Lycopene intake induces colonic regulatory T cells in mice and suppresses food allergy symptoms.

BACKGROUND: Food allergy (FA) is a common disease in children; thus, a high level of safety is required for its prevention and treatment. Colonic regulatory T cells (Tregs) have been suggested to attenuate FA. We investigated the Treg-inducing ability and anti-FA effects of carotenoids, a pigment contained in vegetables and fruits. METHODS: C57BL/6N mice were fed a diet containing 0.01% (w/w) of lycopene, ß-carotene, astaxanthin or lutein for 4 weeks, and the population of colonic Tregs was assessed. Subsequently, to evaluate the Treg-inducing ability of lycopene, splenic naïve CD4+ T cells from BALB/c mice were cultured with anti-CD3/CD28 antibody, TGF-ß and lycopene, and the frequencies of Tregs were examined. The effect of 0.1% (w/w) lycopene containing diet on FA was investigated in OVA-induced FA model BALB/c mice. RESULTS: In screening, only lycopene significantly increased the frequency and number of colonic Tregs. Lycopene also increased Treg differentiation in splenic naïve CD4+ T cells. In FA mice, lycopene feeding significantly increased the number of colonic Tregs and attenuated allergic symptoms. The expression levels of IL-4, IL-9 and IL-13 mRNA in colonic mucosa were also significantly reduced by lycopene. IL-9 is known to induce proliferation of mast cells, and we found that lycopene feeding significantly reduced the number of mast cells in the colonic mucosa of FA mice. CONCLUSION: Our results suggest that lycopene, a carotenoid present in many common foods on the market, may have the potential to induce colonic Tregs and suppress FA symptoms.

Possible benefits of tomato juice consumption: a pilot study on irradiated human lymphocytes from healthy donors.

BACKGROUND: Reactive oxygen species (ROS) mediate much of the DNA damage caused by ionizing radiation. Among carotenoids, lycopene and ß-carotene, present in tomato juice, are known to be strong radical scavengers. The aim of the study was to investigate the effect of tomato juice intake on the levels of DNA damage and oxidative stress in human whole blood induced by in vitro exposure to X-rays. METHODS: Ten healthy adults were asked to drink 190 g of tomato juice, containing 17 mg lycopene and 0.25 mg ß-carotene, per day for 3 weeks and then refrain from drinking it for 3 weeks. Peripheral whole blood samples were collected before and after the intake period of tomato juice and after the washout period. The blood samples were exposed in vitro to X-ray doses of 0, 0.1, 0.5, and 2 Gy. Cytogenetic damage was measured using the cytokinesis-block micronucleus (CBMN) assay and the dicentrics (DIC) assay. The level of oxidative stress was determined using serum 8-oxo-7, 8-dihydro-2-deoxyguanosine (8-oxo-dG) and plasma reactive oxygen metabolite-derived compounds (d-ROMs). The concentration of carotenoids in plasma was measured at the three time points. RESULTS: The levels of 8-oxo-dG tended to decrease during the intake period and increase during the washout period. A non-significant inverse correlation was noted between the plasma concentration of lycopene plus ß-carotene and the level of 8-oxo-dG (P = 0.064). The radiation-induced MN and DIC frequencies increased in a dose-dependent manner, and when compared at the same dose, the MN and DIC frequencies decreased during the intake period compared with those at baseline and then increased during the washout period. The results suggest that continuous tomato juice consumption non-significantly decreases extracellular 8-oxo-dG, d-ROMs, and MN. Tomato juice intake had minimal or no effect on radiation-induced 8-oxo-dG and d-ROMs. For most radiation doses, continuously tomato juice intake lowered the levels of MN and DIC. CONCLUSION: Tomato juice consumption may suppress human lymphocyte DNA damage caused by radiation, but further examination is required. TRIAL REGISTRATION: 2014-001 and 2014-R06.

Effect of combined consumption of Lactobacillus brevis KB290 and ß-carotene on minor diarrhoea-predominant irritable bowel syndrome-like symptoms in healthy subjects: a randomised, double-blind, placebo-controlled, parallel-group trial.

