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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


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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.
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Nutrients 2019, 11, 1177; doi:10.3390/nu11051177
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
Mie Nishimura
, Naoki Tominaga
, Yuko Ishikawa-Takano
, Mari Maeda-Yamamoto
Jun Nishihira
Department of Medical Management and Informatics, Hokkaido Information University, Ebetsu,
Hokkaido 069-8585, Japan;
Plant Breeding Experiment Station, Takii & Co., Ltd., Konan, Shiga 520-3231, Japan; naoki-
Functional Food Factor Laboratory, Food Function Division, National Food Research Institute, National
Agriculture and Food Research Organization (NARO), Tsukuba, Ibaraki 305-8642, Japan;
National Agriculture and Food Research Organization (NARO), Tsukuba, Ibaraki 305-8517, Japan;
* Correspondence:; Tel.: +81-011-385-4411
Received: 18 April 2019; Accepted: 22 May 2019; Published: 25 May 2019
Abstract: 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.
Keywords: LDL-cholesterol; lipid metabolism; lycopene; PR-7; randomized controlled trial;
semidried tomato.
1. Introduction
Dyslipidemia is a major risk factor for coronary heart disease, and in Japan, the number of
patients with this condition is increasing. Through a survey, the Ministry of Health, Labor and
Welfare reported that 2.1 million patients received treatment for this condition in 2014. It is well
known that dietary improvements are important for the prevention of dyslipidemia, and research on
functional foods that affect lipid metabolism is receiving increased attention. In 2015, the system of
Nutrients 2019, 11, 1177 2 of 13
“Foods with Function Claims” was established in Japan. As this system permits health claims for
fresh vegetables, the research on and development of such vegetables containing highly functional
components, also known as “functional vegetables”, is expected.
Lycopene, a carotenoid, has antioxidant effects and exhibits the highest physical quenching rate
constant for singlet oxygen [1]. It has also been reported to inhibit the production of serum lipid
peroxide and oxidize low-density lipoprotein (LDL) in a concentration-dependent manner [2]. A
previous clinical trial with obese subjects suggested that the continuous ingestion of a diet containing
high lycopene increased serum high-density lipoprotein (HDL)-2 and HDL-3, which are subtypes of
HDL cholesterol (HDL-C) [3]. The biological mechanism was suggested to be through a reduction in
3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase activity in the liver [4], activation
of LDL-receptors [5], and increased expression of the ABCA1 transporter gene, which is the key
component of HDL-C production [6]. An epidemiological survey also revealed that the continuous
intake of lycopene contributes to the prevention of prostate cancer [7] and reduces risks related to the
onset of cardiovascular disease [8].
Tomato (Solanum lycopersicum) is the main source of lycopene, possessing an amount that
normally ranges from 3 to 5 mg lycopene per 100 g of raw tomato [9]. Takii & Co., Ltd. succeeded in
breeding a high-lycopene tomato variety named “PR-7” (GOCHISO TOMATO), using a high-
lycopene line selected from an edible tomato. PR-7 contains more lycopene than conventional
tomatoes. This makes it possible to obtain the required amounts of lycopene from raw tomatoes to
improve lipid metabolism. In addition, PR-7 contains high amounts of glutamic acid.
The effects of lycopene and tomato on lipid metabolism have been shown in previous clinical
trials; however, almost all trials used tomato juice or tomato extract as the test food in double-blind,
placebo-controlled studies [10–12]. This is because it is difficult to produce a placebo for raw tomato
and to deliver such food products to subjects. We therefore opted to produce semidried tomato
(semidried tomato contained 22% water content) and used lycopene-free tomato as the placebo. By
using this test food in a double-blind, placebo-controlled study, we demonstrated that semidried
tomato is similar to raw tomato and its lycopene-induced effect is the same as that of processed
tomato such as juice or extract.
In 2017, we conducted a pilot clinical trial called “Effect of Daily Ingestion of High-Lycopene
Tomato PR-7 on Lipid Metabolism for 8 Weeks: A Randomized, Double-Blind, Placebo-Controlled,
Parallel-Group (UMIN registration number: UMIN000026524)”. In this pilot study, continuous intake
of 50 g of semidried PR-7 for 8 weeks tended to improve the lipid profile; therefore, we expected that
the effect of ingesting high-lycopene tomato on lipid metabolism could be improved by extending
the intake period.
Thus, we conducted a randomized, double-blind, placebo-controlled, parallel-group
comparative study to evaluate the effects of continuous intake of PR-7 for 12 weeks using healthy
subjects with LDL-C levels 120 to <160 mg/dL.
2. Materials and Methods
2.1. Study Design
This placebo-controlled, randomized, double-blind, parallel-group comparative study was
conducted at Hokkaido Information University, Health Information Science Research Center (Ebetsu,
Hokkaido, Japan). The schedule for the trial is summarized in Table 1. Written informed consent was
obtained from subjects on their first visit prior to being enrolled. The subjects ingested 50 g semidried
tomato (active or placebo) every day for 12 weeks without cooking. Medical interviews,
measurements of vital signs and body composition, saliva and urinary assessments, and
hematological and biological assessments were conducted during the second (week 0; baseline), third
(week 4), fourth (week 8), and fifth (week 12) visits. In addition, all subjects completed a Food
Frequency Questionnaire Based on Food groups (FFQg) (Kenpakusha, Tokyo, Japan) at visits 2–4.
During the entire course of this study, subjects were asked to maintain their daily activities including
food consumption and exercise habits, to avoid any supplements, tomatoes, and processed foods
Nutrients 2019, 11, 1177 3 of 13
containing tomatoes, and to avoid drinking any vegetable juices; the test food was the only tomato
derivative that was allowed to be consumed. The subjects used a diary to record their daily activities,
which was reviewed by a medical doctor or nurse at each visit.
The primary outcome assessed was the change in LDL-C. Secondary outcomes assessed were as
follows: lipid profiles comprising total cholesterol (TC), HDL-C, triglycerides (TG), LDL-C/HDL-C
ratio, and non-HDL; adiponectin; serum lycopene; serum β-carotene; malondialdehyde LDL-C
(MDA-LDL); lectin-like oxidized LDL receptor-1 (LOX) index; soluble LOX LDL receptor-1 (sLOX-
1); LOX-1 ligand containing apolipoprotein B (LAB); lipid peroxidases (LPO); saliva volume; salivary
chromogranin A (CGA); results of the visual analog scale (VAS) questionnaire on fatigue and stress;
the Profile of Mood States Second Edition (POMS-2) full-length version for adults. The efficacy of the
active test food was evaluated at week 12 and its safety at weeks 4, 8, and 12.
Table 1. Clinical trial schedule.
POMS-2: Profile of Mood States Second Edition; : performed.
2.2. Study Subjects
We screened 234 volunteers on their first visit, and all provided written informed consent to
participate in this study. After screening, 100 healthy Japanese subjects were enrolled in the study
(ages, 30 to <70 years; LDL-C, 120 to <160 mg/dL). The range of LDL-C was based on the “Guideline
for Prevention of Arteriosclerosis Disease” published by the Japan Atherosclerosis Society. It defines
the range of 120–139 mg/dL as representing borderline high cholesterol and the range of 140–159
mg/dL as indicating mild hypercholesterolemia. Inclusion and exclusion criteria are summarized in
Table 2. The eligible subjects were randomly assigned to either the active test food (PR-7) or placebo
food (lycopene-free tomato) groups stratied by sex, age, and LDL-C during the first visit.
Assignments were computer generated based on stratied block randomization at a third-party data
center (Media Educational Center, Hokkaido Institute of Information Technology, Ebetsu, Hokkaido,
Japan). Medical doctors, nurses, clinical research coordinators, and statistical analysts were blinded
to the assignment information during the trial period. The test foods were controlled by the food-
controlled numbers printed on the food package. The information was disclosed only after all
analytical data were collected and the subjects in the efficacy analysis and the method used for
statistical analyses were nalized.
