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Cosmetic and Therapeutic Applications of Fish Oil’s Fatty Acids on the Skin

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Fish oil has been broadly reported as a potential supplement to ameliorate the severity of some skin disorders such as photoaging, skin cancer, allergy, dermatitis, cutaneous wounds, and melanogenesis. There has been increasing interest in the relationship of fish oil with skin protection and homeostasis, especially with respect to the omega-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). The other PUFAs, such as α-linolenic acid (ALA) and linoleic acid (LA), also show a beneficial effect on the skin. The major mechanisms of PUFAs for attenuating cutaneous inflammation are the competition with the inflammatory arachidonic acid and the inhibition of proinflammatory eicosanoid production. On the other hand, PUFAs in fish oil can be the regulators that affect the synthesis and activity of cytokines for promoting wound healing. A systemic review was conducted to demonstrate the association between fish oil supplementation and the benefits to the skin. The following describes the different cosmetic and therapeutic approaches using fatty acids derived from fish oil, especially ALA, LA, DHA, and EPA. This review summarizes the cutaneous application of fish oil and the related fatty acids in the cell-based, animal-based, and clinical models. The research data relating to fish oil treatment of skin disorders suggest a way forward for generating advances in cosmetic and dermatological uses.
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Mar. Drugs 2018, 16, 256; doi:10.3390/md16080256 www.mdpi.com/journal/marinedrugs
Review
Cosmetic and Therapeutic Applications of Fish Oil’s
Fatty Acids on the Skin
Tse-Hung Huang 1,2,3,, Pei-Wen Wang 4,, Shih-Chun Yang 5, Wei-Ling Chou 1
and Jia-You Fang 6,7,8,9,*
1 Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital at Keelung, Keelung 20401,
Taiwan; huangtsehung@gmail.com (T.-H.H.); chouweiling@gmail.com (W.-L.C.)
2 School of Traditional Chinese Medicine, Chang Gung University, Kweishan, Taoyuan 33303, Taiwan
3 School of Nursing, National Taipei University of Nursing and Health Sciences, Taipei 11219, Taiwan
4 Department of Medical Research, China Medical University Hospital, China Medical University, Taichung
40402, Taiwan; pan@mail.cgu.edu.tw
5 Department of Cosmetic Science, Providence University, Taichung 43301, Taiwan; phageyang@gmail.com
6 Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan,
Taoyuan 33302, Taiwan
7 Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University,
Kweishan, Taoyuan 33302, Taiwan
8 Research Center for Food and Cosmetic Safety and Research Center for Chinese Herbal Medicine, Chang
Gung University of Science and Technology, Kweishan, Taoyuan 33302, Taiwan
9 Department of Anesthesiology, Chang Gung Memorial Hospital at Linkou, Kweishan, Taoyuan 33305,
Taiwan
* Correspondence: fajy@mail.cgu.edu.tw; Tel.: +886-3-2118-800; Fax: +886-3-2118-236
These authors contributed equally to this work.
Received: 14 June 2018; Accepted: 28 July 2018; Published: 30 July 2018
Abstract: Fish oil has been broadly reported as a potential supplement to ameliorate the severity of
some skin disorders such as photoaging, skin cancer, allergy, dermatitis, cutaneous wounds, and
melanogenesis. There has been increasing interest in the relationship of fish oil with skin protection
and homeostasis, especially with respect to the omega-3 polyunsaturated fatty acids (PUFAs),
docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). The other PUFAs, such as α-
linolenic acid (ALA) and linoleic acid (LA), also show a beneficial effect on the skin. The major
mechanisms of PUFAs for attenuating cutaneous inflammation are the competition with the
inflammatory arachidonic acid and the inhibition of proinflammatory eicosanoid production. On
the other hand, PUFAs in fish oil can be the regulators that affect the synthesis and activity of
cytokines for promoting wound healing. A systemic review was conducted to demonstrate the
association between fish oil supplementation and the benefits to the skin. The following describes
the different cosmetic and therapeutic approaches using fatty acids derived from fish oil, especially
ALA, LA, DHA, and EPA. This review summarizes the cutaneous application of fish oil and the
related fatty acids in the cell-based, animal-based, and clinical models. The research data relating to
fish oil treatment of skin disorders suggest a way forward for generating advances in cosmetic and
dermatological uses.
Keywords: fish oil; polyunsaturated fatty acid; omega-3; skin; cosmetology; dermatology
1. Introduction
The effect of fish oils in disease prevention and management has been studied for more than 50
years. Fish oils, which are rich in fatty acids, show evidence of potential health benefits [1]. Large
Mar. Drugs 2018, 16, 256 2 of 20
amounts of polyunsaturated fatty acids (PUFAs) are found in the extracts of fish oils.
Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which are long-chain omega-3 fatty
acids, are the predominant PUFAs derived from fish oils. The interest in fish oils arose from the
reports on Eskimos’ high dietary intake of fish oils associated with a very low occurrence of
inflammation-related diseases and ischemic heart disorders [2]. Besides vitamins and minerals, fish
oils are the most frequently used nutritional supplements in older adults >65 years of age [3]. The
PUFAs in fish oils have proved to be beneficial for treating rheumatoid arthritis, psoriasis, ulcerative
colitis, asthma, Parkinson’s disease, osteoporosis, diabetes mellitus, cardiovascular events, cancers,
and depression [4]. PUFAs also demonstrate beneficial activity on the development of the nervous,
immune, visual, and cutaneous systems in infants [5].
It is believed that the bioactivities of fish oils are chiefly due to the effect of PUFAs. The
epidemiological studies show a significant improvement of asthma symptoms in patients receiving
fish oil supplements rich in DHA and EPA [6]. The use of omega-3 fatty acids in fish oil capsules has
been associated with a reduction in plasma triglyceride concentration, leading to the decreased
incidence of hyperlipidemia [7]. The PUFA supplementation can diminish the risks of cardiovascular
diseases such as thrombosis, high blood pressure, and low high-density-lipoprotein cholesterol [8].
The meta-analysis studies have shown that fish oil consumption and dietary omega-3 PUFAs
decrease the risk factor of type 2 diabetes mellitus via enhanced insulin sensitivity [9]. The
consumption of fish oil containing a high level of PUFAs can play a role in cancer prevention and
therapy [10]. The anticancer effect of omega-3 PUFAs is ascribed to the capability of downregulating
proinflammatory eicosanoid synthesis from cyclooxygenase-2 (COX-2) [11]. The PUFAs from fish oils
or cod liver oils can also be employed with a high level of safety as natural antibacterial and anti-
infectious agents [12]. Intravenous lipid emulsions are a component of parenteral nutrition used as a
resource for essential fatty acids for supplying energy to patients. Soybean oil is the traditional source
of lipid emulsions. However, a high percentage of omega-6 PUFAs in soybean oil contributes to the
immunosuppressive effect [13]. Recently, fish oil has been used to replace soybean oil in lipid
emulsions to reduce the possible risk of inflammatory complications [14].
The benefits of fish oil are primarily attributed to omega-3 fatty acids, found mainly in oily fish.
Since fish liver is high in lipids, most fish oils are derived from the hepatic region. The fish oil
formulations are available from different species, including shark, tuna, lemuru, capelin, polar cod,
saithe, mackerel, herring, and sprat [15]. The composition of omega-3 PUFAs in the commercially
available products depends upon the source of the fish, the body part of the fish, and the extraction
methods employed. The public awareness of the need to take fish oils to benefit the skin has been
identified with the increasing research in the fields of cosmetology and dermatology. The lack of
PUFAs can cause increased transepidermal water loss (TEWL), resulting in skin barrier function
deficiency [16]. PUFA insufficiency also elicits the upregulation of proliferative keratins (K6 and K16)
and inflammation-related keratin (K17) [17]. These findings highlight the importance of PUFAs for
epidermal homeostasis. Some topically applied formulations of fish oil extract are developed for
cosmetic and pharmaceutical products [18]. The application of fish oil is expected to change the
landscape of dermatological therapy. In this review, we highlight recent advances in the application
of fatty acids in fish oils for preventing or treating skin-associated disorders. Fish oil-based therapy
is reported to treat various diseases such as photoaging, skin cancers, dermatitis, melanogenesis, and
cutaneous infection. The promising perspective in this emerging application is also discussed.
2. Fatty Acids of Fish Oil
Fish oil is abundant in fats and fatty acids, which can contain vitamin A, vitamin D, cholesterol,
monoglycerides, diglycerides, triglycerides, free fatty acids, phospholipids, and sterylesters [19,20].
