Food and Chemical Toxicology 154 (2021) 112328

Contents lists available at ScienceDirect

Food and Chemical Toxicology

journal homepage: www.elsevier.com/locate/foodchemtox

Potential health benefits of carotenoid lutein: An updated review

Saikat Mitra a, Abdur Rauf b, **, Abu Montakim Tareq c, Shamima Jahan c, Talha Bin Emran d,
Talukder Galeeb Shahriar a, Kuldeep Dhama e, Fahad A. Alhumaydhi f, Abdullah S.M. Aljohani g,
Maksim Rebezov h, i, Md Sahab Uddin j, Philippe Jeandet k, Zafar Ali Shah b,
Mohammad Ali Shariati l, Kannan RR. Rengasamy m, *
a
Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka, 1000, Bangladesh
b
Department of Chemistry, University of Swabi, Swabi, Anbar, 23430, Khyber Pakhtunkhwa (KP), Pakistan
c
Department of Pharmacy, International Islamic University Chittagong, Chittagong, 4318, Bangladesh
d
Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, 4381, Bangladesh
e
Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, 243122, Uttar Pradesh, India
f
Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
g
Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah, Saudi Arabia
h
V M Gorbatov Federal Research Center for Food Systems of Russian Academy of Sciences, 26 Talalikhina St., Moscow, 109316, Russian Federation
i
Prokhorov General Physics Institute of the Russian Academy of Science, 38 Vavilova str., Moscow, 119991, Russian Federation
j
Department of Pharmacy, Southeast University, Dhaka, Bangladesh
k
University of Reims Champagne-Ardenne, Research Unit, Induced Resistance and Plant Bioprotection, EA 4707, SFR Condorcet FR CNRS 3417, Faculty of Sciences, PO
Box 1039, 51687, Reims Cedex 2, France
l
K.G. Razumovsky Moscow State University of Technologies and Management (the First Cossack University (MSUTM), Russian Federation
m
Green Biotechnologies Research Centre of Excellence, University of Limpopo, Private Bag X1106, Polokwane, Sovenga, 0727, South Africa

A R T I C L E I N F O A B S T R A C T

Handling Editor: Dr. Jose Luis Domingo Carotenoids in food substances are believed to have health benefits by lowering the risk of diseases. Lutein, a
carotenoid compound, is one of the essential nutrients available in green leafy vegetables (kale, broccoli,
Keywords: spinach, lettuce, and peas), along with other foods, such as eggs. As nutrition plays a pivotal role in maintaining
Lutein human health, lutein, as a nutritional substance, confers promising benefits against numerous health issues,
Carotenoids
including neurological disorders, eye diseases, skin irritation, etc. This review describes the in-depth health
Health benefits
beneficial effects of lutein. As yet, a minimal amount of literature has been undertaken to consider all its
Neurological disorders
Lifestyle diseases promising bioactivities. The step-by-step biosynthesis of lutein has also been taken into account in this review.
Bioactive food ingredients Besides, this review demonstrates the drug interactions of lutein with β-carotene, as well as safety concerns and
dosage. The potential benefits of lutein have been assessed against neurological disorders, eye diseases, cardiac
complications, microbial infections, skin irritation, bone decay, etc. Additionally, recent studies ascertained the
significance of lutein nanoformulations in the amelioration of eye disorders, which are also considered in this
review. Moreover, a possible approach for the use of lutein in bioactive functional foods will be discussed.

1. Introduction
There is a substantial piece of literature showing that consuming an
antioxidant-rich diet reduces inflammation (Bjørklund and Chirumbolo,
2017; Daniele et al., 2017; Jia et al., 2017). Carotenoids, which tend to
have antioxidant attributes, are nutrients broadly distributed in food
products, particularly vegetables and fruits (Fiedor and Burda, 2014;
Mezzomo and Ferreira, 2016; Young and Lowe, 2018). In recent years,
there has been growing interest for the study of their influence on
health, a higher amount of dietary consumption of carotenoids being
related to favorable impacts in many systemic disorders and eye prob­
lems, as well as defense of the retina against exposure to phototoxic light
damages (Álvarez-Barrios et al., 2021; Lima et al., 2016). Most of the
research reports on carotenoids are based on the compound lutein,
which exerts a significant antioxidant activity in vitro related to a
decreased incidence of age-related maladies (Black et al., 2020; Buscemi

* Corresponding author.
** Corresponding author.
E-mail addresses: abdurrauf@uoswabi.edu.pk (A. Rauf), rengasamy@iceir.net (K.RR. Rengasamy).

https://doi.org/10.1016/j.fct.2021.112328
Received 9 April 2021; Received in revised form 30 May 2021; Accepted 4 June 2021
Available online 8 June 2021
0278-6915/© 2021 Elsevier Ltd. All rights reserved.
S. Mitra et al.
et al., 2018; Pérez-gálvez, Viera and Roca, 2020). Several reports have
indicated that a high lutein intake, either by food or as nutritional
supplements, is beneficial for vision problems, such as cataract (Buscemi
et al., 2018; G. & S., 2017; Karppi et al., 2012; Y. C. Liu, Wilkins, Kim,
Malyugin and Mehta, 2017; Ma et al., 2014) and age-related macular
degeneration (AMD) (Beatty et al., 2013; Eisenhauer et al., 2017; Feng
et al., 2019; Sawa et al., 2020; Weigert et al., 2011). Nevertheless, few
works in the literature also reported conflicting data (Berrow et al.,
2013; Chew et al., 2013; Korobelnik et al., 2017; Obana et al., 2015;
Sasamoto et al., 2011). More recently, several studies have suggested,
however, that lutein has a positive influence on inflammatory behavior,
neuroprotection, reduction of the incidence of coronary disorders as
well as other systemic disorders (Chung, Leanderson, Lundberg and
Jonasson, 2017a; Johnson et al., 2013; Leermakers et al., 2016).
Epidemiological researches carried out to date have indicated that di­
etary lutein can improve cognitive and visual function over its existence
(Akuffo et al., 2017; Hendrickson, 2016; Stringham et al., 2015;
Stringham, Stringham, & O’brien, 2017; Tanprasertsuk et al., 2016;
Zarubina et al., 2018). Its function as an anti-inflammatory and anti­
oxidant agent may be attributed to neuroprotection. Among caroten­
oids, lutein builds up preferably in the child and adult brain. Several
data suggest a relationship between lutein status and vision and cogni­
tive performances in young, older adults as well as pre-adolescent
children, including retrospective or intervention trials. Based on lutein
diets associated with a lower incidence of AMD, which has comparable
risks of age-related cognitive impairment, the overall intake of lutein for
adults is small. The elderly can be an especially susceptible population
for factors such as a reduced sense of smell and taste, owing to inade­
quate diet (Stringham et al., 2019). More recent research shows that
lutein is probably also essential for early life brain growth and cognition.
Breast milk is the best source of lutein for infants. As an additional
source of lutein in children, augmented formulations can be used
(Stringham et al., 2019).
The neuroprotective action of lutein has been appraised in plenty of
literature works. An investigation by Sasaki M. et al. has indicated that
lutein can effectively protect against retinal neural impairments. The
same group also reported that lutein exerts a potential activity regarding
diabetic retinopathy in C57BL/6 mice (Sasaki et al., 2010). Nataraj et al.
outlined that lutein protects dopaminergic neurons by reducing mito­
chondrial injury and oxidative stress (OS) against MPTP (1-methyl-4-­
phenyl-1,2,3,6-tetrahydropyridine)-induced apoptotic death and motor
dysfunction (Nataraj et al., 2016). In addition to neuroprotective func­
tions, lutein’s efficacy has been established with regards to microbial
diseases. According to Kiplimo al., lutein blocks the growth and prolif­
eration of many bacteria, including Enterococcus faecium, Staphylococcus
saprophyticus, S. aureus, Escherichia coli, Pseudomonas aeruginosa, etc., at
concentrations ranging from 8 to 256 μg/mL (Kiplimo et al., 2011).
Besides, dietary lutein facilitates the antibody’s reaction to vaccination
against the infective bronchitis virus. Another protective role of lutein
has been illustrated against cardiac diseases. A systematic review and
meta-analysis conducted by Leermakers et al. (2016) reported that
lutein might likely play a role in blood pressure problems and signs of
artery inflammation in people with elevated cholesterol, high tri­
glycerides, and/or blood glucose. In addition to these mentioned po­
tential activities, lutein has been described for its efficacy in malarial
disease, skin irritation, wound healing, cell proliferation, osteoporosis,
as well as oral and dental diseases. For example, lutein derived from
Cassia fistula was found to exhibit antiplasmodial activity at a concen­
tration of 7.1 ± 0.2 μg/mL through in vitro experiments (Grace et al.,
2012). Besides, Juturu et al. experimented to find out the skin lightning
and toning effects of lutein by oral administration of the extract: their
study found advantages of the method at a dosage of 10 mg daily (Juturu
et al., 2016). In another investigation, Li et al. (Y. Li et al., 2018a) have
shown that lutein supplementation can prevent cell proliferation, cell
invasion, and HES1-mediated breast cancer cell migration. Moreover,
Bovier et al. have addressed the effectiveness of macular lutein in
2
Food and Chemical Toxicology 154 (2021) 112328
amplified bone density of young adults (Bovier and Hammond, 2017).
In the examples mentioned above, we have seen that lutein possesses
many biological activities; this compound could be thus utilized as a new
source of functional food ingredients in the future. This review thus aims
to present the pharmacology and bioactivities of lutein.
2. Structure and sources of lutein
Lutein is a member of the carotenoid family that includes around 700
compounds in nature. The molecular formula of lutein is (C40H56O2) (see
its structure in Fig. 1 showing it comprises 40 carbon atoms and six
double carbon-carbon bonds with attached methyl groups). Remark­
ably, the presence of two hydroxyl groups on both ends of the molecule
differentiates lutein and zeaxanthin from several other carotenoids, and
this is liable for their elevated chemical reactivity with singlet oxygen.
The structure of lutein is similar to that of other carotenoids. Caroten­
oids are divided into two classes according to their chemical structures:
the carotenes (pure hydrocarbons including, for example, lycopene and
β-carotene) and the xanthophylls (polar compounds containing oxygen
atoms, such as lutein and its structural isomer zeaxanthin) (Perrone
et al., 2016).
Lutein has been documented to have anti-inflammatory properties
and is an essential antioxidant. Eating foods rich in carotenoids, such as
green vegetables, fruits, etc. can lower the risk of age-related macular
degeneration. Therefore, varieties of fruit and vegetables may be used as
potential dietary supplements for carotenoids (Ravikrishnan et al.,
2011; Vijay et al., 2018).
Lutein is a carotenoid pigment that confers a yellow or orange color
to various common foods such as cantaloupe, orange/yellow peppers,
pasta, corn, carrots, salmon, and fish. Besides, egg yolk may be an
essential source of lutein, the high-fat content of yolk improving ab­
sorption of this compound. The role of lutein in human health, partic­
ularly in eye health, has been well established from epidemiological,
clinical, and interventional studies (Abdel-Aal et al., 2013). LC/MS
identified lutein in the edible flowers and leaves of Tropaeolum majus L.
A study of the carotenoid content of 24 fruits and vegetables available in
Panama has revealed the existence of seven sources with a high lutein
content (5–20 μg/g dry weight) and 8 with a very high content (>20
μg/g) (Murillo et al., 2010). Using food consumption data from the
Spanish National Dietary Intake Survey (2009–2010), the average
intake of carotenoids was 4290.8 μg/d (67.1% total carotenoid intake),
mainly from vegetables (3414.0 μg/d), followed by fruits (393.5 μg/d),
oils/fats (204.0 μg/d), and eggs/egg products (170.0 μg/d). The main
sources of lutein are vegetables (62.9% total diet, 1235.2 μg/person/d)
(Estévez-Santiago, Beltrán-De-Miguel, & Olmedilla-Alonso, 2016).
3. Biosynthesis of lutein
The biosynthesis of lutein occurs through the mevalonate pathway
(Fig. 1). In this pathway, HMGCoA-reductase reduces hydroxy-methyl-
glutaryl-coenzyme A (HMGCoA) to mevalonic acid, which is the pre­
cursor of the universal 5-carbon isoprenoid units, i.e., isopentenyl py­
rophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). Catalytic
elongation of DMAPP leads first to the C-10 metabolite geranyl pyro­
phosphate (GPP) and then to the C-15 isoprenoid farnesyl pyrophos­
phate (FPP) under the enzymic action of farnesyl pyrophosphate
synthase (FPPS). The enzyme geranylgeranyl pyrophosphate synthase
(GGPPS) catalyzes the FPP elongation to the C-20, isoprenoid ger­
anylgeranyl pyrophosphate (GGPP).
Two molecules of GGPP dimerize with each other into phytoene in
the presence of dimerase enzymes. The phytoene further oxidizes into
α-carotene through lycopene by a reductase. Hydroxylation at the third
position of the two rings of α-carotene by a hydrolase leads to lutein
formation (Niu et al., 2020; Waller et al., 2019).
S. Mitra et al.
Fig. 1. Step wise biosynthesis of lutein.
4. Pharmacological activities of lutein
4.1. Neuroprotective effects
Lutein is one of the most plentiful carotenoids that are mainly
available in nature and the human diet. A substantial part of its functions
has been assessed in nervous tissues (Erdman et al., 2015; Zheng et al.,
2013). Numerous researchers have used in vivo and in vitro experimental
strategies to assess the neuroprotective effects of lutein against the ret­
ina’s neuronal dysfunctions during inflammation. For example, a study
by Sasaki (Sasaki et al., 2010) has reported lutein’s effectiveness against
inflammation-induced retinal neural impairments in C57BL/6 mice. At a
dose of 100 mg/kg body weight, lutein inhibited STAT3 activation, ROS
accumulation, etc. These data showed that lutein, as an antioxidant, was
neuroprotective during endotoxin-induced uveitis, proposing a potential
approach for suppressing inflammation-triggered retinal neural damage.
3
Food and Chemical Toxicology 154 (2021) 112328
Besides, the probable mechanisms of action of lutein in the brain
have also been reported. Docosahexaenoic acid (DHA), a high poly­
unsaturated fatty acid present in the brain, is crucial for the develop­
ment and the functional improvement in children. It is equally essential
to maintain adults’ neural functions (Honold et al., 2016). However, the
presence of DHA and a strong metabolic activity lead to free radical
attacks of the brain. Besides, DHA oxidation in Alzheimer’s disease pa­
tients and cognitively impaired individuals were also reported. Brain
cell injury, impairment and death, and, particularly, loss of nerve con­
nectivity can contribute to cognitive impairment (Erdman et al., 2015).
Lutein is variably localized to membrane regions abundant in poly­
unsaturated fatty acids and thus well placed to protect lipids from
oxidation. Lutein suppresses free radical-induced neural tissue damages
and blocks the oxidation of DHA, a vulnerable lipid (Widomska, 2014)
(Fig. 2). Suppression of DHA oxidation improves membrane stability and
fluidity and enables DHA storage for its use and further transformation
S. Mitra et al. Food and Chemical Toxicology 154 (2021) 112328

