expression and activity, genes involved in lipid metabolism, and ALA concentrations in the livers of mice were examined. The results showed that ALA supplementation resulted in a significant accumulation of ALA in the liver and markedly decreased the steatosis in the ALA group without altering body and liver weights compared to the C group. The mRNA and protein levels of hepatic SIRT1 were higher in the ALA group compared to the C group. SIRT1 activity also was higher in the ALA group, as indicated by the lower levels of acetylated forkhead box class O1 protein levels. In addition, the mRNA level of acetyl CoA carboxylase 1 was significantly lower in the ALA group than in the C group. Because SIRT1 plays a key role in lipid homeostasis, the present study suggests that the lycopene metabolite, ALA, protects against the development of steatosis in ob/ob mice by upregulating SIRT1 gene expression and activity.

Recent findings of an inverse association between b-cryptoxanthin and lung cancer risk in several observational epidemiologic studies suggest that b-cryptoxanthin could potentially act as a chemopreventive agent against lung cancer. However, the biological activity of b-cryptoxanthin and molecular mechanism(s) by which b-cryptoxanthin affects lung tumourigenesis have not been studied. In the present study, we found that b-cryptoxanthin inhibited the growth of A549 cells, a non-small-cell lung cancer cell line and BEAS-2B cells, an immortalized human bronchial epithelial cell line in a dose-dependent manner. b-Cryptoxanthin suppressed the protein levels of cyclin D1 and cyclin E, up-regulated the cell cycle inhibitor p21, increased the number of lung cancer cells in the G1/G0 phase and decreased those in the S phase of the cell cycle. Consistent with inhibition of the lung cancer cell growth, b-cryptoxanthin induced the mRNA levels of retinoic acid receptor b (RARb) in BEAS-2B cells, although this effect was less pronounced in A549 cells. Furthermore, b-cryptoxanthin transactivated RARmediated transcription activity of the retinoic acid response element. These findings suggest a mechanism of anti-proliferative action of b-cryptoxanthin and indicate that b-cryptoxanthin may be a promising chemopreventive agent against lung cancer. ' 2006 Wiley-Liss, Inc.

Our results suggest that C3G exerts its anti-inflammatory effect through inhibiting IkappaBalpha phosphorylation, thereby suppressing NF-kappaB activity in THP-1 cells.

Insulin‐like growth factor 1 (IGF‐1) and its major binding protein, IGF binding protein 3 (IGFBP‐3) are implicated in lung cancer and other malignancies. We have previously shown that the combination of three major antioxidants [β‐carotene (BC), α‐tocopherol (AT) and ascorbic acid (AA)] can prevent lung carcinogenesis in a 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK)‐treated and smoke‐exposed (SM) ferret model, which is highly analogous to humans. The present study is aimed at determining the effect of the combination of BC, AT and AA on antioxidant capacity, lymphocyte DNA damage, plasma IGF‐1 and IGFBP‐3 concentrations, as well as on IGF‐1/IGFBP‐3 mRNA expression in the tissues (lung and liver) of the ferrets. Ferrets were treated with or without combined antioxidant (BC, AT and AA) supplementation (AOX) for 6 months in the following 4 groups: (i) control; (ii) SM+NNK; (iii) AOX; and (iv) SM+NNK+AOX. Combined AOX supplementation significantly attenuated SM+NNK induced lymphocyte DNA damage in the ferret, while increasing resistance to oxidative damage when challenged with H2O2 in vitro. Ferrets treated with SM+NNK had significantly lower IGFBP‐3 mRNA expression in lungs, whereas there was significantly higher IGFBP‐3 mRNA expression in the liver, as well as higher circulating IGFBP‐3 concentrations. Combined AOX supplementation did not affect the plasma or tissue (lung and liver) ratio of IGF‐1/IGFBP‐3. Combined antioxidant supplementation provides protection against smoke‐induced oxidative DNA damage, but does not affect the IGF‐1/IGFBP‐3 system. Differential expression of IGFBP‐3 in different tissues indicates that caution should be taken when using plasma IGFBP‐3 as a biomarker of tissue status. © 2007 Wiley‐Liss, Inc.