People with non-pathological diarrhoea-predominant irritable bowel syndrome (IBS-D)-like symptoms are present at a significant level even in healthy populations, but established prophylaxis is lacking. Previously, we have found that co-administration of Lactobacillus brevis KB290 (KB290) and ß-carotene (ßC) attenuated murine colitis (potential cause of IBS-D-like symptoms) significantly. Here, we investigated the effect of KB290 and ßC on minor IBS-D-like symptoms in healthy volunteers. After a 4-week run-in period, subjects received a KB290 + ßC or placebo capsule for 12 weeks, followed by a 4-week washout period. The KB290 + ßC group showed a significant improvement in intensity of abdominal pain and stool frequency compared with the placebo group. The KB290 + ßC group showed a significantly higher serum concentration of anti-inflammatory cytokine, interleukin-10, compared with the placebo group. In conclusion, we demonstrated that consumption of KB290 + ßC improves minor IBS-D-like symptoms and inflammatory status in healthy volunteers. (UMIN000018002).

Tobacco carcinogen induces both lung cancer and non-alcoholic steatohepatitis and hepatocellular carcinomas in ferrets which can be attenuated by lycopene supplementation.

Early epidemiologic studies have reported that tobacco smoking, which is causally associated with liver cancer, is an independent risk factor for non-alcoholic fatty liver diseases (NAFLD). Lycopene from tomatoes has been shown to be a potential preventive agent against NAFLD and hepatocellular carcinoma (HCC). In the present study, we investigated whether the tobacco carcinogen 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces lesions in both lungs and livers of ferrets with or without lycopene intervention. Male ferrets (6 groups, n = 8-10) were treated either with NNK (50 mg/kg BW, i.p., once a month for four consecutive months) or saline with or without dietary lycopene supplementation (2.2 and 6.6 mg/kg BW/day, respectively) for 26 weeks. Results demonstrate that NNK exposure results in higher incidences of lung tumors, HCC and steatohepatitis (which is characterized by severe inflammatory cell infiltration with concurrent fat accumulation in liver, hepatocellular ballooning degeneration and increased NF-κB expression), as well as elevations in bilirubin and AST levels in ferrets. Lycopene supplementation at two doses prevented NNK-induced expressions of α7 nicotinic acetylcholine receptor in the lung and NF-κB and CYP2E1 in the liver and attenuated the NNK-induced mortality and pathological lesions in both the lungs and livers of ferrets. The present study provided strong experimental evidence that the tobacco carcinogen NNK can induce both HCC and steatohepatitis in the ferrets and can be a useful model for studying tobacco carcinogen-associated NAFLD and liver cancer. Furthermore, lycopene could provide potential benefits against smoke carcinogen-induced pulmonary and hepatic injury.

Toll-like receptors as a target of food-derived anti-inflammatory compounds.

Toll-like receptors (TLRs) play a key role in linking pathogen recognition with the induction of innate immunity. They have been implicated in the pathogenesis of chronic inflammatory diseases, representing potential targets for prevention/treatment. Vegetable-rich diets are associated with the reduced risk of several inflammatory disorders. In the present study, based on an extensive screening of vegetable extracts for TLR-inhibiting activity in HEK293 cells co-expressing TLR with the NF-κB reporter gene, we found cabbage and onion extracts to be the richest sources of a TLR signaling inhibitor. To identify the active substances, we performed activity-guiding separation of the principal inhibitors and identified 3-methylsulfinylpropyl isothiocyanate (iberin) from the cabbage and quercetin and quercetin 4'-O-ß-glucoside from the onion, among which iberin showed the most potent inhibitory effect. It was revealed that iberin specifically acted on the dimerization step of TLRs in the TLR signaling pathway. To gain insight into the inhibitory mechanism of TLR dimerization, we developed a novel probe combining an isothiocyanate-reactive group and an alkyne functionality for click chemistry and detected the probe bound to the TLRs in living cells, suggesting that iberin disrupts dimerization of the TLRs via covalent binding. Furthermore, we designed a variety of iberin analogues and found that the inhibition potency was influenced by the oxidation state of the sulfur. Modeling studies of the iberin analogues showed that the oxidation state of sulfur might influence the global shape of the isothiocyanates. These findings establish the TLR dimerization step as a target of food-derived anti-inflammatory compounds.