Fig. 2. Anti-inflammatory and anti-apoptosis mechanisms of lutein. Lutein inhibits kB-a catabolism and blocks NF–κB translocation, thereby inhibiting inducible
gene transcription and inflammatory mediator synthesis. Lutein reduces the amount of intercellular H2O2 by scavenging superoxide anion and H2O2, which is another
strategy for making lutein an important reducer of inflammatory responses. AOPPs are bound to their cytoplasmic receptor and pass into the plasma, leading to
activation of protein kinase C, production of O2− , activation of Bax/Bcl 2/caspase and ultimately apoptosis and cell death. Lutein can prevent the creation of these
products (AOPPs) and block AOPP-mediated signals that stimulate cell apoptosis (Modified from Perrone et al., 2016).

into anti-inflammatory compounds (E. Miller, Morel, Saso and Saluk, (Sasaki et al., 2010). Besides, in the work of Sun et al. lutein was re­
2014). ported to confer substantial neuroprotection regarding transient cere­
Besides, a report by Nataraj et al. has illustrated that lutein protects bral ischemic damage in mice models. Lutein was indeed proved as an
dopaminergic neurons by alleviating mitochondrial damage and antioxidant against transient cerebral ischemic impairment at doses
oxidative stress (OS) against MPTP-induced apoptotic death and motor ranging from 7.5 to 30 mg/kg. At the mentioned range of doses, this
impairment (Nataraj et al., 2016). Here, the findings established that study stated that lutein prevents nerve damage by decreasing oxidative
lutein offers potential benefits at an assortment of doses ranging from 5 stress and reducing the number of apoptotic cells (Sun et al., 2014).
to 20 mg/kg/day against MPTP-triggered neural abnormalities in mice
models in vivo. Mitochondrial impairment and OS-mediated apoptosis
4.2. Ophthalmological effects
contribute to multiple neurodegenerative diseases, such as Parkinson’s
disease, Huntington’s disease, and Alzheimer’s disease. MPTP is the
Plenty of evidence suggests that lutein has many potential benefits,
most commonly used neurotoxin to develop Parkinson’s disease symp­
notably on eye health. Lutein has indeed been reported as highly pre­
toms by suppressing mitochondrial complex I and activating excessive
ventative against age-related macular disease (AMD), which leads to
intracellular reactive oxygen species (ROS), which eventually contrib­
vision impairment and blindness in progressive stages (Feng et al., 2019;
utes to mitochondrial-dependent apoptosis (Fig. 2). Lutein suppresses
MBiostat et al., 2014). The most hazardous aspects which promote AMD
neuronal damage and apoptosis triggered by MPTP via obstructing the
are the lower consumption of berries and leafy green vegetables
activation of pro-apoptotic markers and increasing anti-apoptotic gene
(Abdel-Aal et al., 2013). An optimum level of macular pigment optical
expression (Nataraj et al., 2016).
density (MPOD) and visual acuity (VA) support a clear vision. Lutein
Additionally, another neural syndrome, the diabetic retinopathy, is
exerts a significant effect to raise both the MPOD (Buscemi et al., 2018;
regarded as a neurodegenerative disorder that triggers vision impair­
Khalighi Sikaroudi, Saraf-Bank, Clayton and Soltani, 2021; Maci et al.,
ment in early diabetes. Sasaki et al. (2010) established the potential
2016; Murray et al., 2013; Weigert et al., 2011) and VA levels (Beatty
benefits of lutein in the case of diabetic retinopathy in C57BL/6 mice.
et al., 2013; R. Liu et al., 2015). Weigert G. et al. (2011) have evaluated
During this study, the authors generated diabetes in mice by injecting
the effects of lutein supplementation on MPOD and VA in patients with
streptozotocin at a dosage of 60 mg/kg for three days. Then, lutein was
age-related macular degeneration. The outcomes reported that intake of
introduced to the diabetic mice at 0.1% (w/w), which resulted in the
lutein improves MPOD by utilizing an objective assessment. This sug­
protection in diabetes-induced visual impairment leading to the
gests that patients with an enhanced MPOD modification have a parallel
conclusion that a constant consumption of dietary lutein prevents local
increase in VA and mean differential light threshold (MDLT) (Weigert
neurodegenerative stress with a positive influence in the diabetic retina
et al., 2011). Lutein has been reported to increase MPOD, improve VA

