Research | C&T ®

KEY POINTS
• Daily exposure to environmental stress
keeps skin under a persistent burden
from excess ROS. This drives premature
skin aging.
• The present article explores the
multiple effects of a single ingredient,
acetyl zingerone, to proactively
manage excess ROS production via
chemical and physical paths.

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Antioxidant Acetyl Zingerone Scavenges/Quenches
Reactive Species, Selectively Chelates Iron
Thomas Meyer and Ratan K. Chaudhuri
Sytheon, Boonton, NJ USA

Reproduction in English or any other language of

24 | www.CosmeticsandToiletries.com all or part of this article is strictly prohibited. Vol. 135, No. 9 | October 2020
© 2020 Allured Business Media.
 Peer-reviewed

• Exposure to sun or air pollution gener-

ates such an abundance of ROS in skin
that its intrinsic antioxidant defenses
are overwhelmed, which then allows an
excess of ROS to build up within skin.5-7
• Even high SPF broad-spectrum sun-
screens cannot prevent sun-induced
ROS formation within skin—especially

T
considering at least 50% of sun-induced
ROS originate from spectral regions
(visible or IR) outside of the protective
capacity of sunscreens.8, 9
• Of all environmental stressors, sun
exposure is the most potent genera-
tor of ROS in skin, accounting for an
he cumulative body of estimated 80% of the visible signs of
research today estab- skin aging.10
lishes that skin aging is • Exposure to air pollution in the form
driven by exposure to key of particulate matter correlates sig-
environmental stressors nificantly with hyperpigmentation and
such as solar light, air wrinkle formation.11
pollution, tobacco smoke and cosmetics, • Sun exposure induces an immediate
which mediate damage largely through the release of iron ions within skin via the
formation of excess ROS.1-4 This advocates Fenton reaction that are believed to be a
for a strategy that topical formulas designed major source of ROS.12
to care proactively for skin on a daily basis, • ROS have been hypothesized as critical
including moisturizers, therapeutic products precursors in novel pathways of DNA
or sunscreens, should incorporate ingre- dimer formation that occurs in skin
dients as prophylactics to reinforce skin’s even hours after sun exposure ends.
ability to cope with excess ROS formation. This has new implications for skin
This is especially true considering that: cancer development.13-15

Reproduction in English or any other language of all or part of this article is strictly prohibited. © 2020 Allured Business Media. Cosmetics & Toiletries® | 25

CT2010_Research_Chaudhuri_fcx.indd 25 9/16/20 5:55 PM

 Omni Antioxidant
Figure 1. General scheme showing common pathway of ROS formation within skin
Left unchecked, excess ROS can oxidize
cellular targets such as lipids, proteins, DNA
and mitochondria; affect cellular signaling; and
influence gene expression pathways, all of which
create oxidative stress, perturb barrier function
and stimulate increases in matrix metal-
loproteinases (MMPs) and pro-inflammatory
cytokines.16-23 Activation of MMPs leads to the
degradation of collagen, skin’s major struc-
tural protein, and also inhibits new collagen
synthesis. Persistent, chronic induction of
inflammatory cytokines leads to a state of ongo-
ing low-grade (i.e., sub-clinical) inflammation,
or inflammaging, another recognized contribu-
tor to aging.24
The good news is ROS levels created within
skin from exposure to environmental stressors
The global cosmetic antioxidant market was
valued at US $109.2 billion in 2018 and is
projected* to reach $163.7 billion by 2026,
growing at a CAGR of 5.18%.
Source: Verified Market Research
*pre-COVID-19 estimate
26 | www.CosmeticsandToiletries.com
can be managed effectively. As shown in Fig-
ure 1,
1 external stressors typically induce ROS
formation through interaction with endogenous
molecules within skin. These form intermediates
that then give rise to ROS. The attenuation of
excess ROS formation can therefore be accom-
plished by using antioxidants to neutralize
ROS once they are formed but also before they
can react to cause damage—by using physical
quenchers that interact with the intermediates
in a way that restores the endogenous molecules
to their original state.
Antioxidants are further challenged by
the diversity of ROS with different chemical
structures and reactivities, which include both
free radicals and non-radical molecules (see
Table 1).
1 Conventional antioxidants typically
show high reactivity toward free radicals with
unpaired electrons ( OH, OOR), which they
• •
neutralize via the donation of an H atom (H ) to
•
restore their original chemical stability. How-
ever, other highly reactive non-radical ROS (1O2,
ONOO-) confer new structural requirements on
antioxidants to endow them with broader and
more effective capabilities.
In this article, combinations of in vitro chem-
ical reactions and cellular assays under stress
from UV, blue light or urban dust particulate
Vol. 135, No. 9 | October 2020
 Excess ROS formation can be
attenuated by using antioxidants
to neutralize ROS once they are
formed but also before they can
react to cause damage.

matter are used to assess the multiple ways by which a single ingredient,
acetyl zingerone [3-(4-hydroxy-3-methoxybenzyl)-pentane-2,4-dione], with
its unique molecular design, can help to manage excess ROS levels.