Dietary tomato powder inhibits alcohol-induced hepatic injury by suppressing cytochrome p450 2E1 induction in rodent models.

Chronic and excessive alcohol consumption leads to the development of alcoholic liver disease (ALD) and greatly increases the risk of liver cancer. Induction of the cytochrome p450 2E1 (CYP2E1) enzyme by chronic and excessive alcohol intake is known to play a role in the pathogenesis of ALD. High intake of tomatoes, rich in the carotenoid lycopene, is associated with a decreased risk of chronic disease. We investigated the effects of whole tomato (tomato powder, TP), partial tomato (tomato extract, TE), and purified lycopene (LYC) against ALD development in rats. Of the three supplements, only TP reduced the severity of alcohol-induced steatosis, hepatic inflammatory foci, and CYP2E1 protein levels. TE had no effect on these outcomes and LYC greatly increased inflammatory foci in alcohol-fed rats. To further support the protective effect of TP against ALD, TP was supplemented in a carcinogen (diethylnitrosamine, DEN)-initiated alcohol-promoted mouse model. In addition to reduced steatosis and inflammatory foci, TP abolished the presence of preneoplastic foci of altered hepatocytes in DEN-injected mice fed alcohol. These reductions were associated with decreased hepatic CYP2E1 protein levels, restored levels of peroxisome proliferator-activated receptor-α and downstream gene expression, decreased inflammatory gene expression, and reduced endoplasmic reticulum stress markers. These data provide strong evidence for TP as an effective whole food prevention strategy against ALD.

Development of singlet oxygen absorption capacity (SOAC) assay method. 4. Measurements of the SOAC values for vegetable and fruit extracts.

Measurements of the second-order rate constants and the singlet oxygen absorption capacity (SOAC) values for the reaction of singlet oxygen ((1)O2) with 23 kinds of food extracts were performed in ethanol/chloroform/D2O (50:50:1, v/v/v) solution at 35 °C. It has been clarified that the SOAC method is useful to evaluate the (1)O2-quenching activity (i.e. the SOAC value) of food extracts having two orders of magnitude different rate constants from 3.18 × 10(4) L g(-1) s(-1) for tomato to 1.55 × 10(2) for green melon. Furthermore, comparison of the observed rate constants for the above food extracts with the calculated ones based on the concentrations of seven kinds of carotenoids included in the food extracts and the rate constants reported for each carotenoids was performed, in order to ascertain the validity of the SOAC assay method developed and to clarify the ratio of the contribution of principal carotenoids to the SOAC value.

Effect of Lycopene Intake on the Fasting Blood Glucose Level: A Systematic Review with Meta-Analysis.

Lycopene is a lipophilic unsaturated carotenoid exhibiting a strong singlet oxygen-quenching ability. Herein, we investigated the effect of lycopene intake on the fasting blood glucose (FBG) level by conducting a systematic review and meta-analyses. We searched 15 databases (from the earliest date to June 2022 for PubMed or to August or September 2018 for the other databases) and included human interventional studies that assessed the effects of oral lycopene intake on FBG levels of participants ≥ 18 years of age. Three authors independently selected applicable studies and then assessed the study quality. Data were pooled as standardized mean difference (SMD) and analyzed by the random-effects model. Heterogeneity was assessed by I2 statistics. A meta-analysis including 11 trial arms (n = 750) revealed a tendency towards a significant decrease in FBG level with not-important heterogeneity [SMD = -0.15 (95% CI: -0.31, 0.00), p = 0.05, I2 = 9%]. Subgroup meta-analysis including two studies (n = 152) in type 2 diabetes patients revealed significantly decreased FBG levels with not-important heterogeneity [SMD = -0.37 (95% CI: -0.69, -0.05), p = 0.02, I2 = 0%]. Most studies meeting the eligibility criteria had a moderate risk of bias. The funnel plot for FBG suggested an absence of publication bias. In conclusion, this systematic review and meta-analyses suggested that lycopene intake exerted an FBG-decreasing effect.

Integration of bioassay and non-target metabolite analysis of tomato reveals that ß-carotene and lycopene activate the adiponectin signaling pathway, including AMPK phosphorylation.