4
S. Mitra et al.
and macular function (Weigert et al., 2011). Besides, a substantial
positive influence of lutein supplementation (10 mg/d) has been noticed
in 90 individuals during the Lutein Antioxidant Supplementation Trial
(LAST) (Murray et al., 2013). Besides, the Age-Related Eye Disease
Study 2 (AREDS2) is the most significant and latest randomized
controlled trial (RCT) to test AMD treatment with oral vitamin and
micronutrient supplementation, including lutein. The initial dietary
treatment described in AREDS has already established lutein’s utility in
minimizing the chances of promoting advanced AMD (Chew et al.,
2012). This test has involved over 4000 individuals at the risk of late
AMD but unfortunately failed to demonstrate the efficiency of lutein in
minimizing AMD development or promoting VA (Chew et al., 2013).
However, upon AREDS2, individuals supplemented with a small portion
of lutein in their dietary consumption displayed a 26% significant
decline of late AMD (Chew et al., 2014).
Cataract is another severe health issue that results in progressive
visual impairment, blurry vision, and lens opacity. Lens opacity caused
by accumulated or excessive light exposure, membrane lipid peroxida­
tion by reactive oxygen species (ROS), and subsequently disruption and
deterioration of the lens protein crystalline lead to cataract disorder. In
vitro experiments have shown that lutein displays a preventative action
against cataracts in bovine cells by obstructing lens cell proliferation and
migration (Babizhayev, 2016; Buscemi et al., 2018). Similarly, several
dietary supplementation trials have demonstrated the favorable benefit
of lutein against cataracts correlating with age (Manayi et al., 2016).
Moreover, it has been observed that lutein at a dose of 10 mg demon­
strated potent activity against cataracts (Chew et al., 2013). Two recent
meta-analysis studies have reported that a decreased incidence of the
nuclear cataract with mild consequences for other cataract types, is
substantially related to lutein intake (X. H. Liu et al., 2014; Ma et al.,
2014).
Fig. 3. Ophthalmological effects of lutein (modified from healthblog.uofmhealth.org).
5
Food and Chemical Toxicology 154 (2021) 112328
Besides, lutein plays a protective role in hypoxia-induced cell dam­
age in the eye as generated by free radical attack. ROS are the most
prevalent free radicals present in the living organism. ROS, mainly
singlet oxygen species, are produced in the retina due to oxygen ab­
sorption. It is assumed that the ROS developed in the retina are
byproducts of additional mitochondrial oxidative phosphorylation in
the outer segment of rod cells. The formation of oxygen radicals and
lipid peroxidation arising from the expanded use of retinal oxygen has
been hypothesized as a possible pathway for photoreceptor apoptosis
(Nita and Grzybowski, 2016). Oxidative disruption in the rod cells’ outer
segment contributes to the discharge of extra-mitochondrial compo­
nents, such as cytochrome C, by which apoptosis occurs. During
oxidative stress (OS), lutein’s primary defensive function is to act as an
oxygen-free radical scavenger in the retina (Koushan et al., 2013; Nita
and Grzybowski, 2016; Panfoli et al., 2012). Li and Lo (S. Y. Li and Lo,
2010) have performed an experimental investigation in vitro to evaluate
the influence of lutein in the protection of retinal ganglion cells (RGC-5)
against oxidative stress and hypoxia. An increased cell count was
observed in the RGC-5 lutein-treated cells at concentrations of 10 μM
and 20 μM compared to that of vehicle-treated cells. Lutein can defend
RGC-5 cells from impairment when these later are subjected to either
CoCl2-induced chemical hypoxia or H2O2-triggered oxidative stress
(Fig. 3). These findings thus suggest that lutein can act as a neuro­
protective agent (S Y. Li. and Lo, 2010).
4.3. Antimicrobial effects
Microbial diseases have become a significant concern in recent years
due to a high spreading rate causing severe life-threatening diseases.
Thus, scientists have thought about the necessity of developing anti­
microbial agents and designed plenty of bioactive compounds having
S. Mitra et al.
potent antimicrobial effects. Carotenoids, especially lutein, have
demonstrated through comprehensive studies their activity against
bacteria, viruses, and fungal pathogens.
4.3.1. Bacteria
Phytochemical analysis of Vernonia urticifolia extracts culminated in
separating a new polyene metabolite, urticifolene as well as lutein, and
sitosterol. The isolated compounds have been applied to several bacte­
rial strains in order to assess their biocidal activity. It was found that
lutein inhibits both the growth and the proliferation of many bacteria,
including Enterococcus faecium, Staphylococcus saprophyticus, S. aureus,
Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, etc. at
concentrations varying from 8 to 256 μg/mL. For instance, lutein at a
concentration of 8 and 256 μg/mL pointedly inhibited the growth of
E. faecium and P. aeruginosa, respectively. A minimum inhibitory con­
centration of 32 μg/mL of lutein was also recorded for S. aureus, E. coli,
and K. pneumonia. This suggests that lutein may be used for the medi­
cation of some bacterial diseases. The mechanism of the antibacterial
activity of lutein is not well known, but Kiplimo proposed that lutein
could contribute to lysozyme accumulation (an immune enzyme that
digests bacterial cell wall) (Kiplimo et al., 2011).
4.3.2. Viruses
In several literature works, lutein has been assessed for its possible
antiviral functions. The in vitro antiviral activity of lutein against the
hepatitis B virus has been identified by Pang et al. (2010). The antiviral
functions of lutein were investigated in stable HBV-producing human
hepatoblastoma HepG2 2.2.15 cells by determining the levels of HBeAg,
HBsAg, and extracellular HBV DNA. Lutein was observed to efficiently
suppress the dose-dependent secretion of HBsAg in HepG2 2.2.15 cells
and also inhibit extracellular HBV DNA. A luciferase reporter gene was
used to assess the impact of lutein on HBV promoters’ activity. Findings
revealed that lutein blocks the activity of the full-length HBV promoter.
This result pointed out that lutein has anti-HBV efficacy, and that its
antiviral actions are mediated through HBV transcription suppression
(Pang et al., 2010).
4.4. Cardioprotective effects
Currently, cardiac diseases have become a significant area of concern
worldwide, as a significant amount of the total world population is
suffering from them (Zaccara et al., 2020), and an increased death rate
has been observed for adults of 30 years and older (Albert and Deo,
2012). Carotenoids have been assessed in numerous studies for their
potential cardioprotective properties and antioxidant actions (M.A., G.,
& N., 2015; Ribeiro et al., 2018). A systematic review and meta-analysis
conducted by Leermakers et al. has reported that lutein may favor
atherosclerosis and inflammatory markers; nevertheless, there were
inconsistent correlations between lutein and blood pressure, resistance
to insulin, adiposity, and blood lipids (Leermakers et al., 2016). Ac­
cording to Chung et al. lutein provides anti-inflammatory action to
coronary artery diseased patients, and this property can diminish cor­
onary artery problems (Chung, Leanderson, Lundberg and Jonasson,
2017b).
4.5. Antiplasmodial effects
Malaria is a plasmodium species-induced disease leading to serious
health challenges for an enormous proportion of the world population.
Many Plasmodium species are susceptible to affect the human body, but
the most threatening one is Plasmodium falciparum (Phillips et al., 2017;
Su et al., 2020). As their infection rates throughout the world are rising
to a greater extent, researchers have undergone many experimental
studies and reported the favorable benefits of carotenoids, vitamins, etc.
Lutein has been found to possess antiplasmodial or protective effects
against the malarial disease when applied alone or combined with other
6
Food and Chemical Toxicology 154 (2021) 112328
ingredients. A study was assessed to check the status of carotenoids in
malaria patients and found a significant portion of lutein. Lutein is the
major exception, and the vital carotene present in the blood samples
containing median concentrations of 3–7 times higher than those of the
significant provitamin a carotenoid in the plasma, beta-carotene (Vish­
wanathan et al., 2014). For the first time, an antiplasmodial activity was
found for lutein at a dose of 7.1 ± 0.20 μg through in vitro experiments
(Grace et al., 2012).
4.6. Skin protection
Skin is one of the most sensitive organs of the human body, which
may lead to severe impairment in the presence of unusual agents. UV
radiations are highly susceptible to induce skin cancer and other
dermatological injuries, like inflammation, irritation, skin redness, scalp
disease, etc. Oxidative damage to the dermal cellular constituents like
DNA, RNA, proteins, lipids, etc., is facilitated through UV photons’ ac­
tion on the oxygen atom (Abdelmegeed and Mukhopadhyay, 2019; D’Or
azio, Jarrett, Amaro-Ortiz and Scott, 2013; Fernández-García, 2014).
However, some damages initiated by environmental factors, especially
UV, can be avoided or limited by many mechanisms. As sunlight expo­
sure produces free radicals, oxidation arises so that a prompt antioxidant
response can be the primary protection. Lutein possesses robust anti­
oxidant properties and is able to mitigate possible oxidative injury by
deactivating the free radicals formed due to sunlight exposure (Augusti
et al., 2017; Gansukh et al., 2019) (Fig. 4).
Li H. et al. performed an in vivo study to establish the role of topical
applications and dietary supplements in amending the oxidative stress in
rat. Lutein supplementation prevents ovariectomized (OVX) rats from
oxidative stress by modulating antioxidant defenses. The rise in oxida­
tive stress markers was seen in OVX rats. Lutein treatment substantially
reduced the concentrations of lipid peroxidation and ROS in the OVX
rats. Inflammatory responses via the activation of NF-μB and an increase
in inflammatory cytokines (TNF-α, IL-6, IL-8) were shown by OVX rats.
In addition, a substantial upregulation was observed in the osteoclast-
specific NFATc1 marker in OVX rats compared to sham rats. Nrf2-
driven antioxidant gene expression (HO-1, NQO1) was triggered by
lutein supplements (Li et al., 2018). In addition to these outputs, ample
research findings have described that sensitivity to sunlight can cause
the antioxidant potential to be substantially diminished. This can be due
to the instant response of antioxidants to mitigate UV light-induced
oxidative damage to the skin (Abdelmegeed and Mukhopadhyay,
2019; Ribeiro et al., 2018). Two other defense mechanisms, namely
hyperplasia and melanin formation, exert a delayed response to skin
damage, but they cannot provide a prompt response to sunlight radia­
tion and related impairments. This makes the antioxidants crucially
significant as prompt skin protective agents against light-induced injury
(Black et al., 2020; Nascimento et al., 2018; Panich and Slominski, 2020;
Shirazi et al., 2012). Besides, melanin deposition, which is also referred
to as skin tanning, makes available protection to the dermal constituents
by filtering sunlight, as it is proficient in absorbing sunlight. However,
the dietary consumption of lutein showed protection against UV
light-induced skin damage in quite a lot of animal study-based literature
(Balić and Mokos, 2019; Chuyen and Eun, 2017; Fernández-García,
2014). These studies have revealedthat lutein has potential benefits
against hyperplasia and skin swelling (edema) triggered by UV exposure
(Žmitek et al., 2020).
Additionally, in vivo studies also reported lutein efficacy to work
against UV light to inhibit the skin’s immune function. An experimental
investigation was carried out to check out the skin toning and lightning
properties of orally-administrated lutein. This study found that a dose of
lutein of 10 mg showed potential benefits (Juturu et al., 2016).
4.7. Effects of lutein on wound healing and cell proliferation
Several researchers have assessed the effects of lutein on the
S. Mitra et al.
Fig. 4. Skin protection activity of lutein from UV-induced oxidative damage. Sunlight emits UV rays, causing oxidative damage to the skin by interacting with
an oxygen molecule, leading to the formation of free radical derivatives, including hydroxyl radicals, superoxide’s, and hydrogen peroxides. Free radicals attack
cellular constituents such as proteins, lipids, DNA, and RNA, modifying their structure and affecting their functions. Protective and detoxifying enzymes, including
superoxide dismutase, catalase, and glutathione peroxidase, produce lower cell oxidative species. Lutein works by blocking the interactions between UV rays and
atomic oxygen, by which oxidative damage can be minimized.
proliferation and the migration of bovine lens epithelial cells during in
vitro experiments, seeking to identify a medication that can obstruct
after-cataract. According to a study, bovine lens’s epithelial cells have
been cultured, introducing lutein at various concentrations to the second
and third-generation cultures. MTT assays were used to determine the
lutein efficacy on epithelial cell proliferation. Lutein demonstrated a
significant reduction in cell proliferation at various concentrations
ranging from 1 to 16 μmol/L. As well, one μmol/L application of lutein
for 24 h considerably reduced cell proliferation from 0.603 ± 0.008 to
0.540 ± 0.006, which was 0.445 ± 0.010 for 72 h. Besides, findings also
demonstrated modifications in BLECs’ healing rate at various concen­
trations for 6, 12, and 24 h, respectively. Here, at 1 or 2 μmol/L, lutein
enlarged the wound as the period elongated, though at 4, 8, and 16
μmol/L, a substantial wound healing was observed (Y. Li et al., 2018b; E.
J. Miller, 2014). Another experimental study (Y. Li et al., 2018a) has
underlined the efficacy of lutein in inhibiting cell proliferation, cell in­
vasion, and hypoxic breast cancer cell migration through down­
regulation of HES1 (hairy and enhancer of split 1). During this work,
authors have gone through the cell proliferation test and the wound
healing assay at varying lutein concentrations. It was concluded that
lutein suppressed cell proliferation along with a significant reduction in
both the migration and the invasion of breast cancer cells in a
dose-dependent manner (Y. Li et al., 2018a). Another study (Kumar and
Swetha, 2015) has evaluated the bioconjugation capacity between lutein
and oligodeoxynucleotides (ODNs) in N-nitrosodimethylamine-induced
fibrosis. Fibrosis is characterized as a wound-healing process, usually
occurring from inflammatory reactions, which induces the accumulation
of connective tissue elements and eventually remodel and damage the
normal cells’ framework. This investigation has been performed to
assert ODNs bioconjugation’s impact with lutein on the antifibrotic
function, utilizing cultured human retinal pigment (ARPE-19) epithelial
cells as a model. Study’s findings stated that p38 MAPK expression,
fibronectin, HGF/cMet, collagen type I, and the related reactive oxygen
7
Food and Chemical Toxicology 154 (2021) 112328
species that lead to fibrosis in ARPE-19 cells, were substantially sup­
pressed by the bioconjugation between lutein and ODNs (Kumar and
Swetha, 2015).
4.8. Antiosteoporosis effects
Osteoporosis is a physiological malady associated with human bone,
characterized by bone loss, low bone density, bone tissue degradation,
and interruption in bone microarchitecture, which may contribute to
decreased bone strength and a rise in the incidence of fractures. The
bone mass progressively develops and touches its peak with puberty
initiation, subsequently declining after the end of this period (Sozen,
Ozisik, & Calik Basa ran, 2017; Yang et al., 2018). However, the ca­
rotenoids present in animals and humans have been shown to possess
anabolic effects on bone (Yamaguchi, 2012). Lutein, which is also a
carotenoid compound, has been revealed to be involved in osteoporosis
in comprehensive research studies. Yamaguchi (2012) has investigated
the influence of lutein on bone resorption, bone development, and
femoral bone mass in mice at varying doses and observed that lutein
significantly facilitates the development of mineralized bone nodules in
osteoblast cultures.
Conversely, lutein explicitly inhibits the 1α, 25-dihydroxy vitamin
D3-mediated resorption of bone as assessed by pit development of
mouse calvaria. Namely, lutein restricted the formation of 1α, 25-dihy­
droxy vitamin D3-triggered osteoclasts (Takeda et al., 2017). This study
concluded that lutein both acts on osteoblast formation as well as
osteoclast degeneration. At first, lutein acts on macrophages, decreases
bone degradation by reducing the number of osteoclast cells, and keeps
down the RANKL-dependent osteoclast formation. Secondly, lutein acts
on osteoblast formation as well as the suppression of the RANKL–in­
duced mRNA expression (Takeda et al., 2017). Besides, Bovier and
Hammond’s investigation (Bovier and Hammond, 2017) has addressed
the macular lutein’s role on bone density augmentation in young adults.
S. Mitra et al. Food and Chemical Toxicology 154 (2021) 112328

Sixty-three healthy adults were involved in this study where macular
pigment optical density was shown to be significantly correlated with
bone density in the lumbar spine and proximal femur. Data pointed out
that some individuals with higher areal bone mineral density often
appear to have elevated MPOD. However, the relations observed be­
tween the skeletal mass and serum lutein were not statistically mean­
ingful. This could be due to the fact that macular pigment and bone
density are more likely to reflect long-term habits, whereas serum lutein
is more likely to reflect short-term dietary intake (Bovier and Hammond,
2017). Another experimental study conducted by Tominari et al. (2017)
reported that lutein prevents bone tissue degradation induced by oste­
oclastic resorption and promotes bone development in bone marrow cell
cultures mice. Researchers have analyzed the lutein bone-resorbing ac­
tivity at the various concentrations of 3, 10, and 30 μM, resulting in a
significant reduction of bone resorption. This study also demonstrated
lutein activity at 30 μM on the survival of mature osteoclasts formed
from bone marrow macrophages. The mineralized area, a bone-inducing
factor, was significantly improved at lutein concentrations varying from
lower to higher ones (Tominari et al., 2017). Moreover, lutein’s food
consumption showed benefits in lowering hip fracture in humans (Dai
et al., 2014).

