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The effect of Vitamin C on melanin pigmentation – A systematic review

Authors:
  • Dr GD Pol Foundation Y.M.T. Dental College & Hospital

Abstract and Figures

Vitamin C, also known as ascorbic acid, is used as a treatment modality in depigmentation of hyperpigmented spots on the skin and gingiva. This systematic review discusses the studies conducted to assess the effect of Vitamin C on melanin pigmentation. The primary objective was to evaluate the effect of Vitamin C on melanin pigmentation. The secondary objective was to analyze the effect of Vitamin C administration on melanin pigmentation. An electronic database search was conducted from the following databases: PubMed, EBSCOhost, ScienceOpen, EMBASE and Google Scholar. Randomized controlled trials, experimental studies, case-control studies and cohort studies published in peer-reviewed journals in English language were included. Case reports, case series, animal model studies, in vitro studies, studies where Vitamin C was used along with other agents and unpublished research were excluded. Out of 22,580 studies, only 7 studies satisfied the selection criteria. Data extraction sheet was prepared, and the studies were analyzed. Out of the 7 studies analyzed, 1 was a randomized controlled trial and 6 were experimental studies. Vitamin C has been used widely as a depigmenting agent in dermatology. However, there are limited studies conducted on the use of Vitamin C for gingival depigmentation.
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374 © 2020 Journal of Oral and Maxillofacial Pathology | Published by Wolters Kluwer - Medknow
The effect of Vitamin C on melanin pigmentation – A
systematic review
Rizwan M Sanadi1, Revati S Deshmukh2
1Department of Periodontics, Dr GD Pol Foundation’s YMT Dental College, Kharghar, Sector ‑ 4, Navi Mumbai and PhD Student,
2Department of Oral Pathology and Microbiology, Bharati Vidyapeeth Deemed to be University, Dental College and Hospital,
Satara Road, Katraj, Dhankawadi, Pune, Maharashtra, India
INTRODUCTION
Vitamin C, also known as ascorbic acid (AA) and ascorbate,
abounds in nature and is highly labile. It is a water‑soluble
vitamin that is lost in large amounts during food
processing.[1] AA is vital for the growth and maintenance of
healthy bones, teeth, gums, ligaments and blood vessels and
is involved in important metabolic functions. The minimal
daily requirement for AA in healthy adults is 40–60 mg.[2]
Vitamin C plays signicant functions in the body. The
biochemical functions of Vitamin C include stimulation
of certain enzymes, collagen biosynthesis, hormonal
activation, antioxidant, detoxification of histamine,
phagocytic functions of leukocytes, formation of
nitrosamine and proline hydroxylation.[1]
AA is required for the hydroxylation of prolyl and lysyl
residues during collagen biosynthesis, which is essential
Vitamin C, also known as ascorbic acid, is used as a treatment modality in depigmentation of hyperpigmented
spots on the skin and gingiva. This systematic review discusses the studies conducted to assess the effect
of Vitamin C on melanin pigmentation. The primary objective was to evaluate the effect of Vitamin C on
melanin pigmentation. The secondary objective was to analyze the effect of Vitamin C administration on
melanin pigmentation. An electronic database search was conducted from the following databases: PubMed,
EBSCOhost, ScienceOpen, EMBASE and Google Scholar. Randomized controlled trials, experimental studies,
case–control studies and cohort studies published in peer-reviewed journals in English language were
included. Case reports, case series, animal model studies, in vitro studies, studies where Vitamin C was used
along with other agents and unpublished research were excluded. Out of 22,580 studies, only 7 studies
satisfied the selection criteria. Data extraction sheet was prepared, and the studies were analyzed. Out of
the 7 studies analyzed, 1 was a randomized controlled trial and 6 were experimental studies. Vitamin C has
been used widely as a depigmenting agent in dermatology. However, there are limited studies conducted
on the use of Vitamin C for gingival depigmentation.
Keywords: Ascorbic acid, depigmentation, gingival melanin hyperpigmentation, melanin pigmentation,
melanogenesis, tyrosinase, Vitamin C
Abstract
Address for correspondence: Dr. Rizwan M Sanadi, Bhara Vidyapeeth Deemed to be University, Dental College and Hospital, Satara Road, Katraj,
Dhankawadi, Pune ‑ 411 043, Maharashtra, India.
Department of Periodoncs, Dr. G D Pol Foundaon’s, YMT Dental College, Kharghar, Sector – 4, Navi Mumbai ‑ 410 210, Maharashtra, India.
E‑mail: drriz28@yahoo.com
Submied: 14‑May‑2020, Revised: 30‑Jun‑2020, Accepted: 04‑Jul‑2020, Published: 09‑Sep‑2020
Access this article online
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DOI:
10.4103/jomfp.JOMFP_207_20
How to cite this article: Sanadi RM, Deshmukh RS. The e󰀨ect of Vitamin
C on melanin pigmentation – A systematic review. J Oral Maxillofac Pathol
2020;24:374‑82.
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Sanadi and Deshmukh: Vitamin C and melanin pigmentation – A systematic review
Journal of Oral and Maxillofacial Pathology | Volume 24 | Issue 2 | May-August 2020 375
for wound healing. Vitamin C has been associated with
reduction in incidence of cancer. Vitamin C is effective
in protecting against oxidative damage in tissues and also
suppresses the formation of carcinogens like nitrosamines.
