Omega-9 fatty acids: potential roles in inflammation and cancer management

Abstract

Background
Omega-9 fatty acids represent one of the main mono-unsaturated fatty acids (MUFA) found in plant and animal sources. They are synthesized endogenously in humans, though not fully compensating all body requirements. Consequently, they are considered as partially essential fatty acids. MUFA represent a healthier alternative to saturated animal fats and have several health benefits, including anti-inflammatory and anti-cancer characters.

The main body of the abstract
This review capitalizes on the major omega-9 pharmacological activities in context of inflammation management for its different natural forms in different dietary sources. The observed anti-inflammatory effects reported for oleic acid (OA), mead acid, and erucic acid were directed to attenuate inflammation in several physiological and pathological conditions such as wound healing and eye inflammation by altering the production of inflammatory mediators, modulating neutrophils infiltration, and altering VEGF effector pathway. OA action mechanisms as anti-tumor agent in different cancer types are compiled for the first time based on its anti- and pro-carcinogenic actions.

Conclusion
We conclude that several pathways are likely to explain the anti-proliferative activity of OA including suppression of migration and proliferation of breast cancer cells, as well stimulation of tumor suppressor genes. Such action mechanisms warrant for further supportive clinical and epidemiological studies to confirm the beneficial outcomes of omega-9 consumption especially over long-term intervention.

Full text

Faragand Gad
Journal of Genetic Engineering and Biotechnology (2022) 20:48
https://doi.org/10.1186/s43141-022-00329-0
REVIEW
Omega-9 fatty acids: potential roles
ininammation andcancer management
Mohamed A. Farag1* and Mohamed Z. Gad2
Abstract
Background: Omega-9 fatty acids represent one of the main mono-unsaturated fatty acids (MUFA) found in plant
and animal sources. They are synthesized endogenously in humans, though not fully compensating all body require-
ments. Consequently, they are considered as partially essential fatty acids. MUFA represent a healthier alternative to
saturated animal fats and have several health benefits, including anti-inflammatory and anti-cancer characters.
The main body of the abstract: This review capitalizes on the major omega-9 pharmacological activities in context
of inflammation management for its different natural forms in different dietary sources. The observed anti-inflamma-
tory effects reported for oleic acid (OA), mead acid, and erucic acid were directed to attenuate inflammation in several
physiological and pathological conditions such as wound healing and eye inflammation by altering the production of
inflammatory mediators, modulating neutrophils infiltration, and altering VEGF effector pathway. OA action mecha-
nisms as anti-tumor agent in different cancer types are compiled for the first time based on its anti- and pro-carcino-
genic actions.
Conclusion: We conclude that several pathways are likely to explain the anti-proliferative activity of OA including
suppression of migration and proliferation of breast cancer cells, as well stimulation of tumor suppressor genes. Such
action mechanisms warrant for further supportive clinical and epidemiological studies to confirm the beneficial out-
comes of omega-9 consumption especially over long-term intervention.
Keywords: MUFA, PUFA, Omega-9, Inflammation; anti-cancer; oleic acid
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Background
Omega-3, -6, and -9 fatty acids (FAs) are unsaturated
fatty acids which impose several biological effects and
health benefits. e three omega FAs are generally pre-
sent in several vegetable oils and in pharmaceutical
formulations [1]. Omega-3 and omega-6 FAs are well
characterized regarding their benefits to human health
[2]. However, omega-9 FAs have recently received wide
attention due to emerging studies and discoveries regard-
ing their biological benefits and or risks.
Omega-9 FAs (ω−9 FAs or n−9 FAs) are group of
unsaturated FAs that have a double bond in the 9th
position from the methyl end. ey are either mono-
unsaturated or polyunsaturated. Unlike the 3s and 6s,
Omega-9 FAs, they are considered “non-essential” FAs
[3].
e most common omega-9 FAs are hypogeic acid
(16:1 (n-9), (Z)-hexadec-7-enoic acid), oleic acid (18:1
(n-9), (Z)-octadec-9-enoic acid), elaidic acid (18:1 (n-9),
(E,)-octadec-9-enoic acid), gondoic acid (20:1 (n-9), (Z)-
eicos-11-enoic acid), mead acid (20:3 (n-9), (5Z,8Z,11Z)-
eicosa-5,8,11-trienoic acid), erucic acid (22:1 (n−9),
(Z)-docos-13-enoic acid), nervonic acid (24:1 (n−9), (Z)-
tetracos-15-enoic acid) (Fig. 1) [3]. Oleic acid received
the most attention in research (23,588 citations in Pub-
Med) as compared to hypogeic acid (5 results in Pub-
Med), elaidic acid (516 results in PubMed), gondoic acid
(34 results in PubMed), mead acid (145 results in Pub-
Med), erucic acid (699 results in PubMed), and nervonic
Open Access
Journal of Genetic Engineering
and Biotechnology
*Correspondence: mfarag73@yahoo.com
1 Pharmacognosy Department, College of Pharmacy, Cairo University,
Kasr El Aini St., P.B, Cairo 11562, Egypt
Full list of author information is available at the end of the article

