Lycopene can be cleaved by carotene 9′,10′‐oxygenase at its 9′,10′ double bond to form apo‐10′‐lycopenoids, including apo‐10′‐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′‐lycopenoic acid, in a time‐ and dose‐dependent manner, results in the nuclear accumulation of transcription factor Nrf2 (nuclear factor E₂‐related factor 2) protein in BEAS‐2B human bronchial epithelial cells. The activation of Nrf2 by apo‐10′‐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′‐lycopenoic acid treatment increased total intracellular glutathione levels and suppressed both endogenous reactive oxygen species generation and H₂O₂‐induced oxidative damage in BEAS‐2B cells. In addition, both apo‐10′‐lycopenol and apo‐10′‐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′‐lycopenoids via activating Nrf2 and inducing phase II detoxifying/antioxidant enzymes.

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 G₁ to S phase and increased cell cycle regulators p21 and p27 protein levels. In addition, apo-10′-lycopenoic acid transactivated the retinoic acid receptor β (RARβ) promoter and induced the expression of RARβ. 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.

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.

Ferroptosis has been linked to the pathogenesis of hepatic injury induced by ischemia/reperfusion (I/R). However, the mechanistic basis remains unclear. In this study, by using a mouse model of hepatic I/R injury, it is observed that glutathione (GSH) and cysteine depletion are associated with deficiency of the reducing power of nicotinamide adenine dinucleotide phosphate (NADPH). Genes involved in maintaining NADPH homeostasis are screened, and it is identified that I/R‐induced hepatic ferroptosis is significantly associated with reduced expression and activity of NADP⁺‐dependent malic enzyme 1 (Me1). Mice with hepatocyte‐specific Me1 gene deletion exhibit aggravated ferroptosis and liver injury under I/R treatment; while supplementation with L‐malate, the substrate of ME1, restores NADPH and GSH levels and eventually inhibits I/R‐induced hepatic ferroptosis and injury. A mechanistic study further reveals that downregulation of hepatic Me1 expression is largely mediated by the phosphatase and tensin homologue (PTEN)‐dependent suppression of the mechanistic target of rapamycin/sterol regulatory element‐binding protein 1 (mTOR/SREBP1) signaling pathway in hepatic I/R model. Finally, PTEN inhibitor, mTOR activator, or SREBP1 over‐expression all increase hepatic NADPH, block ferroptosis, and protect liver against I/R injury. Taken together, the findings suggest that targeting ME1 may provide new therapeutic opportunities for I/R injury and other ferroptosis‐related hepatic conditions.