Management of Exciton Distribution for High-Performance Organic Light-Emitting Diodes Based on Interfacial Exciplex Architecture.

Interfacial exciplex has recently been adopted as an effective host to achieve phosphorescent organic light-emitting diodes (OLEDs) with high efficiencies and low driving voltages. However, a systematic understanding of exciton recombination behavior in either host of interfacial exciplex is still deficient. Herein, the strategic design rule of interfacial exciplex host is proposed to overcome the negative effects of direct trapping recombination by systematically investigating exciton recombination behavior in interfacial exciplex hosts. As a result, blue and orange phosphorescent devices acquire peak external quantum efficiencies of 23.5% and 29.2% with low turn-on voltages. These results provide a simple method to realize highly efficient OLEDs aiming for general lighting and display applications.

Adversarial feature hybrid framework for steganography with shifted window local loss.

Image steganography is a long-standing image security problem that aims at hiding information in cover images. In recent years, the application of deep learning to steganography has the tendency to outperform traditional methods. However, the vigorous development of CNN-based steganalyzers still have a serious threat to steganography methods. To address this gap, we present an end-to-end adversarial steganography framework based on CNN and Transformer learned by shifted window local loss, called StegoFormer, which contains Encoder, Decoder, and Discriminator. Encoder is a hybrid model based on U-shaped network and Transformer block, which effectively integrates high-resolution spatial features and global self-attention features. In particular, Shuffle Linear layer is suggested, which can enhance the linear layer's competence to extract local features. Given the substantial error in the central patch of the stego image, we propose shifted window local loss learning to assist Encoder in generating accurate stego images via weighted local loss. Furthermore, Gaussian mask augmentation method is designed to augment data for Discriminator, which helps to improve the security of Encoder through adversarial training. Controlled experiments show that StegoFormer is superior to the existing advanced steganography methods in terms of anti-steganalysis ability, steganography effectiveness, and information restoration.

Ultrasonic/electrical dual stimulation response nanocomposite bioelectret for controlled precision drug release.

Electret materials have attracted extensive attention because of their permanent polarization and electrostatic effect. However, it is one of problem that needs to be solved in biological application to manipulate the change of surface charge of electret by external stimulation. In this work, a drug-loaded electret with flexibility and no cytotoxicity was prepared under relatively mild conditions. The electret can release the charge through stress change and ultrasonic stimulation, and the drug release can be accurately controlled with the help of ultrasonic and electric double stimulation response. Here, the dipoles like particles of carnauba wax nanoparticles (nCW) are fixed in the matrix based on the interpenetrating polymer network structure, and "frozen" oriented dipolar particles that are treated by thermal polarization and cooled at high field strength. Subsequently, the charge density of the prepared composite electret can reach 101.1 â€‹nC/m2 at the initial stage of polarization and 21.1 â€‹nC/m2 after 3 weeks. In addition, the stimulated change of electret surface charge flow under cyclic tensile stress and cyclic compressive stress can generate a current of 0.187 â€‹nA and 0.105 â€‹nA at most. The ultrasonic stimulation results show that when the ultrasonic emission power was 90% (Pmax â€‹= â€‹1200 â€‹W), the current of 0.472 â€‹nA can be generated. Finally, the drug release characteristics and biocompatibility of the nCW composite electret containing curcumin were tested. The results showed that it not only had the ability to accurately control the release by ultrasound, but also triggered the electrical effect of the material. The prepared drug loaded composite bioelectret provides a new way for the construction, design and testing of the bioelectret. Its ultrasonic and electrical double stimulation response can be accurately controlled and released as required, and it has broad application prospects.

Structural characteristics of pea protein isolate (PPI) modified by high-pressure homogenization and its relation to the packaging properties of PPI edible film.

This study modified pea protein isolate (PPI) structure by high-pressure homogenization (HPH) and investigated PPI structural relation to the packaging properties of PPI film. HPH decreased PPI particle size, reduced surface charge, increased surface hydrophobicity, and increased free sulfhydryl, providing greater potential for covalent bonding during film formation. HPH decreased opacity of PPI films from 7.39 to 4.82 at pressure of 240 MPa with more homogeneous surface. The tensile strength and elongation at break were increased from 0.76 MPa to 1.33 MPa and from 96% to 197%, respectively, after treatment at 240 MPa. This improvement was due to the enhanced protein-protein and protein-glycerol hydrogen bonding as evidenced by FTIR. Increased ß-sheet and decreased α-helix by HPH was also observed, and ß-sheet was highly correlated to film tensile strength (Pearson coefficient of 0.973, P < 0.01). Principle component analysis visualized the influence of HPH treatment, and confirmed the association between structural characteristics and film properties.