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Faragand Gad Journal of Genetic Engineering and Biotechnology (2022) 20:48
acid (204 results in PubMed) as searched in April 2021.
Oleic acid is the most abundant in many vegetable oils
as compared to other omega-9 fatty acids. It represents
40.7% of sesame oil, 17.5% of flaxseed oil, 74.8% of olive
oil, 58.8% of rapeseed oil, and 32.7% of pumpkin seed oil.
In general, foods rich in omega-9 FAs include safflower,
sunflower, macadamia nut, hazelnut, olive oil, soybean
oil, almond butter, avocado oil, and canola oil [4]. Differ-
ent omega-9 FAs possess diverse pharmacological actions
including modulating inflammatory, lipid, cardiovascular
(CV) and cancer disorders. is review presents most
updated literature on two of the major effects of omega-9
including anti-inflammatory and anti-cancer effects.
Main text
Anti‑inammatory andanti‑cancer actions ofomega‑9
fatty acids
Oleic acid (OA)
In healthy people, OA is the most abundant FA, found in
adipocytes, cell membranes, and plasma [5]. Various ani-
mal and plant sources including olive oil, cod oil, corn oil,
and palm oil are rich in OA. It has drawn much attention
recently due to the widespread use of the Mediterranean
food that is wealthy in olive oil, one of the best source of
OA among dietary sources [6]. Also, OA is present endog-
enously as a component of hormones production and
cellular membranes [7]. OA is considered a healthier alter-
native to saturated animal fats and to possess several ther-
apeutic effects. Additionally, OA is used in pharmaceutical
industry as a solubilizing agent or emulsifier [8, 9].
Anti‑inammatory actions
OA-rich diet has positive outcomes in inflammatory-
related disorders. It modulates immune system by
activation of various immune competent cell pathways
[10]. However, controversial data exist in literature
regarding its biological value in different cellular func-
tions. Here are some positive studies that show the anti-
inflammatory actions of OA in several organs systems.
Eye inammation
OA possesses an anti-inflammatory effect against hyper-
lipidemia-induced retinal inflammation in male Wistar
rats. High OA diet (17.5% olive oil rich diet) adminis-
tered for 90 days lowered the levels of the proinflamma-
tory serum and retinal cytokines like IL-1-β, TNF-α and
MCP-1. It also decreased the expression of serum C reac-
tive protein (CRP), serum pro-inflammatory eicosanoids
(LTC4, LTB4, and PGE2), and retinal expression of BLT-1,
EP-4, EP-1, and COX-2 compared to control rats fed with
7.0% lard rich diet [10, 11]. It has been demonstrated that
OA have possible therapeutic benefits in enhancing both
hydrophilic and lipophilic compound ocular drug deliv-
ery [12]. Moreover, several studies have indicated that
lipid-based lubricants can help relieve some symptoms
of dry eye [13]. us, we believe, due to its inflammatory
actions, enhancing drug delivery and improving dry eye
effects, OA addition to topical ophthalmic preparations is
worth to be extensively studied in certain eye disorders.
Skin inammation
OA was shown to alleviate skin inflammation by altering
neutrophils’ role in immunity; however, binding to albu-
min diminishes its anti-inflammatory activity. A study
investigated the effect of incorporation of OA within
nano-structured lipid carriers (OA-NLC) in improv-
ing the anti-inflammatory actions. Results showed that
in the presence of albumin, the OA-NLC, in contrast
Fig. 1 Common omega-9 fatty acids and their natural sources in plant and animals