Materials and Methods

Acetyl zingerone: The synthesis and identification of acetyl zingerone
(AZ) has been described elsewhere.25 The producta, used in the present
study, was > 99% pure. In addition, a-tocopherolb (96.5% pure) and trans-
resveratrolc (100% pure) were procured for comparison.
ROS quenching: The in vitro methods used to measure the performance
of AZ to neutralize ROS or physically quench singlet oxygen were reported
previously.25 Additional tests comprised the following.
Photostability assessment: AZ, a-TOC and resveratrol were solubilized
in ethanol or aqueous ethanol and aliquots were irradiated with 13 J cm-2 of
UVB and UVA radiation using a photochemical reactord to simulate daylight
conditions. Extents of degradation were monitored by an HPLC method
described25 elsewhere.
Fluorometric iron chelation assay: A fluorometric assay modeled
on the method reported by Ou, et al., was employed.26 This assay uses
fluorescein as a sensitive probe for hydroxyl radical, which reacts rapidly
with fluorescein to destroy its fluorescent properties. Loss of fluorescence
over time was then used to monitor the effectiveness of different chelators

a
Synoxyl AZ (INCI: Acetyl Zingerone), Sytheon
b
Millipore Sigma
c
Nutrivita
d
Raynonet RPR-100, Southern New England Ultraviolet Company

Table 1. Common ROS Formed Within Skin by

Environmental Stressors

Reactive Oxygen Species (ROS) Chemical Symbol

Superoxide anion O2 _ •

Hydroxy radical OH
•

Peroxy radical ROO •

Singlet oxygen 1
O2
Hydrogen peroxide H2O2
Peroxynitrite ONOO–

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 Omni Antioxidant
In skin, UVA causes a release of iron from
the iron storage protein ferritin, which reacts
with hydrogen peroxide to form OH.
to inhibit the formation of hydroxyl radical as
FeCl2 (200 μM) reacted with H2O2 (0.055 μM) via
the Fenton reaction in PBS at pH 7 by chelat-
ing and removing Fe+2 as a reactant. Chelating
agents were dissolved in ethanol and diluted
to concentration in PBS buffer at pH 7 to yield
assay concentrations of 600 μM for AZ, AZ
methyl ether and Deferiprone; or 200 μM for
EDTA, EDDS or Desferal.
Physical quenching of AGEs: The ability of
AZ to physically quench photoexcited states of
advanced glycation end products (AGEs) was
performed by following the plasmid DNA cleav-
age assay reported by Wondrak et al.27 Briefly,
200 ng of fX-174 RF bacteriophage supercoiled
DNA was irradiated in the presence of 25 ng of
filtered glycated bovine serum albumin (20 mg/
mL BSA reacted for 3 weeks with 180 mg/mL
glucose at 37°C) in a final volume of 100 μL.
Irradiation was performed in a 96-well plate
without the lid using a UVA lampe at 6.4 mW/
cm2 for 2 hr. Following irradiation, 10 μL of the
e
Ultra-lum UVA-28T
Figure 2. The design of AZ (a) was inspired by the molecular structures of curcumin (d)
and zingerone (e) from ginger; AZ exists in keto-enol tautomers: keto (a) and enol (b and c)
28 | www.CosmeticsandToiletries.com
•
sample was mixed with 2 μL of loading buffer,
resolved in 1% agarose gel (at 90 V for 20 min)
and stained with ethidium bromide. Bands from
supercoiled and uncoiled DNA were visualized
using a transilluminatorf and photographs of
the gels were processedg to calculate a ratio of
unwound to supercoiled DNA.
Intracellular ROS in keratinocytes: Mea-
surement of intracellular ROS was carried out in
cell cultures of human epidermal keratinocytes
grown using a mediumh (60 uM calcium) supple-
mented with 0.2% bovine pituitary extract, 1 μg/
mL recombinant human insulin-like growth
factor-1, 0.18 μg/mL hydrocortisone, 5 μg/mL
bovine transferrin and 0.2 ng/mL human epider-
mal growth factor, which were incubated at 37 ±
2°C and 5 ± 1% CO2. After sufficient cell numbers
were grown, they were seeded into 96- or 24-well
plates and grown to confluency, loaded with 2’,
7’-dichloro-dihydrofluorescein diacetate (DCF-
DA), then rinsed with PBS.
h
EpiLife
f
Hoefer
g
NIH ImageJ
Vol. 135, No. 9 | October 2020
 Table 2. Effectiveness of AZ with a-Tocopherol and Resveratrol to Neutralize Different ROS

