Dual Effects of Alpha-Hydroxy Acids on the Skin

Sheau-Chung Tang1,2 and Jen-Hung Yang1,3,*

Sheau-Chung Tang

1Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien 97004, Taiwan;
wt.ude.uct.smg@1500616s
2Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien 97004, Taiwan
Find articles by Sheau-Chung Tang
Jen-Hung Yang
1Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien 97004, Taiwan;
wt.ude.uct.smg@1500616s
3Department of Dermatology, Buddhist Tzu Chi General Hospital, Hualien 97004, Taiwan
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Author information Article notes Copyright and License information Disclaimer
1Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien 97004, Taiwan;
wt.ude.uct.smg@1500616s
2Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien 97004, Taiwan
3Department of Dermatology, Buddhist Tzu Chi General Hospital, Hualien 97004, Taiwan
*Correspondence: wt.ude.uct.smg@ude.dem.hj; Tel.: +886-3-8565301 (ext. 2001)
Received 2018 Feb 26; Accepted 2018 Apr 9.

Copyright © 2018 by the authors.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the
terms and conditions of the Creative Commons Attribution (CC BY) license
(http://creativecommons.org/licenses/by/4.0/).
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Abstract
AHAs are organic acids with one hydroxyl group attached to the alpha position of the acid.
AHAs including glycolic acid, lactic acid, malic acid, tartaric acid, and citric acid are often used
extensively in cosmetic formulations. AHAs have been used as superficial peeling agents as well
as to ameliorate the appearance of keratoses and acne in dermatology. However, caution
should be exercised in relation to certain adverse reactions among patients using products with
AHAs, including swelling, burning, and pruritus. Whether AHAs enhance or decrease photo
damage of the skin remains unclear, compelling us to ask the question, is AHA a friend or a foe
of the skin? The aim of this manuscript is to review the various biological effects and
mechanisms of AHAs on human keratinocytes and in an animal model. We conclude that
whether AHA is a friend or foe of human skin depends on its concentration. These mechanisms
of AHAs are currently well understood, aiding the development of novel approaches for the
prevention of UV-induced skin damage.
Keywords: alpha-hydroxy acids, UVB, apoptosis, keratinocyte, glycolic acid
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1. Introduction
Alpha-hydroxy acids (AHAs) include glycolic acid (GA), citric acid (CA), malic acid (MA), tartaric
acid (TA), and lactic acid (LA), all of which are naturally-occurring organic acids present in many
foods and milk sugars [1]. Structurally, AHAs are weak organic acids with one or more hydroxyl
groups attached to the alpha carbon, which is the first carbon following the acid group (Figure
1).
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Figure 1
The structures of AHAs commonly used in dermatology including glycolic acid, lactic acid, malic
acid, tartaric acid, and citric acid. AHAs are weak organic acids with one or more hydroxyl group
attached to the alpha carbon, indicating α. Malic acid and citric acid contain a hydroxyl group in
the α-position to one carboxyl group and in the β-position to the other carboxyl group. Tartaric
acid is a dicarboxylic acid with two hydroxyl groups at the alpha position of the acid. Malic acid
and citric acid are also prominent representatives in alpha hydroxyl acids and beta hydroxyl
acids.
In 1974, Van Scott and Yu indicated that AHAs could have profound effects on disorders related
to keratinization. AHAs can be used to easily peel all types of skin with minimal risk. AHAs
diminish corneocyte cohesion immediately above the granular layer by detaching and
desquamating the stratum corneum [2]. Thus, AHA peels have been popular in dermatological
practice for many years. AHAs are usually applied in the form of superficial and medium-depth
peels such as those used to treat acne, scars, melasma, hyperpigmentation, roughness, age
spots, and seborrhea [3]. AHAs can improve wrinkled skin by increasing the synthesis of
glycosaminoglycans and thickening skin [4]. Because of these factors, AHAs are a widely used
and popular treatment. Reports have demonstrated that AHAs can prevent ultraviolet (UV)-
induced skin tumor development [5], and many dermatologists have suggested that AHAs may
also play other roles, such as antioxidant activity [6]. However, other scholars hold opposing
views and have published studies that refute these assertions; studies have indicated that
topical application of AHAs can increase the photosensitivity of skin to UVB-irradiation When
paired with sunlight exposure, and AHAs also induced uneven skin pigmentation [1,7].
The question of whether AHAs are a friend or foe of the skin remains. The influence of AHAs on
phototoxicity and photoprotection is uncertain. Available nonclinical data disclosed by the U.S.
Food and Drug Administration (FDA) do not raise serious safety concerns regarding GA used
topically at low concentrations. However, caution is required in relation to adverse reactions to
AHA products, which can include redness, swelling, burning, and pruritus. Notably, factors
influencing the safety and effectiveness of AHA products include concentration, pH, exposure
time, and the amount of free acid present.
Our laboratory has analyzed a series of related studies on AHAs, which we also highlight in this
article [8,9,10,11,12,13,14,15,16,17]. GA regulates several signaling pathways, such as
epigenetic factors and apoptotic mediators. Our research has determined the critical
concentration of GA which, when combined with UVB at this concentration, results in
phototoxicity and inflammation. We provide new data to investigate the phototoxicity or
photoprotection in other AHAs, including CA, MA, and LA by ELISA assay. This review article
summarizes the related findings of studies that have investigated the phototoxicity or
photoprotective properties of AHAs.
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2. Role of AHAs in the Biological Responses of Skin Cells
2.1. The Effectiveness of AHAs
AHAs are found throughout nature in sugarcane (glycolic acid), sour milk (lactic acid), and fruits
(citric acid and malic acid). AHAs used in dermatologic and cosmetic products are usually
synthetically produced. Vorarat et al. and Parker et al. have reported that AHAs could be
separated in complex mixtures from fruits using capillary electrophoresis and through direct UV
detection at 200 nm [18]. Therefore, obtaining a signal and determining compound purity are
feasible. AHAs are small polar molecules and will disrupt the cohesion of corneocytes of the
skin barrier [19], but their dermal absorption remains obscure. According to many studies, the
effectiveness of AHAs is dependent on pH, concentration, and exposure time [18]. For example,
AHAs are one of the ingredients for cleaning products. AHAs in rinse-off shampoos and
conditioners are almost entirely removed from the skin within minutes by rinsing, resulting in
an application that is extensive and fast. In chemical peeling, AHAs are used in exposure time
intervals such as 35% (4 min), 52.5% (3 min), 70% (2 min) at varying intervals for up to 6 months
[20]. The preceding research provide evidence that the effectiveness of AHAs is dependent on
exposure time.
Over the preceding two decades, many studies have investigated the biological function and
clinical application of AHAs, and results have indicated that the effectiveness of AHAs is
determined by concentration and exposure time. Some clinical studies have examined the
effects of topically applied GA on markers for UV-light-induced damage. UVB (280–320 nm)-
induced DNA damage plays a key role in the initiation phase of skin cancer. Apoptosis and
efficient repair mechanisms of DNA damage protect human keratinocytes against UVB [21].
One study determined that that topical application of 10% GA for 12 weeks increased the
