The Role of Circulating Lycopene in Low-Grade Chronic Inflammation: A Systematic Review of the Literature.

BACKGROUND AND AIMS: In recent years, it has become clear that low-grade chronic inflammation is involved in the onset and progression of many non-communicable diseases. Many studies have investigated the association between inflammation and lycopene, however, results have been inconsistent. This systematic review aims to determine the impact of circulating lycopene on inflammation and to investigate the effect of consuming tomato products and/or lycopene supplements on markers of inflammation. METHODS: Eligible studies, published before March 2020, were identified from PubMed, EBSCOhost and ScienceDirect. Human studies published in English, that evaluated the effect of circulating lycopene in relation to inflammation biomarkers were screened and included. Studies assessing lycopene intake or general intake of carotenoids/antioxidants without measuring circulating lycopene, as well as those not reporting inflammation biomarkers as outcomes, were excluded. RESULTS: Out of 80 publications identified and screened, 35 met the inclusion criteria. Results from 18 cross-sectional studies suggest that lycopene levels are adversely affected during inflammation and homeostatic imbalance. Most of the 17 included intervention studies reported increased circulating lycopene levels after tomato/lycopene supplementation, but almost no changes in inflammation biomarkers were observed. CONCLUSIONS: There is little evidence that increasing tomato intake or lycopene supplementation diminuates this inflammation. However, depletion of lycopene may be one of the first signs of low-grade inflammation. The available data thereby imply that it is beneficial to consume lycopene-rich foods occasionally to stay healthy and keep circulating lycopene at a basal level.

Daily watermelon consumption decreases plasma sVCAM-1 levels in overweight and obese postmenopausal women.

Postmenopausal status is associated with an increase in total and abdominal body fat as well as increased incidence of insulin resistance and cardiovascular disease. The purpose of this study was to determine if watermelon supplementation affects select systemic markers of atherosclerosis and measures of insulin resistance in overweight and obese postmenopausal women. We hypothesized that overweight and obese postmenopausal women consuming 100% watermelon puree daily for 6 weeks would have improved levels of select systemic markers connected with cardiovascular disease without changing markers of insulin resistance. To test this hypothesis, overweight and obese postmenopausal women were recruited to participate in this study. Participants were randomly assigned to either the control group (no intervention) or the watermelon puree group (WM) for 6 weeks. Plasma concentration of markers connected with atherosclerosis and glycemic control were measured pre- and poststudy. A significant 6% decrease in soluble vascular cell adhesion molecule-1 occurred pre- to poststudy in WM, P = .003. The pattern of change in fasting blood glucose (P = .633), insulin (P = .158), and homeostatic model assessment-estimated insulin resistance (P = .174) did not differ between groups. Pre- to poststudy increases were measured in the fasting plasma concentration of l-arginine (8%, P = .005), cis-lycopene (32%, P = .003), and trans-lycopene (42%, P = .003) in WM. We conclude that 6 weeks of watermelon supplementation improved soluble vascular cell adhesion molecule-1 levels, a marker connected to atherogenesis, independent of changes in body composition or glycemic control.

Effect of 12-Week Daily Intake of the High-Lycopene Tomato (Solanum Lycopersicum), A Variety Named "PR-7", on Lipid Metabolism: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study.

Tomato (Solanum lycopersicum) is a rich source of lycopene, a carotenoid that confers various positive biological effects such as improved lipid metabolism. Here, we conducted a randomized, double-blind, placebo-controlled, parallel-group comparative study to investigate the effects of regular and continuous intake of a new high-lycopene tomato, a variety named PR-7, for 12 weeks, based on 74 healthy Japanese subjects with low-density lipoprotein cholesterol (LDL-C) levels ≥120 to <160 mg/dL. The subjects were randomly assigned to either the high-lycopene tomato or placebo (lycopene-free tomato) group. Each subject in the high-lycopene group ingested 50 g of semidried PR-7 (lycopene, 22.0-27.8 mg/day) each day for 12 weeks, while subjects in the placebo group ingested placebo semidried tomato. Medical interviews were conducted, vital signs were monitored, body composition was determined, and blood and saliva samples were taken at weeks 0 (baseline), 4, 8, and 12. The primary outcome assessed was LDL-C. The intake of high-lycopene tomato increased lycopene levels in this group compared to levels in the placebo group (p < 0.001). In addition, high-lycopene tomato intake improved LDL-C (p = 0.027). The intake of high-lycopene tomato, PR-7, reduced LDL-C and was confirmed to be safe.

