Molecules 2009, 14, 540-554; doi:10.3390/molecules14010540
Biological and Pharmacological Activities of Squalene and
Related Compounds: Potential Uses in Cosmetic Dermatology
Zih-Rou Huang 1, Yin-Ku Lin 2,3 and Jia-You Fang 1,*
1 Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, 259
Wen-Hwa 1st Road, Kweishan, Taoyuan 333, Taiwan
2 Graduate Institute of Clinical Medical Sciences, Chang Gung University, Kweishan, Taoyuan,
3 Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan
* Author to whom correspondence should be addressed: E-mail: firstname.lastname@example.org; Tel.: +886-3-
2118800 ext. 5521; Fax: +886-3-2118236.
Received: 8 January 2009; in revised form: 19 January 2009 / Accepted: 21 January 2009 /
Published: 23 January 2009
Abstract: Squalene is a triterpene that is an intermediate in the cholesterol biosynthesis
pathway. It was so named because of its occurrence in shark liver oil, which contains large
quantities and is considered its richest source. However, it is widely distributed in nature,
with reasonable amounts found in olive oil, palm oil, wheat-germ oil, amaranth oil, and
rice bran oil. Squalene, the main component of skin surface polyunsaturated lipids, shows
some advantages for the skin as an emollient and antioxidant, and for hydration and its
antitumor activities. It is also used as a material in topically applied vehicles such as lipid
emulsions and nanostructured lipid carriers (NLCs). Substances related to squalene,
including β-carotene, coenzyme Q10 (ubiquinone) and vitamins A, E, and K, are also
included in this review article to introduce their benefits to skin physiology. We
summarize investigations performed in previous reports from both in vitro and in vivo
Keywords: Squalene, skin surface lipid, skin, antioxidant, topical delivery.
Molecules 2009, 14
Human skin, covering the entire outer surface of the body, is the largest organ and is constantly
exposed to sunlight stress, including ultraviolet (UV) light irradiation. The skin tissue is rich in lipids,
which are thought to be vulnerable to oxidative stress from sunlight. Squalene (Figure 1A) is a
structurally unique triterpene compound that is one of the main components (about 13%) of skin
surface lipids . It was so named because it was first isolated from shark (Squalus spp.) liver oil,
which contains large quantities and is considered its richest source . It is transported in serum
generally in association with very low density lipoproteins and is distributed ubiquitously in human
tissues, with the greatest concentration in the skin.
Figure 1. Chemical structures of (A) squalene, (B) β-carotene, (C) coenzyme Q10, and (D)
vitamins A, (E) E, and (F) K1.
(C) Coenzyme Q10
(D) Vitamin A
(E) Vitamin E
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Figure 1. Cont.
(F) Vitamin K1
Experimental studies have shown that squalene can effectively inhibit chemically induced skin,
colon, and lung tumorigenesis in rodents . The protective effect is observed when squalene is given
before and/or during carcinogen treatment. The mechanisms involved in the chemopreventive activity
of squalene may include inhibition of Ras farnesylation, modulation of carcinogen activation, and
antioxidative activities . However, several factors must be considered when the evidence for the
inhibition of carcinogenesis by squalene is examined. These include the effective dose used and the
time of exposure . This type of information is obtained from animal bioassays, and the long-term
effects of consuming increased levels of squalene are not known. Although animal studies have
enhanced our understanding of the possible actions of squalene in decreasing carcinogenesis, one must
apply caution in extrapolating the information obtained in animal studies to humans, because of
possible differences among species.
Many other polyprenyl compounds structurally similar to squalene exist in nature and perform
critical biological functions. These include β-carotene (Figure 1B), coenzyme Q10 (Figure 1C), and
vitamins A (Figure 1D), E (Figure 1E), and K1 (Figure 1F), which are introduced here because of their
benefits to skin physiology. For example, animals utilize prenyl groups to form the side chain of
coenzyme Q10. The coenzyme Q10 designation indicates that the molecule has 10 prenyl groups in its
side-chain. Other well-known substances require prenyl groups for their synthesis, and therefore are
structurally similar to squalene. In the present work, we attempted to introduce the activities and
benefits of squalene and related molecules to skin tissue, the largest organ of the human body. Some
important in vivo and clinical studies of squalene and its derivatives are also summarized and reviewed
in this article.