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Faragand Gad Journal of Genetic Engineering and Biotechnology (2022) 20:48
to unconjugated free OA, aborted elastase release and
superoxide generation, and suggestive for the improved
nano-formulation impact on OA anti-inflammatory
effect that has yet to be reported for other functions.
Topical application of OA-NLC as an ointment alleviated
neutrophil infiltration and relieved skin inflammation
severity [7, 14]. Whether such disease improvement is
correlated with increased OA levels inside the skin tissue
should be determined to be more conclusive.
Additionally, OA plays a crucial role in wound heal-
ing by inducing rapid wound closure which is essential
to prevent superimposing infections and delayed heal-
ing. Cutaneous application of OA on wounds in Wistar
rats resulted in accelerated proliferative stage, regen-
eration of epithelial cells, and proper collagen and
keratin formation. In addition, neovascularization was
enhanced in the initial inflammatory phase because
of an increase in vascular endothelial growth factor
(VEGF) expression, which exhibits an essential func-
tion in the angiogenesis process [15]. Another report
by Rodrigues etal. indicated that OA enhances NF-κB
and TNF-α secretion after 1 h of wound formation in
rats. However, a decrease in IL-6, IL-1, and MIP-3α
levels, and NF-κB release, was observed 24 h after
wounding suggesting that OA hastens wound healing’s
inflammatory processes [14].
Further studies on the anti-inflammatory action of OA
in skin included a study by [16]. e study determined
the potential of OA to act as an alternative to corticoster-
oids for the treatment of UV-induced skin inflammation.
OA was added to semisolid preparations based on Lan-
ette® or Pemulen® TR2. Both formulations reduced ear
edema in mice after repeated treatments at 24, 48, and
72 h after UVB exposure. e anti-inflammatory prop-
erty appeared to be mediated by glucocorticoid recep-
tors. e authors suggested the use of OA as a promising
alternative to glucocorticoids given that OA is safe and
not photosensitive even at relatively high dose (13%) [16].
Figure2 summarizes the postulated effects of OA on skin
inflammation.
Lung inammation
Pneumonitis is a general term that refers to lung tissue
inflammation. Physicians commonly use the term pneu-
monitis to refer to noninfectious causes of lung inflam-
mation. Lung inflammation may be acute or chronic,
and there are a variety of causes, including environmen-
tal factors, infections, and diseases such as asthma and
bronchitis [17]. Lung damage caused by OA is a common
used model that closely resembles human disease [18].
However, OA has been found to possess anti-inflamma-
tory activities towards activated neutrophils. OA-based
Fig. 2 Summary of the action mechanisms of oleic acid (OA) in modulating skin inflammation and wound healing effects