Vitamin C increases the levels of antibodies that ght
against germs and viruses. Vitamin C regulates the urinary
excretion of hydroxyproline.[1]
This vitamin is needed for the proper metabolism of drugs
in the body through adequate hepatic mixed‑function oxidase
system. There is an inverse relationship with blood pressure
and Vitamin C. Vitamin C has a lowering effect on blood
pressure, especially on systolic pressure more than diastolic
pressure. Low levels of plasma Vitamin C are associated with
stroke and with an increased risk of mortality.[1]
Vitamin C (AA) is synthesized by all plants and most
animals.[3] It is an essential vitamin for humans because
the gene for gulonolactone oxidase, the terminal enzyme
in the AA synthesis pathway, has undergone mutations
that make it nonfunctional in humans.[4] Therefore,
humans obtain this vitamin from diet and/or vitamin
supplements.[2] It is an essential nutrient for the biosynthesis
of collagen, L‑carnitine and the conversion of dopamine
to norepinephrine.[5]
Under physiological conditions, Vitamin C plays a role in
photoprotection, skin strengthening, immunomodulation
and cancer therapy and is used for the removal of
hyperpigmented spots. It is also a potent antioxidant.[6]
Vitamin C interacts with the copper (Cu) ions at the
tyrosinase active site and inhibits action of the enzyme
tyrosinase, thereby reducing melanin formation. It also acts
on the perifollicular pigment. However, it is an unstable
compound. Therefore, it is used in combination with soy
and liquorice for depigmentation in dermatology.[7]
Vitamin C is used as a treatment modality in depigmentation
of hyperpigmented spots on the skin. It can be used
topically, transdermally as well as intravenously. It is a
water‑soluble antioxidant and an essential nutrient for
cells.[8] Despite its tremendous signicance, humans are
unable to synthesize this vitamin due to mutation of the
gene needed for its synthesis.[9]
It also plays a signicant role in collagen synthesis,[10]
provides photoprotection[11] and reduces the melanin,[12]
scavenger (free radicals)[13] and immunomodulation.[14]
Vitamin C was found to be effective in depigmentation as
a result of its direct effect on melanogenesis. Melanin is
said to be a reservoir for reactive oxygen species (ROS),
Cu and calcium (Ca) within the cells. Following its entry
into the target tissue, it binds to melanin. This causes a
deciency of the ROS, Cu and Ca, resulting in reduction
of melanin production.[15]
RATIONALE
Studies have been conducted to determine the effect of
Vitamin C on melanin pigmentation on skin and gingiva.
Different formulations were used either in the form of
oral administration or topical application or intravenous
injection or intraepithelial injection. Although the use
of Vitamin C as a depigmenting agent is common in
dermatology, there is limited documentation on the use of
Vitamin C as a depigmenting agent for gingival melanin
hyperpigmentation. Therefore, this systematic review
attempts to analyze the existing evidence on the effect
of Vitamin C on melanin pigmentation on the skin and
gingiva.
Focused question
Is there a possible effect of Vitamin C on melanin
pigmentation?
Another research question
Does administration of Vitamin C reduce melanin
pigmentation?
Primary objective
To evaluate the effect of Vitamin C on melanin
pigmentation.
Secondary objective
To analyze the effect of Vitamin C administration on
melanin pigmentation.
MATERIALS AND METHODS
Study design
This is a systematic review of randomized controlled trials,
experimental studies, case–control studies and cohort
studies which aims to analyze the effect of Vitamin C on
melanin pigmentation and administration of Vitamin C as
a depigmenting agent.
Inclusion criteria
1. Randomized controlled trials, experimental studies,
case–control studies and cohort studies
2. Full‑text articles published in peer‑reviewed journals
in English language
3. Vitamin C levels, tyrosinase levels or melanin
pigmentation index scores assessed.
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Sanadi and Deshmukh: Vitamin C and melanin pigmentation – A systematic review
376 Journal of Oral and Maxillofacial Pathology | Volume 24 | Issue 2 | May-August 2020
Exclusion criteria
1. Case reports and case series
2. Animal model studies and in vitro studies
3. Studies where Vitamin C was used along with other
agents or in conjunction with other treatment modality
4. Unpublished research.
Search strategy
An electronic database search for randomized controlled
trials, experimental studies, case–control studies and
cohort studies published in peer‑reviewed journals in
English was conducted from the following databases:
PubMed, EBSCOhost, ScienceOpen, EMBASE and
Google Scholar.
The search terms used were:
Vitamin C OR Ascorbic acid OR
AND Melanin pigmentation OR Melanin synthesis OR
Melanin production OR melanocyte activity OR
Melanin hyperpigmentation AND Depigmentation
Study selection
Study selection was carried out in two phases:
i. Assessment of titles and abstracts
ii. Assessment of full text.
Data collection process
Data extraction sheet was prepared based on variables
associated, and the articles were analyzed. Using data
extraction sheet, the following data were collected: authors,
year of publication, country, aim, tissue assessed, type of
study, sample size, comparison group and control group,
methodology and conclusion.
RESULTS
A total of 22,580 articles were found after electronic
search. 22,100 articles, which were of other languages
and duplicates, were excluded leaving 480 articles. 450
articles were excluded as they did not fulll the eligibility
criteria leaving 30 articles. Figure 1 shows the Flow chart
of literature search results and study selection.
Studies included for the analysis
Seven studies were included for the qualitative synthesis. Out
of the 7 studies, 1 was a randomized controlled trial and 6
were experimental studies. In all, 7 studies suggested that
Vitamin C has a role in melanin pigmentation. An overview
of the included studies for the analysis is presented in Table 1.
Assessment of risk of bias in included studies
This assessment was conducted using the recommended
approach for assessing the risk of bias in studies included
in Cochrane Reviews (Higgins 2011)22 using the tool
RevMan 5.0.
We used the two‑part tool to address the six specic
domains (namely random sequence generation, allocation
concealment, blinding, incomplete outcome data, selective
reporting and other bias). Each domain includes one or
more specic entries in a risk of bias table. Within each
entry, the rst part of the tool involves describing what
was reported to have happened in the study. The second
part of the tool involves assigning a judgment relating to
the risk of bias for that entry: either low risk, unclear risk
or high risk.
The domains of random sequence generation, allocation
concealment, blinding, incomplete outcome data and
selective reporting are addressed in the tool by a single
entry for each study. We completed a “risk of bias’ table
for each included study. The risk of bias of the included
studies is presented in Table 2 and Graphs 1, 2.
Studies excluded from the analysis
Twenty‑three studies were excluded, in which 2 were
animal studies, 8 were in vitro studies, 2 were case reports,
7 were studies where Vitamin C was used along with
other agents, 2 were studies where Vitamin C was used
for the purpose of scar reduction, 1 study where Vitamin
C was used in conjunction with iontophoresis and 1 study
where Vitamin C was used in conjunction with uorescent
pulsed light (FPL). An overview of the excluded studies is
presented in Table 3.
DISCUSSION
Skin pigmentation is the result of melanin synthesis in the
Random sequence generation (selection bias)
Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias)
Blinding of outcome assessment (detection bias)
Incomplete outcome data (attrition bias)
Selective reporting (reporting bias)
Other bias
0% 25% 50% 75% 100%
Low risk of bias Unclear risk of bias High risk of bias
Graph 1: Risk of bias
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Sanadi and Deshmukh: Vitamin C and melanin pigmentation – A systematic review
Journal of Oral and Maxillofacial Pathology | Volume 24 | Issue 2 | May-August 2020 377
Contd...