Adiponectin, an adipokine, regulates glucose metabolism and insulin sensitivity through the adiponectin receptor (AdipoR). In this study, we searched for metabolites that activate the adiponectin signaling pathway from tomato (Solanum lycopersicu). Metabolites of mature tomato were separated into 55 fractions by liquid chromatography, and then each fraction was examined using the phosphorylation assay of AMP-protein kinase (AMPK) in C2C12 myotubes and in AdipoR-knockdown cells by small interfering RNA (siRNA). Several fractions showed AMPK phosphorylation in C2C12 myotubes and siRNA-mediated abrogation of the effect. Non-targeted metabolite analysis revealed the presence of 721 diverse metabolites in tomato. By integrating the activity of fractions on AMPK phosphorylation and the 721 metabolites based on their retention times of liquid chromatography, we performed a comprehensive screen for metabolites that possess adiponectin-like activity. As the screening suggested that the active fractions contained four carotenoids, we further analyzed ß-carotene and lycopene, the major carotenoids of food. They induced AMPK phosphorylation via the AdipoR, Ca2+/calmodulin-dependent protein kinase kinase and Ca2+ influx, in addition to activating glucose uptake via AdipoR in C2C12 myotubes. All these events were characteristic adiponectin actions. These results indicated that the food-derived carotenoids, ß-carotene and lycopene, activate the adiponectin signaling pathway, including AMPK phosphorylation.

Effects of lycopene intake on HDL-cholesterol and triglyceride levels: A systematic review with meta-analysis.

Lycopene is a lipophilic unsaturated carotenoid and has a very strong singlet oxygen-quenching ability. Increased serum or plasma lycopene levels have been reported to be associated with a lower risk of metabolic syndrome. We aimed to investigate the effects of lycopene intake on blood HDL-cholesterol (HCL-c) and triglyceride (TG) levels, which are metabolic syndrome biomarkers, by systematic review and meta-analyses of human interventional trials. We searched 15 databases and included studies that assessed the effects of oral lycopene intake on blood HDL-c and TG levels of participants ≥18 years of age. Three reviewers independently selected applicable studies, then assessed study qualities. Data were pooled as standardized mean difference (SMD) and analyzed by random-effects model. Heterogeneity was assessed by I2 statistics. Meta-analysis including 12 trial arms (n = 781) revealed a significantly increased HDL-c level in the lycopene group compared with that in the control group (SMD = 0.33 [95% CI: 0.12, 0.54], p = 0.002) and moderate heterogeneity (I2  = 45%). Most subgroup meta-analyses (restricted to study design, test food type, intake period, and participants' characteristics) showed similar results for HDL-c level. On the other hand, meta-analysis including 11 studies (n = 854) revealed no significant difference in TG level between the lycopene and control groups. Most studies which met eligibility criteria had moderate risk of bias. Funnel plots for HDL-c and TG suggested an absence of publication bias. In conclusion, this systematic review and meta-analyses suggested that lycopene intake significantly improved blood HDL-c levels but not TG levels.

Matrix-assisted laser desorption/ionization mass spectrometry-guided visualization analysis of intestinal absorption of acylated anthocyanins in Sprague-Dawley rats.

It is unknown whether intestinal absorption of acylated anthocyanins occurs in their intact or metabolized form. In this study, with the aid of matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) imaging, intestinal absorption of acylated anthocyanins was visually investigated. Anthocyanin extracts from purple carrots were orally administered to Sprague-Dawley rats. Acylated cyanidins were absorbed into portal and circulating blood systems in their intact form, and aglycon; cyanidin 3-O-(6-O-feruloyl-ß-d-glucopyranosyl)-(1 â†’ 6)-[ß-d-xylopyranosyl-(1 â†’ 2)]-ß-d-galactopyranoside (Cy3XFGG), and showed a high absorption of 39.3 ± 0.1 pmol/mL-plasma at 60 min after administration. MALDI-MS imaging analysis of the rat jejunum membranes showed that an organic anion transporting polypeptide (OATP) transporter was involved in Cy3XFGG transport, while deacylated anthocyanins were incorporated through both the glucose transporter 2 and OATP routes. In conclusion, acylated anthocyanin, Cy3XFGG, can be absorbed in its intact form through intestinal OATP.