Table 1
Pharmacological activities of lutein based on experimental studies.
Pharmacological effects Doses Subjects Assay Outcomes References

Neuroprotective effects 5, 10, and 20 Mice Western blotting assay Protects dopaminergic neurons, inhibits apoptotic (Nataraj et al.,
mg/kg/day death and motor dysfunction 2016)
0.1% (w/w) C57BL/6 TUNEL assay Prevents ROS production in the retina and visual (Sasaki et al.,
Mice injury triggered by diabetes 2010)
7.5–30 mg/kg Mice TUNEL assay Neuroprotective against transient cerebral Sun et al.
ischemic impairment (2014)
500 mg/kg body Rat Immunoblot analysis, Protective against inflammation-induced retinal (Woo et al.,
weight immunohistochemistry, neural impairments 2013)
electroretinogram
Ophthalmological effect n. m. Human ETDRS Increases MPOD, improves VA and macular Weigert et al.
function (2011)
10 mg Human AREDS2 Diminishes the risk of progression to AMD Chew et al.
(2013)
10 mg Human AREDS2 Prevents age-related cataract (ARC) Chew et al.
(2013)
300 μg/day Human n. m. Reduces the risk of ARC, particularly nuclear (Ma et al.,
cataract, in a dose-dependent manner 2014)
10 μM and 20 RGC-5 n. m. Defends RGC-5 cells from impairments, increases Li & Lo (2010)
μM cells cell count in lutein-treated cells
Antimicrobial effect 8 μg/mL ATCC NMR, COSY, NOESY, HMBC, HSQC Inhibits the growth of Enterococcus faecium bacteria (Kiplimo et al.,
19434 2011)
strain
256 μg/mL ATCC Inhibits the growth of Staphylococcus saprophyticus
35552 bacteria
strain
32 μg/mL ATCC Inhibits the growth of S. aureus bacteria
29212
strain
32 μg/mL ATCC Inhibits the growth of Escherichia coli bacteria
25922
strain
256 μg/mL ATCC Inhibits the growth of Pseudomonas aeruginosa
35032 bacteria
strain
32 μg/mL ATCC Inhibits the growth of Klebsiella pneumoniae
25922 bacteria
strain
Skin protection 10 mg Human MPA 580 Skin tone improved Juturu et al.
(2016)
Antiplasmodial effect 7.1 ± n. m. Spectroscopic methods, MTT assay Protection against malarial disease Grace et al.
0.20 μg/mL (2012)
Wound healing and cell n. m. Human Cell proliferation test and wound healing Suppresses the proliferation of cells along with (Y. Li et al.,
proliferation of lutein assay significant inhibition of the migration and invasion 2018a)
of breast cancer cells in dose-dependent manners
20 μL Human HGF/c-Met expression assay, p38 MAP HGF/cMet, p38 MAPK expression, collagen type I, (Kumar and
kinase assay, Collagen type I, and fibronectin, and quenches the associated reactive Swetha, 2015)
fibronectin assay oxygen species contributing to fibrosis progress.
Antiosteoporosis activity 1% of dietary Male mice DEXA Reduces the number of osteoclast cells, osteoblast (Takeda et al.,
consumption formation, inhibition of osteoclast formation 2017)
n. m. Human DXA Promotes bone density Bovier &
Hammond
(2017)
3, 10, and 30 μM Mice n. m. Significant reduction of bone resorption, increment Tominari et al.
in mineralized area, prevention of bone tissue (2017)
degradation

n. m.: Not mentioned; DEXA: Dual X-ray absorptiometry; DXA: Dual-energy X-ray absorptiometry; MPOD: Macular pigment optical density ETDRS: Early Treatment
Diabetic Retinopathy Study; VA: Visual acuity; LAST: Lutein antioxidant supplementation trial; AREDS2: Age-Related Eye Disease Study 2; HPLC: High-performance
liquid chromatography; COSY: correlation spectroscopy; NOESY: Nuclear overhauser enhancement spectroscopy, HMBC: Heteronuclear multiple bond spectroscopy;
HSQC: Heteronuclear single quantum coherence; NMR: Nuclear Magnetic Resonance.

8
S. Mitra et al.
4.9. Effects on oral and dental diseases
Oral and dental diseases are considered as inflammations and irri­
tations of the mouth. Gum infections, oral cancers, cavities, plaque,
tooth infection, etc. are oral and dental diseases. Lutein has been
documented for having antioxidant and anti-inflammatory activities.
Due to its antioxidant activity, lutein can minimize the risk of oral and
dental diseases. However, lutein is a lipophilic molecule, slightly water-
soluble with limited bioavailability. Some works have reported the ad­
vantages of oral or topical lutein applications and its isomer zeaxanthin,
where they significantly reduce the possibility of oral diseases (Mitri,
Shegokar, Gohla, Anselmi and Müller, 2011b). The cumulative oral or
topical lutein and zeaxanthin applications offer the most significant
antioxidant defensive action against oral disease (Mitri, Shegokar,
Gohla, Anselmi and Müller, 2011c). The major therapeutics activities
based on experimental studies of lutein are summarized in Table 1.
5. Lutein at the different stages of life
5.1. Infants and children
Lutein supplementation can raise lutein in breast milk and lactating
mother plasma, resulting in plasma lutein concentration in their infants
(Sherry et al., 2014). In addition, formulations supplemented with lutein
enrich its level in tissues, including the retina and cortex, relative to
infants who consume it to a lesser extent. Higher lutein intakes can be
justified for promoting brain growth and cognition, and advice for
breastfeeding mothers may be needed to maintain suitable breast milk
lutein content (Jeon et al., 2017).
Dietary lutein seems to play a significant role in children’s visual and
cognitive development. If subsequent interventions confirm these initial
cross-sectional findings with children, so they must also encourage a
desire to change nutrition in earlier life. Lutein consumption in Amer­
ican adults is low (total: 1–2 mg/d), but is tending to be much smaller in
early adolescent years (total: 300–500 μg/d). As for many other dietary
aspects, certain childhood deficiencies may only begin a cascade that
increases with age. Child interventions are expected to produce lifelong
benefits (Johnson et al., 2010; Stringham et al., 2019).
5.2. Adults
It is possible that making a recommendation for lutein consumption
in the diet to promote cognitive performance is premature. However,
intakes of <6 mg/d were attributed to lower incidence of AMD, a dis­
order that shares common risk factors with age-related cognitive
impairment (Woo et al., 2012). In addition, the age-related eye disease
study 2 (AREDS2), a multicenter phase III randomized clinical trial,
confirmed that the development of advanced AMD in people with low
dietary lutein supplements (10 mg/d) on top of the AREDS supplement,
was lowered in the secondary analysis (Chew et al., 2013). Moreover, an
intervention of 12 mg/d of lutein was eventually used in older adults to
improve cognition. Although these levels (6–12 mg) can be obtained
through proper food choices, the bulk of American adult populations do
not meet these consumptions (Rasmussen and Johnson, 2013).
6. Lutein nanoformulations as therapeutic agents
Lutein belongs to the family of hydrophobic carotenoids found in
abundance in dark green leafy vegetables. Lutein has restricted use since
it has low solubility in water and is easily affected by oxygen, light, or
heat (Boon et al., 2010; Qv et al., 2011). Lutein encapsulation in poly­
vinylpyrrolidone, soy protein isolate, and whey protein products has
good advantages over lutein microencapsulation utilizing porous starch
and gelatin mixture sprayed into a droplet using high-pressure homog­
enization (Wang et al., 2012). Lutein encapsulation was carried out 1)
with hydroxypropyl methylcellulose phthalate using the supercritical
9
Food and Chemical Toxicology 154 (2021) 112328
antisolvent method (Anandharamakrishnan, 2014; Dasgupta & Ranjan,
2018), 2) through the formation of lipid nanoparticles for dermal de­
livery by high-pressure homogenization (Mitri, Shegokar, Gohla,
Anselmi and Müller, 2011a), and 3) emulsification of lutein with various
emulsifiers, such as soy protein isolate, polyvinylpyrrolidone, as well as
whey protein products, for example (Chen, 2015; Frede et al., 2014;
Changdong Zhao, Cheng, Jiang, Yao and Han, 2014). Suitable packaging
materials must be chosen to ensure bioactive substances’ safety and
bio-accessibility (Changhui Zhao, Shen and Guo, 2018). Bodoki et al.
(2019) reported the topical nano delivery of lutein to treat cataract
induced by selenite. Selenite-induced cataract incidence was reduced
when some amounts of lutein-loaded nanoparticles (NPs) were added
topically to the eyes. Increased durability of lutein in its nano-entrapped
shape contributes to improved bioavailability when added topically. The
groups who used the low dose of lutein-loaded zein NPs and the high
dose of poly (lactic-co-glycolic acid) (PLGA) NPs had an overall lower
performance but not a statistically relevant cataract incidence reduc­
tion. Lutein-loaded PLGA NPs at a low dosage did not display a sub­
stantial difference in cataract lowering because the eye did not receive
adequate amounts of lutein. Despite administering free lutein or
lutein-loaded NPs, no measurable decrease in cataract incidence was
found (Bodoki et al., 2019).
Other results indicate that polymeric nanoparticles filled with lutein
and decorated with biotin improve lutein absorption in retinal cells
(Bolla et al., 2020). Despite several challenges, the polymeric nano­
particles were successfully decorated with lutein and biotin and used as
a lutein delivery vehicle. Nanoparticles with particle size less than 250
nm and closely spaced sizes were collected. Biotin-conjugated nano­
particles were able to encapsulate a larger volume of medicine and also
demonstrate better loading ability. Biotin-decorated nanoparticles
showed a better absorption of lutein when examined in in vitro cell up­
take experiments. Cytotoxicity analysis revealed that the nanoparticles
were more effective than lutein in saving cell viability. In the case of
AMD and other retinal disorders, it was discovered that the
biotin-conjugated nanoparticles may be an effective formulation for
selective drug delivery (Bolla et al., 2020).
Furthermore, Pradeep and co-authors prepared and characterized
lutein-loaded polylactide-co-glycolide–polyethylene glycol–folate