Table 1: Characteristics of the studies included in the Systematic Review
Authors
& Year of
Publication
Country Aim Tissue
assessed
Gingiva/Skin
Type of study Sample size,
Comparison group
& control group
Methodology Conclusion
Shimada Y,
Tai H, Tanak
A, Suzuki
I, Takagi K
(2009) 16
Japan To investigate the
inhibitory effects
of a gel containing
ascorbic acid
2‑glucoside (AS‑G
gel) on gingival
melanin
pigmentation.
Gingiva Double‑masked
placebo‑
controlled
clinical trial,
split‑mouth
design
(randomised
controlled trial)
73 subjects with
symmetric gingival
melanin
pigmentation.
(22 males and 51
females). The mean
age was 37.2±1.0
years (range, 25 to
57 years).
AS‑G test gel was applied
to left the side and placebo
gel was applied to the right
side of the gingiva. Using
a spectrophotometer the
color of the keratinized
gingiva was measured
at four points (canine
and lateral incisor; and
between lateral incisor
and incisor) in each
subject. Three consecutive
measurements were
taken at one site, and
the mean of individual
measurements was
calculated at 0 weeks, 4
weeks, 8 weeks and 12
weeks.
Ascorbic acid
(AS‑G) seems to
have potential for
the treatment of
gingival melanin
pigmentation at
home.
Yussif NM,
Zayed SO,
Hasan SA,
Sadek SS
(2016) 5
Cairo
University,
Egypt
To evaluate
the efficiency
of injectable
Vitamin C as a
depigmenting
agent in
physiologic
gingival
hyperpigmentation
Gingiva Experimental
Study
40 patients in
age range of
20‑44 years with
physiologic gingival
melanin
hyperpigmentation
A 200‑300mg (1‑1.5 ml)
ascorbic acid (ampoule)
was injected in the gingival
tissues once per week until
no visible pigmentation.
The patients were recalled
after 1, 3& 6 months for
follow up. Decrease in
pigmentation indices
scores & reduction in
area of pigmentation was
assessed.
Vitamin C
injection is a safe,
minimally invasive
non‑surgical
depigmenting
technique for
gingival tissue.
Yussif NM,
Abdel Rahman
AR, Elbarbary
E (2019)17
Cairo
University,
Egypt
To evaluate the
efficacy of intra‑
epidermal vitamin
C injection in
comparison to
the conventional
surgical technique
in gingival
hyperpigmentation
Gingiva Experimental
Study
30 patients with
mild to severe
hyperpigmented
gingival tissues
were divided into
Group 1(Control
group‑conventional
scalpel
depigmentation
performed) &
Group 2(Test
group‑ Vitamin C
was injected intra‑
epidermal)
Maximum 0.1 ml of
ascorbic acid was
recommended for each
point with 2‑3 mm apart.
The same dose was
repeated once per week
for maximum 4 visits till no
further color improvement
gained. The same operator
performed all the surgical
procedures. For gingival
ablation, epithelial layer
and part of the connective
tissue layer were removed
using 15c blades till the
pigment disappeared.
Caution was taken at the
canine region to avoid
bone exposure. Two
different color assessment
indices (Takashi and Kumar
indices) were assessed.
The pain and itching grades
were reported using VAS
Scale.
Usage of vitamin
C injection for
depigmentation
showed
comparative results
to the conventional
surgical technique.
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Sanadi and Deshmukh: Vitamin C and melanin pigmentation – A systematic review
378 Journal of Oral and Maxillofacial Pathology | Volume 24 | Issue 2 | May-August 2020
Ratnam AV,
Sastry PB,
Satyanarayana
BV (1977)18
India To estimate
the content
of ascorbic
acid in normal
pigmented skin in
comparison to the
depigmented skin
of vitiligo.
Skin Experimental
study
Control group‑10
subjects with
normal pigmented
skin.
Study group‑12
vitiligo cases with
variable loss of
pigmentation and 1
was albino.
The estimations of
ascorbic acid levels were
repeated after saturation
with
daily doses of 70 mg
ascorbic acid per stone
body weight. The skin
samples were obtained
from the lateral aspect
of the leg in all the
subjects and extracts
were prepared from
full thickness skin. The
ascorbic acid contents
of skin, plasma and urine
were assessed
Ascorbic acid
has an important
role to play in the
metabolic functions
of the epidermis,
the most important
of these being
keratinization and
melanogenesis.
Kameyama
K, Sakai C,
Kondoh S,
Yonemoto K,
Nishiyama
S, Tagawa M
(1996)19
California To examine
the effect on
pigmentation
of magnesium‑
L‑ascorbyl‑
2‑phosphate
(VC‑PMG), a
stable derivative
of Ascorbic acid.
Skin Experimental
study
34 patients with
phelides. chloasma,
senile freckles,
nevus of Ota, or
healthy skin
VC‑PMG cream 10% was
applied twice a day to the
skin. The effectiveness
of the lightening of the
pigmentation was judged
by a color‑difference meter
VC‑PMG was
effective
in lightening the
skin of some
patients with
hyperpigmentation
disorders and
some subjects with
normally
pigmented healthy
skin.
Kim HM, An
HS, Bae JS,
Kim JY, Choi
CH, Kim JY
(2017)20
Korea To investigate
the effects of
palmitoyl‑KVK‑L‑
ascorbic acid on
skin aging, the
anti‑wrinkle and
depigmentation.
Skin Experimental
study
21 healthy Korean
women aged
between 41 and 55
years
The cream with 0.075%
(0.75 mg/mL) of Palm‑
KVK‑AA or without
Palm‑KVK‑AA was
applied to each half of
the participant’s face,
twice daily for 12 weeks.
The allocation of the
cream was based on a
double‑blind randomized
method. Skin replica
images were evaluated
using a visiometer.
Visual assessment was
performed using the
global photodamage score
at baseline, 4, 8 and 12
weeks after the application
of the cream
Palmitoyl‑KVK‑L‑
ascorbic acid is an
effective anti‑
aging agent that
reduces wrinkles
and abnormal skin
pigmentation.