Compound Type of Reactive Oxygen Species (ROS)*

Peroxyl Hydroxyl Superoxide Peroxynitrite Singlet
radical radical anion anion oxygen
Acetyl Zingerone 25,325 9,723 ND+ 1,139 7,180
α-Tocopherol 1,432 94 ND 9 2,636
Effectiveness Ratio
17.7 39.6 NA 126.6 2.7
(AZ/α-Tocopherol)
Resveratrol 68.9 20.7 5.3 2.7 45.6
Effectiveness Ratio
367.6 469.7 NA 421.9 157.5
(AZ/Resveratrol)

*Results expressed as μmole Trolox equivalent/g ± 5%; ND = not detected; NA = not applicable

Blue light exposure: Cells were treated with
either AZ at different concentrations prepared in
a media of phenol red-free Hanks Balanced Salt
Solution, or the media alone as an untreated
control. They were then irradiated with blue
light at a distance of 25 cm in a humidified
incubator at 37± 2°C. The blue light source com-
prised a panel of 225 blue LED lights arranged
in a 15 cm x 15 cm square with an output of 22
watts of 450 nm blue light.

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 Omni Antioxidant

Results showed protective capabilities of AZ, as measured through ROS, against blue light and urban dust.

Baseline measurements were recorded on but were covered with aluminum foil to block
the underside of the wells prior to irradiation blue light exposure.
with a fluorometerj having an excitation wave- Urban dust exposure: Cells were treated
length of 485 nm and an emission wavelength with 10 μL of a 10 mg/mL stock solution of
of 518 nm. Cells were irradiated for 30 min and urban dustk prepared in supplementedg media or
60 min, which corresponds to ~1 hr to 2 hr of media alone as the untreated control. Baseline
outside midsummer sunlight, based on solar fluorescence measurements were recorded as
irradiance in the visible range9 of about 50 mW described previously. Cells were incubated for
cm-2, and the fluorescence was recorded. Non- 3 hr with fluorescence measurements recorded
irradiated cells were also placed in the incubator at 1 hr, 2 hr and 3 hr time points.
Lipid peroxidation: To
test effects against urban
Table 3. Amount of Ingredients Remaining Over Time After dust-induced lipid peroxida-
Exposure to Singlet Oxygen (1O2) tion, cells were treated with
urban dust as before, then
placed in the incubator for
% Remaining by HPLC 4 hr. After 3.5 hr, cells were
Time (min) Acetyl Zingerone α-Tocopherol Resveratrol treated with 10 μL of 100 μM
2 96 73 99 peroxidation sensorm and
incubated for an additional
4 91 58 97
30 min. This sensor localizes
6 88 47 90
8 85 39 87 j
Fluoroskan Ascent
k
Sigma Chemicals, standard
10 82 35 85
reference material 1649b
m
Image-It Lipid Peroxidation Sensor

30 | www.CosmeticsandToiletries.com Vol. 135, No. 9 | October 2020

in cell membranes and
upon reaction with lipid
hydroperoxides, becomes
highly fluorescent. One set
of cells was not treated as
a blank to correct for back-
ground fluorescence. At
the end of the incubation
period, cells were washed
three times with PBS then
read with a fluorometer
using 485 nm excitation
and 518 nm emission
wavelengths.