(PLGA-PEG-FOLATE-PLGA) NPs, as well as significantly increase the
absorption of this substance in neuroblastoma (SK–N-BE) cells. The
prepared NPs were stable in scale, shape, and concentration, with well-
distributed sizes. Neuroblastoma cells exhibited enhanced cellular up­
take of lutein through folate receptor-mediated endocytosis, as demon­
strated in in vitro experiments utilizing flow cytometry, confocal
microscopy, and cellular uptake studies. It can be inferred that PLGA-
PEGFOLATE NPs loaded with lutein, which can have beneficial effects
on hypoxic-ischemic encephalopathy, represent a potential new thera­
peutic strategy (Bolla et al., 2020).
7. Drug interactions with β-carotene: safety concerns and dosing
Interactions between carotenoids during absorption and their post­
absorptive metabolism have been observed in both human and animal
studies. New data have been reported regarding the postprandial
β-carotene and retinyl ester responses in the triglyceride-rich plasma
lipoprotein (TRL) fraction of volunteers after a single test meal with
β-carotene alone or β-carotene combined with lutein. Results indicated
an inhibitory effect of lutein on β-carotene absorption but not on
β-carotene cleavage. In a comparative study with two β-carotene/lutein
ratios (2:1 and 1:2, respectively), the inhibitory effect of lutein was more
marked when lutein was the predominant carotenoid. In studies on
plasma (serum) response, an inhibitory effect of β-carotene on lutein’s
function was also observed (Kopec et al., 2014).
The possible health effects of dietary carotenoids stem from the
findings through epidemiological studies that persons with a higher
intake of fruits and vegetables are at reduced risk of coronary heart
S. Mitra et al.
disease, stroke, and cancer. Of the many phytochemicals found in these
foods, carotenoids may have a possible role in a reduced risk of cancer
and coronary heart disease (Black et al., 2020). Lutein is the second most
prevalent carotenoid in human serum. It is abundantly found in leafy
green vegetables such as spinach, kale, and lettuce (2–15 mg/100 g)
(Deis et al., 2021; Nian and Lo, 2018; Toti, Oliver Chen, Pa lmery,
Valencia and Peluso, 2018; Walsh et al., 2015). A daily intake of 5–12
mg lutein is recommended for positive health effects. A study focuses on
the pathogenesis of early atherosclerosis and the impact of the
oxygenated carotenoid lutein, a pigment found in dark green leafy
vegetables, egg yolks, and other foods. Data are presented from an
epidemiological study of atherosclerosis progression (as measured by
the change in carotid intima-media thickness, IMT), an in vitro model of
oxidation in the artery wall in vivo mouse models of atherosclerosis in
the aortic arch (Shegokar and Mitri, 2012).
8. Clinical trials with lutein
Lutein is called the macular pigment as it supports visual functions,
owing to its antioxidant, anti-inflammatory, and anti-angiogenic prop­
erties. Lutein plays a vital role in the destruction of age-related macular
degeneration, cataracts (ocular complications), and diabetic retinopathy
due to its radical scavenging properties (Bernstein et al., 2016). Thus,
lutein is also significant as a food and drug in treating ocular compli­
cations (Chang et al., 2018; Rafi et al., 2015; Wu et al., 2015).
Several clinical trials have been considered to date to establish the
therapeutic potential of lutein in humans, especially in eye health. Ma
and coworkers (Ma et al., 2012) have monitored the effects of macular
pigment supplementation for 48 weeks in patients with AMD. The
treatment groups consisted of 107 participants, who were offered the
placebo, 10 mg/day, or 20 mg/day of lutein. Except for the 10 mg lutein
group, they found a substantial rise in MPOD in all sample levels. The
control group got the same results as before the treatment. Regardless of
supplementation, subjects with the lowest baseline MPOD had the
highest growth in MPOD. All treatment groups improved in terms of
visual acuity (VA), but not substantially. At 48 weeks, all treatment
groups had vastly different contrast sensitivity (CS). MPOD levels were
slightly higher at 24 weeks, but VA and CS did not change until 48
weeks, implying that visual function cannot be improved until MPOD
levels exceed and maintain high levels (Ma et al., 2012). Besides, the
CARMA study observed the function of lutein in combination with other
antioxidants, minerals and vitamins, in people who were at high risk of
becoming advanced AMD. In terms of CS, improvements have been
observed, but not to a greater extent. Few participants in the treatment
community improved their status compared to the control group (41.7%
versus 47.4%, respectively). There was a gradual rise in the Macular
Pigment values in the experimental population, whilst the placebo group
displayed a constant reduction over time. After six months of lutein
supplementation, serum concentrations of all antioxidants improved.
The rise in these serum levels did not correspond to any rise in VA.
However, a rise in serum lutein levels was correlated with a reduced
progression of AMD (Beatty et al., 2013). Additionally, Lutein supple­
mentation on the early phase AMD was measured in the CLEAR study,
which assessed participants over a year. After 8 months of supplemen­
tation, this group displayed a substantial improvement in mean MPOD,
whereas the control group showed no progress. The VA of the study
group increased, while the VA of the placebo group decreased signifi­
cantly. Additionally, the serum lutein levels increased by 1.8–7.6 fold or
more within the participants to this study (Murray et al., 2013).
Unfortunately, humans are unable to synthesize lutein and therefore
must get it through dietary supplements. The FAO/WHO Committee
(FAO/WHO Joint Committee on Food Additives) recommended a daily
intake of lutein of 2–12 mg/kg body weight. However, it has been re­
ported that the effective dose of lutein required to prevent ocular
complications is much higher than the recommended amount of the
Joint Expert Committee for Food Additives (JECFA) (Frede et al., 2014).
10
Food and Chemical Toxicology 154 (2021) 112328
As a result, various commercial lutein formulations for food safety have
appeared on the market. Lutein bioavailability is an unfavorable factor
due to its hydrophobic nature, poor binding, lower solubility in water,
poor stability to light, heat, and oxygen stress. These limitations
constitute a hindrance to the use of lutein in the food and pharmaceu­
tical industries (Boon et al., 2010).
9. Conclusion and future perspectives
Due to its antioxidant and anti-inflammatory properties as well as it
safety use, lutein has been considered a promising molecule in several
fields of application. To date, considerable research has been conducted
on lutein and its beneficial nutritional effects on human health. Many
scientists have successfully formulated and characterized
nanotechnology-based delivery systems for lutein (Bhat et al., 2020;
Bodoki et al., 2019; Bolla et al., 2020; dos Santos et al., 2018). Much
evidence suggests that lutein may protect against several age-related
diseases, heart diseases, cataracts, oral diseases and possesses neuro­
protective effects, antiplasmodial activity, anthelmintic activity, and
some forms of antimicrobial activity. Though the data about its neuro­
protective effect is compelling, DHA oxidation in Alzheimer’s disease
and cognitively impaired individuals has been established. Lutein has
many potential benefits, notably on eye health. Lutein has been reported
as highly preventative against age-related macular disease (AMD),
cataract, etc., leading to vision impairment and blindness in progressive
stages.
Lutein, due to its nutritional value, offers preventative action in
terms of cataract. Lutein has also been established to possess an anti­
plasmodial effect or be protective against malarial disease when applied
alone or combined with other ingredients. Some of the putative benefits
of lutein are substantiated. They may also reflect a simple and inde­
pendent action or a synergistic role of lutein and zeaxanthin combined
with other antioxidants, including hydrocarbon carotenoids and related
phytochemicals. However, such complex defense networks are not
readily defined partially because of the complicating influences of
physiological and genetic factors affecting both the bioavailability and
the metabolism of these compounds and the pathogenic processes.
Lutein plays a role in skin protection via its antioxidant properties, and
this aims to mitigate possible oxidative injury by deactivating the free
radicals formed during sunlight exposure. This article provides a review
on lutein and health benefits comprising all the available literature
about lutein and may help developing new pharmacological active
functional foods in the future.
Funding
This work is conducted with the individual funding of all authors.
Disclosure statement
No potential conflict of interest was reported by the authors.
CRediT authorship contribution statement
Saikat Mitra: Conceptualization, Formal analysis, Investigation,
Writing – original draft. Abdur Rauf: Conceptualization, Formal anal­
ysis, Writing – review & editing, Supervision. Abu Montakim Tareq:
Conceptualization, Formal analysis, Writing – review & editing, Visu­
alization. Shamima Jahan: Formal analysis, Investigation, Writing –
original draft. Talha Bin Emran: Conceptualization, Formal analysis,
Writing – review & editing, Supervision. Talukder Galeeb Shahriar:
Formal analysis, Investigation, Writing – original draft. Kuldeep
Dhama: Resources, Formal analysis, Writing – review & editing, Visu­
alization. Fahad A. Alhumaydhi: Formal analysis, Writing – review &
editing, Visualization. Abdullah S.M. Aljohani: Formal analysis,
Writing – review & editing, Visualization. Maksim Rebezov: Formal
S. Mitra et al. Food and Chemical Toxicology 154 (2021) 112328