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Faragand Gad Journal of Genetic Engineering and Biotechnology (2022) 20:48
nanosystems mitigated against acute respiratory distress
syndrome in mice via the suppression of neutrophils [19].
Liver inammation
When a disease-causing microbe or drug attacks liver
cells, liver inflammation occurs. e term hepatitis refers
to liver inflammation. Hepatitis is mainly caused by a
viral infection, but it may also be caused by an autoim-
mune disorder. Alcohol, toxins, and some medications
can also cause liver damage, which can lead to inflam-
mation. Hepatitis may also be caused by hereditary dis-
orders, as well as a chronic obstruction of bile flow. e
type of hepatitis determines the severity, treatment,
and outcome of the liver inflammation. Fibrosis, cirrho-
sis, and hepatocellular carcinoma may all be caused by
chronic liver inflammation [20].
Extra virgin olive oil, rich in OA, can help prevent
inflammation, mitochondrial dysfunction, insulin resist-
ance, endoplasmic reticulum (ER) stress, and oxidative
stress by activating various signaling pathways in hepatic
parenchymal cells. e following are the most impor-
tant pathways that lead to the resolution or prevention of
liver injury: (1) induction of the nuclear factor erythroid
2-related factor 2 (Nfr2), leading to antioxidant signals;
(2) suppression of (NF-κB), which prevents the cellular
inflammation response; and (3) suppression of the PERK
signaling pathway that results in prevention of autophagy,
ER stress, and lipogenic response [21]. OA also reduces
hepatocellular lipotoxicity caused by palmitic acid by
inhibiting pyroptosis and ER stress [22].
Sepsis
Sepsis is a potentially fatal disease, which occurs when
the body’s immune system starts to attack its own tis-
sues in response to an infection. Septic shock may
develop from sepsis. This dangerously low blood pres-
sure can lead to organ failure and death. While any
infection—viral, bacterial, or fungal—may cause sep-
sis, infections of the lungs, urinary tract and digestive
systems, blood (bacteremia), and skin (catheter sites,
burns or wounds) are the most common causes [23].
In a study by Medeiros-de-Moraes etal., mice devel-
oped sepsis using cecal ligation and puncture (CLP)
model and upon treatment for 14 days with omega-9
elevated levels of the anti-inflammatory IL-10 con-
current with reduction of proinflammatory IL-1β and
TNF-α levels in fluid of septic animals. Furthermore,
omega-9 intake reduced systemic levels of corticos-
terone. According to the authors, omega-9 can play a
positive anti-inflammatory role in sepsis by reducing
leukocyte influx and rolling, neutralizing cytokine out-
put, and regulating bacterial growth through a PPAR-γ
signaling pathway [24].
In another study, OA pretreatment for 14 days
improved longevity, prevented kidney and liver damage,
and reduced plasma levels of NEFA in mice exposed to
CLP sepsis model. OA intake also decreased reactive oxy-
gen species (ROS) and increased 5’ AMP-activated pro-
tein kinase (AMPK), carnitine palmitoyltransferase IA
(CPT1A), and uncoupling protein 2 (UCP2) levels [25].
Ulcerative colitis andintestinal inammation
Ulcerative colitis (UC) is an inflammatory bowel disor-
der that causes ulcers and inflammation in the gastroin-
testinal tract. UC occurs when the colon or/and rectum
lining becomes inflamed. Genetic predisposition, dys-
regulated immune responses, defects in epithelial bar-
rier, and environmental factors all contribute in the
pathogenesis of that disease. Despite the fact that there
is no cure, medication can significantly reduce signs
and symptoms of the disease and can lead to long-term
remission [26].
In a trial to reduce the burden of meat products diet
in cases of ulcerative colitis, Fernández etal. fed experi-
mentally induced UC rats with acorn-fed ham rich in
OA. e gut microbiota was altered because of the
diet, with significant increase in bacterial genera hav-
ing anti-inflammatory properties (Alistipes, Blautia,
Dorea, Parabacteroides). It also had a powerful anti-
inflammatory effect, which helped to avoid UC symp-
toms including macroscopic score of colitis, disease
activity index, density of inflammatory cell in colon,
epithelium alteration in colon mucosa, proinflamma-
tory IFN-γ and IL-17 levels, and myeloperoxidase titers
in colon as compared to rats fed conventional vegeta-
ble diet [27]. In another report, Cariello etal. examined
whether extra-virgin olive oil (EVO) intake is able to
exert a prophylactic role in a dextran sodium sulfate
(DSS) colitis-mediated animal model. Results revealed
that EVO administration reduced the rectal bleeding,
loss in body weight, and TGFβ, IL-1β, and IL-6 levels.
It also reduced intestinal permeability and inflamma-
tion-related histopathological features [28]. A summary
of OA anti-inflammatory actions in different organs is
depicted in Fig.3.
Insulin resistance (IR) andtype 2 diabetes mellitus (T2DM)
Among the main factors involved in the development
and activation of IR and T2DM is mitochondrial dys-
function that may lead to inefficient fatty acid oxida-
tion (FAO). OA enhanced FAO genes expression by
PGC1α deacetylation through PKA-dependent stimula-
tions of SIRT1-PGC1α complex. e anti-inflammatory
actions of OA also included lowering the expression of
the inflammatory mediators; E-selectin and sICAM,

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Faragand Gad Journal of Genetic Engineering and Biotechnology (2022) 20:48
upregulating free fatty acid receptor-4 (FFAR4), pro-
moting M2 expression, decreasing phosphate and
tensin homolog (PTEN), increasing adiponectin, and
downregulating protein phosphatase 2A (PP2A). OA
also controlled IR and T2DM by improving β cell func-
tion and endothelial functions, oxidative stress, hypo-
thalamic function, glucolipotoxicity, apoptosis, and
dysregulation of enzymes [29]. Whether administration
of OA with anti-diabetic agents like metformin could
lead to a synergized action has yet to be determined.
Anti‑cancer actions
OA has been shown in numerous reports to inhibit cellu-
lar proliferation in several tumor cell lines. OA inhibited
HER2 overexpression, a well-known oncogene involved
in the development, and metastasis of numerous human
cancers. In carcinoma cells, OA also plays a signifi-
cant role in the intracellular calcium signaling pathways
related to apoptosis and growth induction. e mecha-
nisms underlying the apoptotic event caused by OA are
linked to the rise in intracellular caspase 3 activity and
the development of ROS [30].
OA downregulated cancer activity of human esopha-
geal cells (HEC) through several mechanisms includ-
ing suppressing cell proliferation, and cellular migration
and adhesive properties as mediated via activating tumor
suppressor genes (p27, p21 and p53). Although OA
treatment of HEC did not influence the number of colo-
nies, it inhibited the colony size remarkably. Further, OA
is recognized for its anti-proliferative effect in other types
of cancer including colorectal cancer, where OA induced
apoptosis as well as breast cancer by regulating HER2
gene expression [6]. Nevertheless, more studies using
in vivo animal grafted models should be performed to
confirm OA anti-tumor actions.
Jiang et al. explored OA anti-cancer properties and
mechanisms in tongue squamous cell carcinoma (TSCC).
Results revealed that OA efficiently suppressed prolif-
eration of TSCC cells. It markedly promoted cell cycle
G0/G1 arrest, decreased Bcl-2 and Cyclin D1 expres-
sion, and elevated the proportion of apoptotic cells, con-
current with increased p53 expression and caspase-3
cleavage. OA also caused autolysosome formation and
decreased p62 expression as well as LC3 I/LC3 II ratio.
Furthermore, post-OA therapy, expression of p-mTOR,
p-Akt, p-4E-BP1, p-S6K, and p-ERK1/2, was dramati-
cally reduced in TSCC cells. It was concluded from the
study that OA possessed an anti-cancer activity in TSCC
through enhancing autophagy and apoptosis via inhibit-
ing the Akt/mTOR signaling pathway [31].
Proteins such as α-lactalbumin and lactoferrins are
among the other macromolecules with which OA inter-
acts and mediates its anti-cancer properties. In patients
with advanced cancer, a combination of OA and Gc
Fig. 3 Oleic acid (OA) anti-inflammatory action mechanisms in the different body organs viz. eye, skin, lung, liver, blood vessels, and intestine