TOMATOMET: A metabolome database consists of 7118 accurate mass values detected in mature fruits of 25 tomato cultivars.

The total number of low-molecular-weight compounds in the plant kingdom, most of which are secondary metabolites, is hypothesized to be over one million, although only a limited number of plant compounds have been characterized. Untargeted analysis, especially using mass spectrometry (MS), has been useful for understanding the plant metabolome; however, due to the limited availability of authentic compounds for MS-based identification, the identities of most of the ion peaks detected by MS remain unknown. Accurate mass values of peaks obtained by high accuracy mass measurement and, if available, MS/MS fragmentation patterns provide abundant annotation for each peak. Here, we carried out an untargeted analysis of compounds in the mature fruit of 25 tomato cultivars using liquid chromatography-Orbitrap MS for accurate mass measurement, followed by manual curation to construct the metabolome database TOMATOMET (http://metabolites.in/tomato-fruits/). The database contains 7,118 peaks with accurate mass values, in which 1,577 ion peaks are annotated as members of a chemical group. Remarkably, 71% of the mass values are not found in the accurate masses detected previously in Arabidopsis thaliana, Medicago truncatula or Jatropha curcas, indicating significant chemical diversity among plant species that remains to be solved. Interestingly, substantial chemical diversity exists also among tomato cultivars, indicating that chemical profiling from distinct cultivars contributes towards understanding the metabolome, even in a single organ of a species, and can prioritize some desirable metabolic targets for further applications such as breeding.

Tomato Juice Consumption Could Improve Breast Skin Adverse Effects of Radiotherapy in Breast Cancer Patients.

BACKGROUND/AIM: We investigated the beneficial effects of drinking tomato juice (TJ) rich in antioxidant carotenoids on irradiated skin following radiotherapy (RT) in breast cancer patients. PATIENTS/METHODS: Twenty-three patients agreed to drink TJ (160 g/day for six months) after the completion of RT. Early and late adverse events (AEs) of irradiated skin were evaluated according to the Common Terminology Criteria for AEs and the European Organization for Research and Treatment of Cancer Global Cosmetic Rating System, respectively. RESULTS: With regard to early AEs, acute radiodermatitis of grade 1 was observed in most patients (22/23) at the end of RT. However, the grade of radiodermatitis rapidly changed to 0, 1 month after RT and starting TJ consumption. With regard to late AEs, most patients were in good or excellent dermal condition. CONCLUSION: TJ consumption could help in relieving and recovering from early AEs and decreasing the severity of late AEs of irradiated skin.

Dietary capsanthin, the main carotenoid in paprika (Capsicum annuum), alters plasma high-density lipoprotein-cholesterol levels and hepatic gene expression in rats.

The effects of dietary capsanthin, the main carotenoid in paprika (Capsicum annuum), on lipid metabolism were examined. Young male Wistar rats were fed diets containing paprika powder, paprika organic solvent extract, residue of paprika extract, and purified capsanthin. Administration of purified capsanthin for 2 weeks resulted in a significant increase in plasma HDL-cholesterol (P < 0.05) without detectable differences in plasma total cholesterol and TAG concentrations. A statistically significant correlation (r 0.567; P < 0.001) was found between dietary capsanthin concentrations and plasma HDL-cholesterol concentrations. Animals receiving diets containing two different capsanthin concentrations exhibited dose-dependent increases in plasma HDL-cholesterol (r 0.597; P < 0.005). While capsanthin was absent in the liver of animals fed the basal diet, it increased markedly in capsanthin-fed animals (P < 0.001). Quantitative analyses of hepatic mRNA levels revealed that capsanthin administration resulted in up-regulation of mRNA for apoA5 and lecithin cholesterol acyltransferase (LCAT), without significant differences in other mRNA levels related to HDL-cholesterol metabolism. These results suggest that capsanthin had an HDL-cholesterol-raising effect on plasma, and the potential to increase cholesterol efflux to HDL particles by increasing apoA5 levels and/or enhancement of LCAT activity.

Acylated anthocyanins derived from purple carrot (Daucus carota L.) induce elevation of blood flow in rat cremaster arteriole.

