![Low-income, middle-income, and upper-middle income countries that do not have mandatory programs in place and have the potential to benefit from new LSFF programs or from making voluntary programs mandatory (Global Fortification Data Exchange. Accessed May 23, 2021 [http://www.fortificationdata.org.].).](https://www.researchgate.net/profile/Alok-Patel-3/publication/357589505/figure/fig1/AS:1113888917602305@1642583221446/Low-income-middle-income-and-upper-middle-income-countries-that-do-not-have-mandatory_Q320.jpg)
![Population coverage in low-income, middle-income, and upper-middle income countries towards fortified foods (Global Fortification Data Exchange. Accessed May 23, 2021 [http://www.fortificationdata.org.].).](https://www.researchgate.net/profile/Alok-Patel-3/publication/357589505/figure/fig2/AS:1113888917598209@1642583221495/Population-coverage-in-low-income-middle-income-and-upper-middle-income-countries_Q320.jpg)
Content uploaded by Alok Patel
Author content
All content in this area was uploaded by Alok Patel on Jan 19, 2022
Content may be subject to copyright.
Trends in Food Science & Technology 120 (2022) 140–153
Available online 4 January 2022
0924-2244/© 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Futuristic food fortication with a balanced ratio of dietary
ω
-3/
ω
-6 omega
fatty acids for the prevention of lifestyle diseases
Alok Patel
a
,
*
, Sneha Sawant Desai
b
, Varsha Kelkar Mane
b
, Josene Enman
a
, Ulrika Rova
a
,
Paul Christakopoulos
a
, Leonidas Matsakas
a
a
Biochemical Process Engineering, Division of Chemical Engineering, Department of Civil, Environmental, and Natural Resources Engineering, Luleå University of
Technology, SE-971 87, Luleå, Sweden
b
Department of Biotechnology, University of Mumbai, Kalina, Santacruz (E), Mumbai, 400098, Maharashtra, India
ARTICLE INFO
Keywords:
Food fortication
ω
-3/
ω
-6 fatty acid ratio
Human health
Polyunsaturated fatty acids
ABSTRACT
Background: Over the last three decades, consumption of total and saturated fat has steadily declined in Western
diets as a proportion of calories intake. At the same time, omega (
ω
)-6 fatty acid intake has risen at the expense of
ω
-3 fatty acids, resulting in an
ω
-6/
ω
-3 ratio of 20:1 or higher.
Scope and approach: The observed changes in fatty acids ratio coincide with a signicantly increased prevalence
of coronary heart disease, hypertension, cancer, diabetes, obesity, rheumatoid arthritis, and autoimmune or
neurodegenerative disorders. The low intake of
ω
-3 fatty acids may be attributed to their absence from the diet or
lack of awareness about suitable dietary sources.
Key ndings and conclusions: A sustainable and cost-effective way of reaching a large population with essential
ω
-3
fatty acids is fortication of staple foods. A variety of food items enriched with
ω
-3 have entered the market in
recent years, including beef, sh, dairy products, cereals, cereal bars, and infant formula. The present review
discusses the role of
ω
-3 and
ω
-6 fatty acids, as well as their ratio, on human health. Additionally, it focuses on
the latest developments regarding dietary sources, innovative technologies, and challenges of food fortication
with
ω
-3 fatty acids.
1. Introduction
Fatty acids provide a structural framework for cells, tissues, and
organs, as well as the building blocks for several bioactive ingredients.
They can be divided in omega (
ω
)-6 and
ω
-3 fatty acids based on the
position of the rst double bond counting from the methyl end of the
fatty acid molecule. In the case of
ω
-6 fatty acids, this double bond oc-
curs between the 6th and 7th carbon atoms; whereas in
ω
-3 fatty acids, it
is located between the 3rd and 4th carbon atoms (Saini & Keum, 2018).
Docosahexaenoic acid (DHA; 22:6
n-3
) eicosapentaenoic acid (EPA;
20:5
n-3
), and
α
-linolenic acid (ALA; 18:3
n-3
) are the most important
members of the
ω
-3 family.
ω
−3 fatty acids regulate lipid metabolism in
humans, reducing the risk of cardiovascular illness and neurological
disorders including Alzheimer’s and Parkinson’s disease, as well as the
progression of age-related macular degeneration and dry eye disease
(Kerdiles et al., 2017). They have been shown to exert also a broad
spectrum of anti-inammatory effects, which makes them effective
agents against inammation-related diseases (Giacobbe et al., 2020).
ALA is a precursor for the synhesis of long-chain
ω
-3 fatty acids but,
because it cannot be produced in the human body, it must be taken
through the diet, making it an essential fatty acid (Das, 2010; Patel,
Rova, et al., 2020). Vegetable oils, such as axseed, rapeseed or soybean,
chia seeds, and eggs represent an important source of ALA. Even though
humans can convert ALA into DHA and EPA, the rate is too low to meet
the daily requirement for these fatty acids (Burns-Whitmore et al., 2019;
Patel et al., 2021). Important sources of DHA and EPA include marine
; AA, arachidonic acid; ALA,
α
-linolenic acid; BDNF, brain-derived neurotrophic factor; DHA, docosahexaenoic acid; DGLA, dihomo-γ-linolenic acid; ELOVLs,
elongation of very-long-chain fatty acids; EPA, eicosapentaenoic acid; FAO, Food and Agriculture Organization; GLA, gamma linolenic acid; HDLs, high-density
lipoproteins; IL, interleukin; LA, linoleic acid; LC-PUFAs, long-chain polyunsaturated fatty acids; MAPK, mitogen-associated protein kinase; PUFAs, polyunsaturated
fatty acids; PPAR, peroxisome proliferator-activated receptor; SDA, stearidonic acid; SPMs, specialized pro-resolving mediators; WHO, World Health Organization;
TNF, tumor necrosis factor;
α
, alpha; β, beta; γ, gamma; Δ, delta;
ω
, omega.
* Corresponding author.
E-mail address: alok.kumar.patel@ltu.se (A. Patel).
Contents lists available at ScienceDirect
Trends in Food Science & Technology
journal homepage: www.elsevier.com/locate/tifs
https://doi.org/10.1016/j.tifs.2022.01.006
Received 15 June 2021; Received in revised form 17 December 2021; Accepted 1 January 2022
Trends in Food Science & Technology 120 (2022) 140–153
141
sh oils, krill oils, eggs, and seaweed or microalgae. The minimum daily
consumption of
ω
-3 fatty acids (EPA and DHA) is 0.5 g, but the ideal
amount is two to three times higher (Kris-Etherton et al., 2009). To full
20%–35% of the required daily calorie intake (2500 Kcal), at least 0.5%–
1% of total fats should be in the form of DHA and EPA. When caloric
constraints reduce lipid intake, the proportion of
ω
-3 polyunsaturated
fatty acids (PUFAs) should be increased through supplementation
including with less efcient
ω
-3 PUFAs, such ALA and stearidonic acid
(SDA; C18:4
n-3
). Individuals who follow a reduced- or low-fat diet, for
example, may need up to 3–10% of their dietary lipids to be
ω
-3 PUFAs
(Hamilton et al., 2020; Madore et al., 2020).
Similar to ALA, linoleic acid (LA; 18:2
n-6
) is the parent compound for
ω
-6 fatty acids and it also cannot be synthesized in the human body.
After it is absorbed through the diet, LA is converted to arachidonic acid
(AA; 20:4
n-6
). Generally,
ω
-6 fatty acids are obtained from plant sources,
such as sunower, soybean or nut-derived oils, but also from animal
sources, such as pork, lard, and turkey (Kaliannan et al., 2019; Scan-
ferlato et al., 2019). Unhealthy diets and limited access to healthy foods
are the main reasons why people lack essential fatty acids, such as ALA,
EPA, and DHA. Whereas during the Paleolithic the ratio between
ω
-6
and
ω
-3 fatty acids was quite balanced (Simopoulos, 2016), Western
diets are associated with higher consumption of
ω
-6 and lower con-
sumption of
ω
-3 fatty acids. Ensuring a balanced
ω
-6:
ω
-3 fatty acids ratio
is crucial for a healthy lifestyle, as it allows for the progressive brain,
eyes, and heart development, while also reducing the risk of coronary
heart disease and neurodegenerative disorders (Shetty et al., 2020;
Trebatick´
a et al., 2020). To enable proper neuronal development and
prevent most chronic disorders, a 1:1 or 2:1
ω
-6:
ω
-3 fatty acids ratio
should be maintained. Because this ratio affects body fat metabolisms
through adipogenesis, lipid homeostasis, and adipose tissues browning,
as well as systemic inammation (Simopoulos, 2016). Increasing ratio of
omega-6 to −3 fatty acids has led to obesity due to increase in phos-
pholipids in RBCs membrane and AA eicosanoid metabolites (Simo-
poulos, 2016). Intake of diets rich in
ω
-6 PUFAs before or during
pregnancy can have adverse effects on fetal development and may
impair overall health of the offspring in adulthood (Lee et al., 2018;
Shrestha et al., 2020). There is presently little information about dietary
sources and palatability of foods fortied with
ω
-3 PUFAs. This is a
critical issue, as sh oils are not prevalently used as a source of dietary
lipids, therefore, a broader range of fat-containing foods must be forti-
ed to achieve the 0.5 g/day target of
ω
-3 PUFAs.
Since the beginning of the 20th century, food fortication has been
practiced in developed nations and has helped to eradicate deciency-
related disorders in high-income countries. However, its progress in
low- and middle-income nations has been limited (Pinstrup-Andersen,
2013) due to absence of political will, which has led to government
under-prioritization, lack of funding for the food fortication industry,
inadequate or poor regulation and compliance, and insufcient aware-
ness by customers of the advantages of eating fortied foods (Ponied-
ziałek et al., 2020). Even where there was political will, successful
implementation and control of legislation promoting food fortication
has been beset by difculties. To meet the daily requirements of essen-
tial PUFAs through the diet, food fortication needs better
implementation.
2. Effect of
ω
-3 and
ω
-6 PUFAs on human health
By forming primary structural constituents of phospholipids,
ω
-3 and
ω
-6 PUFAs provide uidity and exibility to cell membranes. LA and
ALA are precursors of
ω
-6 and
ω
-3 PUFAs, respectively (Bali´
c et al.,
2020). They are stored in different lipid fractions, such as triglycerides,
cholesteryl esters, and in minute quantities in phospholipids. While EPA
can be found in all three of the above lipid fractions, DHA and AA are
found preferentially in phospholipids. In humans, large amounts of DHA
are found in the cerebral cortex, retina, testis, and sperm, whereas it
represents the most abundant structural lipid in the brain (Ahmmed
et al., 2020; Calder, 2016). In contrast, AA is found in the phospholipids
of skeletal muscle, liver, brain, spleen, and retina (Hanna & Hafez,
2018). These PUFAs affect gene expression, cell signaling, eicosanoid
metabolism, and organization of the cell membrane (Georgiadi & Ker-
sten, 2012). Fatty acid-induced changes in cell membrane organization
and the availability of the substrates involved in eicosanoid synthesis are
long-standing processes that are thought to be explained by observed
effects. More recently, effects of dietary supplementation of PUFA on
signal transduction pathways and gene expression proles have been
identied (Kalkman et al., 2021; Kitajka et al., 2004).
2.1.
ω
-6 PUFAs
LA is the most abundant PUFA in the human diet and, because it
plays a signicant role in brain development, it is implicated in fetal and
infant growth (Lauritzen et al., 2015; Thomas Brenna, 2016). Reports
suggest consumption of LA is inversely proportional to ischemic heart
disease, diabetes, and blood pressure (Ng & Schooling, 2020). A
reduction in blood cholesterol levels, due to a specic reduction in
low-density lipoprotein-cholesterol is a key metabolic attribute of LA
(Hooper et al., 2018). LA acts also as a precursor of AA, which is
necessary for neural development (Marangoni et al., 2020), and γ-lino-
lenic acid (GLA; C18
n-6
), which is an important constituent of neuronal
membrane phospholipids. Specically, GLA plays a critical role in pre-
serving nerve blood ow by serving as a substrate for prostaglandin
synthesis (Poorani et al., 2020). It is reported to relieve the symptoms of
chronic inammatory diseases, such as rheumatoid arthritis and atopic
dermatitis (Sergeant et al., 2016). Clinical trials have shown that GLA
enhances the treatment of heart disease, obesity, alcoholism, depression,
schizophrenia, Parkinson’s disease, and multiple sclerosis (Sathasivam
et al., 2019). Additionally, it can downregulate inammatory responses
by reducing expression of the cytochrome-c oxidase COX-2 and
prointerleukin-1 (Silva et al., 2018).
GLA is converted to dihomo-γ-linolenic acid (DGLA; C20:3
n-6
) by the
ELOVL-5 fatty acid elongase before being incorporated into cellular
glycerolipids. DGLA and its metabolites strongly inhibit platelet aggre-
gation and inammation (Sergeant et al., 2016). DGLA can be metabo-
lized into eicosanoids, prostaglandin PGE
1
or 15-hydroxyeicosatrienoic
acid, which exert anti-inammatory as well as immunoregulatory effects
(Silva et al., 2018). Moreover, it can prevent both motility and inva-
siveness of human colon cancer cells by enhancing expression of the
metastasis suppressor E-cadherin (Pang et al., 2021). Both GLA and
DGLA suppress the expression of oncogenes Her-2/neu and Bcl2, while
promoting the activity of p53 and, thereby, inducing apoptosis of tumor
cells (Wang et al., 2012).
AA is a key component of cell membranes and a regulator of mem-
brane permeability. AA and its metabolites (lipoxin A4 and epox-
yeicosatrienoic acid) modulate smooth muscle function and
proliferation, regulate voltage-gated ion channels, membrane receptors,
G-coupled receptors, peroxisome proliferator-activated receptors
(PPARs), free radical generation, nitric oxide synthesis, inammation
and immune responses involved in the monitoring of blood pressure and
the pathogenesis of diabetes mellitus (Das, 2018). AA inuences the
function of specic membrane proteins involved in cellular signaling,
thereby maintaining cellular and organellar integrity, as well as vascular
permeability. It is also involved in neuronal function, brain synaptic
elasticity, and potentiation in the hippocampus. Specically, AA is re-
ported to modulate synaptic transmission and neuronal excitability by
acting on sodium, calcium, potassium, and chloride channels, as well as
proton pumps (Tallima & El Ridi, 2018). Dietary AA supplementation in
the elderly has been shown to improve cerebral function by increasing
neural stem/progenitor cell or newborn neuronal proliferation together
with overall hippocampal neurogenesis (Tokuda, Kontani, Kawashima,
Akimoto, et al., 2014; 2014b). Furthermore, AA affects neuromuscular
signaling and improves neurotransmitter ring by stimulating nerve
cells (Tallima & El Ridi, 2018). Owing to its benecial effect on the
A. Patel et al.
Trends in Food Science & Technology 120 (2022) 140–153
142
newborn’s nervous system, the FAO and WHO have recommended AA
supplementation in infant formula. Prostaglandins derived from AA,
such as PGF
2a
, PGE
2
, and PGI
2
, function in skeletal muscle development
and growth by regulating proliferation, differentiation, migration,
fusion, and survival of myoblasts (Mo et al., 2019). PGE
2
and PGI
2
, as
well as leukotrienes B
4
and D
4
stimulate wound healing by monitoring
the synthesis of angiogenic factors and endothelial cell function (Sonn-
weber et al., 2018). Lipoxin A4, another downstream product of AA,
participates in neutrophil inltration, mitigates leukotriene C
4
-induced
bronchoconstriction in asthmatic patients, and reduces eczema severity,
thereby improving life quality by inhibiting innate lymphoid cell type 2
activity (Tallima & El Ridi, 2018). Lipoxin A4 is also reported to inhibit
interleukin (IL)-6 and tumor necrosis factor (TNF), while promoting the
release of reactive oxygen species, further testifying to its potential in
ischemic stroke treatment (Tułowiecka et al., 2021).