Item Guidance &
Agreement Screening Randomization Test Food-Intake Period
Week 0 Week 4 Week 8 Week 12
Visit Visit 1 Visit 2 Visit 3 Visit 4 Visit 5
Date Apr 20–23, 2018 May 21, 2018 June 9–
11, 2018
July 7–9,
Aug 4–6,
Sept 1–3,
Medical interview
Vital sign
Body composition
Blood sampling
Urinary and
salivary test
VAS questionnaire
and POMS-2
Food Frequency
Nutrients 2019, 11, 1177 4 of 13
Table 2. Inclusion and exclusion criteria.
1. Age, 30 years and <70 years old
2. LDL-C, 120 m
/dL and <160 m
Main exclusion
1. Sub
ects who
ated in the
ilot stud
2. Sub
ects who usuall
do not consume raw tomatoes
3. Sub
ects who usuall
consume tomato
4. Sub
ects under
sician’s advice, treatment, and/or medication for d
idemia and/or diabetes
5. Sub
ects with a BMI 30 k
6. Sub
ects with familial h
7. Subjects with serious cerebrovascular, cardiac, hepatic, renal, gastrointestinal diseases, and/or
infectious diseases re
orts to the authorities
8. Subjects with a major surgical history relevant to the digestive system, such as gastrectomy,
, enterectom
, etc.
9. Sub
ects with unusuall
h and/or low blood
ressure and/or abnormal hematolo
ical data
10. Sub
ects with severe anemia
11. Pre- or
ausal women com
of obvious
sical chan
12. Subjects at risk of allergic reactions to drugs or foods especially due to tomato, Japanese cedar,
anese c
ress, or
13. Subjects who regularly take medications, functional foods, and/or supplements, which would affect
lood li
id and/or
lucose metabolism
14. Alcohol addicts or sub
ects with an eatin
15. Subjects who donated either 400 mL of whole blood within 16 weeks (women) or 12 weeks (men),
200 mL of whole blood within 4 weeks (men and women), or blood components within 2 weeks (men
and women
rior to the current stud
16. Pre
nant or lactatin
women or women who ex
ect to be
nant durin
this stud
17. Subjects who currently participate in other clinical trials or have participated in a trial within the last
4 weeks
rior to the current stud
18. Any other medical and/or health reasons unfavorable to participation in the current study, as judged
al investi
2.3. Preparation of the Test Food
The tomato, a variety named PR-7 (Solanum lycopersicum) that was bred by Takii & Co, Ltd
(Kyoto, Japan) and harvested from Kasai (Hyogo, Japan) and Hokuto (Yamanshi, Japan), was used
as the active test food; a lycopene-free tomato harvested from Ishii-cho (Tokushima, Japan) was used
as the placebo. To prepare the semidried tomato: 1) raw tomatoes were disinfected; 2) the calyx on
each tomato was removed prior to slicing; 3) slices were dried and vacuum-packed; 4) packed tomato
was disinfected and refrigerated; 5) bacterial tests, physicochemical tests, and sensory inspections
were conducted. Analyses of the nutrient composition of the active test food and the placebo were
conducted using the methods established by the Japan Food Research Laboratories (Hokkaido,
Japan) and are presented in Table 3. Lycopene was measured using nine randomly extracted samples.
β-Carotene level was measured using high-performance liquid chromatography at Takii & Co., Ltd.
The levels of calories and carbohydrates were different between test foods. However, compared to
the daily intake of nutrition from the diet, this difference was insignificant; therefore, we considered
that this would not affect our data. The active test food and placebo were prepared under strict
quality-control protocols and were identical in appearance.
Table 3. Nutrient compositions of the active test and placebo foods based on daily consumption.
Nutrient Active Test Food Placebo Food
Calories (kcal) 57.5 45.7
Water (g) 33.2 36.5
Proteins (g) 2.1 2.1
Lipids (g) 0.4 0.4
Carbohydrates (g) 12.8 9.8
Ash (g) 1.7 1.2
Total fiber (g) 2.6 2.6
Sodium (mg) 3.1 2.3
Lycopene (mg) 22.0–27.8 n.d.
β-Carotene (mg) 2.8-3.3 n.d.
n.d.: not detected.
Nutrients 2019, 11, 1177 5 of 13
2.4. Physical, Hematological, Biological, Urinary, and Salivary Assessments
Blood was collected from subjects after a 12-h fast and used for the following hematological
examinations: white blood cell (WBC), red blood cell (RBC), hemoglobin (Hb), hematocrit (Ht), and
blood platelet (Plt) counts. Biological examinations included the following: liver function (aspartate
aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyl transpeptidase [γ-GTP],
alkaline phosphatase [ALP], and lactate dehydrogenase [LDH]); renal function (blood urea nitrogen
[BUN], creatinine [CRE], and uric acid [UA]); lipid profiles (TC, LDL-C, HLD-C, and TG); blood
glucose profiles (fasting plasma glucose [FPG], hemoglobin [Hb]A1c, and homeostatic model
assessment of insulin resistance [HOMA-IR]); adiponectin levels; serum carotenoids (lycopene and
β-carotene); and oxidative markers (MDA-LDL, LOX index, sLOX-1, LAB, and LPO).
Saliva was collected using a Salivette® Cotton Swab (Sarstedt K.K., Tokyo, Japan); subjects were
asked to chew the swab for 60 s to stimulate salivation. Saliva volume and chromogranin A (CGA)
were then assessed.
Urine was first collected in the morning, from which, pH, sugar, protein, occult blood,
urobilinogen, and ketones were qualitatively assessed.
Blood, saliva, and urine tests were analyzed at Sapporo Clinical Laboratory, Inc. (Hokkaido,
Japan). Measurements of serum carotenoid and oxidative markers were analyzed at NK Medico Co.,
Ltd (Tokyo, Japan). Body composition and blood pressure were measured using a Body Composition
Analyzer DC-320 (Tanita Corp, Tokyo, Japan) and an Automatic Blood Pressure Monitor HEM-
7080IC (Omron Co., Ltd., Kyoto, Japan), respectively.
2.5. VAS Questionnaire Assessing Fatigue, Stress, and Profile of Mood States
To evaluate the effects of high-lycopene tomato on fatigue and stress, subjects completed a VAS
questionnaire with eight questions assessing fatigue and stress. Subjects were instructed to place an
“X” along a 100-mm line to provide a rating from the worst to the best condition for each question
based on their current health condition. The left end of the line (0 mm) was defined as the worst
condition and the right end (100 mm), the best condition. The questionnaire results were assessed by
evaluating the length from the beginning of the line on the left to the “X.” An increase in VAS score
indicated an improvement in each symptom.
The POMS-2 questionnaire was used to evaluate the effects of high-lycopene tomato on mood
[13]. Total Mood Disturbance (TMD) scores were assessed using the POMS-2 full version for adults,
which comprised 65 questions (Success Bell, Tokyo, Japan). Subjects selected from five answers
ranging from “not at all” to “quite a lot” based on their mood state over the previous week.
2.6. Food Frequency Questionnaire
The FFQg is a semi-quantitative dietary assessment and is used to estimate nutrient intake based
on the subjects’ regular diet [14,15]. This questionnaire comprised 29 food groups and 10 types of
cooking methods. For each question, subjects reported the weekly amount and frequency of food
intake for the past month at each visit, from which regular and nutrient intakes (calories, protein, fat,
carbohydrates, dietary ber, and salt) were estimated.
2.7. Assessment of Safety
We further assessed the incidence of adverse effects or symptoms and abnormal changes in
laboratory variables. The severity of adverse effects and their relation to the test food were classified
according to protocol criteria set by the investigator. Laboratory variables were assessed according
to the guideline of side effect criteria defined by the Japanese Society of Chemotherapy [16]. All
adverse effects were reported as follows: symptoms, occurrence date, severity, relation to test food,
continuation or discontinuation, treatment, and outcome. Adverse effects were monitored during the
intervention for 12 weeks.