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Faragand Gad Journal of Genetic Engineering and Biotechnology (2022) 20:48
protein-derived macrophage activating factor (GcMAF)
was shown to have significant influence on immune sys-
tem activation and decrease of tumor mass [32]. e
release of nitric oxide is linked to the GcMAF stimulat-
ing effects on macrophages. Furthermore, OA increased
the efficacy of cancer drugs in a synergistic manner.
For instance, OA increased the potency of Herceptin, a
breast cancer drug that targets the HER-2/neu gene [33].
In addition, n-butyl and phenyl derivatives of OA exhib-
ited great growth inhibitory activity in human HT-29
colon and MCF-7 breast cell lines [34]. Synthesis of other
OA analogues could help identify even more active anti-
tumor agents based on OA using either in silico drug
modelling or combinatorial chemistry.
A summary of OA anti-cancer effects and action mech-
anisms in different cancer types is depicted in Fig.4.
Elaidic acid (EA)
Elaidic acid, trans-isomer of oleic acid, has received
recently wide consideration being a common trans-fat,
which has been linked to heart disease. EA occurs natu-
rally in bovine and caprine milk (around 0.1% of the FAs)
[35], some meats, in addition to plant sources such as
durian fruits.
Studies in human have found a connection between the
usage of industrial trans-fatty acids (TFAs), such as EA,
and the incidence of cardiovascular diseases, prompting
many countries to pass legislation prohibiting the use of
industrial TFAs in food. However, TFA cannot be totally
removed from human food because they are naturally
found in dairy and meat derived from ruminant animals
[35].
Da Silva etal. assessed the anti-inflammatory proper-
ties of several TFAs, including EA in several cell lines
including (HUVEC) and (HepG2) cells for 24 h at con-
centrations ranging from 5-150 μM. Stearoyl-CoA
desaturase (SCD-1), a main enzyme in FAs biosynthesis,
expression increased after EA was added. EA additionally
decreased expression of inflammatory genes in HUVEC
cells, but not HepG2 cells [36], suggestive for a selective
effect against cancer cell lines.
In general, administration of TFA, including EA, rep-
resents health hazards in many studies. Wang et al.
reported that higher circulating EA is connected with
increased long-term morbidity and mortality in the gen-
eral population [17]. Li etal. presented same conclusion,
reporting that plasma EA levels are linked to an elevated
risk of CVD mortality [37].
EA also induced cholesterogenesis in Hepa1-6
hepatoma cells invitro by activating the sterol regula-
tory element-binding protein (SREBP) cleavage-activat-
ing protein (SCAP), mostly by reducing intracellular free
cholesterol and cholesterol-dependent SCAP repression.
e increase in liver cholesterol and non-alcoholic fatty
liver disease (NAFLD) caused by industrial TFA may be
attributed to this pathway. In contrast to cis-unsaturated
Fig. 4 Summary of oleic acid (OA) action mechanisms as anti-tumor agent in different cancer types