Acylated anthocyanins are more stable than monomeric anthocyanins, but little is known about their physiological effects. We evaluated the hemodynamic effects of single intragastric doses of purple carrot (Daucus carota L.) anthocyanin (PCA) and two monomeric anthocyanins, cyanidin 3-O-glycoside (C3G) and delphinidin 3-O-ruthenoside (D3R). PCA, C3G, or D3R was administered orally to rat and blood flow in the cremaster artery was measured for 60 min using a laser Doppler blood flow meter. After measurements, the aorta of the animal was removed and the extent of phosphorylation of aortic epithelial nitric oxide synthase (eNOS) and Akt were determined by western blotting. PCA (10 mg kg-1) or C3G (1 mg kg-1) significantly increased rat cremaster arteriole blood flow and phosphorylation of eNOS and Akt; D3G (1 mg kg-1) only slightly altered cremaster arteriole blood flow and did not affect the phosphorylation of eNOS and Akt in the aorta. These results suggest that hemodynamic alterations depend more on the chemical structure of anthocyanins, particularly the aglycon, than on the glycoside. In addition, increase of blood flow by a single oral dose of PCA was practically reduced with treatment of carvedilol (CR), a non-specific adrenaline blocker. Blood concentrations of cyanidin or its glycoside 15, 30, or 60 min after the administration of 10 mg kg-1 PCA were below the limit of detection. These hemodynamic changes may have been associated with an indirect adrenergic action induced following a single dose of PCA.

Alleviative effects of quercetin and onion on male reproductive toxicity induced by diesel exhaust particles.

Diesel exhaust particles (DEPs) are particulate matter from diesel exhaust that contain many toxic compounds, such as polyaromatic hydrocarbons (PAHs). Some toxicities of PAH are thought to be expressed via aryl hydrocarbon receptors (AhRs). The male reproductive toxicity of DEPs might depend on AhR activation induced by PAHs. We hypothesized that AhR antagonists protect against the male reproductive toxicity of DEPs. Quercetin is a flavonoid and a well-known AhR antagonist, while onion contains many flavonoids, including quercetin. Hence, we examined whether quercetin and onion have alleviative effects against the male reproductive toxicity induced by DEPs. BALB/c male mice were fed quercetin- or onion-containing diets and received 10 injections of DEP suspension or vehicle into the dorsal subcutaneous layer over 5 weeks. The mice were euthanized at 2 weeks, after the last treatment, and their organs were collected. Daily sperm production and total incidence of sperm abnormalities were significantly affected in the DEP groups as compared with the vehicle group, but the total incidence of sperm abnormalities in the quercetin + DEP-treated mice was significantly reduced as compared with the DEP-treated mice. The numbers of Sertoli cells were significantly decreased in DEP-treated mice as compared with the vehicle-treated mice, but, the numbers of Sertoli cells were significantly increased in the quercetin and the onion + DEP-treated mice as compared with the DEP-treated mice. These results clearly indicate alleviative effects of quercetin and onion against the male reproductive toxicity induced by DEP.

Apo-12'-lycopenal, a Lycopene Metabolite, Promotes Adipocyte Differentiation via Peroxisome Proliferator-Activated Receptor γ Activation.

Apo-lycopenals, lycopene metabolites produced by an initial cleavage by ß,ß-carotene-9',10'-oxygenase, exhibit diverse biologically active effects. In this study, we investigated the effect of apo-lycopenals on the activation of nuclear receptors involved in glucose and lipid metabolism. Only apo-12'-lycopenal exhibited selective and dose-dependent transactivation activity for peroxisome proliferator-activated receptor γ (PPARγ), whereas neither apo-6'- nor apo-8'-lycopenals displayed this activity ((7.83 ± 0.66)-, (1.32 ± 0.10)-, and (1.31 ± 0.37)-fold higher activity relative to control, respectively). Additionally, apo-12'-lycopenal promoted adipocyte differentiation of 3T3-L1 cells and subsequently increased the mRNA levels of PPARγ (a (2.36 ± 0.07)-fold increase relative to control; p < 0.01) and its target genes, as well as enhanced adiponectin secretion (a (3.25 ± 0.27)-fold increase relative to control; p < 0.01) and insulin-stimulated glucose uptake (1486 ± 85 pmol/well; p < 0.001) in 3T3-L1 cells. Our results indicated that apo-12'-lycopenal promoted adipocyte differentiation by direct binding and activation of PPARγ.