Alterations of host-gut microbiome interactions in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) has a complex genetic, immune and metabolic pathophysiology. Recent studies implicated the gut microbiome in MS pathogenesis. However, interactions between the microbiome and host immune system, metabolism and diet have not been studied over time in this disorder. METHODS: We performed a six-month longitudinal multi-omics study of 49 participants (24 untreated relapse remitting MS patients and 25 age, sex, race matched healthy control individuals. Gut microbiome composition and function were characterized using 16S and metagenomic shotgun sequencing. Flow cytometry was used to characterize blood immune cell populations and cytokine profiles. Circulating metabolites were profiled by untargeted UPLC-MS. A four-day food diary was recorded to capture the habitual dietary pattern of study participants. FINDINGS: Together with changes in blood immune cells, metagenomic analysis identified a number of gut microbiota decreased in MS patients compared to healthy controls, and microbiota positively or negatively correlated with degree of disability in MS patients. MS patients demonstrated perturbations of their blood metabolome, such as linoleate metabolic pathway, fatty acid biosynthesis, chalcone, dihydrochalcone, 4-nitrocatechol and methionine. Global correlations between multi-omics demonstrated a disrupted immune-microbiome relationship and a positive blood metabolome-microbiome correlation in MS. Specific feature association analysis identified a potential correlation network linking meat servings with decreased gut microbe B. thetaiotaomicron, increased Th17 cell and greater abundance of meat-associated blood metabolites. The microbiome and metabolome profiles remained stable over six months in MS and control individuals. INTERPRETATION: Our study identified multi-system alterations in gut microbiota, immune and blood metabolome of MS patients at global and individual feature level. Multi-OMICS data integration deciphered a potential important biological network that links meat intakes with increased meat-associated blood metabolite, decreased polysaccharides digesting bacteria, and increased circulating proinflammatory marker. FUNDING: This work was supported by the Washington University in St. Louis Institute of Clinical and Translational Sciences, funded, in part, by Grant Number # UL1 TR000448 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (Zhou Y, Piccio, L, Lovett-Racke A and Tarr PI); R01 NS10263304 (Zhou Y, Piccio L); the Leon and Harriet Felman Fund for Human MS Research (Piccio L and Cross AH). Cantoni C. was supported by the National MS Society Career Transition Fellowship (TA-180531003) and by donations from Whitelaw Terry, Jr. / Valerie Terry Fund. Ghezzi L. was supported by the Italian Multiple Sclerosis Society research fellowship (FISM 2018/B/1) and the National Multiple Sclerosis Society Post-Doctoral Fellowship (FG-190734474). Anne Cross was supported by The Manny & Rosalyn Rosenthal-Dr. John L. Trotter MS Center Chair in Neuroimmunology of the Barnes-Jewish Hospital Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract.

Emerging research supports that triclosan (TCS), an antimicrobial agent found in thousands of consumer products, exacerbates colitis and colitis-associated colorectal tumorigenesis in animal models. While the intestinal toxicities of TCS require the presence of gut microbiota, the molecular mechanisms involved have not been defined. Here we show that intestinal commensal microbes mediate metabolic activation of TCS in the colon and drive its gut toxicology. Using a range of in vitro, ex vivo, and in vivo approaches, we identify specific microbial ß-glucuronidase (GUS) enzymes involved and pinpoint molecular motifs required to metabolically activate TCS in the gut. Finally, we show that targeted inhibition of bacterial GUS enzymes abolishes the colitis-promoting effects of TCS, supporting an essential role of specific microbial proteins in TCS toxicity. Together, our results define a mechanism by which intestinal microbes contribute to the metabolic activation and gut toxicity of TCS, and highlight the importance of considering the contributions of the gut microbiota in evaluating the toxic potential of environmental chemicals.

Impact of excipient emulsions made from different types of oils on the bioavailability and metabolism of curcumin in gastrointestinal tract.