Jaros A,
Zasada M,
Budzisz E,
Debowska R,
Rzepka MG,
Rotsztejn H
(2019)21
Poland To evaluate
selected capillary
skin
parameters
after applying
5% vitamin C
concentrate.
Skin Experimental
study
(50.1 ± 3.9 years)
30 women of
30‑60 years of
age with capillary
skin indicating
visible signs of
erythematous
plaques. Control
group of 11 patients
The participants were
instructed to use 5%
Vitamin C concentrate
once a day during the
evening and apply it on
their facial skin.
The participants were
asked to fill out a
questionnaire where they
evaluated the properties
of the applied concentrate
throughout the period of
6 weeks
5% Vitamin C
concentrate is very
effective in treating
Erythema as well
as decreasing
the visibility of
telangiectasia
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Sanadi and Deshmukh: Vitamin C and melanin pigmentation – A systematic review
Journal of Oral and Maxillofacial Pathology | Volume 24 | Issue 2 | May-August 2020 379
Table 3: Characteristics of Excluded Studies
Authors (Year) Reason for Exclusion
Takenouchi K, Aso K (1964) 23 Animal study
Yussif NM, Koranayb NS, Abbass MMS (2017) 24 Animal study
Matsuda S, Shibayama H, Hisama M, Ohtsuki M, Iwaki M (2008) 25 In‑vitro study
Panich U, Tangsupaanan V, Onkoksoong T, Kongtaphan K, Kasetsinsombat K,
Akarasereenont P et al (2 011) 11
In‑vitro study
Lee SA, Son YO, Kook SH, Choi KC, Lee JC. (2011) 26 In‑vitro study
Taira N, Katsuyama Y, Yoshioka M, Okano Y, Masaki H (2017) 27 In‑vitro study
Katsuyama Y, Taira N, Yoshioka M, Okano Y, Masaki H (2018) 28 In‑vitro study
Taira N, Katsuyama Y, Yoshioka M, Okano Y, Morikawa T (2018) 29 In‑vitro study
Yim S, Lee J, Jo H, Scholten J, Willingham R, Nicoll J, Baswan SM (2019) 30 In‑vitro study
Miao F, Su MY, Jiang S, Luo LF, Shi Y, Lei TC (2019) 31 In‑vitro study
Lee (2008) 32 Case report
Sheel V, Purwar P, Dixit J. and Rai P (2015) 33 Case report
Postaire E, Jungmann H, Bejot M, Heinrich U, Tronnier H. (1997) 34 Used along with other agents
Broekmans WM, Vink AA, Boelsma E, Klöpping‑Ketelaars WA, Tijburg LB, van’t Veer
P, van Poppel G, Kardinaal AF. (2003) 35
Used along with other agents
Hwang SW, Oh DJ, Lee D, Kim JW, Park SW (2009) 36 Used along with other agent
Dormael RD, Bastien P, Sextius P, Gueniche A, Ye D, Tran C, et al (2019) 37 Used along with other agent
Ishikawa Y, Niwano T, Hirano S, Numano K, Takasima K, Imokawa G (2019) 38 Used along with other agents
Kim J, Kim J, Lee YI, Almurayshid A, Jung JY, Lee JH. (2020) 39 Used along with other agents
Rattanawiwatpong P, Wanitphakdeedecha R, Bumrungpert A, Maiprasert M (2020)40 Used along with other agents
Huh CH, Seo KI, Park JY, Lim JG, Eun HC, Park KC (2003) 41 Used in conjunction with Iontophoresis
Shaikh I, Mashood AA (2014) 42 Used in conjunction with fluorescent pulsed light (FLP)
Yun IS, Yoo HS, Kim YO, Rah DK (2013) 43 Used for scar reduction
Amirlak B, Mahedia M, Shah N (2016) 44 Used for scar reduction
melanosomes of melanocytes (MCs), followed by the progressive
transfer of this melanin to keratinocytes. Melanin is the pigment
responsible for skin color and plays normal physiological roles
within the skin.[20] It is worthwhile to note that the antimelanogenic
mechanism employed by most skin‑lightening agents mediates
the suppression of tyrosinase activity at various levels.[31]
When choosing a depigmenting agent, it is important to differentiate
between substances that are toxic to the MC and substances that
interrupt the key steps of melanogenesis. Vitamin C falls into the
latter category of depigmenting agents.[31]
Vitamin C is essential for a number of processes in human
skin, such as dermal collagen synthesis, antiaging and
antioxidation. It is a weak acid and is only slightly stronger
than vinegar. The acidication of MCs by Vitamin C could
inhibit the catalytic activity of tyrosinase, the rate‑limiting
enzyme required for melanin biosynthesis.[31]
Table 2: Risk of Bias of the studies included in the Systematic Review
Author (Year) Type of study Random sequence
generation
Allocation
concealment
Blinding of
participants
Blinding of
outcome
Incomplete
outcome data
Selective
reporting
Shimada Y, Tai H, Tanak
A, Suzuki I, Takagi
K (2009)16
Randomized
controlled clinical trail
yes yes yes not clear not clear not clear
Yussif NM, Zayed
SO, Hasan SA, Sadek
SS (2016)5
Experimental study yes yes not clear not clear not clear not clear
Yussif NM, Abdel
Rahman AR, Elbarbary
E (2019)17
Experimental study no no no no no not clear
Ratnam AV, Sastry
PB, Satyanarayana
BV (1977)18
Experimental study no no no no no not clear
Kameyama K, Sakai C,
Kondoh S, Yonemoto K,
Nishiyama S, Tagawa
M (1996) 19
Experimental study no no no no no not clear
Kim HM, An HS, Bae
JS, Kim JY, Choi CH, Kim
JY (2017) 20
Experimental study not clear not clear yes yes not clear not clear
Jaros A, Zasada M,
Budzisz E, Debowska R,
Rzepka MG, Rotsztejn
H (2019) 21
Experimental study no no no no no not clear
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Sanadi and Deshmukh: Vitamin C and melanin pigmentation – A systematic review
380 Journal of Oral and Maxillofacial Pathology | Volume 24 | Issue 2 | May-August 2020
Vitamin C and its derivatives inhibit tyrosinase activity and
melanin content in a dose‑dependent manner.[7] It is highly
unstable in aqueous solution. The instability of AA is due to
its oxidation to dehydroascorbic acid, which is a reversible
reaction, and subsequently to 2,3‑diketo‑L‑gulonic acid. The
latter reaction is irreversible,[45] thereby resulting in loss of its
physiological properties.