Among these components, esters are the main ingredient and they gain most attention for being
associated with the bioactivities. Fatty acids in fish oil are present in both the neutral lipid and free
acid forms. The typical fatty acid composition of the fish oil extract can be divided into saturated fatty
acids, monounsaturated fatty acids, and PUFAs. The main saturated fatty acids found in fish oil
include myristic acid (14:0), palmitic acid (16:0), stearic acid (18:0), and behenic acid (22:0) [21]. The
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monounsaturated fatty acids in fish oil include myristoleic acid (14:1ω5), palmitoleic acid (16:1ω7),
oleic acid (18:1ω9), eicosenoic acid (20:1ω9), gadoleic acid (20:1ω11), erucic acid (22:1ω9), and catoleic
acid (22:1ω11). The major PUFAs in fish oil are presented as linoleic acid (LA, 18:2ω6), α-linolenic
acid (ALA, 18:3ω3), DHA (22:6ω3), and EPA (22:5ω3). Figure 1 depicts the chemical structures of
these fatty acids. The PUFA content in marine fish is greater than that in freshwater fish [22]. The
marine fish oil usually contains a considerable number of PUFAs with the longer chains (>20 carbon
atoms), whereas the freshwater fish oil reveals the most PUFAs with fewer chain lengths (<20 carbon
atoms) [23].
Figure 1. The chemical structures of fatty acids derived from fish oil.
Both omega-6 and omega-3 PUFAs are essential fatty acids because the mammalian cells lack
the desaturase enzymes capable of placing double bonds at the positions of ω6 and ω3 [24]. Both
PUFAs should be obtained from diet and supplementation. The omega-6 and omega-3 fatty acids are
needed for normal growth and health maintenance. They are metabolized via the lipoxygenase and
cyclooxygenase (COX) pathways. The various types of metabolites are essential in the regulation of
inflammatory and immune responses. LA and ALA, the PUFAs with the shorter chain length (18
carbon atoms), are the precursors to the biosynthesis of the omega-6 and omega-3 PUFAs with the
longer chain lengths, respectively [25]. Both fatty acids are abundant in fish oil, peanuts, canola oil,
Mar. Drugs 2018, 16, 256 4 of 20
and vegetable oil [26]. LA and ALA have similar chemical structures but different functions in the
human body.
LA is a dominant omega-6 PUFA in fish oil. This fatty acid is essential for growth, reproduction,
and skin function. It can be metabolized to γ-linolenic acid (GLA), dihomo-GLA, prostaglandin
(PG)E1, and arachidonic acid (AA). The eicosanoids, such as PGE2 and leukotriene B4, are derived
from AA. These eicosanoids are involved in the inflammation and allergic response in cutaneous
tissue [27,28]. LA is the richest fatty acid in the epidermal layer. It is also the precursor to ceramide
synthesis [29]. Ceramide is a predominant material of the intercellular stratum corneum lipid matrix
producing the skin’s permeability barrier. Several omega-3 fatty acids are produced from ALA. These
include DHA, EPA, and docosapentaenoic acid [30]. ALA is largely found in vegetable oils,
zooplankton, phytoplankton, and fish oils. ALA is fundamental to visual and brain functions through
its effect on membrane fluidity because PUFAs and their derivatives are principally located in the
cell membrane phospholipids [31]. The derivatives of ALA can modify the immune response of the
epidermis via affecting the T cells, acting on Toll-like receptors, and stimulating caspase cascades that
relieve inflammatory dermatoses such as acne, psoriasis, dermatitis, lupus, and skin cancers [32]. The
mechanisms of ALA and the derivatives for inflammation inhibition are based on barrier function
maintenance, stratum corneum maturation, stratum corneum differentiation, proinflammatory
eicosanoid inhibition, lamellar body formation, lipoxygenase inhibition, and cytokine suppression
[33].
The main derivatives of the ALA metabolism are DHA and EPA. Figure 2 illustrates the
metabolic pathways of ALA to produce DHA and EPA. They always act as the indicator components
of fish oil. The first double bond of both long-chain PUFAs is located at the third carbon atom from
the methyl end. DHA and EPA have been used nutritionally and therapeutically in several diseases
with variable success. DHA mainly resides in the retina and brain to maintain the membrane order
and the activity of membrane-bound enzymes. DHA deficiency occurs during aging and dementia,
impairs memory and learning, and promotes age-related neurodegenerative diseases, including
Alzheimer’s disease. DHA is reported to have the ability of tumor inhibition and chemoprevention
against colon cancer, prostate cancer, pancreatic cancer, and breast cancer [34]. EPA can compete with
AA, an omega-6 PUFA, through the same metabolic pathways, but it produces eicosanoids that are
functionally different from the AA derivatives. EPA is less potent as an inflammatory mediator
compared to AA. Because of the competitive relationship, EPA can restrain AA-derived PGE2
synthesis [35]. The same as DHA, EPA is used to prevent or treat neurodegenerative diseases because
of the anti-inflammatory and neuroprotective activity [36].
Mar. Drugs 2018, 16, 256 5 of 20
Figure 2. The possible metabolism pathways of essential fatty acids in the body.
3. Fatty Acids for Skin Disorder Prevention and Treatment
Recent application of fatty acids found in fish oil in skin-related diseases includes therapies for
photoaging, cancer, dermatitis, wound healing, and melanogenesis. The use of PUFAs ameliorates
the symptoms of the skin diseases. Some fatty acids have been approved for clinical use or are under
clinical trial for preventive or therapeutic use. In addition, some fish-oil-containing formulations are
approved to manage various skin diseases in cell-based and animal studies. The following describes
the different cosmetic and therapeutic approaches of fatty acids derived from fish oil, especially LA,
ALA, DHA, and EPA. The pharmacodynamic outcomes of the fatty acids are the main evaluation
platforms used to define the preventive or therapeutic effect for our description.
3.1. Photoaging
Cutaneous aging can be divided into chronological aging and photoaging. Photoaging is
activated via the human skin damage attributable to repeated ultraviolet (UV) exposure from
sunlight. UV irradiation elicits both acute and chronic adverse effects on the skin. These include
sunburn, photosensitivity, inflammation, immunosuppression, and photocarcinogenesis [37]. UV
exposure of the skin creates reactive oxygen species (ROS), leading to the massive infiltration of
immune cells such as neutrophils and macrophages in viable skin [38]. One of the key proteins
mediating the inflammatory signals in UV-induced injury is cyclooxygenase-2 (COX-2), which
catalyzes the biosynthesis process of prostaglandins [39]. In addition to sunscreens, some
photoprotective agents are needed to provide advantages against UV-induced skin damage. The fatty
acids derived from fish oil have been considered to be associated with the skin’s photoprotection.
Omega-3 PUFAs can decrease the production of proinflammatory eicosanoids through direct
competition with the metabolism of AA [40]. The other mechanisms of omega-3 PUFAs for
suppressing UV-induced keratinocyte damage can be the regulation of COX-2, NF-Κb, and mitogen-
activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) pathways [41]. Figure
3 illustrates the possible mechanisms of the photoprotective capability of PUFAs.
Mar. Drugs 2018, 16, 256 6 of 20
Figure 3. The possible mechanisms of the photoprotective capability of omega-3 PUFAs.
Interleukin (IL)-8, a proinflammatory cytokine belonging to the C-X-C chemokine subfamily, is
of major significance in the mediation of UVB-induced keratinocyte inflammation [42]. Storey et al.
[43] investigated whether the inhibition of UVB-induced inflammation by DHA and EPA is mediated
by the modulation of IL-8 in keratinocytes and skin fibroblasts. In keratinocytes, DHA and EPA
reduced the IL-8 level by 65% and 66% after UVB irradiation at 100 mJ/cm2. A similar pattern was
observed in fibroblasts. Oleic acid showed no influence on IL-8 release. Serini et al. [44] explored the
ability of DHA to influence the resistance to UV-activated apoptosis in keratinocytes. DHA reverted
HaCaT cell resistance to UV-induced apoptosis, increasing the Bax/Bcl-2 ratio and caspase-3 activity,
and decreased COX-2 by the inhibition of human antigen R (HuR), a COX-2 mRNA stabilizer in
keratinocytes. The incorporation of DHA at 50 μM to the UV-irradiated cells decreased cytoplasmic
HuR by 71%. UV-induced metalloproteinases (MMPs) elicit connective tissue damage, resulting in
Mar. Drugs 2018, 16, 256 7 of 20
the skin’s aging and wrinkling [45]. Kim et al. [46] investigated the effect of EPA on UV-induced
MMP-1 expression in dermal fibroblasts. The broadband UV (275380 nm) at 2575 mJ/cm2 was used
as the UV source. Pretreatment of EPA at 5 and 10 μM inhibited MMP-1 by 33% and 79% compared
to the UV-treated group, respectively. EPA could suppress MMP-1 by inhibiting the ERK and Jun-N-
terminal kinase (JNK) pathways. On the other hand, AA and oleic acid pretreatment slightly
increased or did not affect MMP-1 expression.
