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Effect of astaxanthin on cutaneous wound healing

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Jitlada Meephansan,1 Atiya Rungjang,1 Werayut Yingmema,2 Raksawan Deenonpoe,3 Saranyoo Ponnikorn3 1Division of Dermatology, Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, Thailand; 2Laboratory Animal Centers, Thammasat University, Pathum Thani, Thailand; 3Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, Thailand Abstract: Wound healing consists of a complex series of convoluted processes which involve renewal of the skin after injury. ROS are involved in all phases of wound healing. A balance between oxidative and antioxidative forces is necessary for a favorable healing outcome. Astaxanthin, a member of the xanthophyll group, is considered a powerful antioxidant. In this study, we investigated the effect of topical astaxanthin on cutaneous wound healing. Full-thickness dermal wounds were created in 36 healthy female mice, which were divided into a control group and a group receiving 78.9 µM topical astaxanthin treatment twice daily for 15 days. Astaxanthin-treated wounds showed noticeable contraction by day 3 of treatment and complete wound closure by day 9, whereas the wounds of control mice revealed only partial epithelialization and still carried scabs. Wound healing biological markers including Col1A1 and bFGF were significantly increased in the astaxanthin-treated group since day 1. Interestingly, the oxidative stress marker iNOS showed a significantly lower expression in the study. The results indicate that astaxanthin is an effective compound for accelerating wound healing. Keywords: astaxanthin, wound healing, reactive oxygen species, antioxidant
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ORIGINAL RESEARCH
open access to scientific and medical research
Open Access Full Text Article
http://dx.doi.org/10.2147/CCID.S142795
Effect of astaxanthin on cutaneous wound healing
Jitlada Meephansan1
Atiya Rungjang1
Werayut Yingmema2
Raksawan Deenonpoe3
Saranyoo Ponnikorn3
1Division of Dermatology, Chulabhorn
International College of Medicine,
Thammasat University, Pathum Thani,
Thailand; 2Laboratory Animal Centers,
Thammasat University, Pathum Thani,
Thailand; 3Chulabhorn International
College of Medicine, Thammasat
University, Pathum Thani, Thailand
Abstract: Wound healing consists of a complex series of convoluted processes which involve
renewal of the skin after injury. ROS are involved in all phases of wound healing. A balance
between oxidative and antioxidative forces is necessary for a favorable healing outcome. Astax-
anthin, a member of the xanthophyll group, is considered a powerful antioxidant. In this study,
we investigated the effect of topical astaxanthin on cutaneous wound healing. Full-thickness
dermal wounds were created in 36 healthy female mice, which were divided into a control
group and a group receiving 78.9 µM topical astaxanthin treatment twice daily for 15 days.
Astaxanthin-treated wounds showed noticeable contraction by day 3 of treatment and complete
wound closure by day 9, whereas the wounds of control mice revealed only partial epithelializa-
tion and still carried scabs. Wound healing biological markers including Col1A1 and bFGF were
significantly increased in the astaxanthin-treated group since day 1. Interestingly, the oxidative
stress marker iNOS showed a significantly lower expression in the study. The results indicate
that astaxanthin is an effective compound for accelerating wound healing.
Keywords: astaxanthin, wound healing, reactive oxygen species, antioxidant
Introduction
Wound healing or repair is a complex and crucial process of response to injury. To
accomplish this, coordination of multiple cells and components is necessary. The heal-
ing process is composed of three overlapping phases: inflammation, proliferation, and
remodeling.1 In the coagulation and inflammatory phase, cutaneous injury affecting
primarily the epithelial and endothelial compartments results in a coagulation cas-
cade forming a blood clot and release of pro-inflammatory mediators. The blood clot
within the vessel lumen provides hemostasis, and the clot within the injury site acts
as a provisional matrix for cell migration, promoting formation of fresh extracellular
matrix (ECM), a reservoir for cytokines and growth factors. Inflammatory white cell
functions include debridement of necrotic material and bacteria, and production of
critical cytokines. Twenty-four to forty-eight hours after injury, monocytes replace
neutrophils and differentiate into tissue macrophages which phagocytose and kill
bacteria, scavenge tissue debris, and release several growth factors. The growth factors
stimulate migration and proliferation of fibroblasts, endothelial cells, and keratino-
cytes, and production and modulation of ECM, constituting the proliferation/migration
phase resulting in reepithelialization and angiogenesis. The remodeling phase begins
5–7 days after injury to break down excess macromolecules. Cells within the wound
are returned to a stable phenotype and ECM material is altered.