2.2.
ω
-3-PUFAs
ALA is known for its neuroprotective, anti-inammatory, and anti-
depressant potential. Enhanced dietary ALA supplementation lowers
the risk of ischemic stroke and carotid atherosclerosis (Bork et al., 2018;
Ding et al., 2020). The cardioprotective effect of ALA stems from its
ability to decrease lipid content, maintain endothelial function, and
counteract both thrombosis and arrhythmia (Shari-Rad et al., 2020).
Intake of ALA has been reported to improve symptoms in children with
attention decit hypersensitivity disorder (Spector & Kim, 2019).
Furthermore, ALA improves brain-derived neurotrophic factor (BDNF)
levels (Rahman et al., 2020), lowers the risk of type 2 diabetes due to
increased insulin sensitivity (Jovanovski et al., 2017), and slows down
cancer cell proliferation owing to its downregulation of anti-apoptotic
genes (e.g., Bcl-2 and Bcl-xl) and upregulation of pro-apoptotic genes
(e.g., BAX and BAD) (Roy et al., 2017).
SDA lowers the level of TNF, thus playing a protective role in
tumorigenesis. Additionally, it has been observed to decrease cyclo-
oxygenase transcription and translation by downregulating nuclear
kappa light chain enhancer of activated B cells and PPAR-γ (Mansour
et al., 2018). It is also reported to inhibit platelet aggregation and
arachidonate oxygenation (Baeza-Jim´
enez et al., 2017). It plays an
important role in rheumatoid and mild asthma through its direct
involvement in terminating the inammatory response by blocking
5-lipooxygenase, which is responsible for catalyzing leukotriene syn-
thesis (Prasad et al., 2021). Whelan et al. (2012) have reported the
atheroprotective potential of SDA, as indicated by its ability to signi-
cantly reduce the levels of the inammatory biomarker C-reactive pro-
tein (Whelan et al., 2012).
DHA amounts to 15% of total fatty acids in the frontal cortex. It is
involved in regulation of the neurotransmitter pathway, synaptic
transmission, and signal transduction (Hsu et al., 2020). It functions at
synaptic terminals, mitochondria, and the endoplasmic reticulum,
where it forms complexes with phosphatidylethanolamine, phosphati-
dylserine, and phosphatidylcholine. It regulates cell membrane uidity,
neurotransmitter release, gene expression, myelination, neuro-
inammation, and neuronal growth (Avallone et al., 2019). It exhibits a
neuroprotective effect by inhibiting nitric oxide synthesis, caspase sig-
nalling pathways, tau hyperphosphorylation, and by regulating the
PI
3
K/Akt signalling pathway. Together with preventing neuronal cell
death, it promotes dopaminergic synaptic plasticity and transmission
(Jackson et al., 2019). DHA is essential for brain development as
demonstrated by demand peaking during the late gestational period
(Chianese et al., 2017). DHA has been shown to induce expression of
BDNF, a vital mediator of synaptic transmission and biomarker of
neurologic disorders, via the p38 mitogen-associated protein kinase
(MAPK) pathway (Sun et al., 2018). In infants, DHA plays a critical role
in ensuring optimal visual and cognitive growth, with improved cerebral
functioning and behaviour following DHA supplementation during
pregnancy and lactation (Garg et al., 2017). Low plasma DHA levels
have been identied in patients with retinitis, leading to speculation that
central retinal cone defects could be associated with DHA deciency
(Bannenberg et al., 2019). DHA is an integral component of cell mem-
brane phospholipids, altering their physical, chemical, and signalling
properties. DHA content is known to inuence cellular behavior and
responses to chemical, antigenic, electrical or hormonal signals (Calder,
2016). It is reported to induce and activate PPARs, which may aid in
lowering fasting plasma triglyceride levels, enhancing insulin sensi-
tivity, and decreasing inammation (Naeini et al., 2020; Skulas-Ray
et al., 2019; Toupchian et al., 2016). DHA affects cell and tissue physi-
ology by altering membrane structure and function, membrane protein
function, cellular signalling, and synthesis of lipid signalling mediators,
eventually lowering the risk of insulin resistance, metabolic syndrome,
hyperlipidemia, and cardiovascular disease (Calder, 2016). Higher DHA
plasma levels have been associated with slower progression of coronary
atherosclerosis in coronary artery disease patients. DHA supplementa-
tion has been observed to signicantly reduce both daytime ambulatory
blood pressure and 24-h measurements, resting heart rate, triglycerides
(Nishizaki et al., 2016); and diastolic blood pressure (Lee et al., 2019). In
Alzheimer’s patients, DHA levels are substantially lower, which may not
be surprising as DHA is required for both synthesis and clearance of
β-amyloid plaques, enhanced vascular health, neuronal membrane ho-
meostasis, and inammation. Importantly, early DHA supplementation
before the onset of Alzheimer-related dementia may delay or decrease
its incidence (Yassine et al., 2017). DHA is also implicated in reducing
dyskinesia in Parkinson’s disease and its supplementation lowers the
risk of depression associated with this disorder (G´
omez-Soler et al.,
2018). DHA counteracts the inammatory processes affecting motor
neurons in the brain stem, spinal cord, and cortex, as indicated by an
increase in glutathione levels in microglial cells, thus improving their
antioxidant capacity (Newton, 2020). Its anti-atherothrombotic poten-
tial is associated with the ability to decrease AA content in blood cells
and prevent thromboxane synthesis in platelets (Lagarde et al., 2018).
DHA is metabolized by 15-lipooxygenase to active lipid mediators (i.e.,
oxylipins), such as resolvin RvD1 and neuroprotectin D1, which resolve
neuroinammation in the brain (Sun et al., 2018). RvD1 and RvD2, as
well as protectin D1 possess anti-inammatory and
inammation-resolving abilities (Calder, 2016).
EPA reduces the release of AA from phospholipids by blocking
phospholipase A2 activity. This, in turn, promotes cyclooxygenase-2-
mediated synthesis of prostaglandin PGE
3
and leukotriene B
5
, favoring
anti-inammatory, anti-mitotic, and anti-allergic activities (Araujo
et al., 2019). It is also reported to inhibit nuclear factor-κB, leading to a
decrease in IL-1 and TNF-
α
, as well as block the MAPK pathway,
resulting in lower protein-1 transcription factor activity Evidence sug-
gests the usefulness of EPA-supplemented food for the treatment of bi-
polar depression disorder (Nasir & Bloch, 2019). The regulation of
microglial activity in the brain and inhibition of chronic inammatory
responses by these cells and/or annexed monocytes is mediated by EPA
and its derivatives. These are potent regulators of the synthesis of
pro-inammatory cytokines by activated microglia (Bazinet et al.,
2020). EPA is known to increase presynaptic serotonin release by
inhibiting the production of PGE
2
(Günther et al., 2010). Importantly,
EPA can replace AA in membrane phospholipids, thereby modifying the
physical properties of membranes (Brinton & Mason, 2017). Specif-
ically, it decreases triglyceride levels and insulin sensitivity by stimu-
lating fatty acid oxidation through increased synthesis of PPAR-
α
(Delarue, 2020). Furthermore, EPA reduces the complex steps involved
in atherogenesis, protects against oxidative stress, and enhances
vascular and endothelial function. It also prevents the movement of
monocytes into early lesions, regulates inammation, participates in
anti-inammatory and antioxidant functions of high-density lipopro-
teins (HDLs), and stimulates HDL-mediated cholesterol efux from
macrophages. EPA retards atherosclerotic plaque formation, develop-
ment, and susceptibility to lysis (Brinton & Mason, 2017). The anti-
atherogenic effect of EPA is attributed chiey to its potential to regulate
A. Patel et al.
Trends in Food Science & Technology 120 (2022) 140–153
143
inammation, thrombosis, and membrane cholesterol metabolism
(Brinton & Mason, 2017). Its antithrombotic activity derives from
obstructing the synthesis of thromboxane A2 involved in platelet ag-
gregation and vasoconstriction (Trebatick´
a et al., 2017). EPA supple-
mentation helps to improve endothelial function and reduce systolic
blood pressure (Borow et al., 2017; Guo et al., 2019). Importantly, EPA
stimulates the neutral sphingomyelinase-mediated pathway, thereby
promoting apoptosis of breast cancer cells (Guo et al., 2019). In general,
EPA retards the growth of cancer cells by blocking the MAPK pathway
via decreased activation of the oncogenic transcription factors Ras and
activator protein-1 (Gorjao et al., 2019). EPA is reported to improve
muscle mass and function without any adverse effects (Ochi & Tsuchiya,
2018). It also downregulates the acute phase response during inam-
mation by decreasing C-reactive protein, TNF-
α
, and IL-6 (Mocellin
et al., 2016), as well as the ubiquitin-proteasome pathway (Mocellin
et al., 2016).
3. Role of omega 3 and 6 fatty acids in the synthesis of bioactive
lipid mediators
Lipid mediators are well-known for their functions in leukocyte
trafcking, which is necessary for host defense (Serhan & Chiang, 2013).
PUFA act as potent source for the synthesis of bioactive lipid mediators
such as oxylipins, pro-resolving mediators and isoprostanes. Oxylipins
are important in immunological and inammatory responses. Eicosa-
noids, a class of bioactive lipid mediators produced from AA, are the
most prevalent oxylipins. After getting stimulation by hormones and
cytokines, PUFA attached with membrane phospholipids are released
and act as a precursor for the synthesis of eicosanoids and docosanoids
by using three families of enzymes cyclooxygenases (COX-1 a constitu-
tive enzyme, or COX-2 an inducible enzyme), lipoxygenases (5-, 12-, or
15-LOX), or cytochrome P450 monooxygenases (Russo, 2009). More
specically, COX enzymes and peroxidases act on AA to make 2-series
prostanoids (prostaglandins E2, prostacyclin I2, and thromboxane A2),
whereas 5-LOX action on AA produces 5-HPETE (arachidonic acid 5-hy-
droperoxide), which is then utilized to produce 4-series leukotrienes
(Fig. 1).
Another important class of bioactive lipids mediators derived from
both omega 3 and 6 fatty acids are specialized pro-resolving mediators
(SPMs) (Bannenberg & Serhan, 2010; Serhan & Chiang, 2013). They are
responsible for turning off inammatory responses during the resolution
phase of inammation in an active fashion (Serhan, 2007). There are
two specic classes of SPMs, S series and R series. S-resolvins, S-pro-
tectins, and S-maresins are S-series SPMs that emerge from
LOX-mediated oxygenation of omega 3 fatty acids such as EPA and DHA
while R-Series is result of aspirin-dependent acetylation of COX-2 where
both omega 3 and 6 Fatty acids (AA, EPA and DHA) were used to
generate aspirin-triggered R-series SPMs. It has been clearly described
the role of omega-3 fatty acids for anti-inammatory function through
these mediators (Calder, 2013; Nicolaou et al., 2014). Isoprotanes are
another group of mediators that are usually produced after exposure of
free radicals to oxidize triple or more double bonds of PUFA (Milne
Fig. 1. Conventional aerobic desaturase (des) and elongase (elovl) pathway for long-chain PUFA synthesis. Fatty acids composition of the cell membrane can be
altered by dietary intake, which can severely affect the production of bioactive lipid mediators.
ω
-3 and
ω
-6 fatty acids precursors give rise to a variety of molecules
with inammatory (orange), anti-inammatory (green), and proresolving (blue) activities. Isoprostanes (yellow) are markers of oxidative stress. (For interpretation
of the references to color in this gure legend, the reader is referred to the Web version of this article.)
A. Patel et al.
Trends in Food Science & Technology 120 (2022) 140–153
144
et al., 2011; Song et al., 2009), hence act as marker for oxidative stress
and also function as pro and anti-inammatory mediators (Czerska
et al., 2016; Montuschi et al., 2004) (Fig. 1).
4. Role of a balanced ratio of dietary
ω
-6/
ω
-3 PUFAs
A 1:1 to 5:1
ω
-6:
ω
3 fatty acid ratio is considered optimal for human
health (Lupette & Benning, 2020). However, a marked decline in the
consumption of
ω
-3 PUFAs and a concomitant increase in
ω
-6 PUFAs
have been observed during the past decades. This has led to an increase
in the
ω
-6:
ω
3 fatty acid ratio from 1:1 to 20:1 in the Western diet
whereas 45:1 in the South Asian diet (Singh et al., 2017). . Because
ω
-6
and
ω
-3 PUFAs depend on the same downstream digestive enzymes, a
greater
ω
-3 intake would lead to less
ω
-6 being available to produce
pro-inammatory signaling molecules (Bhardwaj et al., 2016). Western
societies are characterized by an increased frequency of cardiovascular
diseases, asthma, and cancer, which are associated with higher levels of
pro-inammatory signaling molecules (Lupette & Benning, 2020). In
contrast, daily intake of a diet rich in
ω
-3 PUFAs has been linked with a
lower prevalence of these diseases in the Icelandic population, Inuit
indigenous people, and native Americans in Alaska (Simopoulos, 2016).
The same benecial health effects have been ascribed also to the Med-
iterranean diet, which is rich in sh, fruits, vegetables, and olive oil
(Lupette & Benning, 2020). PUFA composition is particularly important
in depressive patients, because EPA and AA are processed through the
same cyclooxygenase. The pro-inammatory and anti-inammatory
nature of eicosanoids derived from AA and EPA, respectively, points
to a correlation between a higher
ω
-6:
ω
-3 ratio and depression. An
elevated
ω
-6:
ω
-3 ratio could stimulate the secretion of pro-inammatory
cytokines, thereby inducing low-grade inammation and promoting the
hypothalamic-pituitary-adrenal axis in major depression disorders
(Husted & Bouzinova, 2016). The
ω
-6:
ω
-3 ratio modulates also matrix
attachment region binding proteins, scaffold/matrix attachment region
binding protein 1, and CCAAT-displacement protein/cut homeobox.