Nutrients 2019, 11, 1177 6 of 13
2.8. Ethics
The current clinical trial was conducted in compliance with the ethical guidelines on medical
research with humans (Ministry of Education, Culture, Sports, Science and Technology, and Ministry
of Health, Labor and Welfare) and the Declaration of Helsinki (revised by the Fortaleza General
Meeting of the World Medical Association). The trial protocol was approved by the ethics committee
of Hokkaido Information University (Ebetsu, Hokkaido, Japan; approved on 21 February, 2018;
approval number: 2017-25). This trial is registered at (registered on
29 March, 2018; registration number: UMIN000031975).
2.9. Statistical Analysis
Student’s t-tests were used to analyze primary and secondary outcomes, hematological and
biological examinations, and food frequency questionnaire values by comparing the changes in
subject values between the two groups. Changes in subject values were analyzed using repeated
measures of analysis of variance between groups. For subject characteristics, t Fisher’s exact
probability test was used for sex and the Mann–Whitney U-test was used for intake rate; Student’s t-
tests were used for other subject characteristics. Based on subgroup analysis, we analyzed LDL-C in
subjects for whom LDL-C levels were 120–139 mg/dL (borderline high cholesterol subjects) and 140–
159 mg/dL (mild hypercholesterolemia subjects). All statistical analyses were performed using SPSS
v. 25 (IBM Japan, Ltd., Tokyo, Japan), and p < 0.05 was considered statistically signicant.
2.10. Sample Size
Prior to this study, we conducted a placebo-controlled, double-blind, parallel-group comparison
test (registered at; registration number, UMIN000026524; date of
registration, 13 March, 2017) over an 8-week intake period with the same dosages used in this trial.
Based on preliminary data, the sample size was calculated to detect an intergroup difference of 8.70
with respect to changes in LDL-C from baseline to week 8 (SD = 13.7) and an effect size of 0.63 using
a two-sided paired t-test with a statistical power of 80% and an α of 5%. These results indicated that
a sample size of 80 (40 in each group) was necessary. Assuming a 20% loss in follow-up, 100 subjects
(50 in each group) were enrolled.
3. Results
3.1. Subject Dropouts and Characteristics
Subject involvement throughout the trial period is presented in Figure 1. Subjects who provided
informed consent (n = 234) were assessed for eligibility, and after the screening, 100 subjects were
enrolled in this study. All enrolled subjects were randomized into one of the two intervention groups
(placebo group, n = 50; active test food group, n = 50). Prior to trial initiation, two subjects dropped
out because of personal reasons, one subject dropped out because of difficulty ingesting the test food,
three subjects dropped out because of personal reasons after the study began, and one subject
dropped out after beginning other medical treatments. Finally, 93 subjects completed this trial—47
in the active test food group and 46 in the placebo group. There was no reason to stop this study in
the middle, and we did not conduct an interim analysis; therefore, the study was completed as
planned on 3 September 2018. Ninety-eight subjects, excluding the two subjects who dropped out
because of personal reasons before the start of the trial, were included in the safety analysis. We
excluded 19 subjects in the efficacy analysis because of abnormal value variations from mild sickness
or disordered lifestyle (n = 5), compliance problems (n = 3), missing primary outcomes due to absence
(n = 1), not being accustomed to eating raw tomatoes (n = 6), and regularly drinking tomato juice (n =
4). The efficacy analysis comprised 33 subjects in the active test food group and 41 in the placebo
group. Sex ratio, mean age, height, body mass index (BMI), LDL-C at visit 1, and the intake rate for
each group are presented in Table 4. These characteristics did not significantly differ between the two
groups, confirming the appropriate allocation of the number of subjects to each group.
Nutrients 2019, 11, 1177 7 of 13
Figure 1. Subject selection.
Table 4. Characteristics of subjects and intake rates of test foods in the active test food and placebo
Characteristic Placebo Active p
Subjects, n 41 33 -
Male, n 17 8 0.14
Age, years 53.9 ± 9.1 53.7 ± 7.8 0.91
Height, cm 162.7 ± 8.8 160.4 ± 8.3 0.27
Body mass index, kg/m
21.7 ± 2.8 22.1 ± 3.0 0.59
LDL cholesterol, mg/dL 137.3 ± 12.4 139.2 ± 12.5 0.51
Intake rate, % 99.8 ± 0.5 99.9 ± 0.4 0.45
3.2. Effect of High-Lycopene Tomato on LDL-C
The intake of the active test food significantly improved LDL-C in this group compared to that
in the placebo group (Week 12: placebo, 4.1 ± 15.7 mg/dL; high-lycopene tomato, 3.7 ± 13.8 mg/dL;
p = 0.027; Figure 2, Table 5). Based on a subgroup analysis, LDL-C was significantly decreased at week
12 (Week 12: placebo, 4.3 ± 15.1 mg/dL; high-lycopene tomato, 5.1 ± 9.5 mg/dL; p = 0.030) following
the ingestion of high-lycopene tomato in subjects with LDL-C ranging from 120–139 mg/dL (Table 5).
In subjects with LDL-C ranging from 140–159 mg/dL, LDL-C decreased at week 12 but this was not
significant (Table 5).
Nutrients 2019, 11, 1177 8 of 13
Table 5. Lipid profiles and adiponectin levels for the placebo and active food test groups.
Variable Week 0 Week 4 Week 8 Week 12 Time × Food Interaction
LDL-C (mg/dL)
Placebo (n = 41) 133.4 ± 15.6 1.9 ± 12.1 4.0 ± 12.4 4.1 ± 15.7
0.13 Active (n = 33) 140.2 ± 16.9 0.2 ± 15.5 5.9 ± 13.0 3.7 ± 13.8
0.078 0.514 0.511 0.027 *
subjects whose
LDL-C was 120–
139 mg/dL
Placebo (n = 41) 122.1±10.1 1.8±8.5 -2.0±10.6 4.3±15.1
0.048 *
Active (n = 33) 127.8±10.1 3.2±11.9 -6.2±7.8 -5.1±9.5
0.100 0.686 0.180 0.030 *
subjects whose
LDL-C was 140–
159 mg/dL
Placebo (n = 41) 143.2 ± 12.6 2.0 ± 14.9 5.7 ± 13.9 4.0 ± 16.6
Active (n = 33) 153.4 ± 11.8 3.9 ± 18.3 5.6 ± 17.2 2.2 ± 17.5
0.016* 0.286 0.981 0.276
TC (mg/dL)
Placebo (n = 41) 222.5 ± 23.9 0.9 ± 15.1 1.5 ± 18.0 7.9 ± 21.7
Active (n = 33) 231.8 ± 24.6 1.6 ± 18.5 1.3 ± 17.0 1.2 ± 19.1
0.10 0.51 0.96 0.17
HDL-C (mg/dL)
Placebo (n = 41) 75.2 ± 17.5 1.0 ± 5.8 1.9 ± 7.5 0.6 ± 8.4
Active (n = 33) 80.7 ± 17.4 3.0 ± 7.3 3.0 ± 6.5 2.7 ± 7.8
0.18 0.21 0.49 0.27
TG (mg/dL)
Placebo (n = 41) 86.6 ± 30.7 2.4±25.5 3.7 ± 28.5 0.4 ± 24.8
Active (n = 33) 80.8 ± 32.8 3.2±24.1 0.9 ± 20.6 3.2 ± 31.2
0.43 0.89 0.64 0.66
Placebo (n = 41) 1.9 ± 0.4 0.1 ± 0.2 0.0 ± 0.2 0.1 ± 0.2
Active (n = 33) 1.8 ± 0.4 0.1 ± 0.2 0.0 ± 0.2 0.0 ± 0.2
0.67 0.67 0.72 0.33
non-HDL (mg/dL)
Placebo (n = 41) 147.3 ± 15.9 1.9 ± 14.0 0.4 ± 14.1 8.5 ± 17.0
Active (n = 33) 151.2 ± 16.9 1.4 ± 14.1 1.8 ± 13.2 3.9 ± 15.6
0.32 0.87 0.67 0.24
Placebo (n = 41) 10.9 ± 5.9 0.3 ± 1.1 0.6 ± 1.3 0.5 ± 1.2
0.005 **
Active (n = 33) 13.6 ± 7.1 0.1 ± 1.1 0.6 ± 1.4 1.0 ± 1.0
0.085 0.17 0.97 0.053
Values are shown as the mean ± standard deviation. p
: Student’s t-test was performed. p
: repeated
measures of analysis of variance was performed. * p < 0.05, ** p < 0.01 vs. placebo group. Week 4: changes
in values from baseline to week 4; Week 8: changes in values from baseline to week 8; Week 12:
changes in values from baseline to week 12; LDL-C: low-density lipoprotein cholesterol; TC: total
cholesterol; HDL-C: high-density lipoprotein cholesterol; TG: triglycerides; LDL-C/HDL-C ratio: LDL
cholesterol/HDL cholesterol ratio; non-HDL: non-low-density lipoprotein cholesterol.