Low bioavailability currently limits the potential of curcumin as a health-promoting dietary compound. This study therefore explored the potential of excipient emulsions to improve curcumin bioavailability. Oil-in-water excipient emulsions were prepared using different types of oils: corn oil, olive oil, and medium chain triglycerides (MCT). The excipient emulsions increased the transportation rate of curcumin across the Caco-2 cell monolayer and showed ability to protect curcumin from metabolism in the enterocytes, with the olive oil-based systems exhibiting the highest efficacy. In addition, most of curcumin metabolites were present as hexahydro-curcumin (HHC) and its conjugates. Our results show that excipient emulsions can improve curcumin bioavailability by increasing its trans-enterocyte absorption and reducing cellular metabolism. Moreover, they show that these effects depend on the type of oil used to produce them. These findings have important implications for the rational design of lipid-based delivery systems to enhance the bioavailability of hydrophobic nutraceuticals like curcumin.

Gastrointestinal biotransformation and tissue distribution of pterostilbene after long-term dietary administration in mice.

The metabolic fate of dietary compounds is closely related to their biological functions. Pterostilbene (PT) is a methylated stilbene found in many plant foods. Herein, we investigated gastrointestinal biotransformation and tissue distribution of PT in mice fed with 0.05% PT (w/w) for 5 weeks. PT and its major metabolites i.e. PT sulfate (PT-S), pinostilbene, pinostilbene sulfate, hydroxylated PT and hydroxylated PT sulfate were identified and quantified in the mucosa and content of the digestive tissues, blood, urine and vital organs. The results showed PT underwent demethylation, hydroxylation and conjugation in the small intestine, while the conjugated metabolites were largely deconjugated in the colon. Anaerobic fermentation with mouse cecal bacteria demonstrated the microbiota mediated deconjugation and demethylation of PT-S and PT, respectively. In conclusion, oral consumption of PT led to extensive biotransformation in mouse gastrointestinal tract and the metabolites of PT might play important roles in the bioactivity of PT.

Black pepper and vegetable oil-based emulsion synergistically enhance carotenoid bioavailability of raw vegetables in humans.

This study demonstrated the combination of black pepper and a canola oil-based emulsion synergistically enhanced carotenoid bioavailability of raw vegetables in humans. In a randomized crossover design, healthy young adults consumed (1) vegetable salad (control), (2) salad with canola oil emulsion (COE), (3) salad with black pepper (BP), and (4) salad with canola oil emulsion and black pepper (COE + BP). COE + BP led to a higher AUC0-10h of total plasma carotenoids (p < 0.0005) than the control (6.1-fold), BP (2.1-fold), and COE (3.0-fold). COE + BP increased AUC0-10h of plasma lutein, α-carotene, ß-carotene, and lycopene by 4.8, 9.7, 7.6, and 5.5-fold than the control, respectively (p < 0.0001). COE + BP produced a significant synergy in increasing both Cmax and AUC0-10h of total carotenoids, α-carotene, ß-carotene, and lycopene. Moreover, COE + BP produced a stronger enhancement on AUC0-10h of total carotenoids, α-carotene, ß-carotene, and lycopene in females than in males.

Target Adaptive Tracking Based on GOTURN Algorithm with Convolutional Neural Network and Data Fusion.

With the advent of the artificial intelligence era, target adaptive tracking technology has been rapidly developed in the fields of human-computer interaction, intelligent monitoring, and autonomous driving. Aiming at the problem of low tracking accuracy and poor robustness of the current Generic Object Tracking Using Regression Network (GOTURN) tracking algorithm, this paper takes the most popular convolutional neural network in the current target-tracking field as the basic network structure and proposes an improved GOTURN target-tracking algorithm based on residual attention mechanism and fusion of spatiotemporal context information for data fusion. The algorithm transmits the target template, prediction area, and search area to the network at the same time to extract the general feature map and predicts the location of the tracking target in the current frame through the fully connected layer. At the same time, the residual attention mechanism network is added to the target template network structure to enhance the feature expression ability of the network and improve the overall performance of the algorithm. A large number of experiments conducted on the current mainstream target-tracking test data set show that the tracking algorithm we proposed has significantly improved the overall performance of the original tracking algorithm.

Identification of Xanthomicrol as a Major Metabolite of 5-Demethyltangeretin in Mouse Gastrointestinal Tract and Its Inhibitory Effects on Colon Cancer Cells.