sensitivity of the skin to UV light and enhanced the formation of sunburn cells (SBCs) [7]. Our
previous study demonstrated that cotreatment of AHAs with a high concentration of GA (5
mM) and UVB had a synergistic effect on apoptosis in human keratinocyte HaCaT cells [9]. The
results of these studies suggest that the use of AHA substances on the skin requires caution.
2.2. The Safety of AHA
Citric acid, malic acid, and lactic acid are crucial members of the Krebs cycle and fermentation
process in cells. Most studies of citric acid and malic acid focus on cell metabolism and
adenosine 5’-triphosphate (ATP) production. In a 1971 review article, Decker reported the
nature and regulation of energy metabolism in the epidermis [22]. MA and CA are abundantly
present in many fruits and their seeds, such as cocoa pods, grapes, and blackberries [23].
Although many studies have investigated fruit extract compounds, few have investigated the
biological functions of pure MA and CA. In 1997, product formulation data submitted to the
U.S. FDA indicated that malic acid and citric acid are “generally recognized as safe” as direct
food additives used as flavor enhancers, flavoring agents, adjuvants, and for pH control (U.S.
FDA 1997). Ever since, CA and MA have been reported to function as pH adjusters and
humectants (moisturizing agents) in cosmetic formulations [24]. However, MA has been
deemed an irritant through clinical tests, but with less irritation observed as the pH of the
applied material increased. The problems may come from their interactions with the skin,
especially the epidermis.
2.3. AHA-Induced Apoptosis
CA and MA play different roles in relation to skin cells. One study found that CA induced
collagen I and procollagen II proliferation and GA improved the epidermis and dermis, thereby
verifying the usefulness of AHAs for rejuvenating photo-damaged skin [25]. In addition, CA at a
concentration of 20% can increase the thickness of the epidermis and the amount of
glycosaminoglycans in sun-damaged skin. CA has also been found to increase the skin renewal
rate [26] and treat sun-damaged skin. These functions may correlate with promoting
keratinocyte apoptosis.
Apoptosis (also called programmed cell death) can be activated through two main pathways:
the mitochondria-dependent pathway (intrinsic pathway) and the death-receptor-dependent
pathway (extrinsic pathway) [27]. The Fas receptor, Fas ligand, and caspase-8 are parts of an
important cellular pathway that regulates the induction of apoptosis in diverse cell and tissue
types [28]. We investigated the regulatory function of CA in skin cells. HaCaT is an excellent
model to investigate the keratinocyte system in vitro [29]. HaCaT keratinocytes were derived
from a histologically normal skin biopsy at the far periphery of a male melanoma patient [30].
Although HaCaT cells have intrinsic differences (e.g., p53 mutations) in comparison to those in
primary normal human epidermal keratinocytes (NHEK), NHEKs have a limited life span and
could only survive for several passages. Therefore, the immortalized and non-tumorigenic
HaCaT is frequently used as a convenient substitute of NHEK [31].
We found that CA (12.5 mM) activated caspase-9 and caspase-3, which subsequently induced
apoptosis through the caspase-dependent pathway. We clarified that CA also activated death
receptors, increased the level of caspase-8, and activated the BH3-interacting domain death
agonist (BID) protein, apoptosis-inducing factor, and endonuclease G (Endo G). CA induces
apoptosis through the mitochondrial pathway in HaCaT cells [15]. These mechanisms could
cause an increase in the skin renewal rate.
Regarding malic acid, we found that MA had an antiproliferative effect in HaCaT cells through
the inhibition of cell cycle progression at G0/G1. MA (15 mM) induced the expression of
endoplasmic reticulum stress-associated proteins such as GRP78, GADD153, and ATF6α. We
summarized that MA-induced apoptosis was found to occur through two molecular pathways:
(i) endoplasmic reticulum stress and (ii) mitochondria-dependent signaling pathways [16].
Despite the structural differences between CA and MA, these two compounds activate the
same apoptotic pathways. After treatment with CA or MA, HaCaT cells exhibit the apoptotic
features of DNA damage, apoptotic bodies, and an increase of sub-G1 cells, all of which are due
to the activation of caspase-8, -9, and -3 from mitochondria. The molecular pathways involved
in the effects of CA and MA on HaCaT cells are summarized in Figure 2.
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Figure 2
Molecular pathways involved in the effects of citric acid and malic acid on HaCaT cells. Citric
acid inhibits the proliferation of HaCaT cells via the induction of cell-cycle arrest and apoptosis.
Summarizing our previous studies evaluating the effects of treatment with citric acid or malic
acid, HaCaT cells exhibit the apoptotic features of apoptotic bodies, DNA damage, and an
increase of sub-G1 cells, resulting from activation of caspase-8, -9, and -3 and the induction of
AIF and endonuclease G (Endo G) release from mitochondria. Citric acid (CA) and malic acid
(MA)-induced apoptosis occur through multiple molecular pathways including the involvement
of endoplasmic reticulum (ER) stress- and mitochondria-dependent signaling pathways. Red
arrows indicate up-regulation; blue arrows indicate down-regulation. ROS: reactive oxygen
species.
CA has been found to increase the skin renewal rate, which could correlate with inducing
keratinocyte apoptosis. Recently studies have explored the efficacy of MA for treating Listeria
monocytogenes in the skin, and suggest that MA has antibacterial function [32]. Additionally,
the findings of Yamamoto et al. (2006) suggested that AHAs should be used as agents to
rejuvenate photo-aged skin [25]. These new findings demonstrate that MA and CA have more
diverse biological functions in skin cells.
2.4. Lactic Acid and Skin Microbiota
Lactic acid (as sodium lactate) is a well-known part of the skin’s natural moisturizing complex,
and is considered to be an excellent moisturizer. Smith et al. (1996) reported that LA was less
irritating than GA [33]. This may be a result of the presence of LA and LA bacteria in the gut and
skin. LA also contributes to the cell cycle in human keratinocytes. We demonstrated that LA at
7.5–17.5 mM had an antiproliferative effect in HaCaT cells through the inhibition of cell cycle
progression in the G1/S phase, and programmed cell death was induced through caspase-
dependent and caspase-independent pathways [17].
Recently, LA and probiotics have once again become prominent through participation in the
microbiome research boom. Human clinical trials clearly suggest that probiotic
supplementation might be beneficial to the skin [34]. Probiotic bacteria can modulate the
immune system at both local and systemic levels, thereby improving immune defense
mechanisms and/or down-regulating immune disorders such as allergies and intestinal
inflammation. LA maintains intestinal microflora through acid-based balancing properties [35].
Accumulating evidence suggests that intestinal microbiota correlate with many health issues
such as obesity, diabetes, metabolic syndrome, inflammatory bowel disease, autoimmune
disease, colon cancer, and atopic dermatitis (AD) [36]. In one example, Bifidobacterium longum
sp. extract was beneficial to sensitive skin [34]. Researchers have demonstrated that LA can be
regulated by neuropeptides such as Substance P (SP). SP is abundant in the skin [37] and the
gut [38], and acts as a transmitter in the bidirectional gut–skin communication network. SP is an
undecapeptide of the tachykinin family. In the skin, SP is considered a major mediator of
inflammation. SP contributes to the pathogenesis of numerous skin diseases, such as psoriasis,
AD, and acne [39]. SP-regulated LA release may be involved in maintaining the anti-
inflammatory status of the skin, and LA may also play a role in gut–skin immunoregulation.
2.5. The Forms of AHAs