Dietary Tomato Powder Inhibits High-Fat Diet-Promoted Hepatocellular Carcinoma with Alteration of Gut Microbiota in Mice Lacking Carotenoid Cleavage Enzymes.

Both incidence and death rate due to liver cancer have increased in the United States. Higher consumption of lycopene-rich tomato and tomato products is associated with a decreased risk of cancers. ß-Carotene-15, 15'-oxygenase (BCO1), and ß-carotene-9', 10'-oxygenase (BCO2) cleave lycopene to produce bioactive apo-lycopenoids. Although BCO1/BCO2 polymorphisms affect human and animal lycopene levels, whether dietary tomato consumption can inhibit high-fat diet (HFD)-promoted hepatocellular carcinoma (HCC) development and affect gut microbiota in the absence of BCO1/BCO2 is unclear. BCO1/BCO2 double knockout mice were initiated with a hepatic carcinogen (diethylnitrosamine) at 2 weeks of age. At 6 weeks of age, the mice were randomly assigned to an HFD (60% of energy as fat) with or without tomato powder (TP) feeding for 24 weeks. Results showed that TP feeding significantly decreased HCC development (67%, 83%, and 95% reduction in incidence, multiplicity, and tumor volume, respectively, P < 0.05). Protective effects of TP feeding were associated with (1) decreased hepatic inflammatory foci development and mRNA expression of proinflammatory biomarkers (IL1ß, IL6, IL12α, monocyte chemoattractant protein-1, and inducible NO synthase); (2) increased mRNA expression of deacetylase sirtuin 1 and nicotinamide phosphoribosyltransferase involving NAD+ production; and (3) increased hepatic circadian clock genes (circadian locomotor output cycles kaput, period 2, and cryptochrome-2, Wee1). Furthermore, TP feeding increased gut microbial richness and diversity, and significantly decreased the relative abundance of the genus Clostridium and Mucispirillum, respectively. The present study demonstrates that dietary tomato feeding independent of carotenoid cleavage enzymes prevents HFD-induced inflammation with potential modulating gut microbiota and inhibits HFD-promoted HCC development.

Lactobacillus brevis KB290 With Vitamin A Ameliorates Murine Intestinal Inflammation Associated With the Increase of CD11c+ Macrophage/CD103- Dendritic Cell Ratio.

Background: The ratio of colonic anti-inflammatory CD11c+ macrophages (MPs) to inflammatory CD103- dendritic cells (DCs) plays pivotal roles in intestinal inflammation. Little is known about how the ratio is regulated by lactic acid bacteria (LAB) and bifidobacteria (Bif). We investigated the contribution of LAB/Bif to this ratio. Methods: We established an in vitro experimental system using human myeloblastic KG-1 cells, which differentiate into CD11c+ MP-like (CD11c+ MPL) and CD103- DC-like (CD103- DCL) cells, and explored effective LAB/Bif strains. The selected strain's effect on the colonic CD11c+ MP/CD103- DC ratio and intestinal inflammation was examined in mice, and the strain's underlying mechanisms were investigated in vitro. Results: We screened 19 strains of LAB/Bif, and found that Lactobacillus brevis KB290 (KB290) increased the CD11c+ MPL/CD103- DCL cell ratio only in the presence of a vitamin A (VA) metabolite, retinoic acid (RA). Supplementation of KB290 with VA increased the CD11c+ MP/CD103- DC ratio in healthy mouse and prevented the disruption of the ratio during colitis. Supplementation of KB290 with pro-VA (ß-carotene) also increased the ratio in healthy mouse and ameliorated the development of colitis. The ratio was increased by reduction of CD103- DCs (or CD103- DCL cells). Our in vitro data suggested that KB290 induced cell death in CD103- DCL cells in the presence of RA signaling. Conclusions: Supplementation of KB290 with VA increases the colonic CD11c+ MP/CD103- DC ratio associated with the amelioration of murine colitis, suggesting a possible way to control intestinal inflammation by LAB.