Results:
Neutralizing
Radicals
Inspired by curcumin Figure 3. Fluorescence decay curves of fluorescein depicting
and zingerone from ginger, the effectiveness of different chelators to inhibit the Fenton reaction
the molecular structure of by removing Fe+2 as a participating reactant
AZ is unique (see Figure 2),
2

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 Omni Antioxidant
which bestows the molecule with unique capa-
bilities to attenuate different forms of ROS with
high efficiency (see Table 2).
2 Compared with
a-tocopherol (a-TOC) and resveratrol, two anti-
oxidants commonly used in topical products,
the effectiveness ratios show AZ was superior by
factors ranging from 2.7 to 126 against a-TOC,
and by 157 to 469 against resveratrol.
The ability of AZ to neutralize peroxynitrite
and singlet oxygen, two of the most reactive
forms of ROS, with high efficiencies is note-
worthy. Research establishes that peroxynitrite
can react both as an oxidant or a nucleophile28
and as such, undergoes facile reaction with
Figure 4. Effectiveness of AZ to protect
keratinocytes against increases of intracellular ROS
induced upon exposure to blue light (top) or urban
dust (bottom) for varying lengths of time
32 | www.CosmeticsandToiletries.com
enolizable carbonyls such as 3-methyl-2,4-pen-
tanedione.29 Inclusion of this functional group
on AZ equips it with exceptional capabilities,
compared with a-TOC or resveratrol, to scav-
enge ONOO- with high efficiency.
Similarly, the chemical structure of AZ also
promotes the neutralization of 1O2 through
physical quenching, as opposed to a chemical
reaction. Since 1O2 is an electronically excited
state species of molecular oxygen (3O2), it can
be deactivated either through physical quench-
ing or chemical reaction. Physical quenching
restores 1O2 back to its ground state (3O2)
without being consumed in the process. In
contrast, deactivators that work
through chemical reactions
become sacrificed.
Many organic compounds
that neutralize 1O2 have been
shown to work through a
combination of physical
quenching and chemical
reaction; however, physical
quenching appears more favor-
able for electron-rich aromatics
containing phenol or methoxy
groups, both of which reside
on AZ.30, 31 The mechanism
of AZ and resveratrol to
function mainly as physical
quenchers is illustrated by the
data in Table 3,
3 which shows
that during the period of 1O2
exposure, a-TOC undergoes
significantly more chemical
degradation than either AZ or
resveratrol. Deactivation of 1O2
through physical quenching
is a key advantage of AZ over
traditional antioxidants.
Results: Selective
Chelation
In addition to effectively
neutralizing OH, AZ also
•
impedes OH production by
•
virtue of its ability to chelate
iron as a participating reactant
in the Fenton reaction (see
Equation 1):1
Fe+2 + H2O2 → Fe+3 + OH + _OH
•
Eq. 1
Vol. 135, No. 9 | October 2020
Inspired by curcumin from turmeric and zingerone from ginger, the
molecular structure of AZ is unique, which bestows the molecule with
unique capabilities.

Exposure of skin to UVA causes an immediate release of

iron from the iron storage protein ferritin,12 which then
reacts with hydrogen peroxide to form OH. This is pos-
•

tulated as a major source of OH within the skin caused

•

by sun exposure and consequently, a major contributor

to photo-oxidative stress.32
The potential of AZ to inhibit the Fenton reaction
was monitored in simple reactions of Fe+2 with H2O2 by
monitoring the loss in fluorescence of fluorescein. One
might argue that the loss of fluorescence results from
AZ’s chelation as well as its OH-neutralizing abilities.
•

In order to dispel this ambiguity, similar experiments

were carried out with AZ methyl ether, which prevents
•
OH neutralization.
Results in Figure 3 show that AZ and its methyl
ether are superior to EDTA, a common chelator used
in formulations, and even more effective than Desferal
and Deferiprone, two of the most potent iron chelators
known. These results are supported by separate studies
(data not shown) that found AZ to be an efficient and
selective chelator of detrimental Fe+2 and Cu+2 ions

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 Omni Antioxidant

through its di-keto tautomer (see Figure 2a),

2a The results from these in vitro chemical
but not of other ions, such as skin-friendly Zn+2 experiments align AZ’s different functional
and Ca+2, which fulfill important roles in normal groups (see Figure 2a)
2a with its ability to
cellular function. function as a conventional antioxidant,
physical quencher or
selective chelator.