LA and GA are two ingredients that have been familiar to the cosmetic and dermatological
community for many years. LA occurs in two forms, namely the L (+) form found in the human
body and produced by fermentation procedures, and the synthetic form (D (−); 50:50 L (+):D
(−)). The D (−) form can be produced selectively through fermentation by certain bacterial
strains [40]. The two types of LA have been verified as equally effective for increasing cell
renewal function.
Overall, regarding the roles of AHAs in the biological responses of skin cells, we clarified that at
indicated concentrations, CA, MA, and LA all induced cell death in the immortalized HaCaT cell
line [15,16,17]. Furthermore, AHA-induced apoptosis occurred through multiple molecular
pathways, including caspase-dependent and caspase-independent pathways. These results
revealed that AHAs induce cell death in keratinocyte cells, and this evidence expands our
knowledge of the function of AHAs in skin cells.
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3. AHAs, Peeling, and UV Irradiation
A variety of acids can stimulate skin cell renewal, have the potential to irritate the skin, and can
provide long-term cosmetic benefits such as improvements in skin firmness and elasticity and
the reduction of lines and wrinkles. Several studies have investigated how AHAs work to “de-
age” the skin. Some have suggested that the answer lies in the ability of AHAs to increase skin
cell renewal. A well-known major cause of skin aging is chronic microinflammation triggered by
UV irradiation and external pollutants [41]. Many studies have demonstrated that peeling can
increase the sensitivity of the skin to UV light, and even more have indicated that UV light
combined with AHA-associated peeling leads to more serious skin damage [7]. Lask et al. (2005)
reported that patients treated with GA (20–50%) every other day for the removal of the keratin
layer experienced serious UV damage [41]. We demonstrated that GA at high dose (5 mM)
produced a synergistic increase in the level of reactive oxygen species (ROS) in UVB-treated
HaCaT cells [9]. However, some studies have asserted the opposite view. Davidson and Wolfe
(1986) considered chemical peeling and dermabrasion able to counteract to some degree the
premature UV-aging of skin from chronic actinic damage [42]. People live in a sunny
environment, and those undergoing peeling cannot completely avoid sun exposure. To
determine the optimal level of peeling, measurement of UV-light-induced damage in affected
patients could provide valuable information on the clinical significance of the effects of AHAs on
the skin.
3.1. Clinical Peeling Concentration of AHAs
In clinics, the typical measurements used to assess UV damage are decreased minimal
erythemal dose (MED), increased tanning, and increased formation of SBCs [43]. However,
many individual differences in peeling concentrations can be observed. Thus, further cell-based
experiments must be conducted to obtain more detailed information.
In the context of the epidermis, the acidic nature of AHAs reduces the pH, inhibits transferases
and kinases, and interferes with the formation of ionic bonds, all of which contribute to
desmosome resolution and stimulate desquamation. The possible complications due to
chemical peeling are postinflammatory hyperpigmentation, infections, scarring, allergic
reactions, milia, persistent erythema, and textural changes. Antoniou et al. (2010) reported that
1% AHA content can alter the pH of the outer three layers of the stratum corneum, whereas
10% can affect all 10–20 layers [43]. The intensity of GA peeling is determined by the
concentration of the acid [3]. The U.S. FDA has recommended exercising caution in relation to
adverse reactions such as redness, swelling, burning, and pruritus due to use of AHA-containing
products [44]. Similarly, UV-induced phototoxicity has been associated with AHA
concentrations. The Ministry of Health and Welfare, R.O.C, has announced safety concerns
regarding AHA products, specifically chemical peeling agents containing higher concentrations
of AHAs (20–70%) and low pH levels used in hospitals and local practitioners’ clinics (Taiwan
Ministry of Health and Welfare, 2014) [45]. However, further caution is recommended
regarding the effects of AHAs on the epidermis and dermis, as well as the interrelationships
between these effects and concentration and pH.
3.2. Phototoxicity and Photoprotection of GA
AHAs and the skin: friend or foe? Whether AHAs enhance or decrease photo damage of the skin
remains unclear. GA is often used to treat acne, normalize keratinization, and decrease
epidermal thickness, dermal hyaluronic acid, and collagen gene expression [46]. As with other
AHAs, concern has been expressed over whether the topical application of GA can increase the
skin’s photosensitivity to or photoprotection against UV irradiation. Similarly, varying views
regarding this question have been expressed. We demonstrated that GA (5 mM) or UVB alone
had an inhibitory effect on HaCaT cell proliferation, and cotreatment with GA and UVB had a
synergistic antiproliferative effect related to cell cycle arrest and apoptosis in UVB-treated
keratinocytes [9]. However, our findings are contradictory to those of Ahn et al., who claimed
that GA inhibited UVB-induced cytotoxicity and attenuated apoptosis in HaCaT cells treated
with 1 mM of GA (2002) [47]. These conflicting results indicate that whether GA is a friend or
foe of skin cells may depend on its concentration. This turning point led our laboratory
members to believe that GA may exert different effects at different concentrations. We
employed high (5 mM; pH 7.1) and low (0.1 mM; pH 7.4) concentrations of GA to clarify the
photoprotective or phototoxic properties of GA in UVB-radiated skin keratinocytes. The
contradictory data obtained in HaCaT cells with GA depended on the concentrations and
intrinsic property of these compounds, indicating that GA may have an anti-inflammatory effect
via epigenetic modifications at low concentrations, whereas GA at high concentrations had a
synergistic phototoxic effect on HaCaT keratinocytes. GA at high concentrations will disrupt the
cohesion of skin barrier corneocytes, and results in skin irritation or peeling, which will
exacerbate photodamage of the skin.
3.3. Inflammation, ROS and AHAs
UV irradiation induces multiple cell responses, such as ROS accumulation, cell apoptosis, DNA
breakage and damage, cell cycle arrest, and inflammasome formation [48]. Regarding these
notable features, we found that GA at a low concentration (0.1 mM) effectively prevented the
UVB-induced loss of skin cell viability, ROS formation, and DNA damage in primary normal
human epidermal keratinocytes (NHEKs). We demonstrated that GA at a low concentration (0.1
mM) either alone or with UVB radiation reduced the expression of inflammasome genes in
NHEKs and HaCaT cells. These genes include NLRC4 and ASC, and are downregulated through
epigenetic modification by increasing total DNA methyltransferase activity [10]. Through this
mechanism, GA can reduce NLRC4 and ASC gene expression, thereby resulting in inflammasome
collapse and decreasing the quantity of inflammasome downstream cytokine interleukin (IL)-1β
released. These results all indicate that GA at a low concentration (0.1 mM) has a significant
photoprotective effect on human keratinocytes. As we know, UV irradiation typically induces
acute phase responses and stimulates inflammatory factors in the skin such as IL-1, IL-6, IL-7, IL-
8, IL-12, IL-15, monocyte chemoattractant protein (MCP)-1, tumor necrosis factor (TNF), and
granulocyte-macrophage colony-stimulating factor (GM-CSF) from keratinocytes, leading to
inflammation of the skin [49]. Our study clarified that GA at a low concentration (0.1 mM) was
able to specifically downregulate UVB-induced cytokines and chemokine secretion in
keratinocytes. Furthermore, we clearly demonstrated that GA blocked UVB-induced
inflammatory cytokines through the nuclear factor-kappa B (NF-kB) signal pathway [12], as
shown in Figure 3.