Figure 2. Changes in low-density lipoprotein cholesterol (LDL-C) in all subjects. A Student’s t-test
was conducted for data analysis. Statistical signicance: * p < 0.05 vs. placebo group. Values are
presented as the mean ± standard error. Number of subjects (n): placebo: n = 41, active: n = 33.
3.3. Effect of High-Lycopene Tomato on Lipid Profile and Adiponectin Levels
The effects of high-lycopene tomato on lipid profiles comprising TC, LDL-C, HDL-C, TG, LDL-
C/HDL-C ratio, and non-HDL and on adiponectin are summarized in Table 5. There were no
Nutrients 2019, 11, 1177 9 of 13
differences between the high-lycopene tomato and placebo groups in terms of changes in these
3.4. Effect of High-Lycopene Tomato on Serum Carotenoid Levels
To confirm the effects of high-lycopene tomato on serum carotenoid levels, changes in lycopene
and β-carotene contents were evaluated (Table 6). The intake of high-lycopene tomato increased
lycopene levels compared to the corresponding levels in the placebo group (Week 12: placebo, 24.2
± 49.3 μg/dL; high-lycopene tomato, 22.7 ± 47.9 μg/dL; p < 0.001). In addition, β-carotene levels
increased in the high-lycopene tomato group compared to those in the placebo group at week 12
(Week 12: placebo, 0.9 ± 13.6 μg/dL; high-lycopene tomato, 12.0 ± 24.5 μg/dL; p = 0.009).
Table 6. Serum carotenoid levels for the placebo and active food test groups.
Variable Week 0 Week 4 Week 8 Week 12 Time × Food Interaction
p b
Placebo (n = 41) 75.2 ± 45.9 26.1 ± 36.2 20.5 ± 47.8 24.2 ± 49.3
Active (n = 33) 85.9 ± 53.0 14.1 ± 49.0 25.4 ± 42.0 22.7 ± 47.9
p a 0.36 p < 0.001 ** p < 0.001 ** p < 0.001 **
Placebo (n = 41) 37.6 ± 29.2 2.2 ± 10.6 0.3 ± 13.9 0.9 ± 13.6
Active (n = 33) 51.8 ± 45 10.9 ± 20.9 16.2 ± 25.1 12.0 ± 24.5
p a 0.13 0.002 ** 0.001 ** 0.009 **
Values are shown as the mean ± standard deviation. p a: Student’s t-test was performed. p b: repeated
measures of analysis of variance was performed.** p < 0.01 vs. placebo group. Week 4: changes in
values from baseline to week 4; Week 8: changes in values from baseline to week 8; Week 12:
changes in value from baseline to week 12.
3.5. Effect of High-Lycopene Tomato on Oxidative Markers
When the oxidative markers MDA-LDL, LOX index, sLOX-1, LAB, and LPO were examined, no
statistically significant differences were found between the high-lycopene tomato and placebo groups
(Table 7).
Table 7. Oxidative marker levels for the placebo and active food test groups.
Variable Week 0 Week 4 Week 8 Week 12 Time × Food Interaction
p b
Placebo (n = 41) 156.6 ± 47.5 45.6 ± 49.5 19.5 ± 47.9 6.8 ± 54.5
Active (n = 33) 151.5 ± 45.2 41.3 ± 32.7 14.9 ± 48.7 7.8 ± 46.9
p a 0.65 0.65 0.68 0.94
Placebo (n = 41) 459.7 ± 514.9 141.2 ± 299.2 43.8 ± 287.2 698.5 ± 3527.1
Active (n = 33) 303.1 ± 118.4 40.8 ± 165.7 45.2 ± 250.3 278.8 ± 311.4
p a 0.066 0.089 0.17 0.50
Placebo (n = 41) 472.3 ± 511.1 11.3 ± 243.2 19.3 ± 176.2 675.0 ± 3688.7
Active (n = 33) 291.7 ± 127.1 127.6 ± 333.5 103.9 ± 196.3 226.0 ± 242.1
p a 0.034 * 0.087 0.055 0.49
LAB (μg
Placebo (n = 41) 1.1 ± 0.3 0.4 ± 0.3 0.2 ± 0.3 0.0 ± 0.3
Active (n = 33) 1.1 ± 0.2 0.4 ± 0.3 0.2 ± 0.3 0.1 ± 0.3
p a 0.67 0.63 0.63 0.48
Placebo (n = 41) 4.2 ± 0.6 1.1 ± 0.6 0.7 ± 0.6 0.5 ± 0.6
Active (n = 33) 4.1 ± 0.5 1.2 ± 0.6 0.7 ± 0.5 0.5 ± 0.4
p a 0.83 0.32 0.87 0.93
Values are shown as the mean ± standard deviation. p a: Student’s t-test was performed. p b: repeated
measures of analysis of variance was performed. * p < 0.05 vs. placebo group. Week 4: changes in
values from baseline to week 4; Week 8: changes in values from baseline to week 8; Week 12:
changes in value from baseline to week 12; MDA-LDL: malondialdehyde LDL-C; sLOX-1: soluble
lectin-like oxidized LDL receptor-1; LAB: LOX-1 ligand containing apolipoprotein B; LPO: lipid
Nutrients 2019, 11, 1177 10 of 13
3.6. Effect of High-Lycopene Tomato on Fatigue and Stress
To determine the effects of high-lycopene tomato on fatigue and stress, we evaluated changes in
saliva volume, CGA, and results of the VAS and POMS-2 questionnaires. There were no statistically
significant differences between the high-lycopene tomato and placebo groups (data not shown).
3.7. Assessment of Dietary Nutrients among Subjects during the Study
To assess dietary nutrients, subjects completed the FFQg, which revealed no statistically
significant differences in the intake of calories, proteins, lipids, carbohydrates, dietary fiber, and salt
between the high-lycopene tomato and placebo groups (Supplementary Table S1), suggesting that
dietary nutrients from meals did not affect the results of this trial.
3.8. Safety
To analyze the safety of high-lycopene tomato, we evaluated vital signs (SBP, DBP, and pulse
rate), body composition (body weight [BW], BFR, and BMI), complete blood counts (WBC, RBC, Hb,
Ht, and Plt), liver function (AST, ALT, γ-GTP, ALP, and LDH), renal function (BUN, CRE, and UA),
and blood glucose profiles (FPG, HbA1c, and HOMA-IR) in the subjects (Supplementary Table S2),
in addition to performing qualitative urinary assessments (pH, sugar, protein, occult blood,
urobilinogen, and ketones) (data not shown). Mild adverse effects were observed in each group, with
20 adverse effects observed in the high-lycopene tomato group as follows: digestive symptoms (n =
9); malaise (n = 1); nasal discharge and cough (n = 1); numbness of limb (n = 1); skin symptoms (n =
2); abnormal value of prostate marker (n = 1); variation in γ-GTP value (n = 3); variation in UA value
(n = 2). In the placebo group, 21 adverse effects were observed as follows: digestive symptoms (n =
3); injury (n = 1); stomatitis (n = 1); backache (n = 1); skin symptoms (n = 2); toothache (n = 1); urinary
occult blood (n = 1); nasal symptoms (n = 3); variation in ALT (n = 1); variation in DBP (n = 1); variation
in Hb (n = 1); variation in Ht (n = 1); variation in RBC (n = 1); variation in UA (n = 2); variation in γ-
GTP (n = 1). All subjects displayed mild symptoms and recovered within a few days. In addition, no
symptoms were associated with variations in laboratory test values; the principal investigator
inferred that there were no side effects and no serious adverse effects in this trial. Thus, the intake of
high-lycopene tomato had no or minimal unfavorable effects, even at 200 g/day (as a raw tomato).