Results:
Blue
Light and
Pollution-
induced
ROS
Moving from
chemical toward
biological systems,
studies were per-
formed to assess the
ability of AZ to pro-
tect against increases
in intracellular
ROS formation in
human keratinocytes
following exposure
Figure 5. Effectiveness of AZ to protect lipids in keratinocyte to blue light or urban
cell membranes against oxidation by ROS following exposure to dust. Results showed
protective capa-
urban dust for 4 hr
bilities, as measured
through ROS levels,
for blue light and
urban dust (see
Figure 4).
4 Relative
to the non-exposed
control, each stressor
in the absence of AZ
experienced sig-
nificant increases in
ROS levels over time
and exposures. How-
ever, treatment with
AZ prior to exposure
reduced ROS levels
in a dose-dependent
manner—until at
higher doses, where
AZ reduced ROS
levels comparable to
unstressed controls.
A similar dose-
Figure 6. Comparison of the inherent photostability profiles of response profile for
AZ with those of a–TOC and resveratrol performed in solution AZ (see Figure 5)5
was observed for

DM11 | www.CosmeticsandToiletries.com Vol. 135, No. 9 | October 2020

 its ability to protect against lipid peroxidation
in cell membranes of keratinocytes exposed to
urban dust for 4 hr. This demonstrates the ability
of AZ to intercept ROS once formed, but also
before lipid peroxidation was induced. Thus, AZ
was efficient in protecting skin cells against a
buildup of excess ROS induced by two important
environmental stressors faced on a daily basis and
implicated as causes of premature skin aging.
The ability of AZ to curb excess ROS pro-
duction in keratinocytes exposed to blue light
underscores two additional points. First, since
AZ does not absorb blue radiation, its ability to
control ROS levels cannot stem from a sunscreen-
type effect. Second, AZ itself does not sensitize
and cause the formation of ROS when exposed to
blue radiation. This latter point is important since
it has been documented that many compounds,
while effective in chemical assays in the absence
of radiation, can themselves become potent gen-
erators (i.e., photosensitizers) of ROS in systems
exposed to radiation.33
Results: Physical AGE
Quenching
In addition to its ability to physically quench
1
O2 in a non-sacrificial manner, AZ also shows the
capacity to physically quench photoexcited states
of AGEs. With age, these entities accumulate in
abundance on collagen and elastin in the dermis
and have been identified as one of the most potent
sources of ROS formation within skin.34
In reference to Figure 1,1 AGEs (endogenous
molecules) in skin absorb UVA (external stressor)
to form photoexcited states (intermediates) that
generate an excess of ROS. Using the in vitro
plasmid DNA cleavage assay described above to
identify physical quenchers of photoexcited states
of AGEs, AZ was found to reduce ROS formation
by 85%. In addition to neutralizing ROS once
formed, the ability of AZ to prevent excess ROS
production through interactions with the skin’s
own endogenous molecules represents another
pathway by which AZ can help manage ROS
levels in skin. In relation, AZ also was recently
found to decrease the activation of genes strongly
associated with ECM disassembly, reactive oxygen
species metabolism and stress response (data
not shown).36
Results: Photostability
Inherent photostability is an essential property
of molecules intended for use in sunscreens or
Vol. 135, No. 9 | October 2020
CT2010_Research_Chaudhuri_fcx.indd 35
in daily skin care products. AZ also displayed
robust photostability (see Figure 6),
6 compared
with a-TOC and resveratrol, both of which
were completely degraded over the time course
of irradiation.
Discussion
The reported findings for AZ are consistent
with other studies documenting the ingredient’s
ability to attenuate intracellular ROS in kera-
tinocytes under exposure to UVA radiation,25
as well as to inhibit DNA dimer formation in
melanocytes after UV exposure ends—possibly
by scavenging peroxynitrite as a key precursor
in the process.25 This, in turn, improves extracel-
lular matrix integrity with retinoid-like effects,
based on genomic and transcriptomic studies.35
Furthermore, these actions visibly improved the
signs of facial photoaging following the daily
application of a lotion containing 1% AZ over
eight weeks, compared with a placebo lotion
(data not shown).36
Conclusion
In summary, the results presented here
disclose the unique chemical structure of AZ,
which results indicate endows it with the ability
to function through multiple pathways to
attenuate excess ROS levels within skin. These
include efficient and direct neutralization of
the most reactive forms of ROS; high selectiv-
ity for iron as a chelator; and the capability to
physically quench one of the skin’s most potent
endogenous generators of ROS—AGEs—during
sun exposure. These features, combined with its
robust photostability, make AZ an ideal ingredi-
ent for use in various topical products including
sunscreens. This is especially crucial since
topical application remains the quickest and
most effective way to shore up skin’s inherently
weak antioxidant defenses against the damaging
effects imposed by environmental stressors on a
daily basis.
Acknowledgements: The authors thank Tony Chang and Marsha
Sintara (International Chemistry Testing, Milford, MA) for
excellent technical assistance in carrying out experiments.
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Vol. 135, No. 9 | October 2020