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Figure 3
Glycolic acid (GA) had anti-inflammatory and photoprotective effects against UVB-irradiation in
keratinocytes. (Left) UVB-irradiation activated the nuclear factor-kappa B (NF-kB) pathway and
promoted the inflammasome complex assembly, which in ROS accumulation and the release of
several proinflammatory cytokines (e.g., interleukin (IL)-6, IL-8, monocyte chemoattractant
protein (MCP)-1, IL-Iβ, COX-2, and IL-1β; (Right) Pretreatment with GA could activate DNMT-3B
activity and induce the hypermethylation of promoters of NLRC4 and ASC genes, which
subsequently hinder of the assembly of the inflammasome complex. GA also inhibited the UVB-
induced promoter activity of NF-kB in keratinocyte cells.
To clarify the photoprotective or phototoxic properties in other AHAs, LA, CA, and MA were
pretreated in various doses in UVB-irradiated skin keratinocytes, and the proinflammatory
cytokines (IL-6, IL-8, and MCP-1) were determined by ELISA. All of the proinflammatory
cytokines were significantly stimulated in UVB-irradiated keratinocytes. Pretreatment with CA
notably decreased IL-8 and MCP-1 secretion in UVB-irradiated keratinocytes, though not that of
IL-6. LA decreased the MCP-1 release, but not IL-6 in UVB-irradiated cells (data not shown).
Interestingly, LA had a synergistic response on IL-8 cytokines induced by UVB-irradiated
keratinocytes. We consider that both CA and MA have photoprotective properties due to the
decreased IL-6 and MCP-1 released in UVB-irradiated keratinocytes. LA has phototoxicity
properties due to its effects on IL-8 in UVB-irradiated keratinocytes. However, UVB-stimulated
IL-6, IL-8, and MCP-1 proinflammatory cytokines release via multiple pathways, such as NF-kB-
dependent inflammatory mediators, COX-2/PGE2 pathway, and c-Fos/AP-1 pathways [50,51].
These released cytokines also need other cells (e.g., Langerhans cells) to contribute to the
immune response [52]. All of these results indicate that although CA, MA, and LA belong to the
AHAs, the mechanisms of their photoprotective or phototoxic properties may be different.
These questions will need more research in the future.
3.4. GA and in Vivo Study
To more closely reproduce in vivo conditions, we treated the dorsal skin of mice with various
concentrations (1%, 2%, 3%, and 5%) of GA. The high concentrations (3% and 5%) caused skin
irritation or chemical burns, whereas the low concentrations (1% and 2%) substantially
decreased UVB-induced cytokines and chemokines, including MCP-1, TNF-α, IL-1β, IL-6, IL-8,
and COX-2. Therefore, “high concentration” is defined as 5 mM (in vitro) or 3% or higher (in
vivo), whereas “low concentration” is defined as 0.1 mM (in vitro) or 2% or lower (in vivo) in our
series of studies. We suggest that GA is a friend of the skin at low concentrations because of its
protection against UVB. These data are sufficient to explain that the ability of GA to enhance or
decrease photo damage to the skin is dependent on its concentration.
Similar results can be found throughout the literature. Hong et al. suggested an inhibitory effect
of GA (10.5%) on UV-induced skin tumorigenesis in SKH-1 hairless mice (2001) [53]. The
concentration of GA used in these experiments was higher than that used in our animal model.
However, some factors should be considered, such as the skin smear area, GA volume,
adjuvant, and animal strain. The influence of these factors needs to be considered. To better
understand GA at various concentrations (0.1–250 mM), percentages (1–5%), and exposure
types (cells or animal skin), as well as variations in the biological effects of mechanisms
(including epigenetic modification, apoptosis, cell cycle, and inflammation), we have illustrated
a summary of these findings, presented as the graph in Figure 4.
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Figure 4
Review of the various biological effects (phototoxicity or photoprotection) and mechanisms
(apoptosis or anti-inflammation) of GA on human keratinocytes (HaCaT or NHEK), and in the
mice animal model.
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4. Future Prospects
Currently, a considerable volume of research and noteworthy literature on the photoprotective
and anti-inflammatory effects of AHAs is available. However, the photoprotective activity is
dependent on the amounts of these compounds that reach the viable skin layers. Chemical
movement across the skin cell membrane can occur via channel, diffusion, and receptor [54].
Some studies have indicated that the vanilloid-receptor-related transient receptor potential
(TRPV) family is a type of AHA receptor [55]. Therefore, we are now interested in whether the
expression of the TRPV1 receptor changes in human skin treated with AHAs. We have found GA
predominantly reversed the down-regulation of aquaporin 3 (AQP-3) by UVB (data not shown).
AQP-3 protein expressed in the basal layer of the epidermis, and a deficiency of AQP3 reduces
stratum corneum hydration [56]. We also intend to explore whether GA as a water repellent
avoids UVB irradiation and causes dehydration. Many questions still need to be resolved.
Future experiments will provide a clearer and broader perspective of AHAs.
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5. Conclusions
UVB radiation from the sun first encounters the uppermost epidermal keratinocytes and plays a
more active role in regulating several crucial biological responses in skin cells, such as ROS
accumulation, apoptosis, DNA fragmentation, and inflammation. When used on human skin,
the different concentrations of AHAs have therapeutic and cosmetic benefits as an integrated
system that serves as a physical and immunological barrier to harmful external factors and
prevents DNA breakage. Whether AHA is a friend or foe of human skin depends on its
concentration. AHAs used as peeling agents at high concentrations will disrupt cohesion of the
corneocytes of the skin barrier and result in skin irritation, which is harmful to the skin. To the
contrary, AHAs at low concentrations may be beneficial to the skin because of epigenetic
modifications of inflammasome complex. In other words, AHAs have dual effects on the skin.
This article presents various features of AHAs. Our studies on animal models could apply to
human populations, and such application could lead to the development of novel approaches
for the prevention of UV-induced conditions.
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Acknowledgments
This study was supported by the Buddhist Tzu Chi Hospital, Hualien, R.O.C. (TCMMP 10401-01),
and the manuscript was edited by Wallace Academic Editing.
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Abbreviations