Correspondence: Jitlada Meephansan
Division of Dermatology, Chulabhorn
International College of Medicine,
Thammasat University, Rangsit Campus,
99 Moo 18 Phahonyothin Road,
Klongluang, Pathum Thani, 12120,
Thailand
Tel +66 2564 4444 ext 1535
Email kae_mdcu@yahoo.com
Journal name: Clinical, Cosmetic and Investigational Dermatology
Article Designation: ORIGINAL RESEARCH
Year: 2017
Volume: 10
Running head verso: Meephansan et al
Running head recto: Astaxanthin and wound healing
DOI: http://dx.doi.org/10.2147/CCID.S142795
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ROS are involved in all phases of wound healing. ROS are
small chemically reactive molecules of oxygen such as oxygen-
free radicals. They strongly react with multiple molecular com-
ponents such as nucleic acids, proteins, lipids, and other small
inorganic molecules. ROS may alter the function or ir reversibly
destroy the target molecule through their cascading reactions.
On the other hand, low concentrations of ROS play a role in
initiating signaling during the proliferative phase, including
homeostasis,2,3 formation of granulation tissue, reepithelializa-
tion, and angiogenesis.4 The physiological level of ROS, such
as hydrogen peroxide at the wound site, increases after injury
and gradually declines. Prolonged generation or large amounts
of ROS, called oxidative stress, can cause chronic inflamma-
tion by initiating the NF-kB/Rel pathway,4 which is believed
to be the major cause of chronic unhealed wounds. The nega-
tive effects of oxidative stress can be restrained by antioxidant
enzyme systems and dietary antioxidants such as carotenoids.5
The carotenoid structure has a common chemical feature con-
taining a long-conjugated double-bond polyene chain, which
has an ability to quench or scavenge ROS.6 Several kinds of
antioxidants are proposed to regulate the oxidation–reduction
balance, and studies of the effects of various antioxidants on
wound healing have reported accelerated healing outcomes.7,8
Astaxanthin, a member of the xanthophyll group, is a
red-orange carotenoid. Its antioxidative effect has been shown
to exceed those of pro-vitamin A and vitamin E,9 and it is
considered one of the most powerful antioxidants. The inter-
est in antioxidant activity of astaxanthin in the pharmaceutical
industry, aquaculture, and nutritional health is expanding. It
has been used as a highly effective antioxidant in various health
conditions.10 In dermatology, clinical studies suggest that oral
supplementation and topical treatment of an astaxanthin extract
from Haematococcus pluvialis improves the skin condition
and provides protective effects mediated by balanced oxidative
actions. A balance between oxidative and antioxidative forces is
needed for favorable wound healing. Among studies on various
health-promoting effects of astaxanthin, very few studies on
wound healing have been reported. In this study, we investigated
the effect of topical astaxanthin on cutaneous wound healing
in animal models, serving as a preliminary study for the use
of astaxanthin in accelerating wound healing. We evaluated
wound contraction area and histopathology, and determined the
mRNA levels of iNOS, Col1A1, and bFGF at the wound area.
Materials
Drugs
The astaxanthin material, composed of 78.9 µM of astax-
anthin extracted from H. pluvialis, was supplied by China
Jiangsu International Economic and Technical Cooperation
Group, Ltd. The vehicle was palm oil.