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Faragand Gad Journal of Genetic Engineering and Biotechnology (2022) 20:48
and saturated diets, EA increased liver/gonadal fat mass
ratio, hepatic cholesterol content, alanine aminotrans-
ferase activity, steatosis, and markers of fibrosis in mice,
implying increased NAFLD [38]. is provided further
evidence that industrial TFA can cause liver damage, pri-
marily by initiating fatty liver that develop into fibrosis.
In contrast to cis-unsaturated fatty acids, the cancer-
promoting properties of TFAs have been well docu-
mented. Kishi etal. investigated EA’s effects and signaling
in cells of colorectal cancer (CRC). Oral consumption
of EA to mice increased the metastasis of HT29 human
CRC cells, which were inserted into the mice scapu-
lar subcutaneous tissue. EA was incorporated into the
plasma membrane’s cholesterol rafts that embraced epi-
dermal growth factor receptors (EGFR). In HT29 cells,
EA elevated nanog and c-myc levels, while decreasing
PGC-1A levels via lipid raft-linked EGFR signaling [39].
Ohmori etal. also demonstrated the enhancement of sur-
vival, growth, and invasion of the colorectal cancer cell
lines, HT29, and CT26 by EA [40].
Other negative effect of EA included its neurotoxic-
ity. Following treatment of SH-SY5Y neuroblastoma
cells with various levels of EA (10, 20, 50, 100, 200,
400, and 800 μM) for 24 h at 37 oC, suppression of cell
viability, elevation of cell apoptosis, and loss of mito-
chondrial membrane potential (MMP) were observed.
Furthermore, EA caused significant changes in cellular
redox status. Higher doses of EA (200, 400, or 800 μM)
increased the production of ROS, including lipid perox-
ide and malondialdehyde levels, upregulated Nrf-2, and
downregulated heme oxygenase 1 (HO-1), two primary
anti-oxidative players. ese results inferred that EA sup-
pressed SH SY5Y cell growth and enhanced apoptosis by
increasing oxidative stress and triggering the ER stress/
UPR signaling pathway as well as the GRP78/ATF4/
CHOP pathway [41]. Whether examined doses of elaidic
acid in these studies are comparable to its level in natural
resources should be made to be more conclusive for these
effects.
Gondoic acid (GA)
GA, cis-11-Eicosenoic acid, is found in a variety of plant
oils and nuts; in particular jojoba oil [42]. It is also found
in red cell membrane with upsurge levels in children with
regressive autism. No studies were found regarding the
health effects of this particular omega-9 fatty acid and
warranting for future work to verify its health benefits or
toxicity.
Mead acid (MA)
Mead acid is formed de novo in animals derived from
OA. Its elevated level in blood is indicative of “essential”
fatty acid (EFA)deficiency[43]. MA’s functions in normal
physiological conditions had not been thoroughly stud-
ied. Increased metabolism of oleic acid to MA occurs
in the absence of adequate α-linolenic acid and linoleic
acid [44]. MA levels in chicken and human infant carti-
lage have long been recognized to be high, even in the
absence of EFA deficiency. It was proposed that MA pre-
vents cartilage calcification, and also to occur in avascu-
lar tissues like the cornea and lens [45].
With regard to the anti-inflammatory features of MA,
Yoshida et al. investigated the impact of MA-enriched
diet on experimentally induced bowel lesions. Rats
were given either an MA-enriched or a standard diet.
Acute bowel lesions were induced, after 7 days of feed-
ing, by injecting 10 mg/kg indomethacin subcutaneously.
Results indicated that dietary supplementation of MA
(5% M. alpine oil-enriched diet; M. alpine oil contains
17% MA) had both therapeutic and prophylactic actions
on experimentally induced bowel lesions [46]. In a dif-
ferent aspect, simultaneous addition of MA as adjunct
treatment with aggregating agents to platelets enhanced
platelets’ response [47].
Concerning the anti-cancer properties of MA,
Kinoshita etal. explored the impact of MA on the pro-
duction and proliferation of N-methyl-N-nitrosourea
(MNU)-induced mammary carcinoma in rats. All
mammary tumors were found to be luminal A carci-
noma. e MA-containing diet dramatically inhibited
the development and progression of mammary car-
cinogenesis via the suppression of cell proliferation
[48]. MA also inhibited the growth of KPL-1 human
breast carcinoma both invivo and invitro, but had no
effect on angiogenesis. VEGF signaling to tumor cells
was one of the proposed mechanisms of action [49].
Furthermore, MA inhibited some pro-cancerous prop-
erties in three different human cell lines: MCF-7 from
breast, T-24 from urothelium, and HRT-18 from colon
(Heyd and Eynard, 2003).
Erucic acid
Erucic acid is mostly abundant in Brassica seeds (Eruca
sativa), known asarugula(USA) or rocket (UK), in addi-
tion to Indian mustard (Brassica juncea) and rapeseed
(Brassica napus) [50].
Erucic acid is a PPAR-δ ligand, found to lead to
improved cognitive parameters in animal models through
its anti-oxidative and anti-inflammatory actions [51]. It
may also act as a neuroprotective, anti-tumor, and myelin
protective agent in Parkinson’s disease, glioblastoma, and
neuroblastoma [52]. Its remyelinating property might
also be valuable in the management of multiple sclerosis
[52]. e suppression of p38 MAPK and NF-B signaling
are thought to be the molecular mechanisms through