Biological activities of squalene
Squalene appears to be critical for reducing free radical oxidative damage to the skin. Serum
squalene originates partly from endogenous cholesterol synthesis and partly from dietary sources,
especially in populations consuming large amounts of olive oil or shark liver . The endogenous
synthesis of squalene begins with the production of 3-hydroxy-3-methylglutaryl coenzyme A (HMG
CoA). The initial reduction of HMG CoA (a niacin-dependent reaction) results in the formation of
Sebaceous glands are small glands in the skin which secrete an oily matter (sebum) in the hair
follicles to lubricate the skin and hair of animals (Figure 2). In humans, they are found in the greatest
abundance on the face and scalp, although they are distributed throughout all skin sites except the
palms and soles. Squalene is one of the predominant components (about 13%) of sebum (Table 1) .
Molecules 2009, 14
Figure 2. Sectional view of the skin with sebaceous glands.
Table 1. Composition of sebum in humans.
Substance Composition (%)
Wax esters 25
Triglycerides, free fatty acids, and diglycerides 57
Other components 3
Effects of squalene on the skin
Squalene is not very susceptible to peroxidation and appears to function in the skin as a quencher of
singlet oxygen, protecting human skin surfaces from lipid peroxidation due to exposure to UV light
and other sources of oxidative damage , as discussed here.
Truly one of nature’s great emollients, squalene is quickly and efficiently absorbed deep into the
skin, restoring healthy suppleness and flexibility without leaving an oily residue. New cosmetic
emulsions with biomimetic molecules have been investigated using experimental designs . That
study determined the optimal composition of a squalene mixture in an oil-in-water emulsion, using a
design of experiments to elaborate the experimental strategy. For this purpose, the stability,
centrifugation, viscosity, and pH of squalene were measured, and a microscopic analysis was carried
out. Results showed that the stability and viscosity of the emulsions exhibited the greatest influence on
the percentage of squalene.
Molecules 2009, 14
In general, occlusion leads to increased skin hydration due to reduced water loss. Rissmann et al.
 revealed that a vernix caseosa (VC) substitute can be an innovative barrier cream for barrier-
deficient skin. This is because of the excellent properties of VC in facilitating stratum corneum
hydration. Different lipid fractions were isolated from lanolin and subsequently mixed with squalene,
triglycerides, cholesterol, ceramides, and fatty acids to generate semi-synthetic lipid mixtures that
mimic the lipid composition of VC. The results showed that the rate of barrier recovery increased and
was comparable to VC lipid treatment. Okuda et al.  also found that the elevated transepidermal
water loss (TEWL) and riboflavin penetration in 5% sodium lauryl sulfate-treated rat and human skin
were reversed by squalene supplementation (p < 0.05).
Squalene has been reported to possess antioxidant properties. In vitro experimental evidence
indicates that squalene is a highly effective oxygen-scavenging agent. Subsequent to oxidative stress
such as sunlight exposure, squalene functions as an efficient quencher of singlet oxygen and prevents
the corresponding lipid peroxidation at the human skin surface . Kohno et al.  found that the
rate constant for quenching singlet oxygen by squalene is much larger than those of other lipids on the
human skin surface, and was comparable to that of 3,5-di-t-butyl-4-hydroxytoluene. They also
reported that squalene is not particularly susceptible to peroxidation and is stable against attacks by
peroxide radicals, suggesting that the chain reaction of lipid peroxidation is unlikely to be propagated
with adequate levels of squalene present on the human skin surface. Aioi et al.  studied the effects
of squalene on superoxide anion (O2-) generation in rats in order to elucidate the mechanism whereby
this compound decreases erythema induced by 1% lauroylsarcosine (LS) ointment. LS (200~400
μg/mL) caused overt production of O2- from cultured keratinocytes and peritoneal exudate leukocytes.
O2- was significantly reduced by the addition of squalene (100 μg/mL). These results suggest that a
possible role of squalene for alleviating skin irritation is by suppression of O2- production, which is
dependent on different mechanisms of action of superoxide dismutase.