Animals
The animal protocol (no 015/2558) was approved by the
Institutional Animal Care and Use Committee of Thammasat
University, which is accredited by the National Research
Council of Thailand. All animals were housed at the Labo-
ratory Animal Center of Thammasat University according
to guidelines for the care and use of laboratory animals,
National Research Council 2011. Young female BALB/c
mice (8 weeks old) were procured from the National Labo-
ratory Animal Center, Thailand. A total of 36 mice were
randomly assigned to an astaxanthin-treated group and a
control group. During the experiments, the animals were
housed under strict hygiene standards and controlled envi-
ronmental conditions (12-hour light/dark cycle, temperature
approximately 23°C). Standard laboratory food and water
were provided ad libitum.
Animal experiments
Anesthesia and surgical procedure
Mice were anesthetized with 1.5% isoflurane in 100% oxy-
gen at a 0.9 L/minute flow after induction with 5% isoflurane
using a single circuit anesthesia system. Mice were posi-
tioned in ventral recumbency. Hair on the dorsal surface of
the skin was removed with a razor, the skin was aseptically
prepped with 70% alcohol gauze sponges, and a sterile
drape positioned. All wounding procedures were performed
under sterile conditions by one surgeon. The dorsal skin was
picked up and a punch hole extending through the panniculus
carnosus was made using a 4-mm sterile disposable biopsy
punch. Two full-thickness wounds were created at designated
locations. The wounds were left open with no dressing. Each
wound site was digitally photographed and tissues were
collected. Tissues at wound sites were collected for reverse
transcription polymerase chain reaction (RT-PCR) on days
1, 3, 6, 9, 12, and 15 using a disposable biopsy punch (6 mm
in diameter).
Tissues for histopathology were collected from treat-
ment and control groups by elliptical excision on day 3 and
7 post-wounding.
Post-operative and wound care
The wounds were treated topically twice daily with astaxanthin
extract in the treatment group and vehicle in control group
(0.025 mL/wound). A digital image of each wound with a
scale was recorded daily until complete closure. For the wound
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Astaxanthin and wound healing
contraction study, a template containing a 10-mm diameter cir-
cular window was used to standardize the size of each wound.
Outcome measures
Wound contraction
Digital photographs were taken on the day of surgery and
every day from then on. Time to wound closure was defined
as the time point at which the wound bed was filled with new
tissue. Wound area was analyzed by tracing the wound margin
with a fine-resolution computer mouse and calculating the
pixel area using Adobe Illustrator CS6 software, run on an
Intel® Core™ i7-2600K CPU. All tracing was performed by
the same computer graphics professional, without knowledge
of treatment conditions. Wound contraction was calculated
as the percentage decrease in original wound area. Complete
closure was considered when the wound area disappeared,
and became grossly equal to zero.
RT-PCR
Collected tissue samples were stored fresh frozen at -80°C
until use. The RNeasy Mini Kit (Qiagen NV, Venlo, the
Netherlands) was used for extraction and purification of total
RNA from tissues, following the manufacturer’s protocol.
A260/280 ratios of the samples were used to evaluate the
RNA quantity and quality. cDNA synthesis was performed
using the ImProm-II™ Reverse Transcription System (Pro-
mega Corporation, Fitchburg, WI, USA) following the manu-
facturer’s protocol. Expression of the wound healing markers
Col1A1 (Mm00801666_g1), bFGF (Mm00438930_m1),
and iNOS (qMmuCIP0035502) was analyzed using real-
time PCR following the manufacturer’s protocol from iTaq
Universal Probes Supermix (Bio-Rad Laboratories Inc.,
Hercules, CA, USA). The relative ratio of gene expression
for each gene was determined by standard exponential curves
using the CFX 96 TouchTM PCR Detection System (Bio-
Rad Laboratories Inc.). The internal control gene (B2M,
Hs00985689_m1; Thermo Fisher Scientific, Waltham, MA,
USA) was used to normalize target gene expression.