AD atopic dermatitis

AHAs alpha-hydroxy acids

BID BH3-interacting domain death agonist protein

CA citric acid

ELISA enzyme-linked immunosorbent assay

Endo G endonuclease G

GA glycolic acid

GM-CSF granulocyte-macrophage colony-stimulating factor

IL interleukin

LA lactic acid
MA malic acid

MCP-1 monocyte chemoattractant protein-1

MED minimal erythemal dose

MMP matrix metalloproteinase

NF-kB nuclear factor-kappa B

NHEK normal human epidermal keratinocyte

ROS reactive oxygen species

SBCs sunburn cells

SP Substance P

TNF tumor necrosis factor

UVB ultraviolet radiation B

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Author Contributions
Sheau-Chung Tang and Jen-Hung Yang both conceived, designed and performed the
experiments, analyzed the data and wrote the paper.
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Conflicts of Interest
The founding sponsors had no role in the design of the study; in the collection, analyses, or
interpretation of data; in the writing of the manuscript, and in the decision to publish the
results.
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Abstract
1. Introduction
2. Role of AHAs in the Biological Responses of Skin Cells
3. AHAs, Peeling, and UV Irradiation
4. Future Prospects
5. Conclusions
Acknowledgments
Abbreviations
Author Contributions
Conflicts of Interest
References