During the past few years, squalene was found to show protective activities against several
carcinogens . Desai et al.  reported that skin tumors were initiated in 50 female CD-l mice
with 7,12-dimethylbenz[a]anthracene and promoted with 12-O-tetradecanoylphorbol-13-acetate. The
mice were treated with 5% squalene and at the end of the prevention study, there was a 26.67%
reduction in the incidence of tumors in the squalene-treated group. In a related branch of research, a
protective effect was observed when squalene was given before and/or during carcinogen treatment.
Experimental studies have shown that squalene can effectively inhibit chemically induced skin
tumorigenesis in rodents .
Molecules 2009, 14
Squalene as a material in topical formulations
Squalene is also used as a material or additive in topically applied vehicles such as lipid emulsions
and nanostructured lipid carriers (NLCs).
Lipid emulsions are potentially interesting drug delivery systems because of their ability to
incorporate drugs with poor solubility within the dispersal phase (Figure 3). An emulsion is a mixture
of two immiscible (unblendable) liquids. Lipid emulsions have been studied as parenteral drug carriers
for sustained release and organ targeting. By using lipid emulsions, direct contact of the drug with the
body fluid and tissues can also be avoided to minimize possible side effects . Chung et al. 
prepared oil-in-water type lipid emulsions to investigate the effects of different oils on emulsion
particle size and stability. Squalene was shown to form stable emulsions when a lipophilic drug was
loaded in the discontinuous oil phase. Even though the in vitro transfection activity of emulsions was
lower than that of liposomes in the absence of serum, the activity of squalene emulsions, for instance,
was approximately 30 times higher than that of liposome in the presence of 80% (v/v) serum (p <
Kim et al.  found that a squalene emulsion had the most potent transfection activity and showed
the least cytotoxicity in a mouse model after intravenous administration. Squalene as the oil
component can enhance the stability of cationic emulsions more effectively which might be useful for
in vitro and in vivo gene transfer. In addition, Wang et al.  indicated that emulsions with squalene
as the oil phase can act as a potential parenteral drug delivery system for nalbupline and its prodrugs.
Squalene as the oil phase produced the smallest particle size compared to coconut oil. The in vivo
analgesic activity of the emulsions was examined by a cold ethanol tail-flick test. The squalene system
showed the ability to provide controlled delivery to prolong the analgesic duration in rats. The toxicity
determined by erythrocyte hemolysis was also low for squalene emulsions.
Figure 3. A potent drug carrier vehicle: lipid emulsions.
Molecules 2009, 14
Nanostructured lipid carriers (NLCs)
Solid lipid nanoparticles (SLNs) are a new generation of oil-in-water nanoparticulate systems and
are attracting attention as novel colloidal drug carriers. Distinct advantages of SLNs are the solid state
of the particle matrix, the ability to protect chemically labile ingredients, and the possibility of
modulating and prolonging drug release. NLCs are a novel type of lipid nanoparticle with a solid
particle matrix possessing structural specialties and improvements such as an increased loading
capacity, long-term physical and chemical stability, triggered release, and potentially supersaturated
topical formulations. NLCs are produced by mixing solid lipids with spatially incompatible lipids
leading to a lipid matrix with a special structure. Depending on the method of production and
composition of the lipid blend, different types of NLCs can be obtained (Figure 4). The basic idea is
that by giving the lipid matrix a certain nanostructure, the payload of active compounds is increased
and expulsion of the compound during storage is avoided [20-24].
Figure 4. Three different types of nanostructured lipid carriers (NLCs) compared to the
more or less highly ordered matrix of solid lipid nanoparticles (SLNs). The three types of
NLC can be summarized as: (A) the amorphous type, (B) imperfect type, and (C) multiple
type. This figure is modified from reference .
(A) (B) (C)
Fang et al.  found that NLCs consisting of Precirol® and squalene (12% w/v) showed respective
mean particle sizes of 200 nm. The lipophilicity of NLCs decreased with an increase in the squalene
content in the formulations. Psoralen derivatives (i.e. 8-methoxypsoralen) for psoriasis treatment were
loaded in NLCs to examine their ability to permeate via the skin. Enhanced permeation and controlled
release of psoralen were both achieved using NLCs with squalene. The in vitro permeation results
showed that NLCs stabilized with Tween® 80 increased the 8-methoxypsoralen flux 2.8 times over that
of a conventional emulsion.