This, in turn, regulates an intrinsic signal transduction mechanism,
which alters cell growth. Accordingly, reducing the
ω
-6:
ω
-3 ratio in our
diets could affect cancer cell metabolism, as demonstrated by a lowered
risk of breast cancer in premenopausal women consuming a diet rich in
ω
-3 but poor in
ω
-6 PUFAs (Huerta-Y´
epez et al., 2016). The link between
a high
ω
-3:
ω
-6 ratio and lowered breast cancer risk can be attributed to
the anti-carcinogenic activity of
ω
-3 PUFAs, which counteracts the car-
cinogenetic effect of
ω
-6 PUFAs and their ability to generate
pro-inammatory eicosanoids linked to angiogenesis and mitosis (Nin-
drea et al., 2019). An increased prevalence of complex coronary lesions
has been reported in patients with a low plasma EPA:AA ratio (Taka-
hashi et al., 2017). Coronary atherosclerosis development was observed
in coronary artery disease patients treated with certain statins, who
displayed a low serum
ω
-3:
ω
-6 PUFAs ratio (Nozue et al., 2013). Animal
models with a low
ω
-3:
ω
-6 ratio have been found to display abundant
eicosanoid metabolites, which leads to a pro-thrombotic and
pro-aggregatory state with ensuing elevated blood viscosity (Mariame-
natu & Abdu, 2021), as well as vasospasm, vasoconstriction, and cell
proliferation (Simopoulos, 2016). A low
ω
-3:
ω
-6 ratio impairs the syn-
thesis of pro-thrombotic thromboxane and pro-inammatory leukotri-
enes B
4
and C
4
, thus explaining the increased thrombotic phenotype
(Lev et al., 2010). Grootendorst-van Mil et al. (2018) reported an asso-
ciation between maternal plasma
ω
-3 and
ω
-6 PUFA levels and fetal
health, as manifested by a faster fetal growth and greater infant birth
weight at a higher
ω
-3:
ω
-6 PUFAs ratio (Grootendorst-van Mil et al.,
2018). A 70% reduction in mortality due to secondary cardiovascular
disease was found to be associated with a 4:1
ω
-6:
ω
-3 ratio. Similarly, a
2.5:1 ratio was observed to slow down cell growth in colorectal cancer
patients; whereas a 2:1 to 3:1
ω
-6:
ω
-3 ratio curbed inammation in
rheumatoid arthritis patients (Bhardwaj et al., 2016). Also a benecial
effect of a 5:1
ω
-6:
ω
-3 ratio on asthma whereas an adverse effect of 10:1
ω
-6:
ω
-3 ratio is also reported (Mariamenatu & Abdu, 2021). High
subscapular skin-fold thickness in 3-year-old children was correlated
with a high
ω
-6:
ω
-3 ratio in umbilical cord red blood cell membrane
phospholipids. Elevated adiposity in the offspring has been linked to a
higher intake of
ω
-6 PUFAs during the perinatal period. A diet with a
high
ω
-6:
ω
-3 ratio promotes AA-derived endocannabinoid signaling,
which favors inammation, energy homeostasis, and mood swings
(Simopoulos, 2016). Endocannabinoids are group of lipid mediators that
activate central (CB1) and peripheral (CB2) cannabinoid receptors
usually expressed as membrane G-coupled receptors in brain and pe-
ripheral tissue (Chianese et al., 2017; D’Angelo et al., 2020). Berger
et al. (2017) have observed that elevated
ω
-6:
ω
-3 ratios in erythrocyte
membranes could trigger mood disorders in people aged <18 years
presenting with an ultrahigh risk phenotype, suggesting the possibility
of using the
ω
-6:
ω
-3 ratio as a biomarker for mood disorders. A high
ω
-6:
ω
-3 ratio is deleterious to carriers of genetic variations in APOA5,
CD36, TCF7L2, and ALOX5 genes; while lowering it can prevent chronic
disease in these individuals (Bhardwaj et al., 2016). Additionally, a
higher
ω
-3:
ω
-6 supplementation was found to have a positive impact on
periodontal health as seen by a reduction in the levels of prostaglandin
D2, prostaglandin E2 and leukotriene levels (Navarro Hortal et al.,
2018). Muzsik et al. (2020) have observed a lower
ω
-3:
ω
-6 ratio in red
blood cells of postmenopausal women with metabolic syndrome as
compared to those without it (Muzsik et al., 2020). Additionally, acute
coronary syndrome, myocardial infarction, stroke, chronic heart failure,
CAD, PAD and vascular disease was found to be associated with lower
EPA:AA ratio (Nelson & Raskin, 2019). A low EPA:AA ratio and high
C-reactive protein sensitivity were observed in diabetes mellitus patients
with prior myocardial infarction (Nelson & Raskin, 2019). Takahashi
et al. (2017) reported that statin affected the DHA:AA ratio but not the
EPA:AA ratio, thus establishing the latter as a biomarker for cardio-
vascular events (Takahashi et al., 2017). Improved triglyceride, very
low-density lipoprotein-c, glucose, insulin, and insulin resistance were
observed in subjects with a dietary intake characterized by a low
ω
-6:
ω
-3
ratio (Torres-Castillo et al., 2018). Finally, Christian et al. (2016) noted
that a higher AA:DHA ratio in the maternal erythrocyte membrane was
associated with an enhanced risk of premature birth in
African-Americans (Christian et al., 2016).
5. Food sources of dietary
ω
-3/
ω
-6 polyunsaturated fatty acids
LA is the parent compound of
ω
-6 PUFAs and a precursor for the
synthesis of long-chain PUFAs, such as AA and GLA. It is the most
abundant PUFA in many plant oils, such as corn, safower, soybean, and
sunower, as well as in nuts, seeds, meats, and eggs (Ganesan et al.,
2014). In both terrestrial and marine ecosystems, plants are the main
source of
ω
-3 PUFAs. ALA is the most abundant
ω
-3 PUFA in various
foods of both plant (e.g., linseed/axseed, soybean, and rapeseed oils)
(Ganesan et al., 2014; Mardones et al., 2008) and animal origin, and
serves as the precursor for EPA and DHA. These two are produced
mainly by marine algae and further concentrated in the food chain
(Dewhurst & Moloney, 2013). Consequently, sh and sh oils are the
most prominent food sources of EPA and DHA (Ganesan et al., 2014);
their levels can range from several hundred mg to more than 1 g per 100
g of sh (Kawashima, 2019).
The lipids in beef, lamb, poultry, and pork represent a negligible
source of omega-3 PUFAs. As a result, meats display a generally high
ω
-6:
ω
-3 ratio and low polyunsaturated: saturated fatty acids ratio
(Dewhurst & Moloney, 2013). LA is the most common
ω
-6 and ALA the
most common
ω
-3 fatty acid in meat. Ruminant and non-ruminant meats
differ in PUFA composition. While ALA is present at 0.7–1.4% of total
fatty acids for beef, pork, and lamb; LA is considerably higher in pork
(14.2%) than in beef (2.4%) and lamb (2.7%) resulting in a higher
ω
-6:
ω
-3 ratio for pork. Poultry shows a similar fatty acid composition as
pork, i.e., a relatively high content of LA. The
ω
-6:
ω
-3 ratio in ruminant
meat is somewhat more favorable due to intake of grass rich in ALA
(Dewhurst & Moloney, 2013), but the low conversion of ALA to EPA and
A. Patel et al.
Trends in Food Science & Technology 120 (2022) 140–153
145
DHA limits the
ω
-3 fatty acid content in meat (Ganesan et al., 2014). In
ruminants, conjugated linoleic acids (CLAs) represent an important
group of fatty acids (Wood et al., 2004; Woods & Fearon, 2009). AA is
only found in moderate amounts (<200 mg per 100 g) in meat, poultry,
eggs, sh, and dairy products (Kawashima, 2019). Like meat, milk has a
relatively low PUFA content and low polyunsaturated: saturated fatty
acids ratio, with LA and ALA being the most common
ω
-6 (1–3% w/w)
and
ω
-3 (0.5–2% w/w) fatty acids in milk fat, respectively (Jensen,
2002).
6. Food fortication with
ω
-3 fatty acids
Food fortication is an effective strategy to counteract nutrient de-
ciencies and has been applied for a long time, especially in industri-
alized countries, where foods have been fortied with vitamins A, B, and
D, iodine, and iron. “Designer foods” is a concept that denes regular
foods, which besides their traditional nutritional value contain some
compound that provides additional health benets. They are also
referred to as “functional” or “fortied” foods and have a long history of
use in East Asia in traditional medicine to reduce the risk of various
diseases. The use of designer foods avoids the need for changing dietary
habits and adequate amounts of nutrients can be delivered regularly,
thereby improving the diet and preventing deciencies (Rajasekaran &
Kalaivani, 2013). Foods fortied with
ω
-3 fatty acids are taking a
growing share of the market due to their accessibility, low cost, and
increased awareness of the health benets attributed to long-chain
ω
-3
PUFAs. To balance the effect of
ω
-6 fatty acids, a sufcient intake of
ω
-3
fatty acids is required, particularly given the low conversion of ALA into
EPA and DHA (Mariamenatu & Abdu, 2021). This, in turn, requires an
adequate supply of food rich in these fatty acids. The elevated content of
mercury and environmental pollutants in oceanic sh has enhanced
consumer interest in alternative
ω
-3 sources (Ganesan et al., 2014) and
the development of a variety of foods fortied with
ω
-3 PUFAs.
6.1. Meat
Meat and meat products constitute a signicant dietary source, but
are poor in ALA, EPA, and DHA. Meat products obtained by supple-
mentation of
ω
-3 PUFAs in animal feed have been developed; however,
excessive amounts of these fatty acids in feed can adversely affect rumen
activity and milk production (Woods & Fearon, 2009). A common
strategy to increase
ω
-3 content is to add linseed oil to lamb and beef
cattle diet (Pajor et al., 2021). Fish oil or marine algae with long-chain
ω
-3 PUFAs have also been used in animal feed for this purpose
(G´
omez-Cort´
es et al., 2021) and a mixture of these sources was shown to
allow successful incorporation of EPA and DHA in lambs (G´
omez-Cort´
es
et al., 2021). Broiler meat with an improved
ω
-6:
ω
-3 ratio has been
produced by feeding broilers with ultrasonicated axseed oil nano
emulsions (Abbasi et al., 2020). Another method to enrich meat prod-
ucts with
ω
-3 fatty acids is to use walnuts, oils or pre-emulsied oils in
processed foods. This has led to the development of fortied fresh meat
products, such as ground beef patties with sh oil (Raeisi et al., 2021)
and fresh sausages enriched with algal oil emulsions (Lee et al., 2006) or
pre-emulsied linseed/sh oil (Valencia et al., 2008). This has resulted
in cooked sausages fortied with pre-emulsied sh oil (C´
aceres et al.,
2008) and walnut paste (Ayo et al., 2007), as well as pˆ
at´
e, in which pork
fat has been replaced with an oleo gel based on linseed oil with elevated
LA content (Martins et al., 2020).
6.2. Eggs
Eggs are a widely used, inexpensive, and nutrient-dense food source,
which can be conveniently supplemented with additional nutrients. The
idea of eggs as a designer food arose in the 1930s by inducing changes in
fatty acid composition of egg yolk (Cruickshank, 1934). Modication of
the hens’ diet is a common strategy to enrich eggs with
ω
-3 fatty acids.
Saturated fatty acids in the yolk can be replaced with
ω
-3 fatty acids by
feeding hens with sunower, axseed or marine algal oils (Jensen, 2002;
Neijat et al., 2020). Consumption of such
ω
-3 enriched eggs was found to
improve the serum lipid prole and blood pressure in some patient
groups. Other designer eggs have been developed by feeding hens a diet
rich in CLA; the resulting eggs had a pronounced anti-inammatory
effect in mice (Corrales-Retana et al., 2021; Franczyk-Zar´
ow et al.,
2008).
6.3. Dairy
Dairy products fortied with
ω
-3 fatty acids are attractive to con-
sumers. Hence, various designer milks have been developed and their
effects on human health have been evaluated. A common strategy for
increasing
ω
-3 PUFA content in milk is supplementation of the rumi-
nants’ diet with linseeds/linseed oil, marine oils/algae or a combination
of the above (Donovan et al., 2000; Petit & Cˆ
ortes, 2010; Shingeld
et al., 2003). By supplementing the cow diet with sunower seeds,
designer milk with increased CLA content is produced. However, the
increase in
ω
-3 fatty acids in milk is limited by rumen biohydrogenation
(Toral et al., 2017). Partially circumventing this limitation enabled the
production of
ω
-3 milk with more than 10% ALA based on linseed oil
infusion (Petit et al., 2002). Another approach for obtaining
ω
-3 fortied
milk products is through nutrient enrichment. Intake of milk enriched
with sh oil, oleic acid, EPA, DHA, minerals, and vitamins has shown
health benets such as reduced cell adhesion molecules in healthy
children (Romeo et al., 2011), as well as diminished cardiovascular risk
in postmenopausal women and improved bone metabolism (Fonolla--
Joya et al., 2016). Decreased blood lipids (Lopez-Huertas, 2010),
improved composition of red blood cell membranes, and positive effects
on inammatory parameters have also been ascribed to
ω
-3 fortied
milk. Pregnant women receiving powdered milk fortied with
ω
-3 fatty
acids gave birth to children with greater weight and length (Mardones
et al., 2008). Fortied yogurts with microencapsulated salmon oil
(Estrada et al., 2011) and axseed powder have resulted in an increased
PUFA content and a decreased
ω
-6:
ω
-3 ratio. In an attempt to provide
pregnant and breastfeeding women with adequate amounts of DHA, a
yogurt fortied with microalgae oil was formulated. Finally, butter with
increased ALA content has been developed using a axseed oil- and
axseed-whey protein concentrate emulsion (Pandule et al., 2021).
Some fortication techniques such as microencapsulation and emulsi-
cation to entrap omega-3 fatty acids enhance the quality of yogurt for
its water holding-capacity, and textural attributes with a lower oxida-
tion and syneresis rate (Gumus & Gharibzahedi, 2021). The yogurt
fortication with functional omega-3 fatty acids improves bioavail-
ability while also decreasing serum lipidemic prole and obesity-related
risk factors (Gumus & Gharibzahedi, 2021).
6.4. Bakery
During bread manufacturing, fats are added to the dough, making
this type of food a convenient choice for
ω
-3 fatty acid fortication.
Cookies, cakes, and breads have been produced using eggs and dairy
ingredients containing
ω
-3 PUFAs (Ganesan et al., 2014). Breads forti-
ed with axseed displayed a lower
ω
-6:
ω
-3 ratio (Taglieri et al., 2020).
Microencapsulation of axseed oil in β-glucan or yeast cells has been
proposed as a promising strategy for making
ω
-3 fortied bread and
avoiding lipid oxidation (Beikzadeh et al., 2020; Kairam et al., 2021).
Similarly, enriching gluten-free cornbread with anchovy-derived
ω
-3
PUFAs have been proposed, and fortication with the herb purslane
resulted in pasta with a high content of LA and ALA.
6.5. Infant formula
Human milk serves as the ultimate food for proper growth and
development of infants. Its composition is therefore recreated when
A. Patel et al.
Trends in Food Science & Technology 120 (2022) 140–153
146
developing infant formula. Human milk has a complex and balanced
composition of nutrients including lipids, of which DHA and AA
constitute the main long-chain PUFAs. As cow milk does not contain
DHA and AA in sufcient amounts, commercial oils are added to most
infant formulas reformulated from cow milk. Common sources of fat for
infant formula include mixtures of plant oils, as well as sh and algal oils
(D’Ascenzo et al., 2014; Kuratko et al., 2013; Tai et al., 2013; Winwood,
2013; Yeiser et al., 2016). Formulas with a combination of dairy lipids
and plant oils have been shown to stimulate endogenous conversion of
precursors to long-chain
ω
-3 fatty acids in infants.
7. Innovative technologies for food fortication with
ω
-3 fatty
acids
The FAO and WHO have dened fortication as enhancing the
nutritional content of food by increasing the composition of an essential
micronutrient, thus providing health benets with minimal health risks
to consumers (Saeid, 2018). Consumers and producers have become so
comfortable with the notion of fortied foods that promotional public
health campaigns are no longer needed. In particular,
ω
-3 fortied foods,
such as milk-based products, meat, eggs, juices, table spreads, salad
dressings, sauces, breakfast cereals, baked goods, and infant formula,
have been received very positively by the public. Light can oxidize
ω
-3
fatty acids and, hence,
ω
-3 fortied foods should be wrapped in an
opaque packaging. Microencapsulation delays or inhibits the oxidation
of
ω
-3 as well as the development of undesirable avors and odors
(Hegde et al., 2016). Various methods, such as spray drying, freeze
drying, coacervation, extrusion, and uidized bed coating are used for
encapsulating oils rich in
ω
-3 fatty acids (Chang & Nickerson, 2018). The
latter can be spray-dried into powders and mixed with starch or proteins
to protect them from oxidation. Powders are preferred in baked foods
and beverages, where ingredients require greater dispersion and sta-
bility. For liquid applications, they have to be blended with emulsiers
to prevent their separation (Hegde et al., 2016); this can be achieved
through nanocapsules, micelles, liposomes, emulsions, microspheres,
and biopolymer matrices (Zheng & McClements, 2020).