It has good photoprotective ability against ultraviolet
A‑mediated phototoxicity. Effective delivery of AA
through topical preparations is a major factor, as it may be
dependent on the nature or type of the formulation. The
pH of the formulation should be on the acidic side (pH 3.5)
for effective penetration of the vitamin in the skin.[2]
Vitamin C is available in the market as a variety of creams, serum
and transdermal patches. It is in an almost colorless form and
unstable. On exposure to light, gets oxidized to dehydro‑AA, which
imparts a yellow color. Topical AA formulations have been used in
the concentration range of 1%–20%.[46]
From a clinical point of view, it is important to note that
the efcacy of the Vitamin C serum is proportional to
the concentration but only up to 20%. The half‑life in
the skin after achieving maximum concentration is 4 days.
A persistent reservoir of Vitamin C is important for
adequate photoprotection and can be achieved by regular
8‑hourly applications. A combination of tyrosine, zinc and
Vitamin C has been shown to increase the bioavailability
of Vitamin C 20‑times vis‑a‑vis using just Vitamin C.[47]
The present systematic review summarizes the results of
the studies that assessed the effect of Vitamin C on melanin
pigmentation on the skin as well as the gingiva. There
are limited studies available, which assessed the effect of
Vitamin C alone on melanin pigmentation. In vitro studies,
animal studies and case reports were excluded due to the
low level of evidence of these studies.
Lee[32] reported the management of a case of postlaser
hyperpigmentation in a woman suffering from melasma.
He concluded that intravenous administration of Vitamin C
appears to be useful in treating postlaser hyperpigmentation.
Sheel et al.[33] evaluated the efcacy of Vitamin C as a
depigmenting agent after surgical scalpel depigmentation
on the gingiva. They reported satisfactory esthetic results
with low subjective pain levels, and no recurrence was
observed after 9 months of follow‑up. However, as case
reports have a level low of evidence, they were excluded.
In the present review, studies in which Vitamin C was
used along with other agents were excluded. As Vitamin
C is highly unstable, it is often used in combination with
other agents such as Vitamin E, Vitamin B, lycopene and
β‑carotene.[34] We excluded those studies, as we wanted
to analyze the effect of Vitamin C alone on melanin
pigmentation.
Random sequence generation (selection bias)
Jaros A et.al.(2018)
Kameyama K et.al.(1996)
Kim HM et.al. (2017)
Ratnam AV et.al. (1977)
Shimada Y et.al. (2009) +
Yussif NM et.al. (2016) +
Yussif NM et.al. (2019)
Allocation concealment (selection bias)
+
+
Blinding of participants and personnel (performance bias)
+
+
Blinding of outcome assessment (detection bias)
+
Incomplete outcome data (attrition bias)
Selective reporting (reporting bias)
Other bias
+
+
+
+
+
+
+
Graph 2: Risk of bias summary
Records identified
through database
searching (n = 22580)
Additional records
identified through
other sources (n = 0)
Titles screened
(n = 22580) Records excluded after
review of titles (n = 22000)
Titles screened for
duplicate removal (n = 580)
Excluded
duplicate (n = 100)
Records excluded after
review of abstracts (n = 450)
Abstracts screened (n = 480)
Full texts screened
(n = 30)
In vitro studies, case reports and studies
where Vitamin C was used along with
other agents or treatment modality were
excluded after review of full text (n = 23)
Studies included in
qualitative synthesis (n = 7)
0 studies excluded,
Accuracy % not mentioned.
Included Eligibility ScreeningIdentification
Figure 1: Flow chart of literature search results and study selection
[Downloaded free from http://www.jomfp.in on Thursday, September 10, 2020, IP: 49.32.30.126]
Sanadi and Deshmukh: Vitamin C and melanin pigmentation – A systematic review
Journal of Oral and Maxillofacial Pathology | Volume 24 | Issue 2 | May-August 2020 381
Vitamin C has been used in conjunction with other
treatment modalities. Huh et al.[41] used Vitamin C in
conjunction with iontophoresis so as to enhance the
penetration of Vitamin C into the skin tissue with a
favorable outcome. Shaikh and Mashood[42] used Vitamin C
in conjunction with FPL for treating refractory melasma in
Asian patients and reported a favorable outcome. However,
isolated effect of Vitamin C was not assessed; hence, these
studies were excluded.
Seven studies were included for the qualitative synthesis.
Out of the 7 studies, 1 was a randomized controlled trial
and 6 were experimental studies. Three of the studies
analyzed assessed the effect of Vitamin C on the gingiva
and 4 studies assessed the effect of Vitamin C on skin.
Shimada et al.[16] investigated the inhibitory effect of AA
gel on gingival melanin pigmentation in a double‑masked
placebo‑controlled trial with a split‑mouth design and
reported that AA gel inhibited the gingival melanin
pigmentation. As this study was a randomized controlled
trial, when the risk of bias was assessed, the lowest risk of
bias was observed.
Intraepithelial injections were used on gingiva (Yussif et al.,
2016, and Yussif et al., 2019), which helps in direct delivery
of Vitamin C at the site. This provides for assessment
of effect of Vitamin C alone on melanin pigmentation.
However, when the risk of bias was assessed, a higher risk
of bias was observed in the study conducted by Yussif
et al., 2019.
Vitamin C has been used in dermatology for skin
depigmentation in the form of tablets (Ratnam et al., 1977),
cream (Kameyama et al., 1996, and Kim et al., 2017) and
Vitamin C concentrate (Jaros A et al., 2018). The authors
have reported a favorable outcome, suggesting the possible
effect of Vitamin C on melanin pigmentation. However,
when the risk of bias was assessed, these studies showed
a higher risk of bias.
Except for one study, the risk of bias existed in the studies
as randomization of study participants and blinding was
not performed. This could have inuenced the outcome
of the studies. However, based on the studies analyzed, it
was observed that Vitamin C did have an effect on reducing
melanin pigmentation and has been used as a depigmenting
agent on the skin as well as gingiva. There remains a future
scope for randomized controlled studies to be conducted
CONCLUSION
Vitamin C is a naturally occurring substance and
an essential nutrient. It has various biological and
pharmaceutical functions. It inhibits melanin synthesis
through downregulation of tyrosinase enzyme activity.