Amorphous lipid Incorporated drug
Solid lipid (fat)
Molecules 2009, 14
Production of toxins by squalene oxidation
Squalene monohydroperoxide (SQOOH) is a primary oxidized lipid produced from squalene by
solar UV. It is produced at the human skin surface due to natural exposure to sunlight during daily
activities. Recent studies demonstrated that repeated application of SQOOH to the skin can induce skin
roughness and wrinkles in the hairless mouse . Uchino et al.  also reported that SQOOH
induced skin damage in hairless mice. Furthermore, a few papers have also described the cytotoxicity
of SQOOH, which is a primary oxidized form of epidermal lipids produced by solar UV rays. SQOOH
is produced on human forehead skin, and it was suggested that skin squalene may be the principal
target lipid for oxidative stress (e.g., sunlight exposure). Nakagawa et al.  demonstrated that
SQOOH accumulation may be involved in inflammatory skin disorders such as skin cancer, cutaneous
autoimmune disease, and skin aging.
Chiba et al.  studied the effects of SQOOH, i.e., the initial product of UV-peroxidated squalene,
on the skin of hairless mice. Repeated topical application of 10 mM SQOOH to hairless mice for 15
weeks induced definite skin wrinkling. Those results clearly suggested that wrinkling and changes in
dermal collagen content induced by SQOOH qualitatively differ from those induced by UVB exposure
(p < 0.001). This may provide a useful model for studying skin aging, particularly with regard to the
Biological activities of squalene analogs
Many other polyprenyl compounds structurally similar to squalene exist in nature and perform
critical biological functions. β-Carotene is well known to be a potent 1O2 quencher and unique free
radical scavenger . This pro-vitamin A, carotenoid, can accumulate in the human skin through oral
intake. Stahl et al.  demonstrated that oral supplementation of carotenoid from sea algae
Dunaliella salina (94% β-carotene and small amounts of α-carotene, cryptoxanthin, zeaxanthin, and
lutein) protected human skin from UV light-induced erythema. Bando et al.  found that dietary β-
carotene acts as a photoprotective agent in the skin. That in vivo study focused on determining the
mechanism of action of β-carotene against UVA-induced skin damage by characterizing β-carotene
oxidation products. BALB/c mice were fed a β-carotene-supplemented diet, and homogenates from the
dorsal skin were prepared after three weeks for UVA irradiation. The results indicated that dietary β-
carotene accumulated in the skin and acted as a protective agent against UVA-induced oxidative
damage, by quenching 1O2.
A number of studies have demonstrated that dietary β-carotene protects human skin from UV light-
induced erythema, but little is known about the protective effect of dietary β-carotene on UVA-
induced skin photoaging . Antille et al.  showed that topical β-carotene penetrated well into
the human and mouse epidermis and induced 10- (human) and a 3-fold (mouse) increases,
respectively, in epidermal retinyl esters, which demonstrates that topical β-carotene is converted into
retinyl esters by human and mouse epidermis and thus appears as a precursor of epidermal vitamin A.
Molecules 2009, 14
β-Carotene was partially successful in treating a photosensitivity disorder, erythropoietic
protoporphyria, of which singlet oxygen is believed to be an important mediator. Several studies were
performed to examine whether β-carotene protects against UV-induced erythema in healthy humans,
with widely differing reported effects. The incidence of nonmelanoma skin cancer was reported to be
inversely related to serum β-carotene concentrations, and earlier experimental UV-carcinogenesis
studies found β-carotene to be photoprotective . However, the role of β-carotene as an anticancer
agent was questioned as a result of randomized intervention studies in which supplementation did not
reduce the incidence of nonmelanoma skin cancers in humans. Some concern exists over the long-term
(eight weeks) use of high-dose β-carotene because supplements of this substance can have deleterious
effects at higher doses (15 mg/day) in human skin (p < 0.05).
Coenzyme Q10 is an important lipophilic antioxidant synthesized by the body . Topical
coenzyme Q10 treatment may therefore be proposed as a good pharmacological tool in dermatology
and cosmetology . The amount of coenzyme Q10 in skin decreases with age. Topical application
of coenzyme Q10 to human skin was found to be effective in reducing the depth of wrinkles.
Coenzyme Q10 (0, 1, and 100 mg/kg oral administration) was administered daily for two weeks.