analysis, Writing – review & editing, Visualization. Md Sahab Uddin: Bolla, P.K., Gote, V., Singh, M., Patel, M., Clark, B.A., Renukuntla, J., 2020a. Lutein-
loaded, biotin-decorated polymeric nanoparticles enhance lutein uptake in retinal
Formal analysis, Writing – review & editing, Visualization. Philippe
cells. Pharmaceutics 12 (9), 1–17. https://doi.org/10.3390/
Jeandet: Formal analysis, Writing – review & editing, Formal analysis, pharmaceutics12090798. Retrieved from.
Writing – review & editing. Zafar Ali Shah: Formal analysis, Writing – Bolla, P.K., Gote, V., Singh, M., Yellepeddi, V.K., Patel, M., Pal, D., Renukuntla, J.,
review & editing. Mohammad Ali Shariati: Formal analysis, Writing – 2020b. Preparation and characterization of lutein loaded folate conjugated
polymeric nanoparticles. J. Microencapsul. 37 (7), 502–516. https://doi.org/
review & editing. Kannan RR. Rengasamy: Formal analysis, Writing – 10.1080/02652048.2020.1809724. Retrieved from.
review & editing, Formal analysis, Writing – review & editing, Boon, C.S., McClements, D.J., Weiss, J., Decker, E.A., 2010. Factors influencing the
Submission. chemical stability of carotenoids in foods. Crit. Rev. Food Sci. Nutr. 50 (6), 515–532.
https://doi.org/10.1080/10408390802565889. Retrieved from.
Bovier, E., Hammond, B., 2017. The macular carotenoids lutein and zeaxanthin are
related to increased bone density in young healthy adults. Foods 6 (9), 78. https://
Declaration of competing interest doi.org/10.3390/foods6090078. Retrieved from.
Buscemi, S., Corleo, D., Di Pace, F., Petroni, M.L., Satriano, A., Marchesini, G., 2018. The
effect of lutein on eye and extra-eye health. Nutrients 10 (9). https://doi.org/
The authors declare that they have no known competing financial 10.3390/nu10091321. Retrieved from.
interests or personal relationships that could have appeared to influence Chang, D., Ma, Y., Cao, G., Wang, J., Zhang, X., Feng, J., Wang, W., 2018. Improved oral
the work reported in this paper. bioavailability for lutein by nanocrystal technology: formulation development, in
vitro and in vivo evaluation. Artificial Cells, Nanomedicine and Biotechnology 46
(5), 1018–1024. https://doi.org/10.1080/21691401.2017.1358732. Retrieved
References from.
Chen, C., 2015. Functional Characterization of Ph and Ultrasound Treated Soy Protein
Based Nanoemulsions with Lutein, vols. 1–84.
Abdel-Aal, E.S.M., Akhtar, H., Zaheer, K., Ali, R., 2013. Dietary sources of lutein and
Chew, E.Y., Clemons, T.E., SanGiovanni, J.P., Danis, R., Ferris, F.L., Elman, M.,
zeaxanthin carotenoids and their role in eye health. Nutrients 5 (4), 1169–1185.
Sperdut, R., 2013a. Lutein + zeaxanthin and omega-3 fatty acids for age-related
https://doi.org/10.3390/nu5041169. Retrieved from.
macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized
Abdelmegeed, M., Mukhopadhyay, P., 2019. Understanding the roles and mechanisms of
clinical trial. JAMA - Journal of the American Medical Association 309 (19),
oxidative stress in diseases, tissue injury, and cell death in vivo and in vitro:
2005–2015. https://doi.org/10.1001/jama.2013.4997. Retrieved from.
therapeutic possibilities of antioxidants. Food Chem. Toxicol. 127, 70–71. https://
Chew, E.Y., Clemons, T.E., SanGiovanni, J.P., Danis, R.P., Ferris, F.L., Elman, M.J.,
doi.org/10.1016/j.fct.2019.02.040. Retrieved from.
Sperduto, R.D., 2014. Secondary analyses of the effects of lutein/zeaxanthin on age-
Akuffo, K.O., Beatty, S., Peto, T., Stack, J., Stringham, J., Kelly, D., et al., 2017. The
related macular degeneration progression AREDS2 report no. 3. JAMA
impact of supplemental antioxidants on visual function in nonadvanced age-related
Ophthalmology 132 (2), 142–149. https://doi.org/10.1001/
macular degeneration: a head-to-head randomized clinical trial. Investig.
jamaophthalmol.2013.7376. Retrieved from.
Ophthalmol. Vis. Sci. 58 (12), 5347–5360. https://doi.org/10.1167/iovs.16-21192.
Chew, E.Y., Clemons, T., Sangiovanni, J.P., Danis, R., Domalpally, A., McBee, W.,
Retrieved from.
Ferris, F.L., 2012. The age-related eye disease study 2 (AREDS2): study design and
Albert, C.M., Deo, R., 2012. Epidemiology and genetics of sudden cardiac death.
baseline characteristics (AREDS2 Report Number 1). Ophthalmology 119 (11),
Circulation 125 (4), 620–637. Retrieved from. http://circ.ahajournals.org/cgi/doi/1
2282–2289. https://doi.org/10.1016/j.ophtha.2012.05.027. Retrieved from.
0.1161/CIRCULATIONAHA.111.023838%5Cnpapers3://publication/doi/10.1161/
Chew, E.Y., SanGiovanni, J.P., Ferris, F.L., Wong, W.T., Agron, E., Clemons, T.E.,
CIRCULATIONAHA.111.023838.
Bernstein, P., 2013b. Lutein/zeaxanthin for the treatment of age-related cataract:
Álvarez-Barrios, A., Álvarez, L., García, M., Artime, E., Pereiro, R., González-Iglesias, H.,
AREDS2 randomized trial report no. 4. JAMA Ophthalmology 131 (7), 843–850.
2021. Antioxidant defenses in the human eye: a focus on metallothioneins.
https://doi.org/10.1001/jamaophthalmol.2013.4412. Retrieved from.
Antioxidants 10 (1), 1–33. https://doi.org/10.3390/antiox10010089. Retrieved
Chung, R.W.S., Leanderson, P., Lundberg, A.K., Jonasson, L., 2017a. Lutein exerts anti-
from.
inflammatory effects in patients with coronary artery disease. Atherosclerosis 262,
Anandharamakrishnan, C., 2014. Techniques for Nanoencapsulation of Food Ingredients.
87–93. https://doi.org/10.1016/j.atherosclerosis.2017.05.008. Retrieved from.
Techniques For Nanoencapsulation Of Food Ingredients, vols. 43–49. Retrieved from.
Chung, R.W.S., Leanderson, P., Lundberg, A.K., Jonasson, L., 2017b. Lutein exerts anti-
http://link.springer.com/10.1007/978-1-4614-9387-7.
inflammatory effects in patients with coronary artery disease. Atherosclerosis 262,
Augusti, P.R., Brasil, A.V.S., Souto, C., Göethel, G., de Oliveira Rios, A., Emanuelli, T.,
87–93. https://doi.org/10.1016/j.atherosclerosis.2017.05.008. Retrieved from.
et al., 2017. Microcystin-LR exposure induces oxidative damage in Caenorhabditis
Chuyen, H. Van, Eun, J.B., 2017. Marine carotenoids: bioactivities and potential benefits
elegans: protective effect of lutein extracted from marigold flowers. Food Chem.
to human health. Crit. Rev. Food Sci. Nutr. 57 (12), 2600–2610. https://doi.org/
Toxicol. 109, 60–67. https://doi.org/10.1016/j.fct.2017.08.045. Retrieved from.
10.1080/10408398.2015.1063477. Retrieved from.
Babizhayev, M.A., 2016. Generation of reactive oxygen species in the anterior eye
D’Orazio, J., Jarrett, S., Amaro-Ortiz, A., Scott, T., 2013. UV radiation and the skin. Int.
segment. Synergistic codrugs of N-acetylcarnosine lubricant eye drops and
J. Mol. Sci. 14 (6), 12222–12248. https://doi.org/10.3390/ijms140612222.
mitochondria-targeted antioxidant act as a powerful therapeutic platform for the
Retrieved from.
treatment of cataracts and primary open-an. BBA Clinical 6, 49–68. https://doi.org/
Dai, Z., Wang, R., Ang, L.W., Low, Y.L., Yuan, J.M., Koh, W.P., 2014. Protective effects of
10.1016/j.bbacli.2016.04.004. Retrieved from.
dietary carotenoids on risk of hip fracture in men: the Singapore Chinese health
Balić, A., Mokos, M., 2019. Do we utilize our knowledge of the skin protective effects of
study. J. Bone Miner. Res. 29 (2), 408–417. https://doi.org/10.1002/jbmr.2041.
carotenoids enough? Antioxidants 8 (8). https://doi.org/10.3390/antiox8080259.
Retrieved from.
Retrieved from.
Daniele, N. Di, Noce, A., Vidiri, M.F., Moriconi, E., Marrone, G., Annicchiarico-
Beatty, S., Chakravarthy, U., Nolan, J.M., Muldrew, K.A., Woodside, J.V., Denny, F.,
Petruzzelli, M., De Lorenzo, A., 2017. Impact of Mediterranean diet on metabolic
Stevenson, M.R., 2013. Secondary outcomes in a clinical trial of Carotenoids with
syndrome, cancer and longevity. Oncotarget 8 (5), 8947–8979. Retrieved from.
Coantioxidants versus placebo in early age-related macular degeneration.
www.impactjournals.com/oncotarget/.
Ophthalmology 120 (3), 600–606. https://doi.org/10.1016/j.ophtha.2012.08.040.
Dasgupta, N., Ranjan, S., 2018. An Introduction to Food Grade Nanoemulsions. An
Retrieved from.
Introduction To Food Grade Nanoemulsions, vol. 1, pp. 1–179. Retrieved from. http://
Bernstein, P.S., Li, B., Vachali, P.P., Gorusupudi, A., Shyam, R., Henriksen, B.S., Nolan, J.
www.springer.com/series/8380%0Ahttp://link.springer.com/10.1007/978-981-10-
M., 2016. Lutein, zeaxanthin, and meso-zeaxanthin: the basic and clinical science
6986-4.
underlying carotenoid-based nutritional interventions against ocular disease. Prog.
Deis, L., Quiroga, A.M., De Rosas, M.I., 2021. Coloured compounds in fruits and
Retin. Eye Res. 50, 34–66. https://doi.org/10.1016/j.preteyeres.2015.10.003.
vegetables and health. Psychiatry and Neuroscience Update 343–358. https://doi.
Retrieved from.
org/10.1007/978-3-030-61721-9_25. Retrieved from.
Berrow, E.J., Bartlett, H.E., Eperjesi, F., Gibson, J.M., 2013. The effects of a lutein-based
dos Santos, P.P., Andrade, L. de A., Flôres, S.H., Rios, A. de O., 2018. Nanoencapsulation
supplement on objective and subjective measures of retinal and visual function in
of carotenoids: a focus on different delivery systems and evaluation parameters.
eyes with age-related maculopathy - a randomised controlled trial. Br. J. Nutr. 109
J. Food Sci. Technol. 55 (10), 3851–3860. https://doi.org/10.1007/s13197-018-
(11), 2008–2014. https://doi.org/10.1017/S0007114512004187. Retrieved from.
3316-6. Retrieved from.
Bhat, I., Yathisha, U.G., Karunasagar, I., Mamatha, B.S., 2020. Nutraceutical approach to
Eisenhauer, B., Natoli, S., Liew, G., Flood, V.M., 2017. Lutein and zeaxanthin — food
enhance lutein bioavailability via nanodelivery systems. Nutr. Rev. 78 (9), 709–724.
sources, bioavailability and dietary variety in age-related macular degeneration
https://doi.org/10.1093/nutrit/nuz096. Retrieved from.
protection. Nutrients 9 (2). https://doi.org/10.3390/nu9020120. Retrieved from.
Bjørklund, G., Chirumbolo, S., 2017. Role of oxidative stress and antioxidants in daily
Erdman, J., Smith, J., Kuchan, M., Mohn, E., Johnson, E., Rubakhin, S., Neuringer, M.,
nutrition and human health. Nutrition 33, 311–321. https://doi.org/10.1016/j.
2015. Lutein and brain function. Foods 4 (4), 547–564. https://doi.org/10.3390/
nut.2016.07.018. Retrieved from.
foods4040547. Retrieved from.
Black, H.S., Boehm, F., Edge, R., Truscott, T.G., 2020. The benefits and risks of certain
Estévez-Santiago, R., Beltrán-De-Miguel, B., Olmedilla-Alonso, B., 2016. Assessment of
dietary carotenoids that exhibit both anti-and pro-oxidative mechanisms—a
dietary lutein, zeaxanthin and lycopene intakes and sources in the Spanish survey of
comprehensive review. Antioxidants 9 (3). https://doi.org/10.3390/antiox9030264.
dietary intake (2009-2010). Int. J. Food Sci. Nutr. 67 (3), 305–313. https://doi.org/
Retrieved from.
10.3109/09637486.2016.1147020. Retrieved from.
Bodoki, E., Vostinaru, O., Samoila, O., Dinte, E., Bodoki, A.E., Swetledge, S., Sabliov, C.
Feng, L., Nie, K., Jiang, H., Fan, W., 2019. Effects of lutein supplementation in agerelated
M., 2019. Topical nanodelivery system of lutein for the prevention of selenite-
macular degeneration. PloS One 14 (12). https://doi.org/10.1371/journal.
induced cataract. Nanomed. Nanotechnol. Biol. Med. 15 (1), 188–197. https://doi.
pone.0227048. Retrieved from.
org/10.1016/j.nano.2018.09.016. Retrieved from.