A superior capsule design requires that a comparatively large
amount of fatty acid-rich oils is entrapped in food-grade wall material.
Such strategy ensures protection against chemical degradation, allows
the dispersion of bioactive compounds at a specic rate and site in
response to environmental factors, tunability with the neighboring food
matrix without inuencing the nal appearance or texture, and con-
sumer acceptability (Chang & Nickerson, 2018). Fioramonti et al., 2019
have described another strategy for encapsulating axseed oil by using a
mixture of whey protein concentrate, sodium alginate and maltodextrin
(Fioramonti et al., 2019). Shrimp oil nanoliposomes prepared from
cephalothorax of Pacic white shrimp by using phosphatidyl choline in
ethanol, glycerol and deionized water has been described. The freeze
dried as well as spray dried nanoliposomes made by using carboxy
methyl cellulose and fumed silica as wall material and anti-caking agent
provided advantages by masking foul odors and protecting oil against
oxidation (Gulzar & Benjakul, 2020). Microcapsules designed using pea
protein isolate and glucose syrup have been shown to successfully
encase 20% rapeseed oil (Tamm et al., 2016). Emulsion properties, such
as stability, droplet size, and viscosity are known to signicantly affect
microcapsule properties (Chang & Nickerson, 2018). Chen et al. (2016)
have reported the use of transglutaminase to introduce covalent
cross-links and enhance the emulsifying activity of soy protein isolate
when entrapping DHA-rich oil with gum Arabic and maltodextrin (Chen
et al., 2016). Jim´
enez-Martin et al. (2016a, 2016b) reported the prep-
aration of a primary emulsion homogenizing sh oil with sodium
caseinate and lactose monohydrate, which was further combined with
olive oil containing polyglycerol polyricinoleate to synthesize a sec-
ondary emulsion. The latter was subsequently amalgamated with so-
dium caseinate and lactose monohydrate to synthesize feed emulsions
prior to spray drying. This multiple-emulsion step enhanced entrapment
efciency of EPA (94%) and DHA (83%) (Jim´
enez-Martín, Antequera
Rojas, et al., 2016). Trilaksani et al., 2020 have described the prepara-
tion of microcapsules containing tuna virgin sh oil with mangrove fruit
extract encapsulated in sodium caseinate and a mixture of arabic
gum-maltodextrin (Trilaksani et al., 2020). A single-layer emulsion was
developed by blending tuna oil with negatively charged lecithin. Later,
positively charged chitosan solution was added to produce a
double-layer solution by inducing electrostatic interaction. Finally, this
double layered solution was diluted with maltodextrin prior to spray
drying (Kwamman & Klinkesorn, 2015).
Fortied breads containing 100 mg of microencapsulated
ω
-3 fatty
acids per 100 g product have become hugely popular among consumers
(Agriculture and Agri-Food Canada, 2011). They serve as good vectors
for delivering EPA and DHA in adequate quantities. Tip Top Up bread
was launched as a joint endeavor of Nu-Mega Ingredients and George
Weston Foods, and was formulated to contain Nu-Mega’s micro-
encapsulated HiDHA oils (Hegde et al., 2016). Functional bread
encapsulated with axseed oil and garlic oil microcapsules was devel-
oped using nanoemulsions and spray drying (Kairam et al., 2021).
Ingredient compatibility as well as popularity makes dairy products apt
for omega-3 fortication. Examples of
ω
-3 fortied dairy products
include yoghurt, milk drinks, margarines, spreads, plus fresh and
ultra-high temperature milk (Hegde et al., 2016). Bello et al. (2015)
have described the fortication of yoghurt with ALA using axseed oil,
Camelina sativa, raspberry, blackcurrant oil, and Echium plantagineum.
Besides yoghurts supplemented with raspberry and E. plantagineum, the
rest were judged positively by consumers (Dal Bello et al., 2015). Goyal
et al. (2016) have described axseed oil microcapsules incorporation in
dahi (Indian yoghurt) as a means of delivering
ω
-3 fatty acids (Goyal
et al., 2016). Whole milk, yoghurt, cheese, yoghurt drinks, dairy-based
beverages, milk powder, butter and buttermilk can be fortied with
PUFAs to minimize nutrition deciency and related disorders (Minj &
Dogra, 2020). Generally, 200 mL of fortied milk can contain 10–190
mg of EPA and DHA or 800 mg of ALA. Margarines and salad dressings
are fortied with ALA derived from axseed or colza oils; whereas
spreads are fortied with EPA/DHA from sh oils (Feizollahi et al.,
2017). The inclusion of
ω
-3 fatty acids in infant formula has expanded
their usage in uid milk (Hegde et al., 2016). This is particularly true of
the algal DHA market, currently dominated by Martek Biosciences. Most
companies produce infant formula, whose quantities of algae-derived
DHA imitate those in human breast milk (Hegde et al., 2016). Cold
beverages have surpassed hot beverages as the preferred delivery
vehicle for
ω
-3 fortication. Formulation of
ω
-3-enriched chocolate milk
using chia oil to replenish energy in athletes following exercise has been
reported (Gonz´
alez et al., 2021). Minute Maid’s enhanced POM blue-
berry, Tropicana pure premium health heart orange juice, and Indian
Rivers fortied grapefruit juice are some famous fortied fruit juices on
the US market (Hegde et al., 2016). Chicken meat is the fastest growing
sector of the world meat market. Fishmeal, sh oil, and linseed oil have
been used to increase the
ω
-3 fatty acid content of meat (Alagawany
et al., 2019). Jim´
enez-Martin et al. (2016a, 2016b) have described the
preparation of chicken nuggets supplemented with microcapsules of
ω
-3
fatty acids from sh oil. These were formulated using multilayer mi-
crocapsules prepared with lecithin-chitosan and maltodextrin, and
comprising 10% sh oil (Jim´
enez-Martín, P´
erez-Palacios, et al., 2016).
Ainsa et al., 2021 have described the preparation of
ω
-3 and
ω
-6
enriched pasta prepared from trimmings and small pieces of sea bass
(Dicentrarchus labrax), semolina from durum and spelt wheat, bran and
rosemary extract (Ainsa et al., 2021). Anbudhasan and Surendraraj
(2014) have reported the development of
ω
-3 fatty acid-enriched pasta
using rened wheat our, salt, sh meat, sh oil, and water. The protein
content of
ω
-3-enriched pasta was 4.84% higher than in regular pasta
and an
ω
-3 content of 974 mg was measured (Anbudhasan & Sure-
ndraraj, 2014). Chocolate spread formulations using soybean oil and
coconut oil in combination with commercial palm stearin has been re-
ported (Nazir & Azad, 2018). Furthermore, nutritional supplements
A. Patel et al.
Trends in Food Science & Technology 120 (2022) 140–153
147
containing
ω
-3 fatty acids as active ingredients are commercially
available in the form of sh liver oil or cod liver oil encapsulated as soft
gels (Hegde et al., 2016).
8. Drawbacks of food fortication
A signicant disadvantage of food fortication is that the encapsu-
lation process can be more expensive than the
ω
-3 fatty acid ingredient
itself (Feizollahi et al., 2017). The weaker emulsifying property of pro-
teins makes the emulsions unstable when exposed to non-optimal tem-
perature, pH, and salt. Thinner interfacial protein lms affect the ability
to protect oil droplets and control their release (Chang & Nickerson,
2018). Bread fortied with microencapsulated oils was reported to
exhibit a lower water absorption capacity and inferior baking properties
due to increased rmness, leading to unfavorable consumer accept-
ability (Serna-Saldivar et al., 2019). Another issue with the incorpora-
tion of
ω
-3 fatty acids in baked goods is the extended shelf life required,
in some cases over a year, which becomes challenging due to instability
of
ω
-3 fatty acids. The properties and distinct avors of dairy products
make it difcult to include ingredients such as sh oil. Oxidation and the
off-putting sh avor represent other drawbacks of incorporating
ω
-3
fatty acids in foods (Stamenkovic et al., 2019). To overcome these issues,
the industry has introduced novel encapsulation techniques using anti-
oxidants and protein-based emulsions; however, they add to the cost of
the nal product (Chang & Nickerson, 2018). The increasing content of
mercury and pesticides in the marine environment raises further con-
cerns over the use of sh and sh oil for food fortication (Costa et al.,
2019). PUFAs in marine lipids undergo oxidation when exposed to at-
mospheric oxygen, releasing free radicals, free fatty acids, and oxidation
products, which are deleterious for cardiovascular health (Ahmed et al.,
2016). It is also possible that the target population misses out on forti-
cation, because in rural areas people who consume the poorest diets
are less likely to have access to fortied foods (Lalani et al., 2019).
Despite the risk of inadequate nutrient intake through the diet, there are
also concerns whether some individuals are consuming an excess of
nutrients. Choosing a suitable fortication vehicle, addressing target
populations, avoiding overindulgence in untargeted populations, and
examining the nutritional status are important challenges (Chadare
et al., 2019). In summary, poor understanding or lack of consumer
awareness regarding the health benets of
ω
-3 fatty acids, a superior
price range of
ω
-3 fortied products, regulatory restrictions, and the lack
of a globally accepted reference daily intake level for a nutrient are
major market restraints for such products.
9. Fortication of food with
ω
-3/
ω
-6 PUFAs; an incomplete
agenda for low- and middle-income countries
Food systems in many low- and middle-income countries do not
provide nutritionally appropriate meals to all people, leading to
micronutrient deciencies in women and children (Pinstrup-Andersen,
2013). Iron, iodine, folate, vitamin A, and zinc deciencies are the most
frequent, and they contribute to poor growth, poor cognitive develop-
ment, reduced IQ, prenatal problems, and an increased risk of morbidity
and mortality at the individual level (Bailey et al., 2015). Micronutrient
decits in such countries contribute to human capital and economic
development inefciencies at the population level. As a result, pre-
venting them is critical for global health and economic growth.
Although large-scale food fortication (LSFF) is a cost-effective and
extensively used intervention, there is still room for improvement. We
used the Global Fortication Data Exchange (GFDx) to identify nations
that potentially beneted from new fortication projects in order to
identify gaps and possibilities (“Global Fortication Data Exchange
GFDx,” 2021). We identied 84 nations as potential LSFF program re-
cipients. According to Fortication Assessment Coverage Toolkit sta-
tistics, the potential of oil/ghee and salt fortication is not being
realized due to insufcient population coverage of adequately fortied
foods. For regulatory agencies to monitor food fortication, mandatory
fortication imposes a legal obligation. Mandatory legislation is more
cost-effective, egalitarian, and long-term than voluntary fortication
when it is accompanied by sufcient regulatory monitoring to assure
compliance. Foods fortied on a voluntary basis may have lower pop-
ulation coverage, inconsistent manufacturing, and higher costs than
those fortied under mandated laws. However, if adequate nutritional
levels and compounds are specied, food standards that enable volun-
tary fortication also give information to food manufacturers on how to
fortify foods safely and efciently. GFDx populates its database through
a bi-annual survey, aiming to reach 196 countries. In between survey
cycles, the GFDx database is updated when new information is received
directly from fortication partners and/or national stakeholders. Ac-
cording to GFDx, only 27 countries could legally mandate fortication of
a food with oil (Fig. 2). Among these, only three have collected data
showing the proportion of the population that eats the fortied food
vehicle in question (Fig. 3). Ideally, the amount of fortied food
consumed is comparable in the entire population (all households). In
practice, the percentage of families who do not consume a food must be
taken into account, as they cannot be regarded prospective beneciaries.
For example, if they eat predominantly cassava, fortication of wheat
our may not be benecial to them. When these families are included in
the denominator, the projected population coverage is reduced, altering
the manager’s perception of the program’s utility.
10. Microbial production of omega 3 fatty acids
Due to declining sh supplies and contamination of marine ecosys-
tems, the worldwide demand for omega-3 and 6 PUFAs cannot be
satised only by sh oils, which has sparked research in alternate sus-
tainable sources. Some vegetable oils and genetically engineered plant
oilseeds such as Brassica juncea, Arabidopsis thaliana, and Camelina sativa
are a good alternative sources of omega-3 PUFAs in the commodities
(Gill & Valivety, 1997). Despite the various benets of transgenic plants,
their production is limited by seasonal and climatic circumstances, as
well as the availability of arable land. Furthermore, there are public
concerns about transgenic agricultural production in open environ-
ments. These factors, along with regulatory concerns, limit the pro-
duction of genetically modied crops on a wide scale. Now, microbial
oils for PUFA production getting more attention these days due to
similar fatty acids prole to those obtained from plants and animals and
a possible source of nutritionally important omega-3 & 6 PUFAs (Ward
& Singh, 2005). Some oleaginous microbes such as microalgae and
thraustochytrids has high amount of DHA and EPA in their total lipids
content (Patel et al., 2021). Microalgae are mostly autotrophic in nature
and the productivity of theses fatty acids are lower than those obtained
with heterotrophic cultivation (Patel et al., 2018). Only few microalgae
like Crypthecodinium cohnii are good example of heterotrophic micro-
algae that can produce high amount of DHA (Patel, Karageorgou, et al.,
2020). However, among several oleaginous microbes thraustochytrids
are natural producer of omega-3 fatty acids heterotrophically.
11. Conclusions
Our forefathers ate a diet that had an almost equal proportion of
ω
-6
and
ω
-3 fatty acids. Since then, the
ω
-6:
ω
-3 ratio has changed to 15–20:1
through the development of modern agriculture and new dietary habits.
This switch has become problematic because of the low interconversion
between
ω
-6 and
ω
-3 fatty acids. Changes in tissue
ω
-3 fatty acid proles
may have important health consequences because these fatty acids
control essential cell properties and activities, such as membrane
uidity, cell signaling, gene expression, and eicosanoid metabolism. As a
result, a shift in the fatty acid ratio is expected to have signicant clinical
implications for the health of newborns and cardiovascular disease.
Humans require only small amounts of
ω
-6 fatty acids, which are found
in a variety of meals. As a result, people exposed to a Western diet may
A. Patel et al.
Trends in Food Science & Technology 120 (2022) 140–153
148
be already consuming excessive amounts of these foods. While popular,
a combination of
ω
-3-6-9 pills does not offer any signicant benets
besides those brought by supplementation with
ω
-3 fatty acids alone.
The health advantages of
ω
-3 PUFAs are widely recognized. Ultimately,
dietary intake of
ω
-3 PUFAs through incorporation into foods is the most
effective way of delivering them to the average consumer. While
ω
-3
PUFAs themselves do not contribute to the off-putting shy avor of
many
ω
-3 fortied foods, it is important to identify the origin of such
shy taste and attempt its removal to make the end-products more
palatable to the public.
CRediT authorship contribution statement
Alok Patel: Conceptualization, Methodology, Data curation, Writing
– original draft. Sneha Sawant Desai: Writing – original draft. Varsha
Kelkar Mane: Writing – review & editing, Visualization. Josene
Enman: Writing – review & editing. Ulrika Rova: Writing – review &
editing, Visualization, Supervision. Paul Christakopoulos: Formal
analysis, Visualization, Supervision. Leonidas Matsakas: Validation,
Visualization.