5-Demethyltangeretin (5DT) is a unique polymethoxyflavone mainly found in the peel of citrus, and has shown potent suppressive effects on multiple human cancer cells. Biotransformation plays a critical role in the biological activities of dietary bioactive components because their metabolites may exert significant bioactivities. In the present study, the metabolic fate of 5DT in mouse gastrointestinal (GI) tract after long-term oral intake and the anti-cancer effects of its major metabolite were determined. It was found that 5DT underwent extensive biotransformation after oral ingestion in mice. A major demethylated metabolite was produced via phase I metabolism, while conjugates (glucuronide and sulfate) were generated via phase II metabolism. Specifically, 4'-position on the B ring of 5DT was the major site for demethylation reaction, which led to the production of xanthomicrol (XAN) as a major metabolite. More importantly, the level of XAN in the colon was significantly higher than that of 5DT in 5DT-fed mice. Thus, we further determined the suppressive effects of XAN on human colon cancer HCT116 cells. We found that XAN effectively inhibited the proliferation of HCT116 cells by arresting cell cycle and inducing cellular apoptosis, which was further evidenced by upregulated p53 and p21 and downregulated cyclin D and CDK4/6 level. In conclusion, this study identified XAN as a major metabolite of 5DT in mouse GI tract, and demonstrated its suppressive effects on HCT116 colon cancer cells.

Antiviral Strategies of Chinese Herbal Medicine Against PRRSV Infection.

Bioactive compounds from Traditional Chinese Medicines (TCMs) are gradually becoming an effective alternative in the control of porcine reproductive and respiratory syndrome virus (PRRSV) because most of the commercially available PRRSV vaccines cannot provide full protection against the genetically diverse strains isolated from farms. Besides, the incomplete attenuation procedure involved in the production of modified live vaccines (MLV) may cause them to revert to the more virulence forms. TCMs have shown some promising potentials in bridging this gap. Several investigations have revealed that herbal extracts from TCMs contain molecules with significant antiviral activities against the various stages of the life cycle of PRRSV, and they do this through different mechanisms. They either block PRRSV attachment and entry into cells or inhibits the replication of viral RNA or viral particles assembly and release or act as immunomodulators and pathogenic pathway inhibitors through cytokines regulations. Here, we summarized the various antiviral strategies employed by some TCMs against the different stages of the life cycle of PRRSV under two major classes, including direct-acting antivirals (DAAs) and indirect-acting antivirals (IAAs). We highlighted their mechanisms of action. In conclusion, we recommended that in making plans for the use of TCMs to control PRRSV, the pathway forward must be built on a real understanding of the mechanisms by which bioactive compounds exert their effects. This will provide a template that will guide the focus of collaborative studies among researchers in the areas of bioinformatics, chemistry, and proteomics. Furthermore, available data and procedures to support the efficacy, safety, and quality control levels of TCMs should be well documented without any breach of data integrity and good manufacturing practices.

The chemopreventive effect of 5-demethylnobiletin, a unique citrus flavonoid, on colitis-driven colorectal carcinogenesis in mice is associated with its colonic metabolites.

5-Demethylnobiletin (5DN) is a unique flavonoid mainly found in citrus fruits. In this study, we determined the chemopreventive effects of 5DN and its major colonic metabolites on both a colitis-driven colon carcinogenesis mouse model and a human colon cancer cell model. In azoxymethane/dextran sulfate sodium-treated mice, dietary 5DN (0.05% w/w in the diet) significantly decreased the tumor incidence, multiplicity and burden, and showed potent anti-proliferative, proapoptotic, and anti-inflammatory activities in mouse colon tissue. Three major metabolites of 5DN, named 5,3'-didemethylnobiletin (M1), 5,4'-didemethylnobiletin (M2) and 5,3',4'-tridemethylnobiletin (M3), were found in the colonic mucosa of 5DN-treated mice, and the combined level of these metabolites in mouse colonic mucosa was 1.56-fold higher than that of 5DN. Cell culture studies revealed that 5DN and its colonic metabolites profoundly inhibited the growth of human colon cancer cells by inducing cell cycle arrest, triggering apoptosis and modulating key signaling proteins related to cell proliferation and apoptosis. Importantly, the colonic metabolites, especially M1, showed much stronger effects than those produced by 5DN itself. Overall, our results demonstrated that dietary 5DN significantly inhibited colitis-driven colon carcinogenesis in mice, and this chemopreventive effect was associated with its metabolites in the colon.

Synergistic anticancer effects of curcumin and 3',4'-didemethylnobiletin in combination on colon cancer cells.