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Glycolic acid peels for the treatment of wrinkles and photoaging.[J Dermatol Surg Oncol. 1993]
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Effects of alpha-hydroxy acids on photoaged skin: a pilot clinical, histologic, and ultrastructural
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in lipid bilayers and in human skin homogenates.[Biochem Mol Biol Int. 1997]
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Food Chem Toxicol. 2004 Nov; 42(11):1777-84.
Synergistic phototoxic effects of glycolic acid in a human keratinocyte cell line (HaCaT).[J
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Lai WW, Hsiao YP, Chung JG, Wei YH, Cheng YW, Yang JH
J Dermatol Sci. 2011 Dec; 64(3):191-8.
Glycolic Acid Silences Inflammasome Complex Genes, NLRC4 and ASC, by Inducing DNA
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Tang SC, Yeh JI, Hung SJ, Hsiao YP, Liu FT, Yang JH
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Tang SC, Liao PY, Hung SJ, Ge JS, Chen SM, Lai JC, Hsiao YP, Yang JH
J Dermatol Sci. 2017 Jun; 86(3):238-248.
Gallic acid induces apoptosis in A375.S2 human melanoma cells through caspase-dependent
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Parker ET, Cleaves HJ 2nd, Bada JL, Fernández FM
Rapid Commun Mass Spectrom. 2016 Sep 30; 30(18):2043-51.
Hyperkeratinization, corneocyte cohesion, and alpha hydroxy acids.[J Am Acad Dermatol. 1984]
Van Scott EJ, Yu RJ
J Am Acad Dermatol. 1984 Nov; 11(5 Pt 1):867-79.
Chemical peeling--evaluation of glycolic acid in varying concentrations and time
intervals.[Indian J Dermatol Venereol Leprol. 2001]
Gupta RR, Mahajan BB, Garg G
Indian J Dermatol Venereol Leprol. 2001 Jan-Feb; 67(1):28-9.
Review UV-induced DNA damage, repair, mutations and oncogenic pathways in skin cancer.[J
Photochem Photobiol B. 2001]
de Gruijl FR, van Kranen HJ, Mullenders LH
J Photochem Photobiol B. 2001 Oct; 63(1-3):19-27.
Topical glycolic acid enhances photodamage by ultraviolet light.[Photodermatol Photoimmunol
Photomed. 2003]
Kaidbey K, Sutherland B, Bennett P, Wamer WG, Barton C, Dennis D, Kornhauser A
Photodermatol Photoimmunol Photomed. 2003 Feb; 19(1):21-7.
Synergistic phototoxic effects of glycolic acid in a human keratinocyte cell line (HaCaT).[J
Dermatol Sci. 2011]
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J Dermatol Sci. 2011 Dec; 64(3):191-8.
Review Nature and regulation of energy metabolism in the epidermis.[J Invest Dermatol. 1971]
Decker RH
J Invest Dermatol. 1971 Dec; 57(6):351-63.
Comparison of cardioprotective abilities between the flesh and skin of grapes.[J Agric Food
Chem. 2006]
Falchi M, Bertelli A, Lo Scalzo R, Morassut M, Morelli R, Das S, Cui J, Das DK
J Agric Food Chem. 2006 Sep 6; 54(18):6613-22.
Safety Assessment of Citric Acid, Inorganic Citrate Salts, and Alkyl Citrate Esters as Used in
Cosmetics.[Int J Toxicol. 2014]
Fiume MM, Heldreth BA, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks JG Jr,
Shank RC, Slaga TJ, Snyder PW, Andersen FA
Int J Toxicol. 2014 May; 33(2 suppl):16S-46S.
Effects of alpha-hydroxy acids on the human skin of Japanese subjects: the rationale for
chemical peeling.[J Dermatol. 2006]
Yamamoto Y, Uede K, Yonei N, Kishioka A, Ohtani T, Furukawa F
J Dermatol. 2006 Jan; 33(1):16-22.
Alpha-hydroxyacids and carboxylic acids.[J Cosmet Dermatol. 2004]
Yu RJ, Van Scott EJ
J Cosmet Dermatol. 2004 Apr; 3(2):76-87.
Review Apoptosis pathways as promising targets for skin cancer therapy.[Br J Dermatol. 2007]
Eberle J, Fecker LF, Forschner T, Ulrich C, Röwert-Huber J, Stockfleth E
Br J Dermatol. 2007 May; 156 Suppl 3():18-24.
Review Bufadienolides from amphibians: A promising source of anticancer prototypes for
radical innovation, apoptosis triggering and Na⁺/K⁺-ATPase
inhibition.[Toxicon. 2017]
Sousa LQ, Machado KD, Oliveira SF, Araújo LD, Monção-Filho ED, Melo-Cavalcante AA, Vieira-
Júnior GM, Ferreira PM
Toxicon. 2017 Mar 1; 127():63-76.
Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell
line.[J Cell Biol. 1988]
Boukamp P, Petrussevska RT, Breitkreutz D, Hornung J, Markham A, Fusenig NE
J Cell Biol. 1988 Mar; 106(3):761-71.
A circadian clock in HaCaT keratinocytes.[J Invest Dermatol. 2011]
Spörl F, Schellenberg K, Blatt T, Wenck H, Wittern KP, Schrader A, Kramer A
J Invest Dermatol. 2011 Feb; 131(2):338-48.
Citric acid induces cell-cycle arrest and apoptosis of human immortalized keratinocyte cell line
(HaCaT) via caspase- and mitochondrial-dependent signaling pathways.[Anticancer Res. 2013]
Ying TH, Chen CW, Hsiao YP, Hung SJ, Chung JG, Yang JH
Anticancer Res. 2013 Oct; 33(10):4411-20.
Triggering apoptotic death of human epidermal keratinocytes by malic Acid: involvement of
endoplasmic reticulum stress- and mitochondria-dependent signaling pathways.[Toxins (Basel).
2015]
Hsiao YP, Lai WW, Wu SB, Tsai CH, Tang SC, Chung JG, Yang JH
Toxins (Basel). 2015 Jan 9; 7(1):81-96.
Efficacy of malic acid against Listeria monocytogenes attached to poultry skin during
refrigerated storage.[Poult Sci. 2013]
González-Fandos E, Herrera B
Poult Sci. 2013 Jul; 92(7):1936-41.
Effects of alpha-hydroxy acids on the human skin of Japanese subjects: the rationale for
chemical peeling.[J Dermatol. 2006]
Yamamoto Y, Uede K, Yonei N, Kishioka A, Ohtani T, Furukawa F
J Dermatol. 2006 Jan; 33(1):16-22.
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Smith WP
Int J Cosmet Sci. 1996 Apr; 18(2):75-83.
Antiproliferative effects of lactic acid via the induction of apoptosis and cell cycle arrest in a
human keratinocyte cell line (HaCaT).[J Dermatol Sci. 2009]
Hsiao YP, Huang HL, Lai WW, Chung JG, Yang JH
J Dermatol Sci. 2009 Jun; 54(3):175-84.
Bifidobacterium longum lysate, a new ingredient for reactive skin.[Exp Dermatol. 2010]
Guéniche A, Bastien P, Ovigne JM, Kermici M, Courchay G, Chevalier V, Breton L, Castiel-
Higounenc I
Exp Dermatol. 2010 Aug; 19(8):e1-8.
Immunomodulatory Effects of Different Lactic Acid Bacteria on Allergic Response and Its
Relationship with In Vitro Properties.[PLoS One. 2016]
Ai C, Ma N, Zhang Q, Wang G, Liu X, Tian F, Chen P, Chen W
PLoS One. 2016; 11(10):e0164697.
Antipruritic effects of the probiotic strain LKM512 in adults with atopic dermatitis.[Ann Allergy
Asthma Immunol. 2014]
Matsumoto M, Ebata T, Hirooka J, Hosoya R, Inoue N, Itami S, Tsuji K, Yaginuma T, Muramatsu
K, Nakamura A, Fujita A, Nagakura T