Acknowledgement
Alok Patel, Ulrika Rova, Paul Christakopoulos and Leonidas Matsa-
kas would like to thank the Swedish Research Council (FORMAS) and
Kempestiftelserna, Sweden for supporting this work as part of the pro-
jects ‘Green and sustainable approach to valorise high saline and oily
sh processing efuents for the production of nutraceuticals’ (INVEN-
TION; 2020-01028), Boosting the squalene content in thraustochytrids
by genetic engineering using CRISPR–Cas9 System to replace the shark-
Fig. 2. Low-income, middle-income, and upper-middle income countries that do not have mandatory programs in place and have the potential to benet from new
LSFF programs or from making voluntary programs mandatory (Global Fortication Data Exchange. Accessed May 23, 2021 [http://www.forticationdata.org.].).
Fig. 3. Population coverage in low-income, middle-income, and upper-middle income countries towards fortied foods (Global Fortication Data Exchange.
Accessed May 23, 2021 [http://www.forticationdata.org.].).
A. Patel et al.
Trends in Food Science & Technology 120 (2022) 140–153
149
based squalene as an adjuvant for COVID 2019 vaccine (JCK-2115) and
‘Tuned volatile fatty acids production from organic waste for biorenery
platforms (VFA biorenery; reference number 2018–00818).
References
Abbasi, F., Samadi, F., Jafari, S. M., Ramezanpour, S., & Shargh, M. S. (2020). Production
of omega-3-enriched meat through feeding broilers with ultrasonicated axseed oil
nanoemulsions: Performance, serum composition, physicochemical properties and
oxidative stability. Iranian Journal of Applied Animal Science, 9, 487–496.
Agriculture and Agri-Food Canada. (2011). Health and wellness trends for Canada and the
world october 2011.
Ahmed, M., Pickova, J., Ahmad, T., Liaquat, M., Farid, A., & Jahangir, M. (2016).
Oxidation of lipids in foods. Sarhad Journal of Agriculture, 32, 230–238. https://doi.
org/10.17582/journal.sja/2016.32.3.230.238
Ahmmed, M. K., Ahmmed, F., Tian, H., Carne, A., & Bekhit, A. E. D. (2020). Marine
omega-3 (n-3) phospholipids: A comprehensive review of their properties, sources,
bioavailability, and relation to brain health. Comprehensive Reviews in Food Science
and Food Safety, 19, 64–123. https://doi.org/10.1111/1541-4337.12510
Ainsa, A., Marquina, P. L., Roncal´
es, P., Beltr´
an, J. A., & Calanche, M. J. B. (2021).
Enriched fresh pasta with a sea bass by-product, a novel food: Fatty acid stability and
sensory properties throughout shelf life. Foods, 10. https://doi.org/10.3390/
foods10020255
Alagawany, M., Elnesr, S. S., Farag, M. R., Abd El-Hack, M. E., Khafaga, A. F., Taha, A. E.,
Tiwari, R., Iqbal Yatoo, M., Bhatt, P., Khurana, S. K., & Dhama, K. (2019). Omega-3
and omega-6 fatty acids in poultry nutrition: Effect on production performance and
health. Animals, 9. https://doi.org/10.3390/ani9080573
Anbudhasan, P., & Surendraraj, A. (2014). Development of functional pasta enriched
with Omega 3 fatty acids. Fishery Technology, 1–6.
Araujo, P., Belghit, I., Aarsæther, N., Espe, M., Lucena, E., & Holen, E. (2019). The effect
of omega-3 and omega-6 polyunsaturated fatty acids on the production of
cyclooxygenase and lipoxygenase metabolites by human umbilical vein endothelial
cells. Nutrients, 11. https://doi.org/10.3390/nu11050966
Avallone, R., Vitale, G., & Bertolotti, M. (2019). Omega-3 fatty acids and
neurodegenerative diseases: New evidence in clinical trials. International Journal of
Molecular Sciences, 20. https://doi.org/10.3390/ijms20174256
Ayo, J., Carballo, J., Serrano, J., Olmedilla-Alonso, B., Ruiz-Capillas, C., & Jim´
enez-
Colmenero, F. (2007). Effect of total replacement of pork backfat with walnut on the
nutritional prole of frankfurters. Meat Science, 77, 173–181. https://doi.org/
10.1016/j.meatsci.2007.02.026
Baeza-Jim´
enez, R., L´
opez-Martínez, L. X., García-Varela, R., & García, H. S. (2017).
Lipids in fruits and vegetables: Chemistry and biological activities. Fruit Veg.
Phytochem. Chem. Hum. Heal. Second Ed, 1, 423–449. https://doi.org/10.1002/
9781119158042.ch20
Bailey, R. L., West, K. P., & Black, R. E. (2015). The epidemiology of global micronutrient
deciencies. Annals of Nutrition & Metabolism, 66, 22–33. https://doi.org/10.1159/
000371618
Bali´
c, A., Vlaˇ
si´
c, D., ˇ
Zuˇ
zul, K., Marinovi´
c, B., & Mokos, Z. B. (2020). Omega-3 versus
Omega-6 polyunsaturated fatty acids in the prevention and treatment of
inammatory skin diseases. International Journal of Molecular Sciences, 21. https://
doi.org/10.3390/ijms21030741
Bannenberg, G., & Serhan, C. N. (2010). Specialized pro-resolving lipid mediators in the
inammatory response: An update. Biochimica et Biophysica Acta (BBA) - Molecular
and Cell Biology of Lipids, 1801, 1260–1273. https://doi.org/10.1016/j.
bbalip.2010.08.002
Bannenberg, G., Serhan, C. N., Brown, M. S., Goldstein, J. L., Calder, P. C., Carlson, S. J.,
O’Loughlin, A. A., Anez-Bustillos, L., Baker, M. A., Andrews, N. A., Gunner, G.,
Dao, D. T., Pan, A., Nandivada, P., Chang, M., Cowan, E., Mitchell, P. D., Gura, K. M.,
Fagiolini, M., … Valentine, D. L. (2019). Fatty acid analysis of blood plasma of
patients with Alzheimer’s disease, other types of dementia, and cognitive
impairment. Progress in Lipid Research, 11, 420–439. https://doi.org/10.3390/
nu8010006
Bazinet, R. P., Metherel, A. H., Chen, C. T., Shaikh, S. R., Nadjar, A., Joffre, C., & Lay´
e, S.
(2020). Brain eicosapentaenoic acid metabolism as a lead for novel therapeutics in
major depression. Brain, Behavior, and Immunity, 85, 21–28. https://doi.org/
10.1016/j.bbi.2019.07.001
Beikzadeh, S., Shojaee-Aliabadi, S., Dadkhodazade, E., Sheidaei, Z., Abedi, A. S.,
Mirmoghtadaie, L., & Hosseini, S. M. (2020). Comparison of properties of breads
enriched with omega-3 oil encapsulated in β-glucan and saccharomyces cerevisiae
yeast cells. Applied Food Biotechnology, 7, 11–20. https://doi.org/10.22037/afb.
v7i1.25969
Bhardwaj, K., Verma, N., Trivedi, R. K., Bhardwaj, S., & Shukla, N. (2016). Signicance
of ratio of Omega-3 and Omega-6 in human health with special reference to axseed
oil. International Journal of Biological Chemistry, 10, 1–6. https://doi.org/10.3923/
ijbc.2016.1.6
Bork, C. S., Venø, S. K., Lundbye-Christensen, S., Jakobsen, M. U., Tjønneland, A.,
Schmidt, E. B., & Overvad, K. (2018). Dietary intake of
α
-linolenic acid is not
appreciably associated with risk of ischemic stroke among middle-aged Danish men
and women. Journal of Nutrition, 148, 952–958. https://doi.org/10.1093/jn/nxy056
Borow, K. M., Mason, R. P., & Vijayaraghavan, K. (2017). Eicosapentaenoic acid as a
potential therapeutic approach to reduce cardiovascular risk in patients with end-
stage renal disease on hemodialysis: A review. CardioRenal Medical, 8, 18–30.
https://doi.org/10.1159/000479391
Brinton, E. A., & Mason, R. P. (2017). Prescription omega-3 fatty acid products
containing highly puried eicosapentaenoic acid (EPA). Lipids in Health and Disease,
16, 1–13. https://doi.org/10.1186/s12944-017-0415-8
Burns-Whitmore, B., Froyen, E., Heskey, C., Parker, T., & Pablo, G. S. (2019). Alpha-
linolenic and linoleic fatty acids in the vegan diet: Do they require dietary reference
intake/adequate intake special consideration? Nutrients, 11. https://doi.org/
10.3390/nu11102365
C´
aceres, E., García, M. L., & Selgas, M. D. (2008). Effect of pre-emulsied sh oil - as
source of PUFA n-3 - on microstructure and sensory properties of mortadella, a
Spanish bologna-type sausage. Meat Science, 80, 183–193. https://doi.org/10.1016/
j.meatsci.2007.11.018
Calder, P. C. (2013). N-3 Fatty acids, inammation and immunity: New mechanisms to
explain old actions. Proceedings of the Nutrition Society, 72, 326–336. https://doi.org/
10.1017/S0029665113001031
Calder, P. C. (2016). Docosahexaenoic acid. Annals of Nutrition & Metabolism, 69, 8–21.
https://doi.org/10.1159/000448262
Chadare, F. J., Idohou, R., Nago, E., Affonfere, M., Agossadou, J., Fassinou, T. K.,
K´
enou, C., Honfo, S., Azokpota, P., Linnemann, A. R., & Hounhouigan, D. J. (2019).
Conventional and food-to-food fortication: An appraisal of past practices and
lessons learned. Food Sciences and Nutrition, 7, 2781–2795. https://doi.org/10.1002/
fsn3.1133
Chang, C., & Nickerson, M. T. (2018). Encapsulation of omega 3-6-9 fatty acids-rich oils
using protein-based emulsions with spray drying. Journal of Food Science &
Technology, 55, 2850–2861. https://doi.org/10.1007/s13197-018-3257-0
Chen, W., Wang, H., Zhang, K., Gao, F., Chen, S., & Li, D. (2016). Physicochemical
properties and storage stability of microencapsulated DHA-rich oil with different
wall materials. Applied Biochemistry and Biotechnology, 179, 1129–1142. https://doi.
org/10.1007/s12010-016-2054-3
Chianese, R., Coccurello, R., Viggiano, A., Scafuro, M., Fiore, M., Coppola, G.,
Operto, F. F., Fasano, S., Laye, S., Pierantoni, R., & Meccariello, R. (2017). Impact of
dietary fats on brain functions. Current Neuropharmacology, 16, 1059–1085. https://
doi.org/10.2174/1570159x15666171017102547
Christian, L. M., Blair, L. M., Porter, K., Lower, M., Cole, R. M., & Belury, M. A. (2016).
Polyunsaturated fatty acid (PUFA) status in pregnant women: Associations with
sleep quality, inammation, and length of gestation. PLoS One, 11, 1–18. https://doi.
org/10.1371/journal.pone.0148752
Corrales-Retana, L., Ciucci, F., Conte, G., Casarosa, L., Mele, M., & Serra, A. (2021).
Prole of fatty acid lipid fractions of omega-3 fatty acid-enriched table eggs. Journal
of Animal Physiology and Animal Nutrition, 105, 326–335. https://doi.org/10.1111/
jpn.13462
Costa, J. G., Vidovic, B., Saraiva, N., do C´
eu Costa, M., Del Favero, G., Marko, D.,
Oliveira, N. G., & Fernandes, A. S. (2019). Contaminants: A dark side of food
supplements? Free Radical Research, 53, 1113–1135. https://doi.org/10.1080/
10715762.2019.1636045
Cruickshank, E. M. (1934). Studies in fat metabolism in the fowl: The composition of the
egg fat and depot fat of the fowl as affected by the ingestion of large amounts of
different fats. Biochemical Journal, 28, 965–977.
Czerska, M., Zieli´
nski, M., & Gromadzi´
nska, J. (2016). Isoprostanes – a novel major
group of oxidative stress markers. International Journal of Occupational Medicine &
Environmental Health, 29, 179–190. https://doi.org/10.13075/ijomeh.1896.00596
Dal Bello, B., Torri, L., Piochi, M., & Zeppa, G. (2015). Healthy yogurt fortied with n-3
fatty acids from vegetable sources. Journal of Dairy Science, 98, 8375–8385. https://
doi.org/10.3168/jds.2015-9688
D’Angelo, S., Motti, M. L., & Meccariello, R. (2020).
ω
-3 and
ω
-6 polyunsaturated fatty
acids, obesity and cancer. Nutrients, 12, 2751. https://doi.org/10.3390/nu12092751
Das, U. N. (2010). Essential fatty acids and their metabolites in the context of
hypertension. Hypertension Research, 33, 782–785. https://doi.org/10.1038/
hr.2010.105
Das, U. N. (2018). Arachidonic acid in health and disease with focus on hypertension and
diabetes mellitus: A review. Journal of Advanced Research, 11, 43–55. https://doi.
org/10.1016/j.jare.2018.01.002
D’Ascenzo, R., Savini, S., Biagetti, C., Bellagamba, M. P., Marchionni, P., Pompilio, A.,
Cogo, P. E., & Carnielli, V. P. (2014). Higher docosahexaenoic acid, lower
arachidonic acid and reduced lipid tolerance with high doses of a lipid emulsion
containing 15% sh oil: A randomized clinical trial. Clinical Nutrition, 33,
1002–1009. https://doi.org/10.1016/j.clnu.2014.01.009
Delarue, J. (2020). Are marine n-3 fatty acids protective towards insulin resistance?
From cell to human. Proceedings of the Nutrition Society, 79, 417–427. https://doi.
org/10.1017/S0029665120000087
Dewhurst, R. J., & Moloney, A. P. (2013). Modication of animal diets for the enrichment of
dairy and meat products with omega-3 fatty acids, Food Enrichment with Omega-3 Fatty
Acids. Woodhead Publishing Limited. https://doi.org/10.1533/
9780857098863.3.257
Ding, D., Zhong, Q., wei, Z., yuan Ling, S., wen, C., Xiong, F., Ke, Y.bin, & Chen, Y.ming
(2020). Association between erythrocyte membrane n-3 and n-6 polyunsaturated
fatty acids and carotid atherosclerosis: A prospective study. Atherosclerosis, 298,
7–13. https://doi.org/10.1016/j.atherosclerosis.2020.02.013
Donovan, D. C., Schingoethe, D. J., Baer, R. J., Ryali, J., Hippen, A. R., & Franklin, S. T.
(2000). Inuence of dietary sh oil on conjugated linoleic acid and other fatty acids
in milk fat from lactating dairy cows. Journal of Dairy Science, 83, 2620–2628.
https://doi.org/10.3168/jds.S0022-0302(00)75155-1
Estrada, J. D., Boeneke, C., Bechtel, P., & Sathivel, S. (2011). Developing a strawberry
yogurt fortied with marine sh oil 1. Journal of Dairy Science, 94, 5760–5769.
https://doi.org/10.3168/jds.2011-4226
A. Patel et al.
Trends in Food Science & Technology 120 (2022) 140–153
150
Feizollahi, E., Hadian, Z., & Honarvar, Z. (2017). Food fortication with omega-3 fatty
acids; microencapsulation as an addition method. Current Nutrition & Food Science,
14, 90–103. https://doi.org/10.2174/1573401313666170728151350
Fioramonti, S. A., Stepanic, E. M., Tibaldo, A. M., Pav´
on, Y. L., & Santiago, L. G. (2019).