11
S. Mitra et al.
Fernández-García, E., 2014. Skin protection against UV light by dietary antioxidants.
Food and Function 5 (9), 1994–2003. https://doi.org/10.1039/c4fo00280f.
Retrieved from.
Fiedor, J., Burda, K., 2014. Potential role of carotenoids as antioxidants in human health
and disease. Nutrients 6 (2), 466–488. https://doi.org/10.3390/nu6020466.
Retrieved from.
Frede, K., Henze, A., Khalil, M., Baldermann, S., Schweigert, F.J., Rawel, H., 2014.
Stability and cellular uptake of lutein-loaded emulsions. Journal of Functional Foods
8 (1), 118–127. https://doi.org/10.1016/j.jff.2014.03.011. Retrieved from.
G, B., S, C., 2017. Role of oxidative stress and antioxidants in daily nutrition and human
health. Nutrition 33, 311–321. Retrieved from. http://www.embase.com/search
/results?subaction=viewrecord&from=export&id=L613664303%0A. https://doi.
org/10.1016/j.nut.2016.07.018.
Gansukh, E., Mya, K.K., Jung, M., Keum, Y.S., Kim, D.H., Saini, R.K., 2019. Lutein
derived from marigold (Tagetes erecta) petals triggers ROS generation and activates
Bax and caspase-3 mediated apoptosis of human cervical carcinoma (HeLa) cells.
Food Chem. Toxicol. 127, 11–18. https://doi.org/10.1016/j.fct.2019.02.037.
Retrieved from.
Grace, M.H., Lategan, C., Graziose, R., Smith, P.J., Raskin, I., Lila, M.A., 2012.
Antiplasmodial activity of the ethnobotanical plant Cassia fistula. Natural Product
Communications 7 (10), 1263–1266. https://doi.org/10.1177/
1934578x1200701002. Retrieved from.
Hendrickson, A., 2016. Development of retinal layers in prenatal human retina. Am. J.
Ophthalmol. 161, 29–35. https://doi.org/10.1016/j.ajo.2015.09.023 e1. Retrieved
from.
Honold, P.J., Jacobsen, C., Jónsdóttir, R., Kristinsson, H.G., Hermund, D.B., 2016. Health
benefits of docosahexaenoic acid (DHA). Eur. Food Res. Technol. 242 (4), 211–225.
https://doi.org/10.3164/jcbn.30.43. Retrieved from.
Jeon, S., Neuringer, M., Johnson, E.E., Kuchan, M.J., Pereira, S.L., Johnson, E.J.,
Erdman, J.W., 2017. Effect of carotenoid supplemented formula on carotenoid
bioaccumulation in tissues of infant rhesus macaques: a pilot study focused on lutein.
Nutrients 9 (1). https://doi.org/10.3390/nu9010051. Retrieved from.
Jia, Y.P., Sun, L., Yu, H.S., Liang, L.P., Li, W., Ding, H., Zhang, L.J., 2017. The
pharmacological effects of lutein and zeaxanthin on visual disorders and cognition
diseases. Molecules 22 (4). https://doi.org/10.3390/molecules22040610. Retrieved
from.
Johnson, E.J., Maras, J.E., Rasmussen, H.M., Tucker, K.L., 2010. Intake of lutein and
zeaxanthin differ with age, sex, and ethnicity. J. Am. Diet Assoc. 110 (9),
1357–1362. https://doi.org/10.1016/j.jada.2010.06.009. Retrieved from.
Johnson, E.J., Vishwanathan, R., Johnson, M.A., Hausman, D.B., Davey, A., Scott, T.M.,
Poon, L.W., 2013. Relationship between serum and brain carotenoids, α -tocopherol,
and retinol concentrations and cognitive performance in the oldest old from the
Georgia centenarian study. Journal of Aging Research 2013. https://doi.org/
10.1155/2013/951786. Retrieved from.
Juturu, V., Bowman, J.P., Deshpande, J., 2016. Overall skin tone and skin-lightning-
improving effects with oral supplementation of lutein and zeaxanthin isomers: a
double-blind, placebo-controlled clinical trial. Clin. Cosmet. Invest. Dermatol. 9,
325–332. https://doi.org/10.2147/CCID.S115519. Retrieved from.
Karppi, J., Laukkanen, J.A., Kurl, S., 2012. Plasma lutein and zeaxanthin and the risk of
age-related nuclear cataract among the elderly Finnish population. Br. J. Nutr. 108
(1), 148–154. https://doi.org/10.1017/S0007114511005332. Retrieved from.
Khalighi Sikaroudi, M., Saraf-Bank, S., Clayton, Z.S., Soltani, S., 2021. A positive effect of
egg consumption on macular pigment and healthy vision: a systematic review and
meta-analysis of clinical trials. J. Sci. Food Agric. https://doi.org/10.1002/
jsfa.11109. Retrieved from.
Kiplimo, J.J., Everia, C.A., Koorbanally, N.A., 2011. Novel polyene from Vernonia
urticifolia (asteraceae). J. Med. Plants Res. 5 (17), 4202–4211.
Kopec, R.E., Cooperstone, J.L., Schweiggert, R.M., Young, G.S., Harrison, E.H.,
Francis, D.M., Schwartz, S.J., 2014. Avocado consumption enhances human
postprandial provitamin a absorption and conversion from a novel high-β-carotene
tomato sauce and from carrots. J. Nutr. 144 (8), 1158–1166. https://doi.org/
10.3945/jn.113.187674. Retrieved from.
Korobelnik, J.F., Rougier, M.B., Delyfer, M.N., Bron, A., Merle, B.M.J., Savel, H., Creuzot-
Garcher, C., 2017. Effect of dietary supplementation with lutein, zeaxanthin, and ω-3
on macular pigment: a randomized clinical trial. JAMA Ophthalmology 135 (11),
1259–1266. https://doi.org/10.1001/jamaophthalmol.2017.3398. Retrieved from.
Koushan, K., Rusovici, R., Li, W., Ferguson, L.R., Chalam, K.V., 2013. The role of lutein in
eye-related disease. Nutrients 5 (5), 1823–1839. https://doi.org/10.3390/
nu5051823. Retrieved from.
Kumar, M.C., Swetha, K.S., 2015. Effect of bioconjugation of oligodeoxynucleotides with
lutein on N-nitrosodimethylamine induced fibrosis in cultured human retinal
pigment epithelial cells. Asian J. Biochem. 10 (2), 78–85. https://doi.org/10.3923/
ajb.2015.78.85. Retrieved from.
Leermakers, E.T.M., Darweesh, S.K.L., Baena, C.P., Moreira, E.M., Van Lent, D.M.,
Tielemans, M.J., et al., 2016. The effects of lutein on cardiometabolic health across
the life course: a systematic review and meta-analysis. Am. J. Clin. Nutr. 103 (2),
481–494. https://doi.org/10.3945/ajcn.115.120931. Retrieved from.
Li, H., Huang, C., Zhu, J., Gao, K., Fang, J., Li, H., 2018. Lutein suppresses oxidative
stress and inflammation by Nrf2 activation in an osteoporosis rat model. Med. Sci.
Mon. Int. Med. J. Exp. Clin. Res. 24, 5071–5075. https://doi.org/10.12659/
MSM.908699. Retrieved from.
Li, S.Y., Lo, A.C.Y., 2010. Lutein protects RGC-5 cells against hypoxia and oxidative
stress. Int. J. Mol. Sci. 11 (5), 2109–2117. https://doi.org/10.3390/ijms11052109.
Retrieved from.
12
Food and Chemical Toxicology 154 (2021) 112328
Li, Y., Zhang, Y., Liu, X., Wang, M., Wang, P., Yang, J., Zhang, S., 2018a. Lutein inhibits
proliferation, invasion and migration of hypoxic breast cancer cells via
downregulation of HES1. Int. J. Oncol. 52 (6), 2119–2129.
Li, Y., Zhang, Y., Liu, X., Wang, M., Wang, P., Yang, J., Zhang, S., 2018b. Lutein inhibits
proliferation, invasion and migration of hypoxic breast cancer cells via
downregulation of HES1. Int. J. Oncol. 52 (6), 2119–2129. https://doi.org/10.3892/
ijo.2018.4332. Retrieved from.
Lima, V.C., Rosen, R.B., Farah, M., 2016. Macular pigment in retinal health and disease.
International Journal of Retina and Vitreous 2 (1). https://doi.org/10.1186/s40942-
016-0044-9. Retrieved from.
Liu, R., Wang, T., Zhang, B., Qin, L., Wu, C., Li, Q., Ma, L., 2015. Lutein and zeaxanthin
supplementation and association with visual function in age-related macular
degeneration. Investig. Ophthalmol. Vis. Sci. 56 (1), 252–258. https://doi.org/
10.1167/iovs.14-15553. Retrieved from.
Liu, X.H., Yu, R. Bin, Liu, R., Hao, Z.X., Han, C.C., Zhu, Z.H., Ma, L., 2014. Association
between lutein and zeaxanthin status and the risk of cataract: a Meta-analysis.
Nutrients 6 (1), 452–465. https://doi.org/10.3390/nu6010452. Retrieved from.
Liu, Y.C., Wilkins, M., Kim, T., Malyugin, B., Mehta, J.S., 2017. Cataracts. The Lancet 390
(10094), 600–612. https://doi.org/10.1016/S0140-6736(17)30544-5. Retrieved
from.
M.A., G., G., R., & N., D, 2015. Carotenoids: potential allies of cardiovascular health?
Food and nutrition research, 59. Retrieved from. http://www.embase.com/search
/results?subaction=viewrecord&from=export&id=L602099676%0A. https://doi.
org/10.3402/fnr.v59.26762.
Ma, L., Hao, Z.X., Liu, R.R., Yu, R. Bin, Shi, Q., Pan, J.P., 2014. A dose-response meta-
analysis of dietary lutein and zeaxanthin intake in relation to risk of age-related
cataract. Graefe’s Arch. Clin. Exp. Ophthalmol. 252 (1), 63–70. https://doi.org/
10.1007/s00417-013-2492-3. Retrieved from.
Ma, L., Yan, S.F., Huang, Y.M., Lu, X.R., Qian, F., Pang, H.L., et al., 2012. Effect of lutein
and zeaxanthin on macular pigment and visual function in patients with early age-
related macular degeneration. Ophthalmology 119 (11), 2290–2297. https://doi.
org/10.1016/j.ophtha.2012.06.014. Retrieved from.
Maci, S., Fonseca, B., Zhu, Y., 2016. The role of lutein in brain health and function.
Nutrafoods 15, 179–188.
Manayi, A., Abdollahi, M., Raman, T., Nabavi, S.F., Habtemariam, S., Daglia, M.,
Nabavi, S.M., 2016. Lutein and cataract: from bench to bedside. Crit. Rev.
Biotechnol. 36 (5), 829–839. https://doi.org/10.3109/07388551.2015.1049510.
Retrieved from.
MBiostat, W.L.W., Md, X.S., BSc, X.L., Cheung, C.M.G., Md, R.K., Md, D.C.-Y.C., Mbbs, P.
T.Y.W., 2014. Global prevalence of age-related macular degeneration and disease
burden projection for 2020 and 2040: a systematic review and meta-analysis. The
Lancet Global Health 1–11. https://doi.org/10.1016/S2214-109X(13)70145-1%
0Apapers3://publication/doi/10.1016/S2214-109X(13)70145-1. Retrieved from.
Mezzomo, N., Ferreira, S.R.S., 2016. Carotenoids functionality, sources, and processing
by supercritical technology: a review. J. Chem. 2016. https://doi.org/10.1155/
2016/3164312. Retrieved from.
Miller, E.J., 2014. Effects of Grape Seed Extract, Lutein, and Omega-3 Fatty Acids on Lens
Epithelial Cell.
Miller, E., Morel, A., Saso, L., Saluk, J., 2014. Isoprostanes and neuroprostanes as
biomarkers of oxidative stress in neurodegenerative diseases. Oxidative Medicine
and Cellular Longevity 2014. https://doi.org/10.1155/2014/572491. Retrieved
from.
Mitri, K., Shegokar, R., Gohla, S., Anselmi, C., Müller, R.H., 2011a. Lipid nanocarriers for
dermal delivery of lutein: preparation, characterization, stability and performance.
Int. J. Pharm. 414 (1–2), 267–275. https://doi.org/10.1016/j.ijpharm.2011.05.008.
Retrieved from.
Mitri, K., Shegokar, R., Gohla, S., Anselmi, C., Müller, R.H., 2011b. Lutein nanocrystals
as antioxidant formulation for oral and dermal delivery. Int. J. Pharm. 420 (1),
141–146. https://doi.org/10.1016/j.ijpharm.2011.08.026. Retrieved from.
Mitri, K., Shegokar, R., Gohla, S., Anselmi, C., Müller, R.H., 2011c. Lutein nanocrystals as
antioxidant formulation for oral and dermal delivery. Int. J. Pharm. 420 (1),
141–146.
Murillo, E., Meléndez-Martínez, A.J., Portugal, F., 2010. Screening of vegetables and
fruits from Panama for rich sources of lutein and zeaxanthin. Food Chem. 122 (1),
167–172. https://doi.org/10.1016/j.foodchem.2010.02.034. Retrieved from.
Murray, I.J., Makridaki, M., van der Veen, R.L.P., Carden, D., Parry, N.R.A.,
Berendschot, T.T.J.M., 2013. Lutein supplementation over a one-year period in early
AMD might have a mild beneficial effect on visual acuity: the CLEAR study. Investig.
Ophthalmol. Vis. Sci. 54 (3), 1781–1788. https://doi.org/10.1167/iovs.12-10715.
Retrieved from.
Nascimento, E.M.M., Rodrigues, F.F.G., Costa, W.D., Teixeira, R.N.P., Boligon, A.A.,
Sousa, E.O., et al., 2018. HPLC and in vitro evaluation of antioxidant properties of
fruit from Malpighia glabra (Malpighiaceae) at different stages of maturation. Food
Chem. Toxicol. 119, 457–463. https://doi.org/10.1016/j.fct.2017.11.042. Retrieved
from.
Nataraj, J., Manivasagam, T., Justin Thenmozhi, A., Essa, M.M., 2016. Lutein protects
dopaminergic neurons against MPTP-induced apoptotic death and motor
dysfunction by ameliorating mitochondrial disruption and oxidative stress. Nutr.
Neurosci. 19 (6), 237–246. https://doi.org/10.1179/1476830515Y.0000000010.
Retrieved from.
Nian, S., Lo, A.C.Y., 2018. Lutein and the aging eye. Progress in Carotenoid Research.
https://doi.org/10.5772/intechopen.79604. Retrieved from.
Nita, M., Grzybowski, A., 2016. The role of the reactive oxygen species and oxidative
stress in the pathomechanism of the age-related ocular diseases and other
pathologies of the anterior and posterior eye segments in adults. Oxidative Medicine
S. Mitra et al.
and Cellular Longevity 2016. https://doi.org/10.1155/2016/3164734. Retrieved
from.
Niu, G., Niu, G., Guo, Q., Guo, Q., Wang, J., Wang, J., et al., 2020. Structural basis for
plant lutein biosynthesis from a-carotene. Proc. Natl. Acad. Sci. U. S. A. 117 (25),