Supplementation with 100 mg/kg coenzyme Q10 significantly increased serum and epidermal
coenzyme Q10 levels, but did not increase coenzyme Q10 levels in the dermis or other organs. This
indicates that coenzyme Q10 intake elevates the epidermal coenzyme Q10 level, which may be a
prerequisite to reducing wrinkles and for other benefits related to the potent antioxidant and energizing
effects of coenzyme Q10 in the skin .
Coenzyme Q10 is a popular antioxidant used in many skin care products to protect the skin from
free radical damage. The effects of coenzyme Q10 and colorless carotenoids on the production of
inflammatory mediators in human dermal fibroblasts treated with UV radiation and possible
synergistic effects of these two antioxidants were evaluated by Fuller et al. . Treatment of
fibroblasts with 10 µM coenzyme Q10 suppressed the UV- and interleukin (IL)-1-induced increases in
prostaglandin E2, IL-6, and matrix metalloproteinase (MMP)-1. The results suggested that the
combination of carotenoids and coenzyme Q10 in topical skin care products may provide enhanced
protection from inflammation and premature aging caused by sun exposure.
Squalene and some of its related substances, including vitamin A, were examined in an animal
model to determine the existence of chemopreventive effects. Varani et al.  pointed out that topical
vitamin A (retinol) stimulated new collagen deposition in sun-protected aged skin, as it did in
photoaged skin. In a separate group of 53 individuals (80 years of age), topical application of 1%
vitamin A for seven days increased fibroblast growth and collagen synthesis, and concomitantly
reduced the levels of matrix-degrading MMPs. In addition, vitamin A treatment reduced MMP
expression in aged, sun-protected skin. Retinyl esters, a storage form of vitamin A, are concentrated in
the epidermis and absorb UV radiation with a maximum at 325 nm. Antille et al.  applied topical
Molecules 2009, 14
retinyl palmitate onto the back of hairless mice before exposing them to 1 J/cm2 UVB, and assayed the
levels of thymine dimers produced in epidermal DNA 2 h following UVB exposure. The results
demonstrated that epidermal retinyl esters have a biologically relevant filter activity and suggest,
besides their pleomorphic biologic actions, a new role for vitamin A that is concentrated in the
epidermis (p < 0.05). Moreover, Alberts et al.  concluded that vitamin A doses of 50,000 and
75,000 IU/day for one year proved safe, were equally more efficacious than a 25,000 IU/day dose, and
could be recommended for future skin cancer chemoprevention studies.
Vitamin A-derived agents still continue to be used to treat acne. Furthermore, retinoids act as
chemopreventive and/or chemotherapeutic agents for several types of cancer. They have major effects
on the growth and differentiation of normal, premalignant, and malignant epithelial cells both in vitro
and in vivo . Retinol (vitamin A) is widely used in the cosmetics industry as an anti-wrinkle agent.
However, its photoinstability and skin irritation potential make it challenging to use in general
cosmetic formulations . Retinol was applied to skin in either an oil-in-water emulsion or a gel
vehicle. Because of the substantial skin reservoir for retinol (0.3%) found at the end of 24 h in human
skin studies, additional studies were conducted to compare the in vitro and in vivo skin absorption
levels of retinol in the fuzzy rat. Results from those studies were used to help interpret the significance
of the in vitro retinol human skin reservoir in determining systemic absorption (p < 0.001) .
Jenning et al.  evaluated the potential use of solid lipid nanoparticles (SLNs) in dermatology and
cosmetics. The influence on drug penetration into porcine skin of glyceryl behenate SLNs loaded with
vitamin A (retinol and retinyl palmitate) and incorporated in a hydrogel and oil-in-water cream was
tested. Excised full-thickness skin was mounted in an in vitro Franz diffusion assembly, and
formulations were applied for 6 and 24 h. Vitamin A concentrations in the skin tissue suggested a
certain drug localizing effect. High retinol concentrations were found in the upper skin layers
following application of SLN preparations, whereas the deeper regions showed only very low vitamin
A levels (p < 0.05).