Spray dried axseed oil powdered microcapsules obtained using milk whey proteins-
alginate double layer emulsions. Food Research International, 119, 931–940. https://
doi.org/10.1016/j.foodres.2018.10.079
Fonolla-Joya, J., Reyes-García, R., García-Martín, A., L´
opez-Huertas, E., & Mu˜
noz-
Torres, M. (2016). Daily intake of milk enriched with n-3 fatty acids, oleic acid, and
calcium improves metabolic and bone biomarkers in postmenopausal women.
Journal of the American College of Nutrition, 35, 529–536. https://doi.org/10.1080/
07315724.2014.1003114
Franczyk-Zar´
ow, M., Kostogrys, R. B., Szymczyk, B., Jawie´
n, J., Gajda, M., Cichocki, T.,
Wojnar, L., Chlopicki, S., & Pisulewski, P. M. (2008). Functional effects of eggs,
naturally enriched with conjugated linoleic acid, on the blood lipid prole,
development of atherosclerosis and composition of atherosclerotic plaque in
apolipoprotein E and low-density lipoprotein receptor double-knockout mic. British
Journal of Nutrition, 99, 49–58. https://doi.org/10.1017/S0007114507793893
Ganesan, B., Brothersen, C., & McMahon, D. J. (2014). Fortication of foods with omega-
3 polyunsaturated fatty acids. Critical Reviews in Food Science and Nutrition, 54,
98–114. https://doi.org/10.1080/10408398.2011.578221
Garg, P., Pejaver, R. K., Sukhija, M., & Ahuja, A. (2017). Role of DHA, ARA, &
phospholipids in brain development: An Indian perspective. Clinical Epdidemiology
Global Health, 5, 155–162. https://doi.org/10.1016/j.cegh.2017.09.003
Georgiadi, A., & Kersten, S. (2012). Mechanisms of gene regulation by fatty acids. Adv.
Nutr., 3, 127–134. https://doi.org/10.3945/an.111.001602
Giacobbe, J., Benoiton, B., Zunszain, P., Pariante, C. M., & Borsini, A. (2020). The anti-
inammatory role of omega-3 polyunsaturated fatty acids metabolites in pre-clinical
models of psychiatric, neurodegenerative, and neurological disorders. Frontiers in
Psychiatry, 11. https://doi.org/10.3389/fpsyt.2020.00122
Gill, I., & Valivety, R. (1997). Polyunsaturated fatty acids, part 1: Occurrence, biological
activities and applications. Trends in Biotechnology, 15, 401–409. https://doi.org/
10.1016/S0167-7799(97)01076-7
Global Fortication Data Exchange. (2021). GFDx [WWW Document], 5.28.21, URL
https://forticationdata.org.
G´
omez-Cort´
es, P., de la Fuente, M. A., Blanco, F. P., Nú˜
nez-S´
anchez, N., Domenech, F. R.,
& Martínez Marín, A. L. (2021). Feeding algae meal to feedlot lambs with competent
reticular groove reex increases omega-3 fatty acids in meat. Foods, 10, 1–11.
https://doi.org/10.3390/foods10020366
G´
omez-Soler, M., Cordobilla, B., Morat´
o, X., Fern´
andez-Due˜
nas, V., Domingo, J. C., &
Ciruela, F. (2018). Triglyceride form of docosahexaenoic acid mediates
neuroprotection in experimental parkinsonism. Frontiers in Neuroscience, 12, 1–11.
https://doi.org/10.3389/fnins.2018.00604
Gonz´
alez, A., Bord´
on, M. G., Bustos, M. C., C´
ordova Salazar, K. L., Ribotta, P. D., &
Martínez, M. L. (2021). Study of the incorporation of native and microencapsulated
chia seed oil on pasta properties. International Journal of Food Science and Technology,
56, 233–241. https://doi.org/10.1111/ijfs.14623
Gorjao, R., dos Santos, C. M. M., Serdan, T. D. A., Diniz, V. L. S., Alba-Loureiro, T. C.,
Cury-Boaventura, M. F., Hatanaka, E., Levada-Pires, A. C., Sato, F. T., Pithon-
Curi, T. C., Fernandes, L. C., Curi, R., & Hirabara, S. M. (2019). New insights on the
regulation of cancer cachexia by N-3 polyunsaturated fatty acids. Pharmacology &
Therapeutics, 196, 117–134. https://doi.org/10.1016/j.pharmthera.2018.12.001
Goyal, A., Sharma, V., Sihag, M. K., Singh, A. K., Arora, S., & Sabikhi, L. (2016).
Fortication of dahi (Indian yoghurt) with omega-3 fatty acids using
microencapsulated axseed oil microcapsules. Journal of Food Science & Technology,
53, 2422–2433. https://doi.org/10.1007/s13197-016-2220-1
Grootendorst-van Mil, N. H., Tiemeier, H., Steenweg-de Graaff, J., Koletzko, B.,
Demmelmair, H., Jaddoe, V. W. V., Steegers, E. A. P., & Steegers-Theunissen, R. P. M.
(2018). Maternal plasma n-3 and n-6 polyunsaturated fatty acids during pregnancy
and features of fetal health: Fetal growth velocity, birth weight and duration of
pregnancy. Clinical Nutrition, 37, 1367–1374. https://doi.org/10.1016/j.
clnu.2017.06.010
Gulzar, S., & Benjakul, S. (2020). Nanoliposome powder containing shrimp oil increases
free owing behavior and storage stability. European Journal of Lipid Science and
Technology, 122, 1–13. https://doi.org/10.1002/ejlt.202000049
Gumus, C. E., & Gharibzahedi, S. M. T. (2021). Yogurts supplemented with lipid
emulsions rich in omega-3 fatty acids: New insights into the fortication,
microencapsulation, quality properties, and health-promoting effects. Trends in Food
Science & Technology, 110, 267–279. https://doi.org/10.1016/j.tifs.2021.02.016
Günther, J., Schulte, K., Wenzel, D., Malinowska, B., & Schlicker, E. (2010).
Prostaglandins of the e series inhibit monoamine release via EP3 receptors: Proof
with the competitive EP3 receptor antagonist L-826,266. Naunyn-Schmiedeberg’s
Archives of Pharmacology, 381, 21–31. https://doi.org/10.1007/s00210-009-0478-9
Guo, X. fei, Li, K. lei, Li, J. mei, & Li, D. (2019). Effects of EPA and DHA on blood pressure
and inammatory factors: A meta-analysis of randomized controlled trials. Critical
Reviews in Food Science and Nutrition, 59, 3380–3393. https://doi.org/10.1080/
10408398.2018.1492901
Hamilton, H. A., Newton, R., Auchterlonie, N. A., & Müller, D. B. (2020). Systems
approach to quantify the global omega-3 fatty acid cycle. Nature Food, 1, 59–62.
https://doi.org/10.1038/s43016-019-0006-0
Hanna, V. S., & Hafez, E. A. A. (2018). Synopsis of arachidonic acid metabolism: A
review. Journal of Advanced Research, 11, 23–32. https://doi.org/10.1016/j.
jare.2018.03.005
Hegde, M. V., Zanwar, A. A., & Adekar, S. P. (2016). Nutrition, life, disease, and death,
omega-3 fatty acids: Keys to nutritional health. https://doi.org/10.1007/978-3-319-
40458-5_1
Hooper, L., Al-Khudairy, L., Abdelhamid, A. S., Rees, K., Brainard, J. S., Brown, T. J.,
Ajabnoor, S. M., O’Brien, A. T., Winstanley, L. E., Donaldson, D. H., Song, F., &
Deane, K. H. O. (2018). Omega-6 fats for the primary and secondary prevention of
cardiovascular disease. Cochrane Database of Systematic Reviews. https://doi.org/
10.1002/14651858.CD011094.pub3, 2018.
Hsu, M. C., Huang, Y. S., & Ouyang, W. C. (2020). Benecial effects of omega-3 fatty acid
supplementation in schizophrenia: Possible mechanisms. Lipids in Health and Disease,
19, 1–17. https://doi.org/10.1186/s12944-020-01337-0
Huerta-Y´
epez, S., Tirado-Rodriguez, A. B., & Hankinson, O. (2016). Role of diets rich in
omega-3 and omega-6 in the development of cancer. Boletín M´
edico Del Hosp. Infant.
M´
exico (English Ed, 73, 446–456. https://doi.org/10.1016/j.bmhime.2017.11.043
Husted, K. S., & Bouzinova, E. V. (2016). The importance of n-6/n-3 fatty acids ratio in
the major depressive disorder. Med, 52, 139–147. https://doi.org/10.1016/j.
medici.2016.05.003
Jackson, A., Forsyth, C. B., Shaikh, M., Voigt, R. M., Engen, P. A., Ramirez, V., &
Keshavarzian, A. (2019). Diet in Parkinson’s disease: Critical role for the
microbiome. Frontiers in Neurology, 10, 1–21. https://doi.org/10.3389/
fneur.2019.01245
Jensen, R. G. (2002). The composition of bovine milk lipids: January 1995 to December
2000. Journal of Dairy Science, 85, 295–350. https://doi.org/10.3168/jds.S0022-
0302(02)74079-4
Jim´
enez-Martín, E., Antequera Rojas, T., Gharsallaoui, A., Ruiz Carrascal, J., & P´
erez-
Palacios, T. (2016a). Fatty acid composition in double and multilayered
microcapsules of
ω
-3 as affected by storage conditions and type of emulsions. Food
Chemistry, 194, 476–486. https://doi.org/10.1016/j.foodchem.2015.08.046
Jim´
enez-Martín, E., P´
erez-Palacios, T., Carrascal, J. R., & Rojas, T. A. (2016b).
Enrichment of chicken nuggets with microencapsulated omega-3 sh oil: Effect of
frozen storage time on oxidative stability and sensory quality. Food and Bioprocess
Technology, 9, 285–297. https://doi.org/10.1007/s11947-015-1621-x
Jovanovski, E., Li, D., Thanh Ho, H. V., Djedovic, V., De Castro Ruiz Marques, A.,
Shishtar, E., Mejia, S. B., Sievenpiper, J. L., De Souza, R. J., Duvnjak, L., & Vuksan, V.
(2017). The effect of alpha-linolenic acid on glycemic control in individuals with
type 2 diabetes. Med. (United States), 96. https://doi.org/10.1097/
MD.0000000000006531
Kairam, N., Kandi, S., & Sharma, M. (2021). Development of functional bread with
axseed oil and garlic oil hybrid microcapsules. Lebensmittel-Wissenschaft &
Technologie, 136, Article 110300. https://doi.org/10.1016/j.lwt.2020.110300
Kaliannan, K., Li, X. Y., Wang, B., Pan, Q., Chen, C. Y., Hao, L., Xie, S., & Kang, J. X.
(2019). Multi-omic analysis in transgenic mice implicates omega-6/omega-3 fatty
acid imbalance as a risk factor for chronic disease. Communication. Biology, 2.
https://doi.org/10.1038/s42003-019-0521-4
Kalkman, H. O., Hersberger, M., Walitza, S., & Berger, G. E. (2021). Disentangling the
molecular mechanisms of the antidepressant activity of omega-3 polyunsaturated
fatty acid: A comprehensive review of the literature. International Journal of
Molecular Sciences, 22. https://doi.org/10.3390/ijms22094393
Kawashima, H. (2019). (Review) kawashima2019 Intake of arachidonic acid-containing
lipids in adult humans_ dietary surveys and clinical trials. pdf 1–9.
Kerdiles, O., Lay´
e, S., & Calon, F. (2017). Omega-3 polyunsaturated fatty acids and brain
health: Preclinical evidence for the prevention of neurodegenerative diseases. Trends
in Food Science & Technology. https://doi.org/10.1016/j.tifs.2017.09.003
Kitajka, K., Sinclair, A. J., Weisinger, R. S., Weisinger, H. S., Mathai, M.,
Jayasooriya, A. P., Halver, J. E., & Pusk´
as, L. G. (2004). Effects of dietary omega-3
polyunsaturated fatty acids on brain gene expression. Proceedings of the National
Academy of Sciences of the United States of America, 101, 10931–10936. https://doi.
org/10.1073/pnas.0402342101
Kris-Etherton, P. M., Grieger, J. A., & Etherton, T. D. (2009). Dietary reference intakes for
DHA and EPA. Prostaglandins Leukot Essential Fat Acids, 81, 99–104. https://doi.org/
10.1016/j.plefa.2009.05.011
Kuratko, C., Abril, J. R., Hoffman, J. P., & Salem, N. (2013). Enrichment of infant formula
with omega-3 fatty acids, food enrichment with omega-3 fatty acids. Woodhead
Publishing Limited. https://doi.org/10.1533/9780857098863.3.353
Kwamman, Y., & Klinkesorn, U. (2015). Inuence of oil load and maltodextrin
concentration on properties of tuna oil microcapsules encapsulated in two-layer
membrane. Drying Technology, 33, 854–864. https://doi.org/10.1080/
07373937.2014.993474
Lagarde, M., Calzada, C., Guichardant, M., & V´
ericel, E. (2018). In vitro and in vivo
bimodal effects of docosahexaenoic acid supplements on redox status and platelet
function. Prostaglandins Leukot Essential Fat Acids, 138, 60–63. https://doi.org/
10.1016/j.plefa.2016.05.010
Lalani, B., Bechoff, A., & Bennett, B. (2019). Which choice of delivery model(s)works
best to deliver fortied foods? Nutrients, 11. https://doi.org/10.3390/nu11071594
Lauritzen, L., Fewtrell, M., & Agostoni, C. (2015). Dietary arachidonic acid in perinatal
nutrition: A commentary. Pediatric Research, 77, 263–269. https://doi.org/10.1038/
pr.2014.166
Lee, S., Hernandez, P., Djordjevic, D., Faraji, H., Hollender, R., Faustman, C., &
Decker, E. A. (2006). Effect of antioxidants and cooking on stability of n-3 fatty acids
in fortied meat products. Journal of Food Science, 71, 233–238. https://doi.org/
10.1111/j.1365-2621.2006.tb15623.x
Lee, E., Kim, H., Kim, H., Ha, E. H., & Chang, N. (2018). Association of maternal omega-6
fatty acid intake with infant birth outcomes: Korean mothers and children’s
environmental health (MOCEH). Nutrition Journal, 17, 1–9. https://doi.org/
10.1186/s12937-018-0353-y
Lee, J. B., Notay, K., Klingel, S. L., Chabowski, A., Mutch, D. M., & Millar, P. J. (2019).