14150–14157. https://doi.org/10.1073/pnas.2001806117. Retrieved from.
Obana, A., Tanito, M., Gohto, Y., Okazaki, S., Gellermann, W., Bernstein, P.S., 2015.
Changes in macular pigment optical density and serum lutein concentration in
Japanese subjects taking two different lutein supplements. PloS One 10 (10). https://
doi.org/10.1371/journal.pone.0139257. Retrieved from.
Panfoli, I., Calzia, D., Ravera, S., Morelli, A.M., Traverso, C.E., 2012. Extra-mitochondrial
aerobic metabolism in retinal rod outer segments: new perspectives in retinopathies.
Med. Hypotheses 78 (4), 423–427. https://doi.org/10.1016/j.mehy.2011.12.012.
Retrieved from.
Pang, R., Tao, J.Y., Zhang, S.L., Zhao, L., Yue, X., Wang, Y.F., et al., 2010. In vitro
antiviral activity of lutein against hepatitis B virus. Phytother Res. 24 (11),
1627–1630. https://doi.org/10.1002/ptr.3155. Retrieved from.
Panich, U., Slominski, A.T., 2020. Editorial: redox biology of skin aging and
carcinogenesis: the role of natural antioxidants as potential protective agents. Front.
Pharmacol. 11 https://doi.org/10.3389/fphar.2020.00249. Retrieved from.
Pérez-gálvez, A., Viera, I., Roca, M., 2020. Carotenoids and chlorophylls as antioxidants.
Antioxidants 9 (6), 1–39. https://doi.org/10.3390/antiox9060505. Retrieved from.
Perrone, S., Tei, M., Longini, M., Buonocore, G., 2016. The multiple facets of lutein: a call
for further investigation in the perinatal period. Oxidative Medicine and Cellular
Longevity 2016. https://doi.org/10.1155/2016/5381540. Retrieved from.
Phillips, M.A., Burrows, J.N., Manyando, C., Van Huijsduijnen, R.H., Van Voorhis, W.C.,
Wells, T.N.C., 2017. Malaria. In: Nature Reviews Disease Primers, vol. 3. https://doi.
org/10.1038/nrdp.2017.50. Retrieved from.
Qv, X.Y., Zeng, Z.P., Jiang, J.G., 2011. Preparation of lutein microencapsulation by
complex coacervation method and its physicochemical properties and stability. Food
Hydrocolloids 25 (6), 1596–1603. https://doi.org/10.1016/j.foodhyd.2011.01.006.
Retrieved from.
Rafi, M.M., Kanakasabai, S., Gokarn, S.V., Krueger, E.G., Bright, J.J., 2015. Dietary lutein
modulates growth and survival genes in prostate cancer cells. J. Med. Food 18 (2),
173–181. https://doi.org/10.1089/jmf.2014.0003. Retrieved from.
Rasmussen, H.M., Johnson, E.J., 2013. Nutrients for the aging eye. Clin. Interv. Aging 8,
741–748. https://doi.org/10.2147/CIA.S45399. Retrieved from.
Ravikrishnan, R., Rusia, S., Ilamurugan, G., Salunkhe, U., Deshpande, J.,
Shankaranarayanan, J., Soni, M.G., 2011. Safety assessment of lutein and zeaxanthin
(LutemaxTM 2020): subchronic toxicity and mutagenicity studies. Food Chem.
Toxicol. 49 (11), 2841–2848. https://doi.org/10.1016/j.fct.2011.08.011. Retrieved
from.
Ribeiro, D., Freitas, M., Silva, A.M.S., Carvalho, F., Fernandes, E., 2018. Antioxidant and
pro-oxidant activities of carotenoids and their oxidation products. Food Chem.
Toxicol. 120, 681–699. https://doi.org/10.1016/j.fct.2018.07.060. Retrieved from.
Sasaki, M., Ozawa, Y., Kurihara, T., Kubota, S., Yuki, K., Noda, K., Tsubota, K., 2010.
Neurodegenerative influence of oxidative stress in the retina of a murine model of
diabetes. Diabetologia 53 (5), 971–979. https://doi.org/10.1007/s00125-009-1655-
6. Retrieved from.
Sasamoto, Y., Gomi, F., Sawa, M., Tsujikawa, M., Nishida, K., 2011. Effect of 1-year
lutein supplementation on macular pigment optical density and visual function.
Graefe’s Arch. Clin. Exp. Ophthalmol. 249 (12), 1847–1854. https://doi.org/
10.1007/s00417-011-1780-z. Retrieved from.
Sawa, M., Shunto, T., Nishiyama, I., Yokoyama, A., Shigeta, R., Miura, S., Kawasaki, R.,
2020. Effects of lutein supplementation in Japanese patients with unilateral age-
related macular degeneration: the sakai lutein study. Sci. Rep. 10 (1) https://doi.
org/10.1038/s41598-020-62483-0. Retrieved from.
Shegokar, R., Mitri, K., 2012. Carotenoid lutein: a promising candidate for
pharmaceutical and nutraceutical applications. J. Diet. Suppl. 9 (3), 183–210.
https://doi.org/10.3109/19390211.2012.708716. Retrieved from.
Sherry, C.L., Oliver, J.S., Renzi, L.M., Marriage, B.J., 2014. Lutein supplementation
increases breast milk and plasma lutein concentrations in lactating women and
infant plasma concentrations but does not affect other carotenoids. J. Nutr. 144 (8),
1256–1263. https://doi.org/10.3945/jn.114.192914. Retrieved from.
Shirazi, A., Mihandoost, E., Mahdavi, S.R., Mohseni, M., 2012. Radio-protective role of
antioxidant agents. Onco Rev. 6 (2), 130–134. https://doi.org/10.4081/oncol.2012.
e16. Retrieved from.
Sozen, T., Ozisik, L., Calik Basaran, N., 2017. An overview and management of
osteoporosis. European Journal of Rheumatology 4 (1), 46–56. https://doi.org/
10.5152/eurjrheum.2016.048. Retrieved from.
Stringham, J.M., Garcia, P.V., Smith, P.A., Hiers, P.L., McLin, L.N., Kuyk, T.K., Foutch, B.
K., 2015. Macular pigment and visual performance in low-light conditions. Investig.
Ophthalmol. Vis. Sci. 56 (4), 2459–2468. https://doi.org/10.1167/iovs.14-15716.
Retrieved from.
Stringham, J.M., Johnson, E.J., Hammond, B.R., 2019. Lutein across the lifespan: from
childhood cognitive performance to the aging eye and brain. Current Developments
in Nutrition 3 (7). https://doi.org/10.1093/cdn/nzz066. Retrieved from.
Stringham, J.M., Stringham, N.T., O’brien, K.J., 2017. Macular carotenoid
supplementation improves visual performance, sleep quality, and adverse physical
symptoms in those with high screen time exposure. Foods 6 (7), 1–13. https://doi.
org/10.3390/foods6070047. Retrieved from.
Su, X.Z., Zhang, C., Joy, D.A., 2020. Host-malaria parasite interactions and impacts on
mutual evolution. Frontiers in Cellular and Infection Microbiology 10. https://doi.
org/10.3389/fcimb.2020.587933. Retrieved from.
Sun, Y.X., Liu, T., Dai, X.L., Zheng, Q.S., Hui, B. Di, Jiang, Z.F., 2014. Treatment with
lutein provides neuroprotection in mice subjected to transient cerebral ischemia.
13
Food and Chemical Toxicology 154 (2021) 112328
J. Asian Nat. Prod. Res. 16 (11), 1084–1093. https://doi.org/10.1080/
10286020.2014.939584. Retrieved from.
Takeda, H., Tominari, T., Hirata, M., Watanabe, K., Matsumoto, C., Grundler, F.M.W.,
Miyaura, C., 2017. Lutein enhances bone mass by stimulating bone formation and
suppressing bone resorption in growing mice. Biol. Pharm. Bull. 40 (5), 716–721.
https://doi.org/10.1248/bpb.b16-00897. Retrieved from.
Tanprasertsuk, J., Li, B., Bernstein, P.S., Vishwanathan, R., Johnson, M.A., Poon, L.,
Johnson, E.J., 2016. Relationship between concentrations of lutein and stard3
among pediatric and geriatric human brain tissue. PloS One 11 (5). https://doi.org/
10.1371/journal.pone.0155488. Retrieved from.
Tominari, T., Matsumoto, C., Watanabe, K., Hirata, M., Grundler, F.M.W., Inada, M.,
Miyaura, C., 2017. Lutein, a carotenoid, suppresses osteoclastic bone resorption and
stimulates bone formation in cultures. Biosci. Biotechnol. Biochem. 81 (2), 302–306.
https://doi.org/10.1080/09168451.2016.1243983. Retrieved from.
Toti, E., Oliver Chen, C.Y., Palmery, M., Valencia, D.V., Peluso, I., 2018. Non-provitamin
A and provitamin A carotenoids as immunomodulators: recommended dietary
allowance, therapeutic index, or personalized nutrition? Oxidative Medicine and
Cellular Longevity 2018. https://doi.org/10.1155/2018/4637861. Retrieved from.
Vijay, K., Sowmya, P.R.R., Arathi, B.P., Shilpa, S., Shwetha, H.J., Raju, M.,
Lakshminarayana, R., 2018. Low-dose doxorubicin with carotenoids selectively
alters redox status and upregulates oxidative stress-mediated apoptosis in breast
cancer cells. Food Chem. Toxicol. 118, 675–690. https://doi.org/10.1016/j.
fct.2018.06.027. Retrieved from.
Vishwanathan, R., Kuchan, M.J., Sen, S., Johnson, E.J., 2014. Lutein is the predominant
carotenoid in infant brain: preterm infants have decreased concentrations of brain
carotenoids. J. Pediatr. Gastroenterol. Nutr. 59, 659–665.
Waller, D.D., Park, J., Tsantrizos, Y.S., 2019. Inhibition of farnesyl pyrophosphate (FPP)
and/or geranylgeranyl pyrophosphate (GGPP) biosynthesis and its implication in the
treatment of cancers. Crit. Rev. Biochem. Mol. Biol. 54 (1), 41–60. https://doi.org/
10.1080/10409238.2019.1568964. Retrieved from.
Walsh, R.P., Bartlett, H., Eperjesi, F., 2015. Variation in carotenoid content of kale and
other vegetables: a review of pre- and post-harvest effects. J. Agric. Food Chem. 63
(44), 9677–9682. https://doi.org/10.1021/acs.jafc.5b03691. Retrieved from.
Wang, Y., Ye, H., Zhou, C., Lv, F., Bie, X., Lu, Z., 2012. Study on the spray-drying
encapsulation of lutein in the porous starch and gelatin mixture. Eur. Food Res.
Technol. 234 (1), 157–163. https://doi.org/10.1007/s00217-011-1630-6. Retrieved
from.
Weigert, G., Kaya, S., Pemp, B., Sacu, S., Lasta, M., Werkmeister, R.M., Schmetterer, L.,
2011. Effects of lutein supplementation on macular pigment optical density and
visual acuity in patients with age-related macular degeneration. Investig.
Ophthalmol. Vis. Sci. 52 (11), 8174–8178. https://doi.org/10.1167/iovs.11-7522.
Retrieved from.
Widomska, J., 2014. Why has nature chosen lutein and zeaxanthin to protect the retina?
J. Clin. Exp. Ophthalmol. 5 (1) https://doi.org/10.4172/2155-9570.1000326.
Retrieved from.
Woo, S.J., Park, K.H., Ahn, J., Choe, J.Y., Jeong, H., Han, J.W., Kim, K.W., 2012.
Cognitive impairment in age-related macular degeneration and geographic atrophy.
Ophthalmology 119 (10), 2094–2101. https://doi.org/10.1016/j.
ophtha.2012.04.026. Retrieved from.
Woo, T.T.Y., Li, S.Y., Lai, W.W.K., Wong, D., Lo, A.C.Y., 2013. Neuroprotective effects of
lutein in a rat model of retinal detachment. Graefe’s Arch. Clin. Exp. Ophthalmol.
251 (1), 41–51. https://doi.org/10.1007/s00417-012-2128-z. Retrieved from.
Wu, W., Li, Y., Wu, Y., Zhang, Y., Wang, Z., Liu, X., 2015. Lutein suppresses
inflammatory responses through Nrf2 activation and NF-κB inactivation in
lipopolysaccharide-stimulated BV-2 microglia. Mol. Nutr. Food Res. 59 (9),
1663–1673. https://doi.org/10.1002/mnfr.201500109. Retrieved from.
Yamaguchi, M., 2012. Role of carotenoid β-cryptoxanthin in bone homeostasis.
J. Biomed. Sci. 19 (1) https://doi.org/10.1186/1423-0127-19-36. Retrieved from.
Yang, X., Yu, K., Wang, H., Zhang, H., Bai, C., Song, M., Li, X., 2018. Bone impairment
caused by AlCl3 is associated with activation of the JNK apoptotic pathway mediated
by oxidative stress. Food Chem. Toxicol. 116, 307–314. https://doi.org/10.1016/j.
fct.2018.04.057. Retrieved from.
Young, A.J., Lowe, G.L., 2018. Carotenoids—antioxidant properties. Antioxidants 7 (2).
https://doi.org/10.3390/antiox7020028. Retrieved from.
Zaccara, G., Lattanzi, S., Cincotta, M., Russo, E., 2020. Drug treatments in patients with
cardiac diseases and epilepsy. Acta Neurol. Scand. 142 (1), 37–49. https://doi.org/
10.1111/ane.13249. Retrieved from.
Zarubina, A.V., Huisingh, C.E., Clark, M.E., Sloan, K.R., McGwin, G., Crosson, J.N.,
Owsley, C., 2018. Rod-mediated dark adaptation and macular pigment optical
density in older adults with normal maculas. Curr. Eye Res. 43 (7), 913–920. https://
doi.org/10.1080/02713683.2018.1460380. Retrieved from.
Zhao, Changdong, Cheng, H., Jiang, P., Yao, Y., Han, J., 2014. Preparation of lutein-
loaded particles for improving solubility and stability by Polyvinylpyrrolidone (PVP)
as an emulsion-stabilizer. Food Chem. 156, 123–128. https://doi.org/10.1016/j.
foodchem.2014.01.086. Retrieved from.
Zhao, Changhui, Shen, X., Guo, M., 2018. Stability of lutein encapsulated whey protein
nano-emulsion during storage. PloS One 13 (2). https://doi.org/10.1371/journal.
pone.0192511. Retrieved from.
Zheng, Y.F., Bae, S.H., Kwon, M.J., Park, J.B., Choi, H.D., Shin, W.G., Bae, S.K., 2013.
Inhibitory effects of astaxanthin, β-cryptoxanthin, canthaxanthin, lutein, and
zeaxanthin on cytochrome P450 enzyme activities. Food Chem. Toxicol. 59, 78–85.
https://doi.org/10.1016/j.fct.2013.04.053. Retrieved from.
Žmitek, K., Žmitek, J., Rogl Butina, M., Hristov, H., Pogačnik, T., Pravst, I., 2020. Dietary
lutein supplementation protects against ultraviolet-radiation-induced erythema:
results of a randomized double-blind placebo-controlled study. Journal of Functional
Foods 75. https://doi.org/10.1016/j.jff.2020.104265. Retrieved from.