Chemoprevention strategies employing the use of multiple dietary bioactive components and their metabolites in combination offer advantages due to their low toxicity and potential synergistic interactions. Herein, for the first time, we studied the combination of curcumin and 3',4'-didemethylnobiletin (DDMN), a primary metabolite of nobiletin, to determine their combinatory effects in inhibiting growth of human colon cancer cells. Isobologram analysis revealed a synergistic interaction between curcumin and DDMN in the inhibition of cell growth of HCT116 colon cancer cells. The combination treatment induced significant G2 -M cell-cycle arrest and extensive apoptosis, which greatly exceeded the effects of individual treatments with curcumin or DDMN. Proteins associated with these heightened anticarcinogenic effects were p53, p21, HO-1, c-poly(ADP-ribose) polymerase, Cdc2, and Cdc25c; each of the proteins was confirmed to be substantially impacted by the combination treatment, more than by individual treatments alone. Interestingly, an increase in the stability of curcumin was also observed with the presence of DDMN in cell culture medium, which could offer an explanation in part for the synergistic interaction between curcumin and DDMN. This newly identified synergy between curcumin and DDMN should be explored further to determine its chemopreventive potential against colon cancer in vivo. PRACTICAL APPLICATION: This study identifies for the first time the synergistic inhibition of colon cancer cell growth by the dietary component curcumin present in turmeric, in combination with a metabolite of nobiletin, a unique citrus flavonoid. The synergism of the combination may be due to cell-cycle arrest and apoptosis induced by the combination as well as an improvement in the stability of curcumin as a result of the antioxidant property of the nobiletin metabolite. These significant findings of synergism between curcumin and the nobiletin metabolite could offer potential chemopreventive value against colon cancer.

Design of nanoemulsion-based delivery systems to enhance intestinal lymphatic transport of lipophilic food bioactives: Influence of oil type.

The impact of nanoemulsions containing triglycerides with different fatty acid chain lengths on the bioavailability of a highly lipophilic bioactive: 5-demethylnobiletin (5-DN) was investigated. 5-DN was encapsulated in nanoemulsions fabricated using either medium-chain triglycerides (MCT) or long-chain triglycerides (LCT). They were then subjected to in vitro digestion, and the resulting mixed micelles was applied to a Caco-2 cell model. Higher 5-DN bioaccessibility was found for the MCT-nanoemulsion (13%) than for the LCT-nanoemulsion (7%). However, only 30% 5-DN in MCT crossed the Caco-2 monolayer and 50% was metabolized, while 60% 5-DN in LCT crossed the monolayer and only 10% was metabolized. More lipid droplets and chylomicrons were also formed for the LCT nanoemulsions, indicating greater 5-DN transported through lymph. Although MCT gave a higher 5-DN bioaccessibility, the final amount of 5-DN absorbed and transported to the lymph was inferior to that of the LCT formulation.

Dietary resveratrol attenuated colitis and modulated gut microbiota in dextran sulfate sodium-treated mice.

Accumulating evidence suggests that the gut microbiota plays an important role in the pathogenesis of colitis and that its composition could be modulated by exposure to dietary components. Thus, it may be possible to ameliorate the severity of colitis through administration of dietary components. Herein, we determined the effects of orally administered resveratrol on the gut microbiota composition and the resulting inflammatory status of a dextran sodium sulfate (DSS)-induced colitis mouse model. Our results supported our hypothesis that dietary resveratrol altered the microbial composition and restored microbial community diversity in DSS-treated mice. Specifically, resveratrol effectively decreased the abundance of the genera Akkermansia, Dorea, Sutterella and Bilophila, and increased the proportion of Bifidobacterium in colitic mice. Resveratrol was also able to prevent mouse body weight loss, reduce the disease activity index, attenuate tissue damage, and down-regulate the expression of pro-inflammatory cytokines such as IL-2, IFN-γ, GM-CSF, IL-1ß, IL-6, KC/GRO, and TNF-α in the colon of DSS-treated mice. Pearson's correlation analysis indicated significant correlations between the relative levels of these pro-inflammatory cytokines and alterations of the gut microbiota. Our results demonstrated that dietary resveratrol attenuated the inflammatory status and alleviated gut microbiota dysbiosis in a colitis mouse model.

In vitro activity and In vivo efficacy of Isoliquiritigenin against Staphylococcus xylosus ATCC 700404 by IGPD target.