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Faragand Gad Journal of Genetic Engineering and Biotechnology (2022) 20:48
which erucic acid exerts its anti-inflammatory properties
(Liang etal. 2020) [53].
Regarding the anti-tumor effect, erucic acid is pre-
sent abundantly in the Chinese diet and suggestive that
the low brain cancer frequency in children among the
Chinese population is credited to high content of erucic
acid in Chinese women breast milk [54]. Erucic acid is
believed to possess an anti-tumor activity especially in
C6 glioblastoma, where erucic acid suppressed cellular
proliferation by blocking synthesis of DNA (arresting
the cell cycle at S-phase) as well as direct cellular inter-
action [51]. e anti-proliferative action of erucic acid
on the glioblastoma cells is related to its agonistic effect
on peroxisome proliferator-activated receptors (PPARs).
Additionally, co-administration of erucic acid with doxo-
rubicin alleviated the cardio toxic and hepatotoxic effects
of doxorubicin and with doxorubicin better tolerated
with enhanced anti-cancer effect [55]. Nevertheless,
erucic acid has been shown to induce myocardial lipi-
dosis, hepatic steatosis, and cardiac lesions in animals.
ese effects limit its inclusion in edible oils by regula-
tory agencies [56] and reduce its clinical applications.
Nervonic acid (NA)
NA is (Z)-15-tetracosenoic acid, 24:1 (n9) occurs natu-
rally as an extension product of oleic acid, with erucic
acid as the immediate precursor. NA is abundant in
peripheral nervous tissue and in the animal brains white
matter, where nervonyl sphingolipids are abundant in
nerve fiber myelin sheath [52]. NA has received much
attention owing to its close association with brain devel-
opment. NA levels of human brain sphingolipids rise dra-
matically from birth to a peak at 4 years, and to remain
constant afterwards [57]. Natural resources of NA
include oil crop seeds especially seed oils of Lunaria spe-
cies and oil-producing microalgae [58]. NA is required
for the formation of brain myelin and can be used as a
marker of brain maturity. Infants’ neurodevelopment can
be aided by formula feeding, and customers and produc-
ers may benefit from a healthier alternative to milk pow-
der. However, the contradictory findings regarding NA
contents of patients with psychosis, depressive disorders,
Alzheimer’s disease, and cardiovascular disease warrant
further study.
In a study by Lewkowicz etal. on lipids profiling in
an induced model of brain autoimmune encephalo-
myelitis, it was shown that during acute inflamma-
tion, NA biosynthesis was downregulated as a result of
shifting lipids metabolism pathways of common sub-
strates into pro-inflammatory arachidonic acid forma-
tion [59]. NA has been shown to alleviate Parkinson’s
disease-related tremors and multiple sclerosis-related
numbness. It can also be used to treat schizophrenia
and to alleviate the symptoms of Alzheimer’s disease
in the early stages [58].
Hypogeic acid (HA)
Hypogeic acid is found in human milk. Very few studies
involving HA biological effects have been found in the lit-
erature. In one study by Astudillo etal., the anti-inflam-
matory properties of hypogeic acid along with palmitoleic
acid were investigated. e majority of hexadecenoic
fatty acids were esterified in a specific pattern, palmitic
acid at sn-1 location and hexadecenoic acid at sn-2 as
revealed in mouse peritoneal macrophages. When mac-
rophages are stimulated with inflammatory stimuli, this
species decreases dramatically. Although the majority of
the released hexadecenoic acid appeared as a free FA, a
large portion is moved to other phospholipids to con-
struct hexadecenoic acid-containing inositol phospholip-
ids that are further recruited to yield fatty acid esters of
possible anti-inflammatory properties [60]. e findings
suggest that conversion of these fatty acids to other lipid
mediators can account for some of their anti-inflamma-
tory activity. HA has been proposed as a potential marker
for the development of foamy cells in atherosclerosis, but
whether such marker is a reactive homeostasis response
or indicative of disease progression should be clarified.
Conclusions
Omega-9 fatty acids exhibit essential myriad of pharma-
cological activities that pose them as potential candidate
to alleviate many pathological conditions. e observed
anti-inflammatory effects reported for oleic acid, mead
acid, and erucic acid were directed to attenuate inflam-
mation in several physiological and pathological condi-
tions such as wound healing and eye inflammation by
altering the production of inflammatory mediators, mod-
ulating neutrophils infiltration, and altering VEGF effec-
tor pathway.
e anti-neoplastic action of omega-9 fatty acids
is though controversial compared to its anti-inflam-
matory actions, with the effect varies with the type of
cancerous tissue and the effector pathway. Most docu-
mented anti-neoplastic action of omega-9 is evidenced
in case of olive oil-rich diets. ese diets enriched in
oleic acid content are believed to possess chemo pre-
ventive effect against breast cancer. Oleic acid anti-
tumor action is mediated via multiple mechanisms
including suppression of proliferation and migration
and breast cancer cells, as well activation of tumor sup-
pressor genes.
On the other hand, several pathways are believed to
explain the proliferative activity of OA. In MCF-7 and
MDA-MB-231 breast carcinoma lines, OA enhanced