The photoaging animal models were developed to examine the impact of omega-3 fatty acids on
cutaneous photoprotection. The UVB irradiation at 500 mJ/cm2 for 20 min was employed to test the
inhibitory activity of EPA on mouse ear edema [47]. The daily oral dose of 300 mg/kg EPA for 2 weeks
could suppress the ear edema. However, no function was observed in the groups receiving 30100
mg/kg EPA. No amelioration of ear edema was detected with the use of oral DHA and safflower oil
in this case. Topical administration provides a direct and efficient way to deliver the active agents
into the cutaneous nidus with higher bioavailability than the oral route. Rahman et al. [48]
investigated the inhibitory effect of topically applied DHA on UVB-induced skin inflammation in
hairless mice. Topical pretreatment of DHA (2.5 and 10 μmol) significantly decreased COX-2 and
nicotinamide adenine dinucleotide phosphate (NADPH): oxidase-4 (NOX-4) in mouse skin. Both
COX-2 and NOX-4 are important in evoking oxidative stress and inciting inflammation. The
molecular mechanisms of this inhibition could be the suppression of UVB-induced NF-κB activation
and COX-2/NOX-4 expression by blocking the phosphorylation of stress-activated kinase-1 (MSK1),
which is a kinase downstream of ERK and p38. The transcription factor Nrf2 is a major regulator of
anti-inflammatory and antioxidant gene expression [49]. UVB exposure (180 mJ/cm2) for 23 weeks
was used to enhance COX-2 and Nrf2 expression in hairless mouse skin to determine the effect of
topical DHA against photoaging [50]. Topical DHA application (10 μmol) before irradiation induced
the expression of Nrf2 target protein heme oxygenase-1 (HO-1) in the skin and protected against
UVB-activated inflammation and papillomagenesis.
The anti-photoaging effect of PUFAs occurs in cell-based and animal-based studies as well as in
human studies. In the early 1990s, a short-term supplementation of fish oil was conducted in humans
[51]. The volunteers received oral fish oil containing rich omega-3 PUFAs (1.2 g DHA and 2.8 g EPA)
each day for 4 weeks. At the end of the experiment, there was a significant increase in the minimal
erythema dose (MED) to UVB with a decreased serum triglyceride level to 40 mg/dL. Rhodes et al.
[52] examined the photoprotective effect of fish oil on light-sensitive patients. Thirteen patients with
polymorphic light eruption received oral supplementation of fish oil containing DHA, EPA, palmitic
acid, palmitoleic acid, and oleic acid for 3 months. The mean MED increased from 19.8 to 33.8 mJ/cm2
by dietary fish oil. PGE2 increased from 8.6 ng/mL in the sham group to 27.2 ng/mL after UVB
treatment. The PGE2 level decreased to 4.1 and 9.6 ng/mL in the control and irradiated skin,
respectively. Puglia et al. [53] evaluated the percutaneous absorption and the photoprotective effect
of three fish oils rich in DHA and EPA, including mackerel, sardine, and horse mackerel. The in vitro
skin permeation showed that the fish oil from sardines facilely penetrated into the skin as compared
to the oil from the others. The clinical experiment was carried out in ten volunteers with the
irradiation of UVB at doubled MED. The topical application of combined sardine extract and
ketoprofen, an anti-inflammatory drug, inhibited the UVB-induced erythema by 60.5%, which was
greater than the inhibition achieved by sardine oil extract (24.5%) and ketoprofen (46.6%) alone.
The influence of dietary EPA on UVB-generated PGE2 and proinflammatory cytokines was
examined in a double-blind, randomized study [54]. Twenty-eight volunteers received 4 g daily of
95% ethyl esters of EPA or oleic acid for 3 months. The group of EPA but not oleic acid exhibited a
significant enhancement of MED. PGE2’s increase by UVB (26.5 pg/mL) could be eliminated by EPA
(19.3 pg/mL), approximating the baseline data (14.0 pg/mL). However, this study demonstrates no
evidence that the reduced sunburn response by EPA was mediated by cytokines. The PUFAs are not
always beneficial to various facets of cutaneous photoaging. Langerhans cells are sentinels of the
immune system in the skin. Following UV exposure, the loss of this cell in the epidermis is detected
[55]. In a double-blind, randomized controlled study of 79 females, Pilkington et al. [56] explored the
effect of dietary EPA on epidermal Langerhans cells and prostaglandin D2 (PGD2). The healthy
Mar. Drugs 2018, 16, 256 8 of 20
volunteers received EPA-rich capsules (5 g EPA) or control lipid (glyceryl tricoprylate caprate) for 12
weeks. The clinical data revealed that there was no impact of EPA supplementation on the
Langerhans cell number and the PGD2 level after UV irradiation compared to the control. There was
no evidence that EPA reduced UV suppression on skin immunity through this mechanism. Kim et
al. [57] investigated whether topical EPA could inhibit both UV-induced photoaging and intrinsic
aging to young and aged volunteers, respectively. The buttock skin was irradiated with UVB at
doubled MED (about 7090 mJ/cm2). UVB increased epidermal thickness by 214%, and topical EPA
reduced the thickness by 72%. UVB light reduced the procollagen expression to 18% of the untreated
control. EPA could restore the procollagen level to 46% of the control group. This PUFA also
attenuated COX-2, MMP-1, and MMP-9 elevated by UVB.
In addition to the PUFAs with the longer chains (>20 carbon atoms), the short-chain PUFAs are
useful in suppressing UV-induced cutaneous injury. The effect of orally and topically applied oils
enriched with LA and ALA on UV-induced damage was compared in hairless mice [58]. Both LA and
ALA lowered the erythema score compared to the basal cream after topical administration. On the
other hand, dietary ALA demonstrated greater erythema inhibition than LA by the oral route. The
PGE2 expression increased 8-fold after UVB exposure. Dietary LA did not diminish the increased
PGE2, whereas the PGE2 level in the ALA group was 75% lower than that in the LA group. The
results indicated that both omega-6 and omega-3 PUFAs could play a role in the constraint of UVB-
elicited lesions. Conjugated LA represents the positional and geometrical isomers of LA. These
isomers are reported to block LA metabolism to γ-linolenic acid in omega-6 PUFAs [59]. Conjugated
LA is beneficial for decreasing white adipose tissue weight in subcutaneous tissue, an implication of
obesity management [60]. Storey et al. [61] examined the capability of conjugated LA to inhibit IL -8
and PGE2 in UV-irradiated keratinocytes. Supplementation of keratinocytes with c9,t11-conjugated
LA downregulated UVB-induced IL-8 from 37.11 to 14.17 ng/mg. Another LA isomer, tt-conjugated
LA, reduced UVB-induced PGE2 release from 4.8 to 1.6 pg/mg. According to the above description,
it is believed that oral or topical application of PUFAs from fish oil is helpful in preventing or treating
skin aging. This is the appeal of many cosmetic products. These fatty acids are included in some skin
creams for cosmetic purposes [62]. The detailed information about the fatty acids existed in fish oils
for attenuating cutaneous photoaging is summarized in Table 1.
Table 1. The fatty acids existing in fish oils for attenuating cutaneous photoaging.
Composition
Experimental
Model
UV Type
Reference
DHA and EPA
Keratinocytes and
skin fibroblasts
UV 270400 nm,
25100 mJ/cm2
Storey et al.
[43]
DHA
Keratinocytes
UV 290400 nm,
1060 mJ/cm2
Serini et al.
[44]
EPA
Skin fibroblasts
UV 275380 nm,
2575 mJ/cm2
Kim et al.
[46]
EPA
BALB/c mouse
with ear edema
UVB, 500 mJ/cm2
Danno et al.
[47]
DHA
Hairless mouse
with skin
inflammation
UVB 312 nm, 180
mJ/cm2
Rahman
et al. [48]
DHA
Hairless mouse
with skin
inflammation
UVB 312 nm, 180
mJ/cm2
Yum et al.
[50]
Fish oil rich of DHA
and EPA
Human
UVB with a filter to
eliminate
wavelengths <295
nm
Orengo et al.
[51]
Mar. Drugs 2018, 16, 256 9 of 20
Fish oil rich in DHA
and EPA
Human
UV 270400 nm
Rhodes et al.
[52]
Fish oils from
mackerel, sardine,
and horse mackerel
Human
Broadband UVB,
doubled MED
Puglia et al.,
[53]
Ethyl esters of EPA
and oleic acid
Human
UV 270400 nm
Shahbakhti
et al. [54]
EPA
Human
UV 270400 nm, 4 ×
MED
Pilkington
et al. [56]
EPA
Human
UV 285350 nm
Kim et al.