4. Discussion
In this clinical trial, we assessed the effect of daily intake of high-lycopene tomato for 12 weeks
on lipid profiles in Japanese subjects with LDL-C levels 120 mg/dL and <160 mg/dL. The intake of
high-lycopene tomato increased lycopene levels in subjects administered this food compared to those
in the placebo group. In addition, LDL-C, the primary outcome, was improved in the high-lycopene
tomato group.
A previous meta-analysis demonstrated that LDL-C decreases when more than 25 mg per day
of lycopene is ingested [17]. The biological mechanism was associated with a reduction in 3-hydroxy-
3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase activity in the liver [4], activation of LDL-
receptors [5], and increased expression of the ABCA1 transporter gene, the key component of HDL-
C production [6]. Likewise, these results were observed in our clinical trial using semidried tomato.
To our knowledge, this is the first study to investigate the effect of semidried tomato, which is similar
to raw tomato, on lipid profiles based on a double-blind, placebo-controlled trial.
The intake of high-lycopene tomato increased the level of lycopene compared to the
corresponding level in the placebo group. In the present clinical trial, subjects were asked to refrain
from ingesting tomatoes and processed foods containing tomatoes, and to avoid drinking vegetable
juices; thus, the test food was thought to be the only tomato derivative consumed. Serum lycopene
was decreased in the placebo group. In addition, serum β-carotene was increased in the high-
lycopene tomato group. The level of β-carotene contained in the active test food was less than 4
mg/day, but 20 mg/day β-carotene was previously found to be required for an effect on lipid
Nutrients 2019, 11, 1177 11 of 13
metabolism [18]. These results suggest that the improvement of LDL-C in our clinical trial was mainly
due to the effect of lycopene.
MDA-LDL and LPO were not affected by actively consuming the test food; however, based on
the exploratory analysis, a positive correlation was observed between the change in LDL-C and the
change in MDA-LDL in the active test food group (Pearson correlation coefficient, r = 0.444, p = 0.010).
In addition, subjects with improved LDL-C levels due to intake of the active test food were also
suggested to have improved MDA-LDL. Regarding the antioxidant activity of carotenoids, lycopene
has been reported to possess the strongest singlet oxygen scavenging ability among the eight
carotenoids, as measured by the singlet oxygen absorption capacity method [19], and some
researchers have found that lycopene and tomato display antioxidant effects [20–22]. However, other
reports suggest that ingesting lycopene does not affect oxidative markers [23,24], although they
assessed various oxidative markers such as MDA-LDL, antioxidant capacity, 8-iso-PGF, and
antioxidant enzymes, and during the intake period, there was apparent variation in the antioxidant
effect. These findings suggest that a re-evaluation of oxidant markers and the intake period is
The LOX index, sLOX-1, and LAB, did not significantly differ between the active test food and
placebo groups. The LOX index is a biomarker for the early risk of arteriosclerosis, cerebral infarction,
and myocardial infarction [25,26], and is calculated based on LAB and sLOX-1. sLOX-1 recognizes
not only oxLDL, but also other atherogenic lipoproteins, platelets, leukocytes, and CRP [27]. The
antioxidant effects of lycopene comprise the main mechanism associated with singlet oxygen
scavenging. Therefore, lycopene might be ineffective against LAB or sLOX-1, which are the products
of the peroxidation reaction. As subjects in our trials were healthy and the study period was too short
to investigate the effect of lycopene on the LOX index, additional studies with a longer intake period
are required to reveal the effect of tomato on the risk of arteriosclerosis.
One limitation of this study was the ingestion period. Hence, it is imperative to reconsider the
effects of long-term ingestion using other evaluation outcomes. As the absorption of lycopene is
understood to be influenced by food processing, cooking, and meal composition such as type and
amount of fat, subjects were asked to avoid cooking the test food to eliminate such effects on
absorption due to differences in cooking methods. Thus, it is also necessary to examine differences in
the effect of high-lycopene tomato based on various cooking methods. In addition, a previous study
suggested that the plasma lycopene half-life is approximately six days, based on results of the
continuous ingestion of 20 mg lycopene for eight days [28]. We thus need to consider the effect of
high-lycopene tomato after the end of the ingestion period.
5. Conclusions
In this 12-week randomized, double-blind, placebo-controlled, parallel-group comparative
study, the intake of high-lycopene semidried tomato, PR-7, reduced LDL-C and was confirmed to be
safe at a dosage of 200 g/day (as raw tomato). Tomato is an important component of the diet
worldwide, and our findings support the health benefits, especially with respect to lipid metabolism,
of consuming tomatoes rich in lycopene.
Supplementary Materials: The following are available online at, Table
S1: Nutrient composition of the diets of the subjects during the study; Table S2: Vital signs, body composition,
complete blood count, liver function, renal function, and blood glucose profiles.
Author Contributions: Conceptualization, M.N., N.T, Y. I.-T., M. M.-Y., and J.N.; Design of Test Food, N.T, Y.
I.-T., and M. M.-Y.; Investigation, J.N.; Formal Analysis, M.N.; Writing- Review and Editing, M.N. and J.N.
Funding: This research was supported by grants from the Project of the NARO Bio-oriented Technology
Research Advancement Institution (the special scheme project on regional developing strategy).
Acknowledgments: We thank Salad Bowl Co., Ltd., Hyogo Next Farm Co., Ltd., T-Farm Co., Ltd., and
Agrivision Co., Ltd., for providing the materials for the test foods. We also thank the staff at Hokkaido
Information University, Health Information Science Research Center (Anzai Y., Enya A., Fukuda Y., Hatakeyama
M., Ito M., Kamo S., Katsuyama-Kagami H., Miyao A., Ohshima M., Saito T., Sasaki M., Sato K., Shima N.,
Nutrients 2019, 11, 1177 12 of 13
Teramoto M., Tsutsumi H., Yamazaki N., and Yokomoto H.) for their technical assistance with the clinical trial.
We would like to thank Editage ( for English language editing and publication support.
Conflicts of Interest: The authors declare no conflicts of interest.
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... Moreover, no significant difference between saturated fatty acid, Although biofortified tomato has a significant effect on lipid metabolism, it is activity on the lipid profile, including HDL (Yang et al., 2019) and LDL-c (Michalickova et al., 2019), was found to be inconsistent, which may reflect that the level of lycopene is unchanged in fortified tomato juice when compared with standard tomato juice (Michalickova et al., 2019). On the other hand, lycopene is considered to be the main constituent of tomato fruit (Friedman, 2013;Kong & Ismail, 2011;Renju et al., 2014), which is reported to have significantly reduced LDL-c levels in semidried tomato (with a dosage of 200 mg/day) in a recent 12-week, randomized, double-blinded, placebo-controlled, parallel-group comparative study that used healthy volunteers from Japan (Nishimura, Tominaga, Ishikawa-Takano, Maeda-Yamamoto, & Nishihira, 2019). Henceforth, investigators around the world should consider the optimized dosage of lycopene in their trials on healthy volunteers, which will address the relationship of lycopene with the lipid profile. ...
... Additionally, in mice, lycopene has an established role in insulin resistance (Zeng, He, Jia, & Hao, 2017). Henceforward, the optimized dosage of 200 mg/day (Nishimura et al., 2019) can be used in further randomized controlled trials on Type-2-DM patients. However, the review has included the various randomized controlled trials that used healthy volunteers that had neither obesity (Blum et al., 2006;Michalickova et al., 2019;Valderas-Martinez et al., 2016) nor central obesity (Cuevas-Ramos et al., 2013;Thies et al., 2012;Yang et al., 2019), and these are known predisposing factors for insulin resistance, Type 2 DM and CVD (Barroso et al., 2017;Goran, Ball, & Cruz, 2003;Westphal, 2008). ...