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Faragand Gad Journal of Genetic Engineering and Biotechnology (2022) 20:48
metastasis and cellular proliferation through activation of
free fatty acid receptor 1 (FFAR1) and FFAR4 receptors
that are activated by medium-chain FAs like OA. Such
receptors are also present on the surface of other cells
such as insulin secreting in pancreatic β cells and adipose
tissue, and upon activation, they alter the intracellular
Ca2+ concentration. In addition, OA activates AKT path-
way (protein kinase B) where AKT2 induces production
of Integrin B that facilitates invasion along with AKT-1
activation that promotes cell migration as well along with
epidermal growth factor receptor (EGFR) OA-dependent
activation [61].
In general, reports on the anti-inflammatory and
anti-cancer actions of omega-9 FAs, other than oleic
acid, are quite scarce especially for the clinical studies.
Further research is warranted to provide more conclu-
sive data about their prophylactic and therapeutic value
in those two widespread disorders. Figure 5 summa-
rizes the pro- and anti-cancer actions of omega-9 FAs.
ese results pose omega-9 FAs as promising therapeu-
tic agents warranted to be further studied in different
pathological conditions, especially in inflammation and
cancer. ese effects have yet to be confirmed though
using randomized controlled trials to reveal solid con-
clusive evidence for comparative actions using isolated
oils enriched in certain omega-9 fatty acids or better
using individual fatty acids. Execution of more epide-
miological studies with more advanced methodologies
(lipidomics, metabolomics, and molecular techniques)
will yield more reliable information about omega-9
action mechanisms at different cellular levels and pro-
vide the optimum ratio of these different fatty acids to
be recommended for dietary fat intake. How gut micro-
biota interact with omega-9 to mediate for its anti-
inflammatory effects if any is also an area less explored
and should be considered using ex vivo or ideally
invivo assays. Modification of these fatty acids using
different techniques, i.e., nanoformulation, nanoemul-
sion, and encapsulation, should also help improve their
bioavailability and ultimate biological effects.
Abbreviations
FAs: Fatty acids; ω−9 FAs: Omega-9 FAs; OA: Oleic acid; IR: Insulin resist-
ance; T2DM: Type 2 diabetes mellitus; TSCC: Tongue squamous cell
carcinoma; EA: Elaidic acid; SREBP: Sterol regulatory element-binding
protein; SCAP: Cleavage-activating protein; NAFLD: Non-alcoholic fatty
liver disease; TFAs: Trans-fatty acids; SCD-1: Stearoyl-CoA desaturase; CRC
: Colorectal cancer; GA: Gondoic acid; MA: Mead acid; NA: Nervonic acid;
HA: Hypogeic acid; FFAR1: Free fatty acid receptor 1; EGFR: Epidermal
growth factor receptor.
Acknowledgements
Not applicable.
Authors’ contributions
MF conceived the concept. MG wrote the manuscript. MF and MG cor-
rected and shaped the manuscript. All authors read and approved the final
manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Fig. 5 Anti- or pro-cancer actions of omega-9 fatty acids

Page 10 of 11
Faragand Gad Journal of Genetic Engineering and Biotechnology (2022) 20:48
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
The authors agree on publishing rules of this journal.
Competing interests
The authors declare that they have no competing interests.
Author details
1 Pharmacognosy Department, College of Pharmacy, Cairo University, Kasr El
Aini St., P.B, Cairo 11562, Egypt. 2 Department of Biochemistry, Faculty of Phar-
macy & Biotechnology, The German University in Cairo, Cairo, Egypt.
Received: 6 January 2022 Accepted: 9 March 2022
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