[57]
LA and ALA
Hairless mouse
UVB at 312.5 nm,
3.6× MED
Takemura
et al. [58]
Conjugated LA
Keratinocytes
UV 270400 nm,
25100 mJ/cm2
Storey et al.
[61]
COX-2, cyclooxygenase-2; ERK, extracellular-signal-regulated kinase; JNK, Jun-N-terminal kinase;
LA, linoleic acid; MED, minimal erythema dose; MMP, metalloproteinases; MSK1, stress-activated
kinase-1; NOX-4, nicotinamide adenine dinucleotide phosphate (NADPH): oxidase-4; PGD2,
prostaglandin D2; PGE2, prostaglandin E2.
3.2. Cutaneous Carcinogenesis
Skin cancers are generally classified into melanoma and non-melanoma skin carcinoma (NMSC).
UVB radiation is the most prevalent risk factor responsible for the development of skin cancers.
However, it has been recognized that UVA is also responsible for procarcinogenic action on the skin
[63]. The oxidative stress and continuous inflammation are responsible for the main pathologic
generation in UV-induced skin photocarcinogenesis [64]. Another important contribution of UV to
developing skin cancers is the suppression of cutaneous immunity [65]. The PUFAs from fish oil are
found to inhibit both the initiation and promotion phases of cutaneous carcinogenesis. Both DHA
and EPA were tested for their effectiveness on premalignant keratinocyte apoptosis [66]. The HaCaT
cell growth was significantly inhibited by both omega-3 fatty acids at 30 and 50 μM. DHA or EPA at
50 μM lowered the number of viable keratinocytes by 60–80% compared to the control. The combined
anti-cancer drugs and dietary PUFAs may be advantageous to achieving synergistic inhibition on
carcinogenesis. Chiu et al. [67] elucidated the effect of non-steroidal anti-inflammatory drugs
(NSAIDs) and DHA combination for melanoma cell growth inhibition. Celecoxib and indomethacin
revealed additive effects on DHA-induced inhibition. Aspirin promoted DHA-induced growth
inhibition by 43% at 480 μM. The IC50 of DHA on melanoma growth inhibition was 160 μM. Piroxicam
could decrease the IC50 to 40 μM. The administration of high-dose COX inhibitors would create the
unwanted adverse effects [68]. An ideal strategy to attenuate the risk raised by NSAIDs is the use at
low dose with the supplement of chemopreventive agents such as long-chain PUFAs.
Imiquimod is a toll-like receptor 7/8 agonist prescribed as a topical drug for treating actinic
keratosis, skin warts, and malignancy [69]. Nevertheless, it is known to cause severe skin
inflammation. Based on the concept of synergistic carcinoma inhibition for lowering the administered
dose, fish oil was used in combination with imiquimod to treat human basal (BCC) and squamous
carcinoma cells (SCC) [70]. The fish oil utilized in this case was composed of 21% DHA and 42% EPA.
The combined imiquimod and fish oil demonstrated greater cell viability inhibition and
immunomodulatory potency as compared to imiquimod alone. The pure DHA or EPA was more
potent than fish oil for the immunomodulatory effect against the carcinoma cells. The omega-3
PUFAs served as the inducers of IL-10, an anti-inflammatory cytokine, and as the suppressors of IL-
6 and TNF-α to depress cell growth. Rehman and Zulfakar [71] further developed the imiquimod-
Mar. Drugs 2018, 16, 256 10 of 20
loaded fish oil bigel colloidal delivery system for treating skin cancer in a mouse model. Bigel is
defined as an intimate hydrogel/oleogel colloidal semisolid vehicle for topical application [72]. Fish
oil as a source of DHA and EPA is also employed as the permeation enhancer to improve drug
delivery into the skin [73]. After topical delivery of the imiquimod formulations on the mouse bearing
the skin tumor induced by 7,12-dimethylbenz(a)anthracene (DMBA), there was a significant
reduction of the tumor size by bigel (2.07 mm) and the commercial imiquimod cream (1.98 mm) as
compared with the sham control (6.48 mm). The mouse treated with bigel exhibited greater IL-10
expression (40.86 pg/mL) than commercial cream (27.82 pg/mL) and the control (0.63 pg/mL). The
fish oil rich in omega-3 PUFAs was topically applied on the mouse skin with papilloma prompted by
benzo(a)pyrene and croton oil [74]. Fish oil blocked the binding of benzo(a)pyrene to DNA, resulting
in the reduction of the mean papilloma number per mouse from 6.0 to 3.1. In addition to topical
delivery, the oral administration of a high-fat diet containing fish oil rich in omega-3 PUFAs in mice
also repressed UVB-induced carcinogenesis [75]. Fish oil intake could increase the latency to the
development of UVB-induced tumor and decrease the size of the papilloma, keratoacanthoma, and
carcinoma in mice by 98%, 80%, and 83%, respectively. The tumor inhibition was not observed in the
group receiving the high-fat diet rich in omega-6 fatty acids.
The varied effects of different classes of dietary fatty acids on cutaneous carcinogenesis suggest
that fatty acid composition is an important determining factor in tumor development. In the previous
study [76], the association between dietary n-3 and n-6 fatty acid intake and the risk of SCC was
explored. The results taken from a population-based case-control study demonstrated a consistent
tendency toward a lower SCC risk with higher omega-3 PUFA consumption. The risk of SCC
decreased following the increase of omega-3/omega-6 ratio fatty acid intake. In another case-control
study of melanoma patients [77], the higher uptake of fish oil rich in omega-3 fatty acids was defined
as more than one portion a week and was associated with a lower risk of melanoma development.
This result was based on the participants’ completion of a food frequency questionnaire. A phase 2
open-label clinical study was performed to investigate the response rate and safety of DHA-paclitaxel
conjugate in metastatic melanoma patients [78]. Paclitaxel is an anti-melanoma drug with a narrow
therapeutic window. DHA-paclitaxel is a covalent conjugate showing a greater therapeutic index
than paclitaxel alone [79]. This conjugate had been successfully targeted to the tumor with minimal
deposition in normal tissue [80]. Thirty patients were enrolled to receive a DHA-paclitaxel
intravenous infusion at 500 mg/m2/week for 5 weeks. The median survival period could be prolonged
to 14.8 months. It is indicated that the weekly DHA-paclitaxel is a solidly tolerable single agent for
melanoma patients.
Conjugated LA was orally administered to the mouse bearing skin cancer to determine the
presence of peroxisome proliferator-activated receptor (PPAR)-δ and keratinocyte fatty acid binding
protein (K-FABP), which are involved in cutaneous tumor promotion [81]. The skin malignancy was
developed by topical administration of DMBA and 12-O-tetradecanoylphorbol-13-acetate (TPA). The
results showed that PPAR-δ and K-FABP in the mRNA level were decreased by feeding the diet
containing 0.51.5% conjugated LA. It is suggested that conjugated LA inhibited skin tumor
promotion via the mechanism of PPAR-δ. Table 2 depicts the related information of fatty acids existed
in fish oils for preventing or treating cutaneous carcinogenesis.
Table 2. The fatty acids existing in fish oils for preventing or treating cutaneous carcinogenesis.
Composition
Experimental
Model
Tumor-Induced
Approach
Benefit
Reference
DHA and EPA
Keratinocytes
HaCaT
Growth factors in
3% FBS
Induced pre-malignant
keratinocyte apoptosis
Nikolakopoul
ou et al. [66]
DHA
Melanoma A-
375
Standard culture
medium
Synergistic growth
inhibition combined
with NSAIDs
Chiu et al. [67]
Fish oil, DHA, and
EPA
BCC TE 354
and SCC A431
Standard culture
medium
Synergistic growth
inhibition combined
with imiquimod
Rehman et al.
[70]
Mar. Drugs 2018, 16, 256 11 of 20
Fish oil
Swiss albino
mouse
DMBA-induced
papilloma
Reduced tumor size
and enhanced IL-10
Rehman and
Zulfakar [71]
Fish oil
Swiss albino
mouse
Benzo(a)pyrene
and croton oil
Reduced papilloma
number per mouse
Ramesh and
Das [74]
Fish oil
Hairless
mouse
UV 280320 nm,
30 mJ/cm2
Reduced size of
papilloma,
keratoacanthoma, and
carcinoma
Lou et al. [75]
Omega-3 and
omega-6 fatty acids
Human
SCC patients
Lower SCC risk with
the higher omega-
3/omega-6 intake
Hakim et al.
[76]
Fish oil rich in
omega-3 PUFAs
Human
Melanoma patients
Lower melanoma risk
with the fish oil intake
Fortes et al.
[77]
DNA-paclitaxel
conjugate
Human
Melanoma patients
Prolonged median
survival period
Homsi et al.