Ann Allergy Asthma Immunol. 2014 Aug; 113(2):209-216.e7.
Effects of a skin neuropeptide (substance p) on cutaneous microflora.[PLoS One. 2013]
Mijouin L, Hillion M, Ramdani Y, Jaouen T, Duclairoir-Poc C, Follet-Gueye ML, Lati E, Yvergnaux
F, Driouich A, Lefeuvre L, Farmer C, Misery L, Feuilloley MG
PLoS One. 2013; 8(11):e78773.
Review Neuropeptides and inflammatory bowel disease.[Curr Opin Gastroenterol. 2009]
Margolis KG, Gershon MD
Curr Opin Gastroenterol. 2009 Nov; 25(6):503-11.
Substance P enhances lactic acid and tyramine production in <i>Enterococcus faecalis</i> V583
and promotes its cytotoxic effect on intestinal Caco-2/TC7 cells.[Gut Pathog. 2017]
Biaggini K, Borrel V, Szunerits S, Boukherroub R, N'Diaye A, Zébré A, Bonnin-Jusserand M,
Duflos G, Feuilloley M, Drider D, Déchelotte P, Connil N
Gut Pathog. 2017; 9():20.
Citric acid induces cell-cycle arrest and apoptosis of human immortalized keratinocyte cell line
(HaCaT) via caspase- and mitochondrial-dependent signaling pathways.[Anticancer Res. 2013]
Ying TH, Chen CW, Hsiao YP, Hung SJ, Chung JG, Yang JH
Anticancer Res. 2013 Oct; 33(10):4411-20.
Triggering apoptotic death of human epidermal keratinocytes by malic Acid: involvement of
endoplasmic reticulum stress- and mitochondria-dependent signaling pathways.[Toxins (Basel).
2015]
Hsiao YP, Lai WW, Wu SB, Tsai CH, Tang SC, Chung JG, Yang JH
Toxins (Basel). 2015 Jan 9; 7(1):81-96.
Antiproliferative effects of lactic acid via the induction of apoptosis and cell cycle arrest in a
human keratinocyte cell line (HaCaT).[J Dermatol Sci. 2009]
Hsiao YP, Huang HL, Lai WW, Chung JG, Yang JH
J Dermatol Sci. 2009 Jun; 54(3):175-84.
The utilization of nonthermal blue (405-425 nm) and near infrared (850-890 nm) light in
aesthetic dermatology and surgery-a multicenter study.[J Cosmet Laser Ther. 2005]
Lask G, Fournier N, Trelles M, Elman M, Scheflan M, Slatkine M, Naimark J, Harth Y
J Cosmet Laser Ther. 2005 Dec; 7(3-4):163-70.
Topical glycolic acid enhances photodamage by ultraviolet light.[Photodermatol Photoimmunol
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Kaidbey K, Sutherland B, Bennett P, Wamer WG, Barton C, Dennis D, Kornhauser A
Photodermatol Photoimmunol Photomed. 2003 Feb; 19(1):21-7.
Synergistic phototoxic effects of glycolic acid in a human keratinocyte cell line (HaCaT).[J
Dermatol Sci. 2011]
Lai WW, Hsiao YP, Chung JG, Wei YH, Cheng YW, Yang JH
J Dermatol Sci. 2011 Dec; 64(3):191-8.
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Davidson TM, Wolfe DP
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Review Photoaging: prevention and topical treatments.[Am J Clin Dermatol. 2010]
Antoniou C, Kosmadaki MG, Stratigos AJ, Katsambas AD
Am J Clin Dermatol. 2010; 11(2):95-102.
Review Photoaging: prevention and topical treatments.[Am J Clin Dermatol. 2010]
Antoniou C, Kosmadaki MG, Stratigos AJ, Katsambas AD
Am J Clin Dermatol. 2010; 11(2):95-102.
Review Glycolic acid peel therapy - a current review.[Clin Cosmet Investig Dermatol. 2013]
Sharad J
Clin Cosmet Investig Dermatol. 2013 Nov 11; 6():281-8.
Alpha hydroxy acids for skin care.[FDA Consum. 1998]
Kurtzweil P
FDA Consum. 1998 Mar-Apr; 32(2):30-5.
Glycolic acid treatment increases type I collagen mRNA and hyaluronic acid content of human
skin.[Dermatol Surg. 2001]
Bernstein EF, Lee J, Brown DB, Yu R, Van Scott E
Dermatol Surg. 2001 May; 27(5):429-33.
Synergistic phototoxic effects of glycolic acid in a human keratinocyte cell line (HaCaT).[J
Dermatol Sci. 2011]
Lai WW, Hsiao YP, Chung JG, Wei YH, Cheng YW, Yang JH
J Dermatol Sci. 2011 Dec; 64(3):191-8.
Inhibitory effect of glycolic acid on ultraviolet B-induced c-fos expression, AP-1 activation and
p53-p21 response in a human keratinocyte cell line.[Cancer Lett. 2002]
Ahn KS, Park KS, Jung KM, Jung HK, Lee SH, Chung SY, Yang KH, Yun YP, Pyo HB, Park YK, Yun
YW, Kim DJ, Park SM, Hong JT
Cancer Lett. 2002 Dec 5; 186(2):125-35.
Review Damage to skin extracellular matrix induced by UV exposure.[Antioxid Redox Signal.
2014]
Watson RE, Gibbs NK, Griffiths CE, Sherratt MJ
Antioxid Redox Signal. 2014 Sep 1; 21(7):1063-77.
Glycolic Acid Silences Inflammasome Complex Genes, NLRC4 and ASC, by Inducing DNA
Methylation in HaCaT Cells.[DNA Cell Biol. 2016]
Tang SC, Yeh JI, Hung SJ, Hsiao YP, Liu FT, Yang JH
DNA Cell Biol. 2016 Mar; 35(3):124-34.
Gene profiling of narrowband UVB-induced skin injury defines cellular and molecular innate
immune responses.[J Invest Dermatol. 2013]
Kennedy Crispin M, Fuentes-Duculan J, Gulati N, Johnson-Huang LM, Lentini T, Sullivan-Whalen
M, Gilleaudeau P, Cueto I, Suárez-Fariñas M, Lowes MA, Krueger JG
J Invest Dermatol. 2013 Mar; 133(3):692-701.
Topical application of glycolic acid suppresses the UVB induced IL-6, IL-8, MCP-1 and COX-2
inflammation by modulating NF-κB signaling pathway in keratinocytes and mice skin.[J
Dermatol Sci. 2017]
Tang SC, Liao PY, Hung SJ, Ge JS, Chen SM, Lai JC, Hsiao YP, Yang JH
J Dermatol Sci. 2017 Jun; 86(3):238-248.
Ultraviolet radiation-induced non-melanoma skin cancer: Regulation of DNA damage repair and
inflammation.[Genes Dis. 2014]
Kim Y, He YY
Genes Dis. 2014 Dec 1; 1(2):188-198.
Review Current concept of photocarcinogenesis.[Photochem Photobiol Sci. 2015]
Nishisgori C
Photochem Photobiol Sci. 2015 Sep 26; 14(9):1713-21.
Review New insights into the molecular control of the lymphatic vascular system and its role in
disease.[J Invest Dermatol. 2006]
Cueni LN, Detmar M
J Invest Dermatol. 2006 Oct; 126(10):2167-77.
Inhibitory effect of glycolic acid on ultraviolet-induced skin tumorigenesis in SKH-1 hairless mice
and its mechanism of action.[Mol Carcinog. 2001]
Hong JT, Kim EJ, Ahn KS, Jung KM, Yun YP, Park YK, Lee SH
Mol Carcinog. 2001 Jul; 31(3):152-60.
TRP Channels as Potential Drug Targets.[Annu Rev Pharmacol Toxicol. 2018]
Moran MM
Annu Rev Pharmacol Toxicol. 2018 Jan 6; 58():309-330.
Intracellular proton-mediated activation of TRPV3 channels accounts for the exfoliation effect
of α-hydroxyl acids on keratinocytes.[J Biol Chem. 2012]
Cao X, Yang F, Zheng J, Wang K
J Biol Chem. 2012 Jul 27; 287(31):25905-16.
Review Aquaporin-3 functions as a glycerol transporter in mammalian skin.[Biol Cell. 2005]
Hara-Chikuma M, Verkman AS
Biol Cell. 2005 Jul; 97(7):479-86.
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Sharad J
Clin Cosmet Investig Dermatol. 2013 Nov 11; 6():281-8.