Effect of Tomato Nutrient Complex on Blood Pressure: A Double Blind, Randomized Dose⁻Response Study.

Oxidative stress is implicated in the pathogenesis of essential hypertension, a risk factor for cardiovascular morbidity and mortality. Tomato carotenoids such as lycopene and the colorless carotenoids phytoene and phytofluene induce the antioxidant defense mechanism. This double-blind, randomized, placebo-controlled study aimed to find effective doses of Tomato Nutrient Complex (TNC) to maintain normal blood pressure in untreated hypertensive individuals. The effect of TNC treatment (5, 15 and 30 mg lycopene) was compared with 15 mg of synthetic lycopene and a placebo over eight weeks. Results indicate that only TNC treatment standardized for 15 or 30 mg of lycopene was associated with significant reductions in mean systolic blood pressure (SBP). Treatment with the lower dose standardized for 5 mg of lycopene or treatment with 15 mg of synthetic lycopene as a standalone had no significant effect. To test carotenoid bioavailability, volunteers were treated for four weeks with TNC providing 2, 5 or 15 mg lycopene. The increase in blood levels of lycopene, phytoene, and phytofluene was dose dependent. Results suggest that only carotenoid levels achieved by the TNC dose of 15 mg lycopene or higher correlate to a beneficial effect on SBP in hypertensive subjects while lower doses and lycopene alone do not.

Lycopene and Metabolic Syndrome: A Systematic Review of the Literature.

Cardiometabolic risk factors increase the likelihood of cardiovascular disease development by 2-fold. Lycopene, a potent lipophilic antioxidant, may be able to mediate oxidative stress, a mechanism underpinning metabolic syndrome (MetS) and its risk factors. This is, to our knowledge, the first systematic review of the literature with the purpose of investigating the relation between circulating lycopene or dietary intake of lycopene and MetS as well as its risk factors. The review was conducted using PubMed and EBSCOhost databases with the search terms "lycopene" and "metabolic syndrome."  Inclusion criteria included human studies published in English in a scholarly, peer-reviewed journal and evaluation of lycopene in relation to ≥3 of the 5 MetS risk factors as defined by the National Cholesterol Education Program's Adult Treatment Panel III (ATP III) report. The process identified 11 studies, including 8 cross-sectional and 3 intervention studies. Cross-sectional studies were grouped into 3 categories, with several studies falling into >1 category, based on results reporting associations of lycopene with the prevalence and outcomes of MetS (5 studies), presence of ATP III risk factors (4 studies), and variables mediating lycopene's influence on MetS risk (3 studies). All studies in each category reported significant protective associations. Of the 3 intervention studies, all reported significant protective effects from a lycopene-rich beverage, despite varying doses and durations of intake. Although a protective relation between lycopene and MetS was generally supported, different MetS components appeared to be influenced by lycopene rather than demonstrating consistent improvement in a single component. Thus, additional research is needed to elucidate the mechanistic effects of lycopene on MetS, as well as to determine evidence-based recommendations concerning dose-durational effects of lycopene and MetS risk reduction. In conclusion, the evidence of lycopene's benefit exists such that lycopene status or lycopene consumption may be associated with favorable alterations to the components of MetS.

ProDiet: A Phase II Randomized Placebo-controlled Trial of Green Tea Catechins and Lycopene in Men at Increased Risk of Prostate Cancer.