Tomato (Solanum lycopersicum) phytochemicals, which include phytoene, phytofluene, beta‐carotene, flavonoids, lycopene, and polyphenols, have been shown to improve the effects of fasting on plasma triglyceride (TG), low‐density lipoprotein cholesterol (LDL), high‐density lipoprotein cholesterol (HDL), total cholesterol (TC), and fasting blood sugar (FBS). The aim of this study was to systematically evaluate the effects of Tomato TC, TG, HDL, LDL, and FBS in humans. A systematic literature search was conducted in PubMed/MEDLINE, Web of sciences, and SCOPUS databases by two researchers for studies published until August of 2019 without language and time limitations. Results were combined with random effect models. Six studies were included in this meta‐analysis. Combined results reveal a significant reduction in cholesterol (weighted mean difference [WMD]: −4.39 mg/dl, 95% CI: −7.09, −1.68, I2 = % 48, p heterogeneity: .05), TG (WMD: −3.94 mg/dl, 95% CI: −7.67, −0.21, I2 = % 90, p heterogeneity: .001), LDL levels (WMD: −2.09 mg/dl, 95% CI: −3.73, −0.81, I2 = % 78, p heterogeneity: .001), and increasing in HDL levels (WMD: 2.25 mg/dl, 95% CI: 0.41, 4.10, I2 = % 97, p heterogeneity: .001). Tomato was found to have a higher reduction effect on TG and LDL in younger participants. While pooled results indicate no significant effect on FBS levels (WMD: 0.59 mg/dl, 95% CI: −0.28, 1.46, I2 = % 95, p heterogeneity: .001). In conclusion, the results indicate a significant reduction in total cholesterol, TG, and LDL and increase in HDL levels that is caused by tomato consumption.
... In their commentary, the authors repeatedly cited the results of their own search [23][24][25][26][27][28][29][30][31][32][33][34][35] to claim that the included literature for this study was inadequate and to suggest that their search results needed to be incorporated. However, these papers were excluded because they did not meet the inclusion criteria of this study. ...
... 43 A cross-sectional study showed diabetic patients having low carotenoid levels, with statistically significant differences between them and healthy patients in the concentration of β-carotene, which is a risk factor for type 2 diabetes. 44 The basic information and reasons for exclusion of some literature [23][24][25][26][27][28][29][30][31][32][33][34][35] are shown in Table S1. † ...
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Here, we re-emphasise the purpose of the meta-analysis of the association between carotenoids and overweight individuals and respond to some of the points raised in the review of this work by Nafiseh Shokri-mashhadi et al .
... According to the authors, the plaque load was inversely proportional to 5-cis-lycopene, all cis-lycopene isomers, trans-lycopene, and total lycopene isomers (all, p < 0.05). In 2019, Nishimura et al., in a clinical study, evaluated the effect of daily consumption of tomato with a high content of lycopene for 12 weeks on lipid profiles in Japanese patients with LDL-C ≥120 mg/dL and <160 mg/dL [92]. Consumption of semi-dried tomatoes with high lycopene content (PR-7) increased their plasma lycopene levels and improved lipid profile compared to the placebo group. ...
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Cardiovascular diseases (CVDs) are the leading cause of human mortality worldwide. Oxidative stress and inflammation are pathophysiological processes involved in the development of CVD. That is why bioactive food ingredients, including lycopene, are so important in their prevention, which seems to be a compound increasingly promoted in the diet of people with cardiovascular problems. Lycopene present in tomatoes and tomato products is responsible not only for their red color but also for health-promoting properties. It is characterized by a high antioxidant potential, the highest among carotenoid pigments. Mainly for this reason, epidemiological studies show a number of favorable properties between the consumption of lycopene in the diet and a reduced risk of cardiovascular disease. While there is also some controversy in research into its protective effects on the cardiovascular system, growing evidence supports its beneficial role for the heart, endothelium, blood vessels, and health. The mechanisms of action of lycopene are now being discovered and may explain some of the contradictions observed in the literature. This review aims to present the current knowledge in recent years on the preventive role of lycopene cardiovascular disorders.
... However, the additional pooled analysis regarding lipid profiles were conducted without considering their definitions and keywords through investigation at the baseline. In this case, the other eligible studies that examined the impact of carotenoids on lipid profiles could include in this study 6,7,[11][12][13] . Consequently, further analysis taking into account MESH terms for circulating body lipids are suggested. ...
... The gut and liver are physiologically connected, and their interactions also affect the regulation of inflammation and lipid metabolism through gut-liver axis. Analysis of several human intervention trials has shown that dietary supplementation with lycopene and/or tomato products reduces plasma LDL cholesterol and can inhibit cholesterol uptake by enterocytes through mediating the liver X receptor (LXR)α-NPC1L1 signalling pathway [186][187][188]. Lycopene treatment modulates signalling pathways (RXRα, RXRβ, and PPARγ) associated with cholesterol metabolism, cell proliferation, and lipid metabolism to suppress hepatocellular carcinoma development. ...
Dietary interventions are key nutritional strategies to prevent, improve, and prolong the survival of cancer patients. Lycopene, one of the strongest natural antioxidants, and its biologically active metabolites, have shown significant potential to prevent a variety of cancers, including prostate, breast, and stomach cancers, making it a promising anti-cancer agent. We review the potential regulatory mechanisms and epidemiological evidences of lycopene and its metabolites to delay the progression of cancers at different developmental stages. Recent studies have revealed that lycopene and its metabolites mediate multiple molecular mechanisms in cancer treatment such as redox homeostasis, selective anti-proliferation, apoptosis, anti-angiogenesis, tumour microenvironment regulation, and anti-metastasis and anti-invasion. Gut microbes and cholesterol metabolism are also the potential regulation targets of lycopene and its metabolites. As a dietary supplement, the synergistic interaction of lycopene with other drugs and nutrients is highlighted especially due to its binding activity with other nutrients in the diet found central to the fight against cancer. Furthermore, the application of several of novel lycopene delivery carriers are on the rise including nanoemulsions, nanostructured liposomes, and polymer nanoparticles for cancer prevention as discussed in this review with future needed development. Moreover, the synergistic mechanism between lycopene and other nutrients or drugs and novel delivery systems of lycopene should now be deeply investigated to improve its clinical application in cancer intervention in the future.
... Studies have also been conducted to understand the possible role of lycopene in cholesterol synthesis. Nishimura et al. (2019) investigated the effect of a high lycopene tomato variety on LDL levels in 74 subjects with high levels of LDL cholesterol (120-160 mg/dl). They reported that the intake of the semi-dried high-lycopene tomato product for 12 weeks was safe and it significantly reduced LDL cholesterol levels in the subjects. ...
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Tomato, a widely consumed vegetable crop, offers a real potential to combat human nutritional deficiencies. Tomatoes are rich in micronutrients and other bioactive compounds (including vitamins , carotenoids, and minerals) that are known to be essential or beneficial for human health. This review highlights the current state of the art in the molecular understanding of the nutritional aspects, conventional and molecular breeding efforts, and biofortification studies under-taken to improve the nutritional content and quality of tomato. Transcriptomics and metabolomics studies, which offer a deeper understanding of the molecular regulation of the tomato's nutrients, are discussed. The potential uses of the wastes from the tomato processing industry (i.e., the peels and seed extracts) that are particularly rich in oils and proteins are also discussed. Recent advancements with CRISPR/Cas mediated gene-editing technology provide enormous opportunities to enhance the nutritional content of agricultural produces, including tomatoes. In this regard, genome editing efforts with respect to biofortification in the tomato plant are also discussed. The recent technological advancements and knowledge gaps described herein aim to help explore the unexplored nutritional potential of the tomato.