Staphylococcus xylosus (S. xylosus) is a type of coagulase-negative Staphylococcus, which was previously considered as non-pathogenic. However, recent studies have linked it with cases of mastitis in cows. Isoliquiritigenin (ISL) is a bioactive compound with pharmacological functions including antibacterial activity. In this study, we evaluated the effect of ISL on S. xylosus in vitro and in vivo. The MIC of ISL against S. xylosus was 80 µg/mL. It was observed that sub-MICs of ISL (1/2MIC, 1/4MIC, 1/8MIC) significantly inhibited the formation of S. xylosus biofilm in vitro. Previous studies have observed that inhibiting imidazole glycerol phosphate dehydratase (IGPD) concomitantly inhibited biofilm formation in S. xylosus. So, we designed experiments to target the formation of IGPD or inhibits its activities in S. xylosus ATCC 700404. The results indicated that the activity of IGPD and its histidine content decreased significantly under 1/2 MIC (40 µg/mL) ISL, and the expression of IGPD gene (hisB) and IGPD protein was significantly down-regulated. Furthermore, Bio-layer interferometry experiments showed that ISL directly interacted with IGPD protein (with strong affinity; KD = 234 µM). In addition, molecular docking was used to predict the binding mode of ISL and IGPD. In vivo tests revealed that, ISL significantly reduced TNF-α and IL-6 levels, mitigated the destruction of the mammary glands and reversed the production of inflammatory cells in mice. The results of the study suggest that, ISL may inhibit S. xylosus growth by acting on IGPD, which can be used as a target protein to treat infections caused by S. xylosus.

Dietary cranberry suppressed colonic inflammation and alleviated gut microbiota dysbiosis in dextran sodium sulfate-treated mice.

Increased consumption of fruits may decrease the risk of chronic inflammatory diseases including inflammatory bowel disease (IBD). Gut microbiota dysbiosis plays an important etiological role in IBD. However, the mechanisms of action underlying the anti-inflammatory effects of dietary cranberry (Vaccinium macrocarpon) in the colon and its role on gut microbiota were unclear. In this study, we determined the anti-inflammatory efficacy of whole cranberry in a mouse model of dextran sodium sulfate (DSS)-induced colitis, as well as its effects on the structure of gut microbiota. The results showed that dietary cranberry significantly decreased the severity of colitis in DSS-treated mice, evidenced by increased colon length, and decreased disease activity and histologic score of colitis in DSS-treated mice compared to the positive control group (p < 0.05). Moreover, the colonic levels of pro-inflammatory cytokine (IL-1ß, IL-6 and TNF-α) were significantly reduced by cranberry supplementation (p < 0.05). Analysis of the relative abundance of fecal microbiota in phylum and genus levels revealed that DSS treatment significantly altered the microbial structure of fecal microbiota in mice. α diversity was significantly decreased in the DSS group, compared to the healthy control group. But, cranberry treatment significantly improved DSS-induced decline in α-diversity. Moreover, cranberry treatment partially reversed the change of gut microbiota in colitic mice by increasing the abundance of potential beneficial bacteria, for example, Lactobacillus and Bifidobacterium, and decreasing the abundance of potential harmful bacteria, such as Sutterella and Bilophila. Overall, our results for the first time demonstrated that modification of gut microbiota by dietary whole cranberry might contribute to its inhibitory effects against the development of colitis in DSS-treated mice.

Dietary 5-demethylnobiletin inhibits cigarette carcinogen NNK-induced lung tumorigenesis in mice.

5-Demethylnobiletin (5DN) is a unique citrus flavonoid with various beneficial bioactivities. In this study, we determined the inhibitory effects of 5DN and its two major metabolites in the 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis mouse model as well as in human and mouse lung cancer cell models. In NNK-treated female A/J mice, dietary administration of 5DN (0.025% or 0.05% w/w in the diet) significantly decreased both lung tumor multiplicity and tumor volume. Immunohistochemical analysis showed strong anti-proliferative effects of 5DN in lung tumors. Two major metabolites of 5DN, named 5,3'-didemethylnobiletin (M1) and 5,4'-didemethylnobiletin (M2), were found in the lung tissue of 5DN-fed mice. Cell culture studies demonstrated that 5DN, M1 and M2 significantly inhibited the growth of human and mouse lung cancer cells by causing cell cycle arrest, inducing apoptosis and modulating key signaling proteins related to cell proliferation and cell death. Interestingly, the metabolites of 5DN, especially M1 produced much stronger inhibitory effects on both human and mouse lung cancer cells than those produced by 5DN itself. Our results demonstrated that dietary administration of 5DN significantly inhibited NNK-induced tumorigenesis in mice, and this effect may be partially associated with the metabolites of 5DN in lung tissues.