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Glycolic Acid Silences Inflammasome Complex Genes, NLRC4 and ASC, by Inducing DNA
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Tang SC, Liao PY, Hung SJ, Ge JS, Chen SM, Lai JC, Hsiao YP, Yang JH
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Ying TH, Chen CW, Hsiao YP, Hung SJ, Chung JG, Yang JH
Anticancer Res. 2013 Oct; 33(10):4411-20.
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Triggering apoptotic death of human epidermal keratinocytes by malic Acid: involvement of
endoplasmic reticulum stress- and mitochondria-dependent signaling pathways.
Hsiao YP, Lai WW, Wu SB, Tsai CH, Tang SC, Chung JG, Yang JH
Toxins (Basel). 2015 Jan 9; 7(1):81-96.
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[PubMed] [Ref list]
Alpha-hydroxyacids and carboxylic acids.
Yu RJ, Van Scott EJ
J Cosmet Dermatol. 2004 Apr; 3(2):76-87.
[PubMed] [Ref list]
Review Apoptosis pathways as promising targets for skin cancer therapy.
Eberle J, Fecker LF, Forschner T, Ulrich C, Röwert-Huber J, Stockfleth E
Br J Dermatol. 2007 May; 156 Suppl 3():18-24.
[PubMed] [Ref list]
Review Bufadienolides from amphibians: A promising source of anticancer prototypes for
radical innovation, apoptosis triggering and Na⁺/K⁺-ATPase
inhibition.
Sousa LQ, Machado KD, Oliveira SF, Araújo LD, Monção-Filho ED, Melo-Cavalcante AA, Vieira-
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Toxicon. 2017 Mar 1; 127():63-76.
[PubMed] [Ref list]
Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line.
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Spörl F, Schellenberg K, Blatt T, Wenck H, Wittern KP, Schrader A, Kramer A
J Invest Dermatol. 2011 Feb; 131(2):338-48.
[PubMed] [Ref list]
Efficacy of malic acid against Listeria monocytogenes attached to poultry skin during
refrigerated storage.
González-Fandos E, Herrera B
Poult Sci. 2013 Jul; 92(7):1936-41.
[PubMed] [Ref list]
Comparative effectiveness of alpha-hydroxy acids on skin properties.
Smith WP
Int J Cosmet Sci. 1996 Apr; 18(2):75-83.
[PubMed] [Ref list]
Bifidobacterium longum lysate, a new ingredient for reactive skin.
Guéniche A, Bastien P, Ovigne JM, Kermici M, Courchay G, Chevalier V, Breton L, Castiel-
Higounenc I
Exp Dermatol. 2010 Aug; 19(8):e1-8.
[PubMed] [Ref list]
Immunomodulatory Effects of Different Lactic Acid Bacteria on Allergic Response and Its
Relationship with In Vitro Properties.
Ai C, Ma N, Zhang Q, Wang G, Liu X, Tian F, Chen P, Chen W
PLoS One. 2016; 11(10):e0164697.
[PubMed] [Ref list]
Antipruritic effects of the probiotic strain LKM512 in adults with atopic dermatitis.
Matsumoto M, Ebata T, Hirooka J, Hosoya R, Inoue N, Itami S, Tsuji K, Yaginuma T, Muramatsu
K, Nakamura A, Fujita A, Nagakura T
Ann Allergy Asthma Immunol. 2014 Aug; 113(2):209-216.e7.
[PubMed] [Ref list]
Effects of a skin neuropeptide (substance p) on cutaneous microflora.
Mijouin L, Hillion M, Ramdani Y, Jaouen T, Duclairoir-Poc C, Follet-Gueye ML, Lati E, Yvergnaux
F, Driouich A, Lefeuvre L, Farmer C, Misery L, Feuilloley MG
PLoS One. 2013; 8(11):e78773.
[PubMed] [Ref list]
Review Neuropeptides and inflammatory bowel disease.
Margolis KG, Gershon MD
Curr Opin Gastroenterol. 2009 Nov; 25(6):503-11.
[PubMed] [Ref list]
Substance P enhances lactic acid and tyramine production in <i>Enterococcus faecalis</i> V583
and promotes its cytotoxic effect on intestinal Caco-2/TC7 cells.
Biaggini K, Borrel V, Szunerits S, Boukherroub R, N'Diaye A, Zébré A, Bonnin-Jusserand M,
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J Cosmet Laser Ther. 2005 Dec; 7(3-4):163-70.
[PubMed] [Ref list]
Sunscreens, Skin Cancer, and Your Patient.
Davidson TM, Wolfe DP
Phys Sportsmed. 1986 Aug; 14(8):65-79.
[PubMed] [Ref list]
Review Photoaging: prevention and topical treatments.
Antoniou C, Kosmadaki MG, Stratigos AJ, Katsambas AD
Am J Clin Dermatol. 2010; 11(2):95-102.
[PubMed] [Ref list]
Alpha hydroxy acids for skin care.
Kurtzweil P
FDA Consum. 1998 Mar-Apr; 32(2):30-5.
[PubMed] [Ref list]
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Glycolic acid treatment increases type I collagen mRNA and hyaluronic acid content of human
skin.
Bernstein EF, Lee J, Brown DB, Yu R, Van Scott E
Dermatol Surg. 2001 May; 27(5):429-33.
[PubMed] [Ref list]
Inhibitory effect of glycolic acid on ultraviolet B-induced c-fos expression, AP-1 activation and
p53-p21 response in a human keratinocyte cell line.
Ahn KS, Park KS, Jung KM, Jung HK, Lee SH, Chung SY, Yang KH, Yun YP, Pyo HB, Park YK, Yun
YW, Kim DJ, Park SM, Hong JT
Cancer Lett. 2002 Dec 5; 186(2):125-35.
[PubMed] [Ref list]
Review Damage to skin extracellular matrix induced by UV exposure.
Watson RE, Gibbs NK, Griffiths CE, Sherratt MJ
Antioxid Redox Signal. 2014 Sep 1; 21(7):1063-77.
[PubMed] [Ref list]
Gene profiling of narrowband UVB-induced skin injury defines cellular and molecular innate
immune responses.
Kennedy Crispin M, Fuentes-Duculan J, Gulati N, Johnson-Huang LM, Lentini T, Sullivan-Whalen
M, Gilleaudeau P, Cueto I, Suárez-Fariñas M, Lowes MA, Krueger JG
J Invest Dermatol. 2013 Mar; 133(3):692-701.
[PubMed] [Ref list]
Ultraviolet radiation-induced non-melanoma skin cancer: Regulation of DNA damage repair and
inflammation.
Kim Y, He YY
Genes Dis. 2014 Dec 1; 1(2):188-198.
[PubMed] [Ref list]
Review Current concept of photocarcinogenesis.
Nishisgori C
Photochem Photobiol Sci. 2015 Sep 26; 14(9):1713-21.
[PubMed] [Ref list]
Review New insights into the molecular control of the lymphatic vascular system and its role in
disease.
Cueni LN, Detmar M
J Invest Dermatol. 2006 Oct; 126(10):2167-77.
[PubMed] [Ref list]
Inhibitory effect of glycolic acid on ultraviolet-induced skin tumorigenesis in SKH-1 hairless mice
and its mechanism of action.
Hong JT, Kim EJ, Ahn KS, Jung KM, Yun YP, Park YK, Lee SH
Mol Carcinog. 2001 Jul; 31(3):152-60.
[PubMed] [Ref list]
TRP Channels as Potential Drug Targets.
Moran MM
Annu Rev Pharmacol Toxicol. 2018 Jan 6; 58():309-330.
[PubMed] [Ref list]
Intracellular proton-mediated activation of TRPV3 channels accounts for the exfoliation effect
of α-hydroxyl acids on keratinocytes.
Cao X, Yang F, Zheng J, Wang K
J Biol Chem. 2012 Jul 27; 287(31):25905-16.
[PubMed] [Ref list]
Review Aquaporin-3 functions as a glycerol transporter in mammalian skin.
Hara-Chikuma M, Verkman AS
Biol Cell. 2005 Jul; 97(7):479-86.
[PubMed] [Ref list]
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