Histopathological evaluation
Histologic evaluation was performed using visible light
microscopy. The samples were fixed in 10% buffered for-
malin. After fixation, sections perpendicular to the anterior–
posterior axis of the wound were dehydrated with graded
ethanol and embedded in paraffin. Hematoxylin and eosin,
and Masson’s trichrome stains were used on sections of
paraffin-embedded tissue. Images were captured at 4× and
10× magnification with a Leica DM3000 LED microscope
under the same exposure. Reepithelialization, granulation
tissue formation, angiogenesis, and inflammatory cell infil-
tration were evaluated.
Statistical analysis
Results were recorded as mean±SD. The Student’s t-test and
Mann–Whitney test were performed to analyze differences
between data obtained from different experimental groups.
A P-value of less than 0.05 was considered significant.
Results
Wound contraction
The astaxanthin extract applied topically on the wounds
showed significant acceleration of wound closure which
was clearly visible at day 3 of the experiment (Figure 1). On
day 9 after wounding, the astaxanthin-treated wounds had
already lost their eschars and appeared fully epithelialized,
whereas the wounds of control mice showed only partial
epithelialization and still carried scabs. Complete wound
closure in the control group was observed only by day 11. The
mean original wound area in the astaxanthin-treated group
was larger than that in the control group, at 14.69 mm2 and
12.42 mm2, respectively. In addition, on day 1 post-injury,
wound area in the astaxanthin-treated group significantly
decreased to 10.33 mm2 (28.15% reduction of the original
wound area), whereas the control group showed an 18.12%
reduction, to 10.23 mm2. On day 7 after wounding, closure
of the wounds in the astaxanthin-treated group was more
pronounced than that in the control group, at 90% (1.27 mm2)
Day 0
Control
A
staxanthin
Day 3 Day 5 Day 7 Day 9 Day 11
Figure 1 Images of wound contraction in astaxanthin and control groups from day 0 to day 11.
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and 82.35% (2.17 mm2), respectively (Figure 2). No mice
were excluded from the study and no wounds showed signs of
infection. At the end of the experiment, mice in both groups
showed complete wound closure without visible scars or
chronic wounds.
The data indicated that wound closure in astaxanthin-treated
mice was significantly accelerated compared with vehicle-
treated mice. A significant difference between the two groups
was observed beginning at day 1 and continued until complete
wound closure in the astaxanthin-treated group at day 10.
Histology
At day 3, almost complete reepithelialization was observed in
the astaxanthin-treated group but poor reepithelialization was
seen in the control group. In the control group, stellate and
spindle fibroblasts were scattered in the granulation tissue with
a moderate to high degree of edema, whereas collagen bundles
with a mild degree of edema were observed in the astaxanthin-
treated group. In addition, a few capillary vessels were present
in the wound area which were poorly arranged in the control
group, but were well arranged in the astaxanthin-treated group.
Mononuclear cells, which were marginated in the vessels and
scattered in perivascular and dermis regions, were markedly
decreased in the astaxanthin-treated group compared to the
control group. At day 7, complete reepithelialization and a well-
elongated epidermis with keratinization was observed in mice
treated with astaxanthin. The degree of infiltrated inflammatory
cells was minimal in both groups. Well-formed granulation tis-
sue, fibroblasts oriented parallel to the skin surface, and abundant
organization of collagen were observed in the astaxanthin-
treated group. Treatment with astaxanthin significantly promoted
the wound healing process in mice (Figure 3).
Day
*
*
*
**
*
***
0123 45678910 11 12 13 14 15
–120.00
–100.00
–80.00
–60.00
Change of baseline (%)
–40.00
–20.00
0.00
Astaxanthin
Control
Figure 2 Wound area contraction in astaxanthin and control groups from day 0 to day 15.
Notes: Error bars indicate standard deviations. *P<0.05.