Docosahexaenoic acid reduces resting blood pressure but increases muscle
sympathetic outow compared with eicosapentaenoic acid in healthy men and
A. Patel et al.
Trends in Food Science & Technology 120 (2022) 140–153
151
women. American Journal of Physiology - Heart and Circulatory Physiology, 316,
H873–H881. https://doi.org/10.1152/ajpheart.00677.2018
Lev, E. I., Solodky, A., Harel, N., Mager, A., Brosh, D., Assali, A., Roller, M., Battler, A.,
Kleiman, N. S., & Kornowski, R. (2010). Treatment of aspirin-resistant patients with
omega-3 fatty acids versus aspirin dose escalation. Journal of the American College of
Cardiology, 55, 114–121. https://doi.org/10.1016/j.jacc.2009.08.039
Lopez-Huertas, E. (2010). Health effects of oleic acid and long chain omega-3 fatty acids
(EPA and DHA) enriched milks. A review of intervention studies. Pharmacological
Research, 61, 200–207. https://doi.org/10.1016/j.phrs.2009.10.007
Lupette, J., & Benning, C. (2020). Human health benets of very-long-chain
polyunsaturated fatty acids from microalgae. Biochimie, 178, 15–25. https://doi.org/
10.1016/j.biochi.2020.04.022
Madore, C., Leyrolle, Q., Morel, L., Rossitto, M., Greenhalgh, A. D., Delpech, J. C.,
Martinat, M., Bosch-Bouju, C., Bourel, J., Rani, B., Lacabanne, C., Thomazeau, A.,
Hopperton, K. E., Beccari, S., Sere, A., Aubert, A., De Smedt-Peyrusse, V., Lecours, C.,
Bisht, K., … Lay´
e, S. (2020). Essential omega-3 fatty acids tune microglial
phagocytosis of synaptic elements in the mouse developing brain. Nature
Communications, 11. https://doi.org/10.1038/s41467-020-19861-z
Mansour, M., van Ginkel, S., Dennis, J. C., Mason, B., Elhussin, I., Abbott, K.,
Pondugula, S. R., Samuel, T., & Morrison, E. (2018). The combination of omega-3
stearidonic acid and docetaxel enhances cell death over docetaxel alone in human
prostate cancer cells. Journal of Cancer, 9, 4536–4546. https://doi.org/10.7150/
jca.26681
Marangoni, F., Agostoni, C., Borghi, C., Catapano, A. L., Cena, H., Ghiselli, A., La
Vecchia, C., Lercker, G., Manzato, E., Pirillo, A., Riccardi, G., Ris´
e, P., Visioli, F., &
Poli, A. (2020). Dietary linoleic acid and human health: Focus on cardiovascular and
cardiometabolic effects. Atherosclerosis, 292, 90–98. https://doi.org/10.1016/j.
atherosclerosis.2019.11.018
Mardones, F., Urrutia, M. T., Villarroel, L., Rioseco, A., Castillo, O., Rozowski, J.,
Tapia, J. L., Bastias, G., Bacallao, J., & Rojas, I. (2008). Effects of a dairy product
fortied with multiple micronutrients and omega-3 fatty acids on birth weight and
gestation duration in pregnant Chilean women. Public Health Nutrition, 11, 30–40.
https://doi.org/10.1017/S1368980007000110
Mariamenatu, A. H., & Abdu, E. M. (2021). Overconsumption of omega-6
polyunsaturated fatty acids (PUFAs) versus deciency of omega-3 PUFAs in modern-
day diets: The disturbing factor for their “Balanced antagonistic metabolic functions”
in the human body. Journal Lipids, 1–15. https://doi.org/10.1155/2021/8848161,
2021.
Martins, A. J., Lorenzo, J. M., Franco, D., Pateiro, M., Domínguez, R., Munekata, P. E. S.,
Pastrana, L. M., Vicente, A. A., Cunha, R. L., & Cerqueira, M. A. (2020).
Characterization of enriched meat-based pˆ
at´
e manufactured with oleogels as fat
substitutes. Gels, 6, 1–14. https://doi.org/10.3390/gels6020017
Milne, G. L., Yin, H., Hardy, K. D., Davies, S. S., & Roberts, L. J. (2011). Isoprostane
generation and function. Chem. Rev., 111, 5973–5996. https://doi.org/10.1021/
cr200160h
Minj, J., & Dogra, S. (2020). Signicance of fortication of benecial natural ingredients
in milk and milk products. In Dairy processing: Advanced research to applications (pp.
87–118). Singapore: Springer Singapore. https://doi.org/10.1007/978-981-15-
2608-4_5.
Mocellin, M. C., Camargo, C. Q., Nunes, E. A., Fiates, G. M. R., & Trindade, E. B. S. M.
(2016). A systematic review and meta-analysis of the n-3 polyunsaturated fatty acids
effects on inammatory markers in colorectal cancer. Clinical Nutrition, 35, 359–369.
https://doi.org/10.1016/j.clnu.2015.04.013
Montuschi, P., Barnes, P. J., & Roberts, L. J. (2004). Isoprostanes: Markers and mediators
of oxidative stress. The FASEB Journal, 18, 1791–1800. https://doi.org/10.1096/
fj.04-2330rev
Mo, C., Wang, Z., Bonewald, L., & Brotto, M. (2019). Multi-staged regulation of lipid
signaling mediators during myogenesis by COX-1/2 pathways. International Journal
of Molecular Sciences, 20, 1–18. https://doi.org/10.3390/ijms20184326
Muzsik, A., Jele´
n, H. H., & Chmurzynska, A. (2020). Metabolic syndrome in
postmenopausal women is associated with lower erythrocyte PUFA/MUFA and n-3/
n-6 ratio: A case-control study. Prostaglandins Leukot Essential Fat Acids, 159. https://
doi.org/10.1016/j.plefa.2020.102155
Naeini, Z., Toupchian, O., Vatannejad, A., Sotoudeh, G., Teimouri, M., Ghorbani, M.,
Nasli-Esfahani, E., & Koohdani, F. (2020). Effects of DHA-enriched sh oil on gene
expression levels of p53 and NF-κB and PPAR-γ activity in PBMCs of patients with
T2DM: A randomized, double-blind, clinical trial. Nutrition, Metabolism, and
Cardiovascular Diseases, 30, 441–447. https://doi.org/10.1016/j.
numecd.2019.10.012
Nasir, M., & Bloch, M. H. (2019). Trim the fat: The role of omega-3 fatty acids in
psychopharmacology. Therapy Advanced Psychopharmacology, 9. https://doi.org/
10.1177/2045125319869791, 204512531986979.
Navarro Hortal, M. D., Bernal Moreno, C., & Varela L´
opez, A. (2018). Efecto de los
macronutrientes en modelos animales de enfermedad periodontal: Una revisi´
on
sistem´
atica. Ars Pharmaceutica, 59, 235–250. https://doi.org/10.30827/ars.
v59i4.7317
Nazir, S., & Azad, Z. (2018). Technological and quality parameters of reduced-calorie
chocolates: A review. Nutrafoods, 17, 33–40. https://doi.org/10.17470/NF-017-
1017-1
Neijat, M., Zacek, P., Picklo, M. J., & House, J. D. (2020). Lipidomic characterization of
omega-3 polyunsaturated fatty acids in phosphatidylcholine and
phosphatidylethanolamine species of egg yolk lipid derived from hens fed axseed
oil and marine algal biomass. Prostaglandins Leukot Essential Fat Acids, 161, Article
102178. https://doi.org/10.1016/j.plefa.2020.102178
Nelson, J. R., & Raskin, S. (2019). The eicosapentaenoic acid:arachidonic acid ratio and
its clinical utility in cardiovascular disease. Postgraduate Medical Journal, 131,
268–277. https://doi.org/10.1080/00325481.2019.1607414
Ng, J. C. M., & Schooling, C. M. (2020). Effect of glucagon on ischemic heart disease and
its risk factors: A mendelian randomization study. Journal of Clinical Endocrinology &
Metabolism, 105, 1–8. https://doi.org/10.1210/clinem/dgaa259
Nicolaou, A., Mauro, C., Urquhart, P., & Marelli-Berg, F. (2014). Polyunsaturated fatty
acid-derived lipid mediators and T cell function. Frontiers in Immunology, 5, 1–15.
https://doi.org/10.3389/mmu.2014.00075
Nindrea, R. D., Aryandono, T., Lazuardi, L., & Dwiprahasto, I. (2019). Association of
dietary intake ratio of n-3/n-6 polyunsaturated fatty acids with breast cancer risk in
Western and Asian countries: A meta-analysis. Asian Pacic Journal of Cancer
Prevention, 20, 1321–1327. https://doi.org/10.31557/APJCP.2019.20.5.1321
Nishizaki, Y., Shimada, K., Tani, S., Ogawa, T., Ando, J., Takahashi, M., Yamamoto, M.,
Shinozaki, T., Miyazaki, T., Miyauchi, K., Nagao, K., Hirayama, A., Yoshimura, M.,
Komuro, I., Nagai, R., & Daida, H. (2016). Association between the docosahexaenoic
acid to arachidonic acid ratio and acute coronary syndrome: A multicenter
observational study. BMC Cardiovascular Disorders, 16, 1–10. https://doi.org/
10.1186/s12872-016-0299-y
Nozue, T., Yamamoto, S., Tohyama, S., Fukui, K., Umezawa, S., Onishi, Y., Kunishima, T.,
Sato, A., Nozato, T., Miyake, S., Takeyama, Y., Morino, Y., Yamauchi, T.,
Muramatsu, T., Hibi, K., Terashima, M., & Michishita, I. (2013). Comparison of
effects of serum n-3 to n-6 polyunsaturated fatty acid ratios on coronary
atherosclerosis in patients treated with pitavastatin or pravastatin undergoing
percutaneous coronary intervention. The American Journal of Cardiology, 111,
1570–1575. https://doi.org/10.1016/j.amjcard.2013.01.327
Ochi, E., & Tsuchiya, Y. (2018). Eicosahexanoic acid (EPA) and docosahexanoic acid
(DHA) in muscle damage and function. Nutrients, 10, 1–13. https://doi.org/10.3390/
nu10050552
Pajor, F., Egerszegi, I., Sz˝
ucs, ´
A., P´
oti, P., & Bodn´
ar, ´
A. (2021). Effect of marine algae
supplementation on somatic cell count, prevalence of udder pathogens, and fatty
acid prole of dairy goats’ milk. Animals, 11, 1–13. https://doi.org/10.3390/
ani11041097
Pandule, V. S., Sharma, M., Devaraja, H. C., & Surendra Nath, B. (2021). Omega-3 fatty
acid-fortied butter: Preparation and characterisation of textural, sensory, thermal
and physico-chemical properties. International Journal Dairy Technology, 74,
181–191. https://doi.org/10.1111/1471-0307.12750
Pang, L., Shah, H., Xu, Y., & Qian, S. (2021). Delta-5-desaturase: A novel therapeutic
target for cancer management. Translational Oncology. https://doi.org/10.1016/j.
tranon.2021.101207
Patel, A., Karageorgou, D., Katapodis, P., Sharma, A., Rova, U., Christakopoulos, P., &
Matsakas, L. (2021). Bioprospecting of thraustochytrids for omega-3 fatty acids: A
sustainable approach to reduce dependency on animal sources. Trends in Food Science
& Technology, 115, 433–444. https://doi.org/10.1016/j.tifs.2021.06.044
Patel, A., Karageorgou, D., Rova, E., Katapodis, P., Rova, U., Christakopoulos, P., &
Matsakas, L. (2020). An overview of potential oleaginous microorganisms and their
role in biodiesel and omega-3 fatty acid-based industries. Microorganisms, 8. https://
doi.org/10.3390/microorganisms8030434
Patel, A., Matsakas, L., Rova, U., & Christakopoulos, P. (2018). Heterotrophic cultivation
of Auxenochlorella protothecoides using forest biomass as a feedstock for sustainable
biodiesel production. Biotechnology for Biofuels, 11, 169. https://doi.org/10.1186/
s13068-018-1173-1
Patel, A., Rova, U., Christakopoulos, P., & Matsakas, L. (2020). Introduction to essential
fatty acids. In A. Patel, & L. Matsakas (Eds.), Nutraceutical fatty acids from oleaginous
microalgae (pp. 1–22). https://doi.org/10.1002/9781119631729.ch1
Petit, H. V., & Cˆ
ortes, C. (2010). Milk production and composition, milk fatty acid prole,
and blood composition of dairy cows fed whole or ground axseed in the rst half of
lactation. Animal Feed Science and Technology, 158, 36–43. https://doi.org/10.1016/
j.anifeedsci.2010.03.013
Petit, H. V., Dewhurst, R. J., Scollan, N. D., Proulx, J. G., Khalid, M., Haresign, W.,
Twagiramungu, H., & Mann, G. E. (2002). Milk production and composition, ovarian
function, and prostaglandin secretion of dairy cows fed omega-3 fats. Journal of
Dairy Science, 85, 889–899. https://doi.org/10.3168/jds.S0022-0302(02)74147-7
Pinstrup-Andersen, P. (2013). Nutrition-sensitive food systems: From rhetoric to action.
Lancet, 382, 375–376. https://doi.org/10.1016/S0140-6736(13)61053-3
Poniedziałek, B., Perkowska, K., & Rzymski, P. (2020). Food fortication. In Vitamins and
minerals biofortication of edible plants (pp. 27–44). Wiley. https://doi.org/10.1002/
9781119511144.ch2.
Poorani, R., Bhatt, A. N., & Das, U. N. (2020). Modulation of pro-inammatory and pro-
resolution mediators by g-linolenic acid: An important element in radioprotection
against ionizing radiation. Archives of Medical Science, 16, 1448–1456. https://doi.
org/10.5114/AOMS.2020.92469
Prasad, P., Anjali, P., & Sreedhar, R. V. (2021). Plant-based stearidonic acid as
sustainable source of omega-3 fatty acid with functional outcomes on human health.
Critical Reviews in Food Science and Nutrition, 61, 1725–1737. https://doi.org/
10.1080/10408398.2020.1765137
Raeisi, S., Ojagh, S. M., Pourashouri, P., Salaün, F., & Quek, S. Y. (2021). Shelf-life and
quality of chicken nuggets fortied with encapsulated sh oil and garlic essential oil
during refrigerated storage. Journal of Food Science & Technology, 58, 121–128.
https://doi.org/10.1007/s13197-020-04521-3
Rahman, H., Anggadiredja, K., Gusdinar, T., Sitompul, J. P., & Tursino, T. (2020). Short
communication: Effects of Canarium indicum oil in enhancing brain-derived
neurotrophic factor in rats. Nusant Bioscience, 12, 168–174. https://doi.org/
10.13057/nusbiosci/n120213
A. Patel et al.
Trends in Food Science & Technology 120 (2022) 140–153
152
Rajasekaran, A., & Kalaivani, M. (2013). Designer foods and their benets: A review.
Journal of Food Science & Technology, 50, 1–16. https://doi.org/10.1007/s13197-
012-0726-8
Romeo, J., W¨
arnberg, J., García-M´
armol, E., Rodríguez-Rodríguez, M., Diaz, L. E.,
Gomez-Martínez, S., Cueto, B., L´
opez-Huertas, E., Cepero, M., Boza, J. J., Fonoll´
a, J.,
& Marcos, A. (2011). Daily consumption of milk enriched with sh oil, oleic acid,
minerals and vitamins reduces cell adhesion molecules in healthy children. Nutrition,
Metabolism, and Cardiovascular Diseases, 21, 113–120. https://doi.org/10.1016/j.
numecd.2009.08.007
Roy, S., Rawat, A. K., Sammi, S. R., Devi, U., Singh, M., Gautam, S., Yadav, R. K.,
Rawat, J. K., Singh, L., Ansari, M. N., Saeedan, A. S., Pandey, R., Kumar, D., &
Kaithwas, G. (2017). Alpha-linolenic acid stabilizes HIF-1
α
and downregulates
FASN to promote mitochondrial apoptosis for mammary gland chemoprevention.
Oncotarget, 8, 70049–70071. https://doi.org/10.18632/oncotarget.19551
Russo, G. L. (2009). Dietary n - 6 and n - 3 polyunsaturated fatty acids: From
biochemistry to clinical implications in cardiovascular prevention. Biochemical
Pharmacology, 77, 937–946. https://doi.org/10.1016/j.bcp.2008.10.020
Saeid, A. (2018). Food biofortication technologies. CRC Press Taylor & Francis Group.