... This carotenoid is involved in the reduction of the activity of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, causing an inhibition of the synthesis of melonovate, a precursor of ubiquinone (coenzyme Q10), which is a key coenzyme in the mitochondrial respiratory chain. Thus, the decrease in ubiquinone levels may lead to mitochondrial dysfunction (Pinieux et al., 1996;Nishimura et al., 2019), which would justify a reduction in the progressive motility of the lycopene-treated groups. ...
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This study was conducted to evaluate the effects of lycopene on quality parameters of cryopreserved ram semen. Semen samples were collected from three Santa Inês rams to form a seminal pool (n = 8). Aliquots from each pool were diluted in Tris-egg yolk extender to create experimental groups containing 0 μΜ (control), 0.1 μΜ, 1 μΜ and 5 μΜ lycopene. The samples were evaluated for sperm kinetics, integrity of plasma and acrosomal membranes, intracellular reactive oxygen species (ROS) production and lipid peroxidation immediately after thawing and after incubation for two hours at 37 °C. The addition of lycopene had no effect on the parameters that were evaluated at the time of thawing when compared with the control. However, after incubation, the groups with added lycopene showed a decrease in progressive motility. All experimental groups showed a significant reduction in linearity and straightness following incubation. Furthermore, the 5 μΜ lycopene group showed a decrease in wobble and an increase in amplitude of lateral head displacement. In conclusion, the addition of lycopene to the freezing extender of ram semen affected the kinetics parameters of cryopreserved spermatozoa after a two-hour incubation period.
Introduction Due to the ever-growing incidence of gastrointestinal disorders accompanied by substantial economic impact, it is of great importance to manage these conditions globally. Since the significant role of oxidative stress has been proved in the initiation and propagation of most of the gastrointestinal disorders, medical science is now moving toward fusing traditional knowledge with advanced technology, aiming to promote the use of antioxidants in gastrointestinal disorders. Areas covered Through PubMed, the Cochrane library, the WHO, and Google Scholar, the US FDA, and EMA, the authors collated and reviewed the appropriate literature published between the 1 January 2015 and 31 March 2020 and provided their expert perspectives on the drug discovery strategies for modulating oxidative stress in gastrointestinal disorders. Expert opinion As with other pharmaceuticals, antioxidants have been generally developed following the basic principles of drug discovery; the recent focus of which is designing multi-potent natural antioxidants mainly through using rational design and target-based drug discovery strategies. Although there have been encouraging in-vivo studies on the use of antioxidants in gastrointestinal disorders, especially inflammatory bowel disease and gastritis, there have been considerable deficits regarding in-vitro and clinical applications that should be immediately addressed.
Introduction. Lycopene is a non-vitamin carotenoid possessing antioxidant, anti-carcinogenic, immunomodulatory, cardioprotective, antiatherogenic, radio-and photoprotective properties. Lycopene not being synthesized in humans, it intakes from food sources, mainly tomatoes and tomato-containing products. The aim of this study is to assess the level of intake of lycopene and its main food sources in the diet of young people and compare the effectiveness of the 24-hours diet recall and food-frequency questionnaire method. Material and methods. The specialized questionnaires contained the main and additional food sources of lycopene. The survey included 106 students. There were formed 6 consumption groups according to the levels of lycopene intake. Results. According to the 24-hour diet recall and food-frequency questionnaires the largest share in the sample belongs to groups with high levels of lycopene intake. Tomatoes and ketchup are priority sources in these groups. The food-frequency questionnaire method allowed estimating the food sources present more often than others in the diet of the respondents. These included raw tomatoes, ketchup, and tomato-containing fast food products (with different frequencies for individual types of products). There were no additional sources of lycopene in the diet of the majority of respondents. Conclusions. The results obtained using these methods do not contradict each other. The complex using of the methods allows obtaining data on the levels of lycopene intake and its food sources present in the diet. The levels of lycopene intake and its priority sources were quantified using the 24-hour recall. The data of the food-frequency questionnaire method determine all sources of lycopene present in the diet.
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Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. The incidence of hepatocellular carcinoma (HCC) is increasing in the United States, and chronic, excessive alcohol consumption is responsible for 32%–45% of all the liver cancer cases in the United States. Avoidance of chronic or excessive alcohol intake is the best protection against alcohol-related liver injury; however, the social presence and addictive power of alcohol are strong. 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. The review will overview the prevention of ALD and HCC through dietary tomato rich in lycopene as an effective intervention strategy and the crucial role of CYP2E1 induction as a molecular target. The review also indicates a need for caution among individuals consuming both alcohol and high dose lycopene as a dietary supplement. Keywords: Tomato, Lycopene, Alcoholic liver disease, Liver cancer, CYP2E1
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Vessel wall inflammation promotes the destabilization of atherosclerotic plaques. The lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) expressed by vascular cells and monocytes. LOX index is calculated by multiplying LOX-1 ligand containing apolipoprotein B level with the soluble LOX-1. A high LOX index reflects an increased risk for stroke and myocardial infarction. However, the change in LOX index after smoking cessation and the relationship between smoking-related variables and LOX index are unknown. Relation of the clinical parameters to the LOX index was examined on 180 subjects (135 males and 45 females) at the first visit to our outpatient clinic for smoking cessation. The impact of smoking cessation on the LOX index was also determined in the 94 subjects (62 males and 32 females) who successfully stopped smoking. Sex-adjusted regression analysis and multivariate analysis identified three independent determinants of the LOX index, namely, low-density lipoprotein-cholesterol (LDL-C; β = 0.311, p < 0.001), high-sensitivity C-reactive protein (β = 0.358, p < 0.001), and expired carbon monoxide concentration reflecting smoking heaviness (β = 0.264, p = 0.003). Body mass index (BMI) significantly increased 3 months after the onset of smoking cessation (p < 0.001). However, the LOX index significantly decreased (p < 0.001), regardless of the rate of increase in BMI post-cessation. The LOX index is closely associated with smoking heaviness as well as dyslipidemia and an inflammation marker. Smoking cessation may induce a decrease in this cardiovascular risk marker, independently of weight gain.
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The hypocholesterolemic effect of tomato juice has been investigated in an intervention study with rats, along with the possible inhibition effect of bioactive tomato compounds binding to the HMGCR enzyme. Two experimental groups (n = 8 Sprague-Dawley rats) were fed ad libitum for five weeks, with water or tomato juice provided to the control and intervention groups, respectively. Total, LDL and HDL cholesterol, and total triglycerides were analysed in plasma, and the lycopene content and the expression and activity of the enzyme HMGCR were determined in liver samples. A computational molecular modelling was carried out to determine the interactions between HMGCR and lycopene, chlorogenic acid and naringenin. Total, LDL and HDL cholesterol were significantly lower in the intervention group after the intake of tomato juice. In addition, a significant reduction in HMGCR activity was observed, although this was not accompanied by changes in gene expression. The molecular modelling showed that components of tomato can bind to the active site of the enzyme and compete with the ligand HMGCoA. Lycopene, from tomato juice, accumulates in the liver and can inhibit the activity of the rate-limiting enzyme of cholesterol biosynthesis, HMGCR.
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Aims/IntroductionThough there are many differences in dietary habits and in the metabolic basis between Western and Asian people, the actual dietary intake in Asian patients with diabetes has not been investigated in a nationwide setting, unlike in Western countries. We aimed to clarify dietary intake among Japanese individuals with type 2 diabetes, and identify differences in dietary intake between Japanese and Western diabetic patients. Materials and Methods Nutritional and food intakes were surveyed and analyzed in 1,516 patients with type 2 diabetes aged 40–70 years from outpatient clinics in 59 university and general hospitals using the food frequency questionnaire based on food groups (FFQg). ResultsMean energy intake for all participants was 1737 ± 412 kcal/day, and mean proportions of total protein, fat, and carbohydrate comprising total energy intake were 15.7, 27.6 and 53.6%, respectively. They consumed a ‘low-fat energy-restricted diet’ compared with Western diabetic patients, and the proportion of fat consumption was within the suggested range that has been traditionally recommended in Western countries. As a protein source, consumption of fish (100 g) and soybean products (71 g) was larger than that of meat (50 g) and eggs (29 g). These results imply that dietary content and food patterns among Japanese patients with type 2 diabetes are quite close to those reported as suitable for prevention of obesity, type 2 diabetes, cardiovascular disease, and total mortality in Europe and America. ConclusionsA large difference was shown between dietary intake by Japanese and Western patients. These differences are important to establish ethnic-specific medical nutrition therapy for diabetes.