[78]
Conjugated LA
Mouse
DMBA- and TPA-
induced tumor
Reduced PPAR-δ and
K-FABP
Belury et al.
[81]
BCC, basal cell carcinoma; DMBA, 7,12-dimethylbenz[a]anthracene; FBS, fetal bovine serum; K-FABP,
keratinocyte fatty acid binding protein; LA, linoleic acid; NSAIDs, non-steroidal anti-inflammatory
drugs; PPAR-δ, peroxisome proliferator-activated receptor; SCC, squamous cell carcinoma; TPA, 12-
O-tetradecanoylphorbol-13-acetate.
3.3. Dermatitis
Dermatitis is an inflammatory and itchy skin condition with a predilection for cutaneous flexure.
It is characterized by symptoms such as intense pruritus, erythematous papules with excoriation,
vesicles over erythematous skin, thickened plaques of skin, accentuated skin marking
(lichenification), and fibrotic papules (prurigo nodularis) [82]. The symptoms of dermatitis can cause
barrier function defects, followed by the invasion of bacteria and allergens, as well as transepidermal
water loss and fat loss. After the diagnosis based on developed criteria, dermatitis can be classified
according to several types: atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis,
seborrheic dermatitis, discoid eczema, and frictional lichenoid dermatitis [83]. Fish oil and the related
fatty acids are reported to be useful for ameliorating dermatitis symptoms. Barcelos et al. [84]
demonstrated the reduction of cutaneous dryness and pruritus by oral supplementation of fish oil in
rats. Dry skin is a consequence of the subtraction of epidermal water content due to stratum corneum
barrier function loss [85]. A 30% increase in cutaneous hydration was detected after fish oil
consumption for 60 days, persisting at 90 days in the acetone-induced dry skin animal model. The
itch-related scratching behavior was also eliminated after supplementation. The 90-day
supplementation led to an increased uptake of DHA (1.8×), EPA (2.2×), and docosapentaenoic acid
(1.7×) into the skin.
Trimellitic anhydride is broadly used in the plastics industry but can prompt cutaneous allergy
via immune cell accumulation such as in atopic dermatitis [86]. In order to ameliorate the cutaneous
allergy sensitized by trimellitic anhydride in rats, omega-3 PUFAs (600 mg/kg) was orally
administered [87]. The results displayed a significant reduction in the ear thickness, cutaneous
eosinophils, and mast cells after fatty acid administration. Fatty acids also decreased the inducible
nitric oxide synthase (iNOS) expression and collagen fibers. Weise et al. [88] investigated the
amelioration of dietary DHA and AA with respect to the severity of ovalbumin-induced dermatitis
in mice. The mice consumed a daily dose of 24 mg/kg DHA and/or 48 mg/kg AA. The clinical outcome
of dermatitis was significantly reduced by combined DHA and AA. The improvement was
accompanied by a significant decrease in Ki67 expression to 62.5% of the control. The elevated IL-10
was also found in the cutaneous lesion of the DHA/AA-treated animal.
The 18:3 PUFAs, especially GLA, can be the dietary supplementation to improve dry skin and
dermatitis. PGE1 and 15-hydroxyeicosatrienoic acid converted from GLA via dihomo-GLA possess
anti-inflammatory characteristics. GLA supplementation was investigated to reverse epidermal
hyperproliferation [89]. The consumption of GLA-rich borage oil modified fatty acid metabolism and
Mar. Drugs 2018, 16, 256 12 of 20
increased the skin barrier function [90]. In the previous report [91], GLA-rich oil was incorporated
into the food for oral consumption in 130 subjects with mild atopic dermatitis. After 4 weeks, the
GLA group revealed lower TEWL and a higher stratum corneum index compared to the control. No
significant side effects were found after GLA administration. The mechanism of skin barrier recovery
has been associated with the possible generation of anti-inflammatory metabolites from GLA. The
dihomo-GLA concentration in the serum of atopic dermatitis patients was lower than that of the
healthy control [92]. Dihomo-GLA is one of the active metabolites of GLA. Since GLA is sometimes
not effectively converted into dihomo-GLA in dermatitis patients, Kawashima et al. [93] examined
whether oral delivery of dihomo-GLA prevented dermatitis-like lesions in NC/Nga mice. The clinical
severity score and scratching behavior manifested lower levels in the mice fed dihomo-GLA. The
total plasma immunoglobulin (IgE) was significantly lower in the dihomo-GLA group (15.6 μg/mL)
than in the control (64.2 μg/mL). In another study utilizing NC/Tnd mice as the animal model [94],
dietary dihomo-GLA but not AA and EPA suppressed the development of dermatitis-like lesions.
The application of dihomo-GLA upregulated prostaglandin D1 (PGD1), resulting in the subsequent
suppression of IgE-mediated degranulation. The amount and duration of scratching were lessened
by dihomo-GLA supplementation. The description of the fatty acids existed in fish oils for preventing
or treating dermatitis is shown in Table 3.
Table 3. The fatty acids existing in fish oils for preventing or treating dermatitis.
Composition
Experimental
Model
Dermatitis-Induced
Approach
Benefit
Reference
Fish oil
Rat
Acetone-induced dry
skin
Increased skin hydration
and scratching
Barcelos et al.
[84]
Omega-3 PUFAs
Rat
Trimellitic anhydride-
induced allergy
Decreased ear thickness,
cutaneous eosinophils,
and mast cells
Abdel Latif
et al. [87]
DHA and AA
Mouse
Ovalbumin-induced
dermatitis
Reduced Ki67 and
elevated IL-10 expression
Weise et al. [88]
GLA
Human
Mild atopic dermatitis
Reduced TEWL and
improved stratum
corneum index
Kawamura
et al. [91]
Dihomo-GLA
NC/Nga mouse
Dermatitis-like skin
lesion
Suppressed clinical
severity score and
scratching behavior
Kawashima
et al. [93]
Dihomo-GLA
NC/Tnd mouse
Dermatitis-like skin
lesion
Upregulated PGD1 and
reduced scratching
behavior
Amagai et al.
[94]
AA, arachidonic acid; GLA, γ-linolenic acid; PGD1, prostaglandin D1; PUFAs, polyunsaturated fatty
acids; TEWL, transepidermal water loss.
3.4. Cutaneous Wounds
Skin wounds, such as second-degree burns, chronic wounds, and ulcers, have affected millions
of people worldwide. Though there are several skin replacement products and wound dressings for
promoting wound healing, the development of efficient and safe approaches for cutaneous wound
healing is urgently needed [95]. Wound healing is divided into three stages: inflammatory response,
proliferation, and maturation [96]. The cellular and molecular processes in the inflammatory phase
of wound healing are initiated and amplified to a large degree by proinflammatory cytokines. The
synthesis and activity of cytokines can be regulated by PUFAs [97]. These fatty acids have been
proved to play a key role in cell membrane structure and anabolic events during skin tissue
reconstruction. It is possible that omega-3 and omega-6 PUFAs modulate or enhance local
inflammatory response at wound areas, accelerating the healing rate [98]. Shingel et al. [99] described
the preparation of a solid emulsion gel for cell-targeted PUFA delivery to skin wounds. The emulsion
hydrogel is a combination of a protein-stabilized lipid emulsion and a hydrogel vehicle. The full-
Mar. Drugs 2018, 16, 256 13 of 20
thickness skin wound reaching muscular fascia was created in the pig with a 25-mm diameter. The
wound treated with the fish-oil-containing gel showed a faster wound closure compared to the gel
containing olive oil. A significant wound closure was achieved at day 2 and day 10 by fish oil and
olive oil, respectively. Fish oil was found to stimulate early angiogenesis for promoting wound
healing.
SMOFlipid, which acts as parenteral nutrition, is a lipid emulsion mixture with four lipid
resources: medium-chain triglycerides, soybean oil, olive oil, and fish oil [100]. Peng et al. [101]
assessed the efficacy of SMOFlipid rich in omega-3 PUFAs on wound healing in rats. SMOFlipid was
intravenously injected at 0.2 mL/kg immediately after excision for 72 h. The SMOFlipid accelerated
the healing process more than the placebo by reducing the surface area of the wound by 2025% at
day 3. The IL-10 level and collagen fiber organization were greater in the SMOFlipid group than the
placebo after 48 h of treatment. The topical use of DHA (30 μM) hastened the skin wound healing
through the inflammatory activity modulation in rats [102]. The wound in the DHA group was
completely healed at day 15, whereas a 30% wound was still unhealed in the control. Upon DHA
treatment, the wound healing was accompanied by the activation of the G-protein-coupled receptor
(GPR)120, a receptor for DHA with anti-inflammatory activity. The expression of transforming
growth factor β (TGF-β) and keratinocyte marker involucrin was upregulated after DHA application.