It is widely used in dermatology as a treatment modality
in depigmentation of hyperpigmented spots on the
skin. It has also been used for treatment of gingival
melanin hyperpigmentation. However, there is limited
documentation on the use of Vitamin C as a depigmenting
agent for gingival melanin hyperpigmentation, although it
has shown promising results.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conicts of interest.
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... Among the non-surgical approaches, vitamin C (ascorbic acid) is a widely used depigmentation agent in dermatology. 9,10 However, a recent systematic review 11 highlights the paucity of studies on the use of vitamin C for gingival melanin hyperpigmentation. The depigmentation action of vitamin C is achieved by its interference in various steps of melanin production. ...
... 16 Vitamin C offers additional advantages of having anti-inflammatory and antioxidant properties and promoting collagen synthesis, making it a suitable therapeutic agent for both skin and gingival health. 1,11,16 Intraepidermal vitamin C mesotherapy involves using fine needles to locally inject ascorbic acid into the superficial layers of the gingiva extending between the basement membrane and adjacent connective tissue. 1,13,14 It has the advantage of targeted and localized vitamin C delivery, enabling increased efficacy and a potent effect. ...
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Full-text available
Background Surgical methods of gingival depigmentation can be challenging, particularly if the gingival phenotype is thin due to the risk of gingival recession and bone exposure. Thus, exploring alternative, non‐surgical, minimally invasive treatment modalities is warranted. In dermatology, vitamin C is extensively used for depigmentation and microneedling for collagen induction, with limited literature about its usage for improving gingival esthetics. The present preliminary case study aims to explore the synergistic use of vitamin C mesotherapy with microneedling for the esthetic management of physiologic melanin gingival hyperpigmentation. Methods Eleven arches from six patients having anterior physiologic melanin hyperpigmentation were recruited. Microneedling was done with a lancet, followed by intra‐epidermal administration of 1.5–2 mL of vitamin C in pigmented gingiva (once weekly/four sessions). Dummett oral pigmentation index (DOPI), gingival pigmentation index (GPI), pigmented surface area (PSA), and gingival luminescence (L*) were assessed at baseline and follow‐up visits of 1 week, 1 month, and 3 months. Gingival thickness (GT) was recorded at baseline and 3 months. Pain, itching, and gingival color were also assessed. Results A significant reduction (p < 0.05) in mean DOPI, GPI, and PSA was observed from baseline to 3 months, while L* and GT increased significantly within that timeframe. Patients reported an improvement in gingival color at 1 and 3 months. Low pain and itching scores were obtained post‐treatment. Conclusion Vitamin C mesotherapy with microneedling is a newer, minimally invasive approach that can effectively reduce gingival melanin pigmentation intensity and extent, and can potentially increase the gingival thickness. Key points Vitamin C mesotherapy (intra‐epidermal injection) is an effective and minimally invasive treatment modality for gingival depigmentation. The adjunctive use of microneedling with vitamin C mesotherapy can potentially increase gingival thickness non‐surgically. Non‐surgical methods for gingival depigmentation can be chosen as an alternative to surgical methods for esthetic management of physiologic melanin hyperpigmentation in cases with thin gingival phenotype. Plain language summary Patients seek treatment for hyperpigmented gingiva caused by increased melanin to improve the smile esthetics. Conventional surgical methods for gingival depigmentation, however, are challenging to perform in areas of thin gingiva as there is an increased risk of gingival damage and bone exposure. Thus, exploring alternative, non‐surgical, minimally invasive options will be advantageous. In dermatology, vitamin C is a popular agent for treating skin hyperpigmentation, and microneedling is a technique used for collagen induction. This preliminary case study synergistically used local vitamin C injections (mesotherapy) in gingiva with microneedling to manage gingival hyperpigmentation in eleven arches from six patients. Microneedling was done with a lancet, following which 1.5–2 mL of vitamin C was injected intra‐epidermally in pigmented gingiva (once weekly for four sessions). From baseline to three months, a significant reduction in melanin pigmentation intensity and extent was observed as assessed by clinical and photographic parameters. Gingival thickness increased significantly within that timeframe. Patients reported favorable outcomes with improved gingival color with low pain and itching scores. Vitamin C mesotherapy with microneedling is a newer, minimally invasive, effective, non‐surgical treatment modality for achieving gingival depigmentation and improving gingival thickness. The results need further validation in future studies with large sample sizes and long‐term follow‐up.
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Objective To assess, clinically and instrumentally, the efficacy of a stabilized 12% Vitamin C (VC)‐based serum (pH 6) on skin photoageing of women of various age and phototype. Materials and Methods Eighty women, with Phototypes I to VI, of various age (45–70y) living in Mauritius, participated in an open, uncontrolled study. After a two‐week period of washout, they applied the Vitamin C‐based serum twice a day for 2 months onto their whole face as well as a hydrating cream every evening to ensure a comparable skin hydration level in all subjects. At set time intervals (D0, D immediate, D14, D28 and D56), a local dermatologist graded eight facial signs by visual or tactile assessments, using a 0–9 structured scale. At each time interval, the facial skin was imaged by standardized technique (Colorface™) and through echography (Dermascan™) to record its thickness and density. Skin elasticity was recorded by a the Cutometer® device under a controlled suctional stress. A questionnaire was filled out by all subjects recording their self‐assessments of the serum's effects and several organoleptic properties. Results Compared with the baseline values (D0), the skin of all subjects showed progressive and significant changes in glow, tone evenness, radiance, firmness, softness and smoothness, associated with a reduction in fine lines. Deep wrinkles, only observed on 26 subjects, were found to be reduced. Self‐assessments corresponded well with both clinical and instrumental results and indicated excellent skin tolerance. Ultrasound recordings exhibited significantly thicker and denser skin at D56. Conclusion If certain changes in some skin facial signs (skin tone and related items, firmness, sagging…) are linked to the high concentration of VC, a complementary impact of increased skin hydration remains possible due to the glycerol present in the serum and hydrating cream. These significant performance results in vivo showed that a very acidic medium (∼pH 3) is not a prerequisite to an efficient VC cosmetic formula, as has long been accepted in the cosmetics industry. Such a low pH can fragilize the skin equilibrium over time. As second originality, the studied formula seemed to fit all phototypes.