Vitamin E is the most potent lipid-soluble antioxidant in vivo. It is thought to play an important role
in skin protection . Uddin et al.  examined the protective efficacy of vitamin E against tumors
induced by UV and arsenite. Hairless mice were exposed to UV plus sodium arsenite (5 mg/L in
drinking water) and fed laboratory chow supplemented with vitamin E (R,R,R-a-tocopheryl acetate,
62.5 IU/kg diet) for 26 weeks. Vitamin E reduced the tumor yield in mice given UV and arsenite by
2.1-fold (p < 0.001). Those results show that vitamin E can strongly protect against arsenite-induced
enhancement of UV-caused carcinogenesis.
Vitamin E is a group of eight different compounds, but only two of the forms, α-tocopherol and γ-
tocopherol, are commonly found in the human body . Lopez-Torres et al.  investigated the
effects of topical α-tocopherol application on epidermal and dermal tissues and its ability to prevent
UV-induced oxidative damage. Hairless mice received a topical application of α-tocopherol 24 h
before a single acute exposure to UV irradiation (10 × minimal erythemal dose). α-Tocopherol
treatment significantly reduced the formation of epidermal lipid hydroperoxides after UV irradiation (p
Molecules 2009, 14
< 0.05). Those results demonstrated that topical administration of α-tocopherol protects cutaneous
tissues against oxidative damage induced by UV irradiation in vivo.
Yoshida et al.  investigated whether the topical application of a novel, water-soluble γ-
tocopherol derivative, γ-tocopherol-N,N-dimethylglycinate hydrochloride (γ-TDMG), could protect
against UV-induced skin damage in hairless mice. Topical pre- or post-application of a 5% (93 mM) γ-
TDMG solution in water/propylene glycol/ethanol (2:1:2) significantly prevented sunburned cell
formation, lipid peroxidation, and edema/inflammation, which were induced by exposure to a single
dose of UV irradiation at 5 kJ/m2 (290~380 nm, maximum 312 nm). Those results suggest that the
topical application of γ-TDMG may be efficacious in preventing and reducing UV-induced
Ekanayake-Mudiyanselage et al.  recently demonstrated that even the use of rinsing products
containing α-tocopherol in concentrations of < 0.2% can lead to significantly increased levels of
vitamin E in the stratum corneum of human skin and protects against lipid peroxidation in vivo.
Therefore, topical formulations containing α-tocopherol at concentrations ranging from 0.1% to 1%
are likely to be effective skin care measures to enhance antioxidative protection of the skin barrier.
According to the antioxidant network theory, combinations with co-antioxidants such as vitamin C
may help enhance the antioxidant effects and stability of vitamin E . A better knowledge of the
unique skin-specific physiology of vitamin E, including its percutaneous penetration, skin barrier
interactions, bioconversion of vitamin E esters, and cutaneous delivery pathways of oral vitamin E
could help in developing more-efficacious skin care products and better evaluating indications and
dosage regimens for preventing and treating acute and chronic skin disorders.
Vitamin K is another squalene-related substance that exhibits benefits to skin physiology. Lou et al.
 examined the safety and efficacy of a topical vitamin K cream for shortening the duration of laser-
induced purpura. From the results of that work, a combination of 1% vitamin K and 0.3% retinol in an
acrylate copolymer cream hastened the resolution of laser-induced purpura.
The application of vitamin K to the skin has also been used to suppress pigmentation and resolve
bruising. Lopes et al.  investigated the in vitro skin penetration and transdermal delivery of
vitamin K (2.5%, w/w), and whether these parameters were enhanced by lipid-based drug delivery
systems. The experimental results demonstrated that the topical delivery of vitamin K incorporated in a
lipophilic vehicle was low. It could be enhanced (~3-fold increase) by monoolein-based systems,
which may be useful in increasing the effectiveness of topical vitamin K therapy.
Squalene appears to be critical in reducing free radical oxidative damage to the skin. Although
epidemiological, experimental, and animal evidence suggests antitumor properties, few human trials
have been conducted to date to verify the role of squalene in cancer therapy. Further studies are needed
to explore the usefulness of squalene for treating skin. Several implications can be drawn from this
review. Squalene shows several advantages for skin tissues. It is also useful as a material in topically
Molecules 2009, 14
applied vehicles. Substances related to squalene such as β-carotene, coenzyme Q10, and vitamins A, E,
and K also exhibit their benefits for skin physiology. Topical administration via the skin is an
important route to supplement these compounds within skin tissues. The present success of squalene
and its analogs shows the promise of further clinical trials for skin use.
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