Saini, R. K., & Keum, Y. S. (2018). Omega-3 and omega-6 polyunsaturated fatty acids:
Dietary sources, metabolism, and signicance — a review. Life Sciences, 203,
255–267. https://doi.org/10.1016/j.lfs.2018.04.049
Sathasivam, R., Radhakrishnan, R., Hashem, A., & Abd_Allah, E. F. (2019). Microalgae
metabolites: A rich source for food and medicine. Saudi Journal of Biological Sciences,
26, 709–722. https://doi.org/10.1016/j.sjbs.2017.11.003
Scanferlato, R., Bortolotti, M., Sansone, A., Chatgilialoglu, C., Polito, L., de Spirito, M.,
Maulucci, G., Bolognesi, A., & Ferreri, C. (2019). Hexadecenoic fatty acid positional
isomers and De Novo PUFA synthesis in colon cancer cells. International Journal of
Molecular Sciences, 20, 1–20. https://doi.org/10.3390/ijms20040832
Sergeant, S., Rahbar, E., & Chilton, F. H. (2016). Gamma-linolenic acid, dihommo-
gamma linolenic, eicosanoids and inammatory processes. European Journal of
Pharmacology, 785, 77–86. https://doi.org/10.1016/j.ejphar.2016.04.020
Serhan, C. N. (2007). Resolution phase of inammation: Novel endogenous anti-
inammatory and proresolving lipid mediators and pathways. Annual Review of
Immunology, 25, 101–137. https://doi.org/10.1146/annurev.
immunol.25.022106.141647
Serhan, C. N., & Chiang, N. (2013). Resolution phase lipid mediators of inammation:
Agonists of resolution. Current Opinion in Pharmacology, 13, 632–640. https://doi.
org/10.1016/j.coph.2013.05.012
Serna-Saldivar, S. O., Perez-Carrillo, E., & Heredia-Olea, E. (2019). Soybean-fortied
wheat our tortillas. In Flour and breads and their fortication in health and disease
prevention (2nd ed.). Elsevier Inc. https://doi.org/10.1016/B978-0-12-814639-
2.00023-X.
Shari-Rad, J., Rodrigues, C. F., Sharopov, F., Docea, A. O., Karaca, A. C., Shari-
Rad, M., Karincaoglu, D. K., Gülseren, G., S
¸enol, E., Demircan, E., Taheri, Y.,
Suleria, H. A. R., ¨
Ozçelik, B., Kasapo˘
glu, K. N., Gültekin-¨
Ozgüven, M., Das¸kaya-
Dikmen, C., Cho, W. C., Martins, N., & Calina, D. (2020). Diet, lifestyle and
cardiovascular diseases: Linking pathophysiology to cardioprotective effects of
natural bioactive compounds. International Journal of Environmental Research and
Public Health. https://doi.org/10.3390/ijerph17072326
Shetty, S. S., Kumari, N. S., & Shetty, P. K. (2020). Ω-6/Ω-3 fatty acid ratio as an essential
predictive biomarker in the management of type 2 diabetes mellitus. Nutrition,
79–80, Article 110968. https://doi.org/10.1016/j.nut.2020.110968
Shingeld, K. J., Ahvenj¨
arvi, S., Toivonen, V., ¨
Ar¨
ol¨
a, A., Nurmela, K. V. V., Huhtanen, P.,
& Griinari, J. M. (2003). Effect of dietary sh oil on biohydrogenation of fatty acids
and milk fatty acid content in cows. Animal Science, 77, 165–179. https://doi.org/
10.1017/s1357729800053765
Shrestha, N., Sleep, S. L., Cuffe, J. S. M., Holland, O. J., Perkins, A. V., Yau, S. Y.,
McAinch, A. J., & Hryciw, D. H. (2020). Role of omega-6 and omega-3 fatty acids in
fetal programming. Clinical and Experimental Pharmacology and Physiology, 47,
907–915. https://doi.org/10.1111/1440-1681.13244
Silva, J. R., Burger, B., Kühl, C. M. C., Candreva, T., dos Anjos, M. B. P., &
Rodrigues, H. G. (2018). Wound healing and omega-6 fatty acids: From
inammation to repair. Mediators of Inammation. https://doi.org/10.1155/2018/
2503950, 2018.
Simopoulos, A. P. (2016). An increase in the Omega-6/Omega-3 fatty acid ratio increases
the risk for obesity. Nutrients, 8, 1–17. https://doi.org/10.3390/nu8030128
Singh, B., Fedacko, J., Saboo, B., Niaz, M., Maheshwari, A., Verma, N., & Bharadwaj, K.
(2017). Association of higher omega-6/omega-3 fatty acids in the diet with higher
prevalence of metabolic syndrome in North India. MOJ Public Health, 6, 456–464.
https://doi.org/10.15406/mojph.2017.06.00193
Skulas-Ray, A. C., Wilson, P. W. F., Harris, W. S., Brinton, E. A., Kris-Etherton, P. M.,
Richter, C. K., Jacobson, T. A., Engler, M. B., Miller, M., Robinson, J. G., Blum, C. B.,
Rodriguez-Leyva, D., De Ferranti, S. D., & Welty, F. K. (2019). Omega-3 fatty acids
for the management of hypertriglyceridemia: A science advisory from the American
heart association. Circulation, 140, E673–E691. https://doi.org/10.1161/
CIR.0000000000000709
Song, W. L., Paschos, G., Fries, S., Reilly, M. P., Yu, Y., Rokach, J., Chang, C. T., Patel, P.,
Lawson, J. A., & FitzGerald, G. A. (2009). Novel eicosapentaenoic acid-derived F3-
isoprostanes as biomarkers of lipid peroxidation. Journal of Biological Chemistry, 284,
23636–23643. https://doi.org/10.1074/jbc.M109.024075
Sonnweber, T., Pizzini, A., Nairz, M., Weiss, G., & Tancevski, I. (2018). Arachidonic acid
metabolites in cardiovascular and metabolic diseases. International Journal of
Molecular Sciences, 19. https://doi.org/10.3390/ijms19113285
Spector, A. A., & Kim, H. Y. (2019). Emergence of omega-3 fatty acids in biomedical
research. Prostaglandins Leukot Essential Fat Acids, 140, 47–50. https://doi.org/
10.1016/j.plefa.2018.11.017
Stamenkovic, A., Ganguly, R., Aliani, M., Ravandi, A., & Pierce, G. N. (2019).
Overcoming the bitter taste of oils enriched in fatty acids to obtain their effects on
the heart in health and disease. Nutrients, 11. https://doi.org/10.3390/nu11051179
Sun, G. Y., Simonyi, A., Fritsche, K. L., Chuang, D. Y., Hannink, M., Gu, Z.,
Greenlief, C. M., Yao, J. K., Lee, J. C., & Beversdorf, D. Q. (2018). Docosahexaenoic
acid (DHA): An essential nutrient and a nutraceutical for brain health and diseases.
Prostaglandins Leukot Essential Fat Acids, 136, 3–13. https://doi.org/10.1016/j.
plefa.2017.03.006
Taglieri, I., Sanmartin, C., Venturi, F., Macaluso, M., Zinnai, A., Tavarini, S., Serra, A.,
Conte, G., Flamini, G., & Angelini, L. G. (2020). Effect of the leavening agent on the
compositional and sensorial characteristics of bread fortied with axseed cake.
Applied Sciences, 10. https://doi.org/10.3390/APP10155235
Tai, E. K. K., Wang, X. B., & Chen, Z. Y. (2013). An update on adding docosahexaenoic
acid (DHA) and arachidonic acid (AA) to baby formula. Food & Function, 4,
1767–1775. https://doi.org/10.1039/c3fo60298b
Takahashi, M., Ando, J., Shimada, K., Nishizaki, Y., Tani, S., Ogawa, T., Yamamoto, M.,
Nagao, K., Hirayama, A., Yoshimura, M., Daida, H., Nagai, R., & Komuro, I. (2017).
The ratio of serum n-3 to n-6 polyunsaturated fatty acids is associated with diabetes
mellitus in patients with prior myocardial infarction: A multicenter cross-sectional
study. BMC Cardiovascular Disorders, 17, 1–10. https://doi.org/10.1186/s12872-
017-0479-4
Tallima, H., & El Ridi, R. (2018). Arachidonic acid: Physiological roles and potential
health benets – a review. Journal of Advanced Research, 11, 33–41. https://doi.org/
10.1016/j.jare.2017.11.004
Tamm, F., Herbst, S., Brodkorb, A., & Drusch, S. (2016). Functional properties of pea
protein hydrolysates in emulsions and spray-dried microcapsules. Food Hydrocolloids,
58, 204–214. https://doi.org/10.1016/j.foodhyd.2016.02.032
Thomas Brenna, J. (2016). Arachidonic acid needed in infant formula when
docosahexaenoic acid is present. Nutrition Reviews, 74, 329–336. https://doi.org/
10.1093/nutrit/nuw007
Tokuda, H., Kontani, M., Kawashima, H., Akimoto, K., Kusumoto, A., Kiso, Y., Koga, Y., &
Shibata, H. (2014). Arachidonic Acid-enriched triacylglycerol improves cognitive
function in elderly with low serum levels of arachidonic acid. Journal of Oleo Science,
63, 219–227. https://doi.org/10.5650/jos.ess13195
Tokuda, H., Kontani, M., Kawashima, H., Kiso, Y., Shibata, H., & Osumi, N. (2014b).
Differential effect of arachidonic acid and docosahexaenoic acid on age-related
decreases in hippocampal neurogenesis. Neurosciences Research, 88, 58–66. https://
doi.org/10.1016/j.neures.2014.08.002
Toral, P. G., Herv´
as, G., Carre˜
no, D., Leskinen, H., Belenguer, A., Shingeld, K. J., &
Frutos, P. (2017). In vitro response to EPA, DPA, and DHA: Comparison of effects on
ruminal fermentation and biohydrogenation of 18-carbon fatty acids in cows and
ewes. Journal of Dairy Science, 100, 6187–6198. https://doi.org/10.3168/jds.2017-
12638
Torres-Castillo, N., Silva-G´
omez, J. A., Campos-Perez, W., Barron-Cabrera, E.,
Hernandez-Ca˜
naveral, I., Garcia-Cazarin, M., Marquez-Sandoval, Y., Gonzalez-
Becerra, K., Barron-Gallardo, C., & Martinez-Lopez, E. (2018). High dietary
ω
-6:
ω
-3
PUFA ratio is positively associated with excessive adiposity and waist circumference.
Obesity Facts, 11, 344–353. https://doi.org/10.1159/000492116
Toupchian, O., Sotoudeh, G., Mansoori, A., Nasli-Esfahani, E., Djalali, M.,
Keshavarz, S. A., & Koohdani, F. (2016). Effects of DHA-enriched sh oil on
monocyte/macrophage activation marker sCD163, asymmetric dimethyl arginine,
and insulin resistance in type 2 diabetic patients. Journal Clinical Lipidol, 10,
798–807. https://doi.org/10.1016/j.jacl.2016.02.013
Trebatick´
a, J., Duk´
at, A., ˇ
Duraˇ
ckov´
a, Z., & Muchov´
a, J. (2017). Cardiovascular diseases,
depression disorders and potential effects of omega-3 fatty acids. Physiological
Research, 66, 363–382. https://doi.org/10.33549/physiolres.933430
Trebatick´
a, J., Hradeˇ
cn´
a, Z., Surovcov´
a, A., Katrenˇ
cíkov´
a, B., Gushina, I.,
Waczulíkov´
a, I., Suˇ
sienkov´
a, K., Garaiova, I., ˇ
Suba, J., & ˇ
Duraˇ
ckov´
a, Z. (2020).
Omega-3 fatty-acids modulate symptoms of depressive disorder, serum levels of
omega-3 fatty acids and omega-6/omega-3 ratio in children. A randomized, double-
blind and controlled trial. Psychiatry Research, 287, Article 112911. https://doi.org/
10.1016/j.psychres.2020.112911
Trilaksani, W., Riyanto, B., & Syifa, A. L. (2020). Extraction and microencapsulation of
tuna virgin sh oil with mangrove fruit extract fortied into extrusion cereals. IOP
Conference Series: Earth and Environmental Science, 420. https://doi.org/10.1088/
1755-1315/420/1/012032
Tułowiecka, N., Kotlęga, D., Bohatyrewicz, A., & Szczuko, M. (2021). Could lipoxins
represent a new standard in ischemic stroke treatment? International Journal of
Molecular Sciences, 22. https://doi.org/10.3390/ijms22084207
Valencia, I., O’Grady, M. N., Ansorena, D., Astiasar´
an, I., & Kerry, J. P. (2008).
Enhancement of the nutritional status and quality of fresh pork sausages following
the addition of linseed oil, sh oil and natural antioxidants. Meat Science, 80,
1046–1054. https://doi.org/10.1016/j.meatsci.2008.04.024
Wang, X., Lin, H., & Gu, Y. (2012). Multiple roles of dihomo-γ-linolenic acid against
proliferation diseases. Lipids in Health and Disease, 11, 1–9. https://doi.org/10.1186/
1476-511X-11-25
Ward, O. P., & Singh, A. (2005). Omega-3/6 fatty acids: Alternative sources of
production. Process Biochemistry, 40, 3627–3652. https://doi.org/10.1016/j.
procbio.2005.02.020
Whelan, J., Gouffon, J., & Zhao, Y. (2012). Effects of dietary stearidonic acid on
biomarkers of lipid metabolism. Journal of Nutrition, 142, 2–6. https://doi.org/
10.3945/jn.111.149138
Winwood, R. J. (2013). Recent developments in the commercial production of DHA and
EPA rich oils from micro-algae. OCL - Oilseeds fats, Crop. https://doi.org/10.1051/
ocl/2013030. lipids 20.
A. Patel et al.
Trends in Food Science & Technology 120 (2022) 140–153
153
Wood, J. D., Richardson, R. I., Nute, G. R., Fisher, A. V., Campo, M. M., Kasapidou, E.,
Sheard, P. R., & Enser, M. (2004). Effects of fatty acids on meat quality: A review.
Meat Science, 66, 21–32. https://doi.org/10.1016/S0309-1740(03)00022-6
Woods, V. B., & Fearon, A. M. (2009). Dietary sources of unsaturated fatty acids for
animals and their transfer into meat, milk and eggs: A review. Livestock Science, 126,
1–20. https://doi.org/10.1016/j.livsci.2009.07.002
Yassine, H. N., Braskie, M. N., Mack, W. J., Castor, K. J., Fonteh, A. N., Schneider, L. S.,
Harrington, M. G., & Chui, H. C. (2017). Association of docosahexaenoic acid
supplementation with alzheimer disease stage in apolipoprotein e
ε
4 carriers: A
review. JAMA Neurology, 74, 339–347. https://doi.org/10.1001/
jamaneurol.2016.4899
Yeiser, M., Harris, C. L., Kirchoff, A. L., Patterson, A. C., Wampler, J. L., Zissman, E. N., &
Berseth, C. L. (2016). Growth and tolerance of infants fed formula with a new algal
source of docosahexaenoic acid: Double-blind, randomized, controlled trial.
Prostaglandins Leukot Essential Fat Acids, 115, 89–96. https://doi.org/10.1016/j.
plefa.2016.09.001
Zheng, B., & McClements, D. J. (2020). Formulation of more efcacious curcumin
delivery systems using colloid science: Enhanced solubility, stability, and
bioavailability. Molecules, 25, 1–25. https://doi.org/10.3390/molecules25122791
A. Patel et al.