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Background: Skin aging has many manifestations such as wrinkles, uneven skin tone, and dryness. Both intrinsic and extrinsic factors, especially ultraviolet light-induced oxidative radicals, contribute to the etiology of aging. Human skin requires both water- and lipid-soluble nutrient components, including hydrophilic and lipophilic antioxidants. Vitamins C and E have important protective effects in the aging process and require exogenous supply. Raspberry leaf extracts contain botanical actives that have the potential to hydrating and moisturizing skin. Topical products with these ingredients may therefore combine to provide improved anti-aging effects over single ingredients. Objectives: To evaluate the anti-aging and brightening effects of an encapsulated serum containing vitamin C (20% w/w), vitamin E, and European raspberry (Rubus idaeus) leaf cell culture extract. Methods: Fifty female volunteers aged 30-65 years were allocated one capsule of serum for topical application on one side of the face for 2 months, in addition to self-use of facial skin products. Both test (treated) and contralateral (untreated) sides were dermatologically assessed after 4 and 8 weeks. Skin color (melanin index), elasticity, radiance, moisture, and water evaporation were measured by Mexameter MX18® , Cutometer® , Glossymeter GL200® , Corneometer CM825® , and Tewameter TM300® instruments, respectively (Courage + Khazaka Electronic GmbH). Skin microtopography parameters, smoothness (SEsm), roughness (SEr), scaliness (SEsc), and wrinkles (SEw), were measured by Visioscan® VC98 USB (Courage + Khazaka Electronic GmbH), and gross lifting effects were measured by VECTRA® H1 (Canfield Scientific), and adverse reactions and satisfaction were also assessed. Results: Skin color, elasticity, and radiance were significantly improved. The smoothness, scaliness, and wrinkles were also revealed significant improvement. Mild adverse reactions were tingling and tightness. Conclusions: The vitamin C, vitamin E, and raspberry leaf cell culture extract serum has anti-aging and brightening effects of skin.
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Background Solar ultraviolet radiation (UV) induces DNA damages in skin via direct absorption of UVB or indirectly by photosensitization mediated through UVA. Recent findings have revealed that UVA induces cyclobutane pyrimidine dimer (CPD) generation via chemiexcitation in melanocytes hours after the exposure. This UVA-induced delayed CPD (dark CPD) constitutes the majority of CPD in melanocytes. These findings indicate that sun light can damage the skin hours after the exposure, suggesting the need for skin care products post sun exposure. The main objective of this study was to investigate whether a blend of Chrysanthemum Morifolium flower extract (Chrys) and vitamin C derivative, Ascorbic Acid-2-Glucoside (AA2G), can provide protective effects against reactive oxygen species, melanin formation and UVA-induced dark CPD. Methods Intracellular ROS levels were measured in epidermal keratinocytes using DHR123 dye. Melanogenesis inhibition efficacy was determined using B16 cells. As for the dark CPD measurement, Melan-a cells were treated with or without actives for 6 days, then irradiated with UVA at various doses. Cells were exposed with anti-CPD mAb followed by secondary Ab. CPD levels were determined by measuring fluorescent intensity using a high content imaging analysis. Results Chrys, AA2G and their blend at various concentrations demonstrated ROS scavenging activity. Though Chrys alone did not show significant melanogenesis inhibition in B16 assay, the blend of Chrys with AA2G demonstrated additive effects in comparison with AA2G alone. The blend of AA2G and Chrys at various concentrations exhibited enhanced efficacy for inhibiting dark CPD compared to AA2G alone. Conclusion The results from this study indicate that the use of natural antioxidant, Chrys in combination with AA2G, provides protection against UVA-induced delayed CPD formation by enhancing ROS scavenging activity and melanogenesis inhibition. These findings could potentially be applied for formulating post-sun exposure skin care products, possibly extending to evening-after care products.
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Although vitamin C (VC, L-ascorbic acid) has been widely used as a skin lightening agent for a long time, the mechanism by which it inhibits melanogenesis remains poorly understood. It is well-documented that the intramelanocytic pH is an important factor in regulating tyrosinase function and melanosome maturation. The activity of tyrosinase, the rate-limiting enzyme required for melanin synthesis, is generally minimal in an acidic environment. Given that VC is an acidic compound, we might speculate that the intracellular acidification of melanocytes induced by VC likely reduces melanin content through the suppression of tyrosinase activity. The results of this study reveal that treatment of melanocytes with VC or its derivatives, magnesium ascorbyl phosphate (MAP) and 3-O-ethyl-L-ascorbic acid (AAE), resulted in significant decreases in the tyrosinase activity and melanin content and in the levels of intracellular reactive oxygen species (ROS), indicating that VC and its derivatives possess antimelanogenic and antioxidative activities. Western blotting analysis indicated that VC, MAP, and AAE exert their antimelanogenic activity by inhibiting the tyrosinase activity rather than by downregulating the expression of melanogenic proteins such as tyrosinase, premelanosome protein 17 (Pmel17) and microphthalmia-associated transcription factor (MITF). Further, we found that the reduced tyrosinase activity of melanocytes treated with VC or its derivatives could be reactivated following intracellular neutralization induced by ammonium chloride (NH 4 Cl) or concanamycin A (Con A). Finally, we examined the expression of sodium-dependent VC transporter-2 (SVCT-2) using western blotting and qPCR, which revealed that there was a significant increase in the expression of SVCT-2 in melanocytes following treatment with VC. VC-mediated intracellular acidification was neutralized by phloretin (a putative SVCT-2 inhibitor) in a dose-dependent manner. Taken together, these data show that VC and its derivatives suppress tyrosinase activity through cytoplasmic acidification that potentially results from enhanced VC transmembrane transport via the VC transporter SVCT-2.