Epidemiologic studies suggest that diet can alter prostate cancer risk. This study aimed to establish the feasibility and acceptability of dietary modification in men at increased risk of prostate cancer. Men were invited with a PSA level of 2.0-2.95 ng/mL or 3.0-19.95 ng/mL with negative prostate biopsies. Randomization (3 × 3 factorial design) to daily green tea and lycopene: green tea drink (3 cups, unblinded) or capsules [blinded, 600 mg flavan-3-ol ()-epigallocatechin-3-gallate (EGCG) or placebo] and lycopene-rich foods (unblinded) or capsules (blinded, 15 mg lycopene or placebo) for 6 months. Primary endpoints were randomization rates and intervention adherence (blinded assessment of metabolites) at 6 months with secondary endpoints of acceptability (from interviews), safety, weight, blood pressure, and PSA. A total of 133 of 469 (28.4%) men approached agreed to be randomized and 132 were followed-up (99.2%). Mean lycopene was 1.28 [95% confidence intervals (CI), 1.09-1.50, P = 0.003] times higher in the lycopene capsule group and 1.42 (95% CI, 1.21-1.66; P < 0.001) times higher in the lycopene-enriched diet group compared with placebo capsules. Median EGCG was 10.7 nmol/L (95% CI, 7.0-32.0) higher in in the active capsule group and 20.0 nmol/L (95% CI, 0.0-19.0) higher in the green tea drink group compared with placebo capsules (both P < 0.001). All interventions were acceptable and well tolerated although men preferred the capsules. Dietary prevention is acceptable to men at risk of prostate cancer. This intervention trial demonstrates that a chemoprevention clinical trial is feasible. Cancer Prev Res; 11(11); 687-96. ©2018 AACR.

Limited appearance of apocarotenoids is observed in plasma after consumption of tomato juices: a randomized human clinical trial.

Background: Nonvitamin A apocarotenoids occur in foods. Some function as retinoic acid receptor antagonists in vitro, though it is unclear if apocarotenoids are absorbed or accumulate to levels needed to elicit biological function. Objective: The aim of this study was to quantify carotenoids and apocarotenoids (ß-apo-8'-, -10'-, -12'-, and -14'-carotenal, apo-6'-, -8'-, -10'-, -12'-, and -14'-lycopenal, retinal, acycloretinal, ß-apo-13-carotenone, and apo-13-lycopenone) in human plasma after controlled consumption of carotenoid-rich tomato juices. Design: Healthy subjects (n = 35) consumed a low-carotenoid diet for 2 wk, then consumed 360 mL of high-ß-carotene tomato juice (30.4 mg of ß-carotene, 34.5 µg total ß-apocarotenoids/d), high-lycopene tomato juice (42.5 mg of lycopene, 119.2 µg total apolycopenoids/d), or a carotenoid-free control (cucumber juice) per day for 4 wk. Plasma was sampled at baseline (after washout) and after 2 and 4 wk, and analyzed for carotenoids and apocarotenoids using high-pressure liquid chromatography (HPLC) and HPLC-tandem mass spectrometry, respectively. The methods used to analyze the apocarotenoids had limits of detection of ∼ 100 pmol/L. Results: Apocarotenoids are present in tomato juices at 0.1-0.5% of the parent carotenoids. Plasma lycopene and ß-carotene increased (P < 0.001) after consuming high-lycopene and ß-carotene tomato juices, respectively, while retinol remained unchanged. ß-Apo-13-carotenone was found in the blood of all subjects at every visit, although elevated (P < 0.001) after consuming ß-carotene tomato juice for 4 wk (1.01 ± 0.27 nmol/L) compared with both baseline (0.37 ± 0.17 nmol/L) and control (0.46 ± 0.11 nmol/L). Apo-6'-lycopenal was detected or quantifiable in 29 subjects, while ß-apo-10'- and 12'-carotenal were detected in 6 and 2 subjects, respectively. No other apolycopenoids or apocarotenoids were detected. Conclusions: ß-Apo-13-carotenone was the only apocarotenoid that was quantifiable in all subjects, and was elevated in those consuming high-ß-carotene tomato juice. Levels were similar to previous reports of all-trans-retinoic acid. Other apocarotenoids are either poorly absorbed or rapidly metabolized or cleared, and so are absent or limited in blood. ß-Apo-13-carotenone may form from vitamin A and its presence warrants further investigation. This trial was registered at clinicaltrials.gov as NCT02550483.

Higher Plasma Selenium Concentrations Are Associated with Increased Odds of Prevalent Type 2 Diabetes.