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The Japan Diabetes Complications Study, a randomised lifestyle intervention study of type 2 diabetes conducted at 59 institutes throughout Japan that enrolled 2033 eligible patients from January 1995 to March 1996, was directed at: (i) determining the incidence and progression rates of complications of diabetes; (ii) exploring clinical risk factors for complications of diabetes; and (iii) determining the association between lifestyle factors, including diet and physical activity, and complications of diabetes, in addition to comparing, in a randomised manner, the effects on type 2 diabetes of an extensive lifestyle intervention and conventional treatment. The protocol for the study originally specified four study populations according to primary outcomes, consisting of: (1) a macroangiopathy group (N = 1771); (ii) a nephropathy group (N = 1607); (iii) a retinopathy-incident group (N = 1221); and (iv) a retinopathy-progression group (N = 410). The primary outcomes were: (i) development of retinopathy; (ii) progression of retinopathy; (iii) development of overt nephropathy; and (iv) occurrence of macroangiopathic events including proven coronary heart disease and stroke. The study was originally planned to follow patients for 8 years, and an extended follow-up is ongoing. Information about primary outcomes, laboratory tests, and other clinical variables for each patient was collected at a central data centre through an annual report from each investigator. Additionally, extensive lifestyle surveys were conducted at baseline and 5 years after the beginning of the study intervention in both the intervention and conventional treatment groups. A description of the occurrence of complications of diabetes and of all-cause mortality, provided in this paper, demonstrated a clear gender-based difference in cardiovascular disease and all-cause mortality.
This study investigated the effect of microencapsulated garlic and/or tomato on endothelial dysfunction induced by the PhenFlex test (PFT) in healthy male smokers. In a randomized, double-blind, placebo-controlled crossover trial, 41 healthy male smokers were randomly assigned to one of four groups to receive the test groups (in microencapsulated garlic powder, tomato extract and a mixture thereof) or the placebo group. Proteomic biomarkers related to endothelial integrity were measured in plasma. Microencapsulated garlic, tomato extract and the mixture affected endothelial integrity biomarkers differently. Garlic consumption increased prothrombin time and decreased SAA and IL-12. Tomato extract intake increased activated partial thrombin time and decreased D-dimer, SAA, sVCAM-1, IL-13 and MCP-3 levels. Consumption of the mixture increased sE-selectin and lowered D-dimer, SAA, IL-13 and IL-10 responses after PFT challenge for 6 h. The different responses became clearer under high compliance in the dietary restriction groups. This single-intake clinical trial addressed the different responses of biomarkers related to endothelial integrity.
We investigated the effects of paraprobiotic Lactobacillus paracasei MCC1849 (LAC-Shield™) on symptoms of the common cold and mood states in healthy young adults. A total of 241 participants were randomised to receive 1×1010 heat-killed L. paracasei MCC1849 cell powder (10LP), 3×1010 heat-killed L. paracasei MCC1849 cell powder (30LP), or placebo powder without any L. paracasei cells once daily for 12 weeks based on the incidence of the common cold in the previous year, so that the risk of the incidence was equal among the groups. The incidence and severity of common cold symptoms were rated daily in a subject diary. Salivary secretory immunoglobulin A concentrations and saliva flow rates were analysed at 0 and 6 weeks. The Profile of Mood States (POMS) was assessed using POMS 2 0, 6, and 12 weeks after the intervention. No significant differences were observed in the incidence of the common cold among the groups. In a prespecified subgroup of subjects who had the common cold in the previous year, the incidence, total number of days of symptoms, and symptom scores of the common cold significantly improved in the 10LP-intake group, and were slightly lower in the 30LP-intake group than in the placebo group. The level of deterioration in the positive mood state caused by stress was less in the MCC1849-intake group than in the placebo group. These results indicate that L. paracasei MCC1849 has the potential to improve resistance to common cold infections in susceptible subjects and maintain a desirable mood state, even under mental stress conditions. Further randomised controlled trials are needed in order to investigate the possible beneficial effects of paraprobiotic L. paracasei MCC1849 on the common cold in susceptible populations.
Background & aims: A few studies reported the beneficial effects of tomato juice on oxidative stress status. However, supporting data in obese subjects is scarce. This study aimed to determine the effects of tomato juice consumption on erythrocyte antioxidant enzymes, namely, superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT), plasma total antioxidant capacity (TAC), and serum malondialdehyde (MDA) in overweight and obese females. Methods: A randomized controlled clinical trial was conducted on 64 overweight or obese (BMI = 25 kg/m(2) or higher) female students of Shiraz University of Medical Sciences. Subjects randomly received tomato juice (n = 32, 330 ml/d) or water (n = 28) for 20 days. Daily dietary intake, anthropometric measures and blood antioxidant parameters were determined at the beginning and after 20 days intervention period. Results: Plasma TAC and erythrocyte antioxidant enzymes increased and serum MDA decreased in the intervention group compared with baseline and with the control group (p < 0.05). In the intervention group, similar results were found in overweight, but not in obese, subjects. Conclusion: Our results suggest that tomato juice reduces oxidative stress in overweight (and possibly obese) females and, therefore, may prevent from obesity related diseases and promote health.
Lycopene/tomato has been discussed as a potential effecter in the prevention and therapy of prostate cancer; however, no systematic review has been reported to illustrate its effect recently. In the present study, a meta-analysis was carried out to determine whether intake of lycopene and tomato/tomato products could reduce the risk of prostate cancer. Eleven cohort studies and six nested case-control studies were identified through searching of international journal databases and reference lists of relevant publications. Two reviewers independently assessed the study quality and extracted data from each identified study; only studies with sufficient quality were included in the review. The main outcome of interest was incidence of prostate cancer. Compared with consumers of lower raw tomato intake, the odds ratio (OR) of incidence of prostate cancer among consumers of higher raw tomato intake was 0.81 [95% confidential interval (CI) 0.59-1.10]; for consumers of higher level of cooked tomato intake versus lower cooked tomato intake, this OR was 0.85 (95% CI 0.69-1.06); the OR of higher lycopene intake versus lower lycopene intake for prostate cancer was 0.93 (95% CI 0.86-1.01) and the OR for higher level of serum lycopene versus lower serum lycopene level was 0.97 (95% CI 0.88-1.08). It's suggested that tomato may play a modest role in the prevention of prostate cancer. Further research would be needed to determine the type and quantity of tomato products regarding their potential in preventing prostate cancer.
Intake of lycopene, a red, tetraterpene carotenoid found in tomatoes is epidemiologically associated with a decreased risk of chronic disease processes, and lycopene has demonstrated bioactivity in numerous in vitro and animal models. However, our understanding of absorption, tissue distribution, and biological impact in humans remains very limited. Lycopene absorption is strongly impacted by dietary composition, especially the amount of fat. Concentrations of circulating lycopene in lipoproteins may be further influenced by a number of variations in genes related to lipid absorption and metabolism. Lycopene is not uniformly distributed among tissues, with adipose, liver, and blood being the major body pools, while the testes, adrenals, and liver have the greatest concentrations compared to other organs. Tissue concentrations of lycopene are likely dictated by expression of and genetic variation in lipoprotein receptors, cholesterol transporters, and carotenoid metabolizing enzymes, thus impacting lycopene accumulation at target sites of action. The novel application of genetic evaluation in concert with lycopene tracers will allow determination of which genes and polymorphisms define individual lycopene metabolic phenotypes, response to dietary variables, and ultimately determine biological and clinical outcomes. A better understanding of the relationship between diet, genetics, and lycopene distribution will provide necessary information to interpret epidemiological findings more accurately and to design effective, personalized clinical nutritional interventions addressing hypotheses regarding health outcomes.