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Background: Repeated nonextreme sun exposures induce skin pigmentation by increasing melanin production and by oxidizing preexisting melanin and melanin precursors. This leads to skin disorders and skin color heterogeneity such as hyperpigmented spots. Objective: We assessed 31 randomized, controlled clinical trials to determine the potential of vitamin C to limit ultraviolet (UV) daylight-induced pigmentation, considering dose response and different skin type populations (Caucasian and Chinese). Materials and Methods: Thirty-one intraindividual, randomized, controlled clinical trials involving Caucasian and Chinese subjects (15–35 healthy male or female volunteers per study, 741 total volunteers) 18 to 50 years of age with Phototype III and individual typology angle (ITA) value between 28 and 49 degrees were analyzed. The 31 studies assessed the potential of vitamin C (formulated with the copolymer Styrène-Anhydride Maléique [SMA]) to decrease pigmentation induced by UV daylight exposure. Results were combined using a Bayesian meta-analysis to provide probabilistic evidence of the effects of vitamin C by dose and population. Results: Vitamin C was effective in reducing pigmentation induced by UV daylight-simulated expositions (4 days at 0.75 Individual Minimal Erythemal Dose [MEDi]) in a dose-dependent manner. During the depigmentation phase, no additive value was provided by the vitamin C, suggesting that the lightening properties described in the literature for vitamin C correspond to an antipigmenting quality rather than a depigmenting effect. Conclusion: Vitamin C is a valuable and safe dermocosmetic antipigmenting compound with a strong effect at 10% possibly useful in preventing signs of photoaging.
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Little is known about the anti-pigmenting effects of whitening agents on solar lentigos (SLs), which comprise ~ 60% of hyperpigmented facial lesions of Asian subjects. Lotions with or without 6% l-ascorbate-2-phosphate trisodium salt (APS) [test lotion (TL) and placebo lotion (PL), respectively] were applied twice daily for 24 weeks in a double-blind half-face study of 27 Japanese females with SLs on both sides of their faces. Pigmentation scores were evaluated using a photo-scale and the skin colors were assessed using a color difference meter and a mexameter for SLs and the non-lesional surrounding skin (NLS). Although the pigmentation scores were not significantly different between the TL and PL-treated SLs after 24 weeks, the L values of TL-treated SLs and NLS increased significantly with a significantly higher △L value in SLs than in NLS. In contrast, the L values of PL-treated SLs and NLS remained unchanged after the treatment. The number of subjects with > 2.0 △L was 7 of 27 (TL) and 0 of 27 (PL) in SLs and 3 of 27 (TL) and 0 of 27 (PS) in NLS. In contrast, the melanin index in TL-treated SLs and NLS significantly decreased with a significantly higher △melanin index in SLs than in NLS. Similarly, the melanin index of PL-treated SLs and NLS were significantly decreased with a significantly higher △melanin index in SLs than in NLS. These findings strongly indicate that APS has a weak but significant anti-pigmenting effect on SLs and a significant whitening effect even on normally pigmented healthy skin.
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Background Ascorbic acid is a substance with confirmed anti‐free‐radical properties. It triggers the collagen synthesis, has a depigmenting effect and seals blood vessels. All these properties have a significant effect of the skin's appearance. The characteristic traits of capillary skin include telangiectasias as well as erythema, which might consolidate in the future, along with the feeling of burning and increased skin sensitivity. Objectives Study and evaluation of selected parameters of capillary skin after the application of 5% vitamin C concentrate throughout the period of 6 weeks with the use of instrumental tests and questionnaires. Methods The research was conducted on a group of 30 women ranging from 30 to 60 years of age with capillary skin indicating visible signs of erythematous plaques. The concentrate was applied once a day. Analyses of skin conditions were conducted four times: before the launch of the research D(0), after two 2D(14), after four 4D(28), and after 6 D(42) weeks of application. The research was conducted with the use of Mexameter MPA equipment, which was used to measure changes in the intensity of erythematous plaques. The depth of wrinkles was measured by PRIMOS system (two times D0 and 6D(42). The research also used VISIA system which allowed to perform visual and numeral skin analyses. Each research was finalized with a questionnaire which provided a subjective evaluation of the examined product among participants. Results Significant reduction in erythema has been widely recorded. After 2 weeks, erythema dropped by 9%. After 4 weeks, it decreased by 16% and by 21% after 6 weeks. The concentrate's efficiency in diminishing erythematous plaques was confirmed by photographs generated by VISIA photograph system. Thanks to PRIMOS, decrease in both depth and volume of nasolabial folds was recorded in 87% of participants after 6 weeks of research. Conclusion 5% vitamin C concentrate is effective in treating capillary and photograph‐aging skin. It decreases erythema and telangiectasias as well as triggers the shallowing of skin wrinkles.
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Background: Extrinsic skin aging caused by atmospheric pollutants is associated with a sustained inflammatory response which is a significant risk factor for lentigines and melasma. Aims: The aim of this study was to evaluate the efficacy of topical application of combination formulation of vitamin C, vitamin E, and ferulic acid as an adjuvant to Q-switched Nd:YAG (QSNY) lasers treatment in individuals with lentigines and melasma. Methods: A single blinded, prospective, randomized split-face trial was conducted. Eighteen men and women between 26 and 53 years old were treated with a combination antioxidant serum on one randomized side of their face immediately after QSNY laser and twice daily for 2 weeks. Patients were evaluated using digital photography and spectrometry to assess the melanin index and erythema index. Melasma severity score and global improvement scores also were assessed. Results: The treated side of the face exhibited a significantly greater reduction in the melanin index. There was no significant difference in post-treatment erythema. More clinical improvement was observed on the treated side compared with the untreated side. Conclusions: Our study suggests that topical application of a combination vitamins C, E, and ferulic acid antioxidant formula may be effective as an adjuvant option in QSNY lasers.
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The formation of skin pigmentation requires multiple steps, namely the activation of melanocytes, the synthesis of melanin, the transport of melanosomes to the tips of melanocyte dendrites and the transfer of melanosomes from melanocytes to surrounding keratinocytes. Recently, we reported that melanosomes accumulate in melanocytes when melanosome transport is disrupted and that they are then degraded by the autophagy system. In this study, we examined whether 3-O-glyceryl-2-O-hexyl ascorbate (VC-HG) suppresses melanogenesis through the activation of autophagy since VC-HG interferes with melanosome transport through the down-regulated expression of MyosinVa and Kinesin. The results demonstrate that VC-HG-treated B16 cells show an activation of autophagy through an increased expression level of Microtubule-associated protein 1 light chain 3 (LC3)-II and a decreased expression level of p62. Furthermore, the decrease of melanin content elicited by VC-HG was partially abolished by hydroxychloroquine or pepstatin A which are inhibitors of autophagy. Taken together, we conclude that VC-HG suppresses melanogenesis by activating the autophagy system. Graphical Abstract Fullsize Image