The DHA analogues 14R,21-dihydroxy-DHA and 14S,21-dihydroxy-DHA were obtained from DHA
catalysis by 12-lipoxygenase and cytochrome P450. 14R,21-dihydroxy-DHA and 14S,21-dihydroxy-
DHA significantly increased the granulation tissue region (>65%) and reduced the epithelial gap
(>30%) in the full-thickness wound of the mice [103]. The healing mechanism could be the
enhancement of the macrophage pro-healing function. In a human study evaluated by McDaniel et
al. [104], the small blisters on the forearms were created to examine the effect of the daily intake of
DHA (1.1 g) and EPA (1.6 g) on the healing rate. A significantly greater IL-expression was detected
in the blister fluid of the DHA/EPA group than in the control. It is hypothesized that the increased
proinflammatory cytokines at the wound site may be responsible for wound healing.
Since the appropriate inflammation in the wound area promotes the cell migration and skin
tissue repair, the AA precursors, such as omega-6 and omega-9 fatty acids, may be responsible for
the healing process because of their role as inflammatory modulators. Cardoso et al. [105]
demonstrated that ALA (omega-3), LA (omega-6), and oleic acid (omega-9) modulated skin wound
healing at different levels. The omega-9 fatty acid induced faster wound closure than omega-3 and
omega-6 fatty acids. The wound treated with oleic acid followed by LA presented less edema
compared with the control. Pereira et al. investigated the effect of LA and oleic acid on the
inflammatory response of skin wounds and the cytokine release by rat neutrophils [106]. The animals
treated with topical LA or oleic acid displayed a 60% greater reduction in the necrotic cell-layer
thickness than the control. The number of neutrophils in the wound site was increased by LA (19.3)
and oleic acid (24.6) as compared to the control (10.8). Oleic acid could stimulate the production of
cytokine-induced neutrophil chemoattractant in inflammation 2 α/β (CINC-2α/β). Rodrigues et al.
[107] investigated the effect of oral LA (0.22 g/kg) for improving wound healing in streptozotocin-
induced diabetic rats. LA reduced the wound area 14 days post-induction. The increased CINC-2α/β,
TNF-α, and leukotriene B4 and the increased leukocyte accumulation and angiogenesis by LA were
responsible for the improved wound closure in the early healing phase. Laser ablation on the skin for
an aesthetic regimen is often associated with erythema, edema, and crusting. Thirty-four subjects
receiving fractional CO2 laser treatment were enrolled for topical application of conjugated LA to
determine the healing efficacy [108]. Conjugated LA showing the ability to stimulate keratinocyte
proliferation and epidermal regeneration was practical to reduce edema and itching at day 3 post-
irradiation. The skin tolerated the topical conjugated LA well with no increased adverse effects. We
summarize the information about the effect of fatty acids in fish oils on cutaneous wounds in Table 4.
Mar. Drugs 2018, 16, 256 14 of 20
Table 4. The fatty acids existing in fish oils for preventing or treating cutaneous wounds.
Composition
Experimental
Model
Wound-Induced
Approach
Benefit
Reference
Fish oil
Pig
Full-thickness skin
excision
Fast wound closure at day 2
Shingel et al. [99]
Fish oil
Rat
Full-thickness skin
excision
Accelerated healing process
and increased IL-10
Peng et al. [101]
DHA
Rat
Full-thickness skin
excision
Accelerated healing process
and increased GPR120 and
TGF-β
Arantes et al. [102]
14R,21-dihydroxy-
DHA and 14S,21-
dihydroxy-DHA
Mouse
Full-thickness skin
excision
Increased granulation tissue
region (>65%) and reduced
epithelial gap
Lu et al. [103]
DHA and EPA
Human
Blisters in the
forearms
Increased IL-1β expression in
the wound sites
McDaniel et al.
[104]
ALA, LA, and oleic
acid
Mouse
Full-thickness skin
excision
Faster wound closure by
oleic acid than ALA and LA
Cardoso et al.
[105]
LA and oleic acid
Rat
Full-thickness skin
excision
Reduced necrotic cell layer
thickness
Pereira et al. [106]
LA
Rat
Streptozotocin-
induced diabetic
wound
Increased leukocyte
accumulation and
angiogenesis
Rodrigues
et al. [107]
Conjugated LA
Human
Fractional laser
ablation
Reduced edema and itching
Wu and Goldman
[108]
ALA, α-linolenic acid; GPR120, G-protein-coupled receptor 120; LA, linoleic acid; TGF-β,
transforming growth factor β.
3.5. Hyperpigmentation
Melanogenesis is a process of generating and distributing melanin, which is synthesized in
melanocytes in specialized membrane-bound organelles known as melanosomes [109]. In the
biosynthesis of melanin, tyrosinase is a rate-limiting enzyme catalyzing the conversion of tyrosine to
3,4-dihydroxyphenylalanine (DOPA) and the oxidization of DOPA to dopaquinone [110]. Skin
hyperpigmentation by melanogenesis is stimulated by UV exposure, endothelin-1, α-melanocyte-
stimulating hormone -MSH), growth factors, and cytokines [111]. Balcos et al. conducted a cell-
based study [112] to explore the effect of DHA on melanin synthesis by using B16F10 melanoma as
the cell model. DHA at 1–25 μM did not influence cell viability but decreased α-MSH-activated
melanin production. Microphthalmia-associated transcription factor (MITF) is a predominant
regulator for tyrosinase expression [113]. The results showed that DHA significantly increased
tyrosinase degradation without affecting MITF expression.
ALA and LA are reported to reveal skin-whitening capability through the mechanism of
tyrosinase inhibition [114]. Ando et al. [115] evaluated the impact of ALA and LA on
hyperpigmentation suppression in the skin. Hyperpigmentation was induced by UVB (1 J/cm2) in
guinea pigs. After a 3-week application, the lightness value (L*) of the skin was increased from 40.6
(UVB-treated control) to 47.1 and 48.8 by ALA and LA, respectively. The melanin content decreased
to 16.4% and 28.0% compared with the control after ALA and LA treatment. Shigeta et al. [116]
prepared LA-loaded liposomes as the carrier for skin whitening in humans. The hyperpigmentation
of the volunteers was induced by UVB exposure (1.2x MED) on the forearm. The whitening effect
was greater for liposomal LA (0.1%) than for free LA according to the measurement of L*. Liposomal
encapsulation was applicable for the protection of unstable LA from oxidation.
4. Conclusions
Fish oil and the related actives, such as omega-3 and omega-6 PUFAs, have been proved helpful
for maintaining skin homeostasis and ameliorating cutaneous abnormalities. The fatty acids in fish
Mar. Drugs 2018, 16, 256 15 of 20
oil can improve skin barrier function, inhibit UV-induced inflammation and hyperpigmentation,
attenuate dry skin and pruritus elicited by dermatitis, accelerate skin wound healing, and prevent
skin cancer development. All the benefits can be achieved by different administration routes,
including oral supplementation, topical application, and intravenous injection. Despite the evidence
indicating the successful application of fish oil and omega-3 PUFAs on skin disorders, there have
been conflicting reports from meta-analysis and systematic review regarding the clinical benefit of
using fish oil over the control or other lipids. Fish oil is a crude extract with very complex ingredients.
It is difficult to control fish oil contents well. The abundant sources of the fish genus also complicate
the quality control. The specific fish type and the PUFA percentage in the fish oil are the importa nt
factors that should be considered for the benefits on the skin. Another issue that should be considered
is that not only PUFAs but also vitamin A, vitamin D, retinol, selenium, and other components may
contribute to the bioactivity of fish oil. The most commonly raised concern for omega-3 PUFA
administration is the potential to raise the risk of bleeding via the anti-platelet effect. Gastrointestinal
disturbance by dietary fish oil is also reported in some cases. Caution should be used in optimizing
the benefits of fish oil or omega-3 fatty acids to ensure a balance between damage or toxicity and the
effectiveness. Although many fish oil products and PUFAs are developed for testing in cell- and
animal-based studies, clinical trials for skin application are still limited. This may be because of the
high cost of clinical trials and some unknown side effects that should be identified and explored first.
Further clinical studies are encouraged for future application of improved therapy.
Authors Contribution: T.-H.H. and P.-W.W. organized and wrote the whole manuscript. S.-C.Y. gave the idea
and careful revision of the manuscript. W.-L.C. searched the related references, drew the related figures and
tables and gave suggestions to improve the manuscript. J.-Y.F. edited and corrected the final version of the
manuscript.
Acknowledgement: The authors are grateful to the financial support by Ministry of Science and Technology of
Taiwan (MOST-105-2320-B-182-010-MY3) and Chang Gung Memorial Hospital at Keelung (CMRPG2G0661-3).
Conflicts of Interest: The authors declare no conflict of interest.