Background: Selenium, an essential trace element, has been investigated as a potential cancer prevention agent. However, several studies have indicated that selenium supplementation may be associated with an increased risk of type 2 diabetes (T2D), although an equivocal relation of this nature requires confirmation. Objective: We examined the association between baseline plasma concentrations of selenium and the prevalence of T2D, as well as whether participant characteristics or intake of other antioxidant nutrients modified this relation. Methods: We conducted cross-sectional analyses of 1727 participants from the Selenium Trial, a randomized clinical trial of selenium supplementation for colorectal adenoma chemoprevention that had data for baseline selenium plasma concentrations, T2D status, and dietary intake. Logistic regression modeling was used to evaluate the associations between plasma selenium concentrations and prevalent T2D, adjusting for confounding factors. Heterogeneity of effect by participant characteristics was evaluated utilizing likelihood-ratio tests. Results: Mean ± SD plasma selenium concentrations for those with T2D compared with those without T2D were 143.6 ± 28.9 and 138.7 ± 27.2 ng/mL, respectively. After adjustment for confounding, higher plasma selenium concentrations were associated with a higher prevalence of T2D, with ORs (95% CIs) of 1.25 (0.80, 1.95) and 1.77 (1.16, 2.71) for the second and third tertiles of plasma selenium, respectively, compared with the lowest tertile (P-trend = 0.007). No significant effect modification was observed for age, sex, body mass index, smoking, or ethnicity. Increased odds of T2D were seen among those who were in the highest tertile of plasma selenium and the highest category of intake of ß-cryptoxanthin (P-trend = 0.03) and lycopene (P-trend = 0.008); however, interaction terms were not significant. Conclusions: These findings show that higher plasma concentrations of selenium were significantly associated with prevalent T2D among participants in a selenium supplementation trial. Future work is needed to elucidate whether there are individual characteristics, such as blood concentrations of other antioxidants, which may influence this relation.

Status of Vitamin A and Related Compounds and Clinical Outcomes in Maternal-Infant Pairs in the Midwestern United States.

BACKGROUND: Vitamin A is an essential nutrient for pregnant women, and other vitamin A-related compounds, including lutein and lycopene, have been associated with maternal-infant outcomes. The objective of this study was to quantify the status of vitamin A and related compounds in maternal-infant pairs at the time of delivery, and to determine its impact on clinical outcomes. METHODS: Maternal and cord blood samples were collected in 189 mother-infant pairs. Concentrations of lutein + zeaxanthin, ß-cryptoxanthin, lycopene, carotenes, and retinol were measured using high-performance liquid chromatography. Descriptive statistics was calculated and Spearman coefficients were used to assess correlations between maternal and cord measurements. Kruskal-Wallis and independent samples t test were used to compare measures between retinol groups. Linear and logistic regression models were used to adjust for relevant confounders. p < 0.05 was considered statistically significant. RESULTS: Ten percent of mothers had serum retinol concentrations ≤0.70 µmol/L; 80% of infants had serum retinol concentrations ≤0.70 µmol/L. Low maternal retinol concentrations were associated with maternal anemia (p = 0.04) and a trend toward low birth weight (p = 0.06). Maternal and infant concentrations of vitamin A compounds were highly correlated. After adjustment for confounders, maternal lutein was associated with a C-section (p = 0.03) and a diagnosis of respiratory distress syndrome in the infant (p = 0.02). Maternal lycopene was associated with growth parameters in the infant. CONCLUSIONS: As vitamin A-related compounds are modifiable by diet, future research determining the clinical impact of these compounds is warranted.

Tomatoes protect against development of UV-induced keratinocyte carcinoma via metabolomic alterations.

Prolonged tomato consumption can mitigate ultraviolet (UV) light induced sunburn via unknown mechanisms. Dietary carotenoids distributed to skin are hypothesized to protect skin against UV-induced damage, although other phytochemicals may play a role. We hypothesize that tomato consumption would protect against skin cancer. SKH-1 hairless and immunocompetent mice (n = 180) were fed AIN-93G or AIN-93G + 10% tangerine or red tomato powder for 35 weeks. From weeks 11-20, mice (n = 120) were exposed to 2240 J/m2 UV-B light, 3x/week, and tumors were tracked weekly. Control mice were fed the same diets but not exposed to UV. Tumor number was significantly lower in male mice consuming red tomato diets (1.73 ± 0.50, P = 0.015) or pooled tomato diets (2.03 ± 0.45, P = 0.017) compared to controls (4.04 ± 0.65). Carotenoid levels in plasma and skin were quantitated, with total lycopene higher in skin of tangerine fed animals despite a lower dose. Metabolomic analyses elucidated compounds derived from tomato glycoalkaloids (including tomatidine and hydroxylated-tomatidine) as significantly different metabolites in skin after tomato exposure. Here, we describe that tomato consumption can modulate risk for keratinocyte carcinomas; however, the role of the newly identified specific phytochemicals possibly responsible for this action require further investigation.