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... Some of these fatty acids, such as long-chain n-3 polyunsaturated fatty acids (PUFAs), are beneficial to human health [1,2] and could be a potential source of oil for various industries. Fish oil has been widely reported as a developing supplement to improve the severity of skin disorders such as dermatitis, photoaging, allergy, skin cancer, melanogenesis, and cutaneous wounds [3]. Omega-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) are said to be responsible for the relationship of fish oil with skin protection and homeostasis [3]. ...
... Fish oil has been widely reported as a developing supplement to improve the severity of skin disorders such as dermatitis, photoaging, allergy, skin cancer, melanogenesis, and cutaneous wounds [3]. Omega-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) are said to be responsible for the relationship of fish oil with skin protection and homeostasis [3]. Owing to their nutrients, fish by-products have been used to produce products for topical administration. ...
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Fish by-product oil and lemon oil have potential applications as active ingredients in many industries, including cosmetics, pharmaceuticals and food. However, the physicochemical properties, especially the poor stability, compromised the usage. Generally, nanoemulsions were used as an approach to stabilize the oils. This study employed an ultrasonication method to form oil-in-water nanoemulsion of lemon and fish by-product oils (NE-FLO). The formulation is produced at a fixed amount of 2 wt% fish by-product oil, 8 wt% lemon oil, 10 wt% surfactant, 27.7 wt% co-surfactants and 42 min of ultrasonication time. The size, polydispersity index (PDI) and zeta potential obtained were 44.40 nm, 0.077, and −5.02 mV, respectively. The biological properties, including antioxidant, antibacterial, cell cytotoxicity, and anti-inflammatory, showed outstanding performance. The antioxidant activity is comparable without any significant difference with ascorbic acid as standard and is superior to pure lemon oil. NE-FLO successfully inhibits seven Gram-positive and seven Gram-negative bacterial strains. NE-FLO’s anti-inflammatory activity is 99.72%, comparable to nordihydroguaiaretic acid (NDGA) as the standard. At a high concentration of 10,000 µg. mL−1, NE-FLO is non-toxic to normal skin cells. These findings demonstrate that the NE-FLO produced in this study has significant potential for usage in various industries.
... One of the important properties of this substance are its anti-inflammatory, angiogenesis, and repair properties [5,15], which have been proven in many studies [5,[16][17][18]. Fish oil, which is rich in omega-3 fatty acids, through changes in the production of growth factors, cytokines, and collagen production, controls the inflammatory stage of the wound, reducing prostaglandins, dilating blood vessels, increasing blood supply and oxygen delivery to the wound site, increasing cell proliferation and accelerating angiogenesis exert their healing effects [19]. Few reports did not show the beneficial effects of fish oil in wound healing [20,21]. ...
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... o Enhancing the protective barrier function of the skin o Reducing the symptoms of dry skin and itching caused by dermatitis o Accelerating wound healing [14]. ...
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... The oil phase of the nanosystem is composed of ω-3, an innovative excipient that has been studied in the field of nanotechnology for its capacity to act as a chemical enhancer of transdermal penetration. Furthermore, its solubilizer, anti-inflammatory, and moisturizer properties make it even more attractive for its administration on the skin [28,29]. The oil phase is also composed of oleic acid, a long-chain monounsaturated fatty acid sourced from different vegetal and animal sources, which Pharmaceutics 2022, 14, 2445 6 of 16 similarly to ω-3, acts as a chemical enhancer of transdermal penetration [30,31]. ...
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... Essential long-chain polyunsaturated fatty acids (PUFAs) are the key nutrients to prevent aging-associated abnormalities. PUFAs are important in regulating cholesterol levels and are the precursor of prostaglandins [52][53][54]. Their role in aging has emerged in recent years and will be detailed in the following paragraphs [55][56][57]. ...
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Aging is a very complex process that is accompanied by a degenerative impairment in many of the major functions of the human body over time. This inevitable process is influenced by hereditary factors, lifestyle, and environmental influences such as xenobiotic pollution, infectious agents, UV radiation, diet-borne toxins, and so on. Many external and internal signs and symptoms are related with the aging process and senescence, including skin dryness and wrinkles, atherosclerosis, diabetes, neurodegenerative disorders, cancer, etc. Oxidative stress, a consequence of the imbalance between pro-and antioxidants, is one of the main provoking factors causing aging-related damages and concerns, due to the generation of highly reactive byproducts such as reactive oxygen and nitrogen species during the metabolism, which result in cellular damage and apoptosis. Antioxidants can prevent these processes and extend healthy longevity due to the ability to inhibit the formation of free radicals or interrupt their propagation, thereby lowering the level of oxidative stress. This review focuses on supporting the antioxidant system of the organism by balancing the diet through the consumption of the necessary amount of natural ingredients, including vitamins, minerals, polyunsaturated fatty acids (PUFA), essential amino acids, probiotics, plants' fibers, nutritional supplements, polyphenols, some phytoextracts, and drinking water.
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The market demand for marine-based cosmetics has shown a tremendous growth rate in the last decade. Marine resources represent a promising source of novel bioactive compounds for new cosmetic ingredient development. However, concern about sustainability also becomes an issue that should be considered in developing cosmetic ingredients. The fisheries industry (e.g., fishing, farming, and processing) generates large amounts of leftovers containing valuable substances, which are potent sources of cosmeceutical ingredients. Several bioactive substances could be extracted from the marine by-product that can be utilized as a potent ingredient to develop cosmetics products. Those bioactive substances (e.g., collagen from fish waste and chitin from crustacean waste) could be utilized as anti-photoaging, anti-wrinkle, skin barrier, and hair care products. From this perspective, this review aims to approach the potential active ingredients derived from marine by-products for cosmetics and discuss the possible activity of those active ingredients in promoting human beauty. In addition, this review also covers the prospect and challenge of using marine by-products toward the emerging concept of sustainable blue cosmetics.
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Introduction: Combretum platypetalum is used in traditional African healing practices against different infections. Unfortunately, no scientific knowledge of its phytochemical composition exists, except for the isolation of two compounds from the leaves. Scientific study has been limited to the leaves only, despite the applications of stems and roots in traditional medicine practice and natural product drug discovery programs. Objective: Omics was applied to identify and classify different volatile and semivolatile bioactive compounds in the leaf, stem, and root parts of C. platypetalum. The thermal stability of the plant constituents at 60-65°C extraction temperature by Soxhlet and maceration at room temperature on the type, class, and concentration of compounds in the leaf was further investigated. Method: A GC-MS untargeted metabolomics approach, automated deconvolution by the Automated Mass Spectral Deconvolution and Identification System (AMDIS) for GC-MS data, preprocessing by Metab R, and multivariate statistical data analysis were employed in this study. Results: A total of 97 phytoconstituents, including 17 bioactive compounds belonging to the terpenoids, flavonoids, long-chain fatty acids, and other unclassified structural arrangements distributed across C. platypetalum, were identified for the first time. A correlation (r = 0.782; P = 0.000) between Soxhlet and maceration extraction methods relative to resolved chromatographic peak areas of metabolites was established. Conclusion: Findings corroborate the reported bio-investigation of its leaf extracts, its traditional uses, and previous findings from the Combretum genus. The results substantiate the possible applications of C. platypetalum in natural product drug discovery and provide a guide for future investigations.
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The present study was intended to explore the effects of endogenously produced ω-3 polyunsaturated fatty acids (PUFAs) on ultraviolet B (UVB)-induced skin inflammation and photocarcinogenesis using hairless fat-1 transgenic mice harboring ω-3 desaturase gene capable of converting ω-6 to ω-3 PUFAs. Upon exposure to UVB irradiation, fat-1 transgenic mice exhibited a significantly reduced epidermal hyperplasia, oxidative skin damage, and photocarcinogenesis as compared to wild type mice. The transcription factor, Nrf2 is a master regulator of anti-inflammatory and antioxidant gene expression. While the protein expression of Nrf2 was markedly enhanced, the level of its mRNA transcript was barely changed in the fat-1 transgenic mouse skin. Topical application of docosahexaenoic acid (DHA), a representative ω-3 PUFA, in wild type hairless mice induced expression of the Nrf2 target protein, heme oxygenase-1 in the skin and protected against UVB-induced oxidative stress, inflammation and papillomagenesis. Furthermore, transient overexpression of fat-1 gene in mouse epidermal JB6 cells resulted in the enhanced accumulation of Nrf2 protein. Likewise, DHA treated to JB6 cells inhibited Nrf2 ubiquitination and stabilized it. Taken together, our results indicate that functional fat-1 and topically applied DHA potentiate cellular defense against UVB-induced skin inflammation and photocarcinogenesis through elevated activation of Nrf2 and upregulation of cytoprotective gene expression.
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We summarize the 2016 update of the 2004 Agency of Healthcare Research and Quality' s evidence review of omega-3 fatty acids and cardiovascular disease (CVD). The overall findings for the effects of marine oil supplements on intermediate CVD outcomes remain largely unchanged. There is high strength of evidence, based on numerous trials, of no significant effects of marine oils on systolic or diastolic blood pressures, but there are small, yet statistically significant increases in high density lipoprotein and low density lipoprotein cholesterol concentrations. The clinical significance of these small changes, particularly in combination, is unclear. The strongest effect of marine oils is on triglyceride concentrations. Across studies, this effect was dose-dependent and related to studies′ mean baseline triglyceride concentration. In observational studies, there is low strength of evidence that increased marine oil intake lowers ischemic stroke risk. Among randomized controlled trials and observational studies, there is evidence of variable strength of no association with increased marine oil intake and lower CVD event risk. Evidence regarding alpha-linolenic acid intake is sparser. There is moderate strength of evidence of no effect on blood pressure or lipoprotein concentrations and low strength of evidence of no association with coronary heart disease, atrial fibrillation and congestive heart failure.
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Background Fish oil supplementation has been shown to be associated with a lower risk of metabolic syndrome and benefit a wide range of chronic diseases, such as cardiovascular disease, type 2 diabetes and several types of cancers. However, the evidence of fish oil supplementation on glucose metabolism and insulin sensitivity is still controversial. This meta-analysis summarized the exist evidence of the relationship between fish oil supplementation and insulin sensitivity and aimed to evaluate whether fish oil supplementation could improve insulin sensitivity. Methods We searched the Cochrane Library, PubMed, Embase database for the relevant studies update to Dec 2016. Two researchers screened the literature independently by the selection and exclusion criteria. Studies were pooled using random effect models to estimate a pooled SMD and corresponding 95% CI. This meta-analysis was performed by Stata 13.1 software. Results A total of 17 studies with 672 participants were included in this meta-analysis study after screening from 498 published articles found after the initial search. In a pooled analysis, fish oil supplementation had no effects on insulin sensitivity compared with the placebo (SMD 0.17, 95%CI -0.15 to 0.48, p = 0.292). In subgroup analysis, fish oil supplementation could benefit insulin sensitivity among people who were experiencing at least one symptom of metabolic disorders (SMD 0.53, 95% CI 0.17 to 0.88, p < 0.001). Similarly, there were no significant differences between subgroups of methods of insulin sensitivity, doses of omega-3 polyunsaturated fatty acids (n-3 PUFA) of fish oil supplementation or duration of the intervention. The sensitivity analysis indicated that the results were robust. Conclusions Short-term fish oil supplementation is associated with increasing the insulin sensitivity among those people with metabolic disorders.
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Mechanistic basis governing the extreme longevity and developmental quiescence of dauer juvenile, a “non-ageing” developmental variant of Caenorhabditis elegans, has remained largely obscure. Using a lipidomic approach comprising multiple reaction monitoring transitions specific to distinct fatty acyl moieties, we demonstrated that in comparison to other developmental stages, the membrane phospholipids of dauer larva contain a unique enrichment of polyunsaturated fatty acids (PUFAs). Esterified PUFAs in phospholipids exhibited temporal accumulation throughout the course of dauer endurance, followed by sharp reductions prior to termination of diapause. Reductions in esterified PUFAs were accompanied by concomitant increases in unbound PUFAs, as well as their corresponding downstream oxidized derivatives (i.e. eicosanoids). Global phospholipidomics has unveiled that PUFA sequestration in membrane phospholipids denotes an essential aspect of dauer dormancy, principally via suppression of eicosanoid production; and a failure to upkeep membrane lipid homeostasis is associated with termination of dauer endurance.
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Many studies have investigated the Mediterranean diet as a risk factor for cancer, none of which has included cutaneous melanoma. The latter is usually fatal, rendering knowledge about prevention extremely important. We assessed the role of some food components of the Mediterranean diet and cutaneous melanoma. A hospital-based case-control study was conducted in the inpatient wards of IDI-San Carlo Rome, Italy including 304 incident cases of cutaneous melanoma and 305 controls, frequency matched to cases. Information on socio-demographic characteristics, medical history, smoking, sun exposure, pigmentary characteristics and diet was collected. Logistic regression was the method used to estimated odds ratio and 95% CIs. After careful control for several sun exposure and pigmentary characteristics, we found a protective effect for weekly consumption of fish (OR, 0.65, 95%CI = 0.43-0.97), shellfish (OR, 0.53, 95%CI = 0.31-0.89), fish rich in n-3 fatty acids (OR, 0.52, 95%CI = 0.34-0.78), daily tea drinking (OR, 0.42, 95%CI, 0.18-0.95; P(trend) = 0.025) and high consumption of vegetables (OR, 0.50, 95%CI = 0.31-0.80, P(trend) = 0.005) in particular carrots, cruciferous and leafy vegetables and fruits (OR, 0.54, 95%CI =0.33-0.86, P(trend) = 0.013), in particular citrus fruits. No association was found for alcohol consumption and any other food items. Overall, our findings suggest that some dietary factors present in the Mediterranean diet might protect from cutaneous melanoma.
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Background: Fractionated, ablative lasers are usually associated with post-treatment erythema, edema, and crusting, which can last from 5 to 14 days. Conjugated linolenic acid, an omega-5 fatty acid, has significant antioxidant and anti-inflammatory properties, and has been shown to stimulate keratinocyte proliferation and epidermal regeneration. By modulating the early inflammatory milieu and directly affecting skin structure and function, conjugated linolenic acid might therefore shorten downtime following fractionated ablative laser resurfacing of the face. Objective: To evaluate the efficacy and subject satisfaction of a topical regimen containing conjugated linolenic acid derived from pomegranate seed extract in accelerating wound healing and improving skin quality following fractionated ablative laser resurfacing of the face. Materials and Methods: Thirty-four subjects were enrolled and received fractionated CO2 laser resurfacing. Subjects were randomized to use the test healing regimen (n=24) or 1% dimethicone ointment (n=10) post-procedure. The primary endpoint was the degree of erythema, edema, crusting, and exudation evaluated by a blinded clinician at post-treatment Days 1,3,7,10, 14, and 30. Secondary endpoints included a blinded evaluator assessment of the degree of wrinkling and elastosis using the Fitzpatrick-Goldman Wrinkle and Elastosis Scale; subject-assessed degree of pain, itching, tightness, oozing, and crusting; and subject overall satisfaction. Results: Subjects who applied the topical conjugated linolenic acid healing regimen experienced significantly reduced edema on post-procedure Day 3 (p=0.04), and itching on Days 1 and 3 (p=0.03 and p=0.04). Both regimens produced significant improvements in wrinkling and elastosis at Days 14 and 30 post-treatment, with conjugated linolenic acid outperforming placebo in improvements in wrinkling at Day 14. Both regimens were well tolerated with no statistical differences in adverse events or subject satisfaction. Conclusion: The topical conjugated linolenic acid formulation outperformed placebo by decreasing acute pruritus and edema, and enabling a faster positive outcome in wrinkle improvement. Additionally, topical conjugated linolenic acid does not raise any safety or tolerability issues as compared to current standard of care.
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Background: Dietary supplements (DSs) have the potential to be both beneficial and harmful to health, especially in adults aged ≥60 y, and therefore it is important to monitor the patterns of their use. Objective: This study evaluated DS use by adults aged ≥60 y to characterize the use of DSs, determine the motivations for use, and examine the associations between the use of DSs and selected demographic, lifestyle, and health characteristics. Methods: Data from 3469 older adults aged ≥60 y from the 2011–2014 NHANES were analyzed. DSs used in the past 30 d were ascertained via an interviewer-administered questionnaire in participants’ homes. The prevalence of overall DS use and specific types of DSs were estimated. The number of DSs reported and the frequency, duration, and motivation(s) for use were assessed. Logistic regression models were constructed to examine the association between DS use and selected characteristics. Results: Seventy percent of older adults in the United States reported using ≥1 DS in the past 30 d; 54% of users took 1 or 2 products, and 29% reported taking ≥4 products. The most frequently reported products were multivitamin or mineral (MVM) (39%), vitamin D only (26%), and omega-3 fatty acids (22%). Women used DSs almost twice as often as men [adjusted OR (aOR), 1.8; 95% CI: 1.5, 2.3). Those not reporting prescription medications were less likely to take a DS than those reporting ≥3 prescription medications (aOR, 0.4; 95% CI: 0.3, 0.6). The most frequently reported motivation for DS use was to improve overall health (41%). Conclusions: Use of DSs among older adults continues to be high in the United States, with 29% of users regularly taking ≥4 DSs, and there is a high concurrent usage of them with prescription medications.