Day 3 Day 7
A
staxanthin
Control
AB
CD
Figure 3 Skin wound sections from the astaxanthin-treated group and the control group at day 3 and day 7 stained with hematoxylin and eosin.
Notes: (A, B) Control; (C, D) astaxanthin-treated group; (A, C) and (B, D) represent day 3 and day 7 of the experiment, respectively.
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Astaxanthin and wound healing
Wound healing markers and oxidative
stress markers
The mRNA expression of tissue-specific wound healing bio-
markers and oxidative stress biomarkers including Col1A1,
bFGF, and iNOS were determined using real-time PCR.
Dynamic gene expression profiles in astaxanthin-treated
mice and the control group were compared on days 1–15
(Figure 4). During the healing process, expression of Col1A1
and bFGF in the astaxanthin-treated group was higher than
that in the control group, throughout the healing period. The
expression of collagen1 mRNA in both groups was mark-
edly increased and reached a maximum on day 6 post-injury.
bFGF mRNA expression in both groups decreased during the
first 3 days post-injury, and then gradually increased until
day 15 in both groups. iNOS was selected as an oxidative
stress marker, for monitoring ROS during the wound heal-
ing process. Real-time PCR analysis revealed a decrease
in expression of iNOS in astaxanthin-treated mice from
day 3 onward, until the end of the experiment. In summary,
astaxanthin treatment caused a significant increase in expres-
sion of wound healing biomarkers Col1A1 and bFGF, but a
significant decrease in expression of oxidative stress (ROS)
biomarker iNOS (Figure 4).
Discussion
Significant accelerated healing effects of astaxanthin were
observed on the first day after injury, during the inflammatory
phase. This effect could be mediated either by suppression of
the inflammation level or by acceleration of the inflammatory
phase. Minimal inflammation is known to contribute to better
wound healing. Astaxanthin may suppress this unfavorable
condition through various mechanisms. First, this effect could
be facilitated by balancing oxidative stress. While the produc-
tion of ROS in the early phase is significantly higher than
normal in order to defend against invading microorganisms
and transmit intercellular signals supporting the process of
inflammation,11,12 astaxanthin may be quenching and scav-
enging excessive ROS and RNS, which is consistent with
our result which showed significantly decreased expression
of iNOS, an oxidative stress marker, in the astaxanthin-
treated group. As a result, activation of the NF-kB pathway
may be prevented, leading to reduced pro-inflammatory
gene transcription and pro-inflammatory cytokine produc-
tion.13,14 Second, astaxanthin may have an inhibitory effect
on the expression of adhesion molecules. The main source of
ROS during inflammation is NADPH oxidase in the plasma
membrane of neutrophils and macrophages. It was found
that traditional antioxidants suppress expression of adhesion
molecules (ICAM-1, VCAM-1, E-selectin) and chemokines
(IL-8) during inflammation.15,16 Astaxanthin may also inhibit
expression of these molecules, leading to inhibition of inflam-
matory cell infiltration. ROS production in mitochondria was
found to be involved in inflammatory signaling pathways,16
and the protective effects of astaxanthin may protect against
Col1A1
bFGF
iNOS
Relative Col1A1
mRNA expression
Relative iNOS mRNA expression
Relative bFGF mRNA expression
Astaxanthin
Control
Astaxanthin
Control
Astaxanthin
Control
0
100
200
300
00
10
20
30
40
50
60
70
80
100
50
150
250
350
200
300
400
500
600
**
*
Day 1 Day 3 Day 6 Day 9 Day 12 Day 15 Day 1 Day 3 Day 6 Day 9 Day 12 Day 15
Day 1 Day 3 Day 6 Day 9 Day 12 Day 15
A B
C
Figure 4 The mRNA expression of tissue-specic wound healing biomarkers.
Notes: Gene expression of wound healing and oxidative stress markers were analyzed using real-time polymerase chain reaction analysis of astaxanthin-treated mice and
control mice, represented by the orange and the blue line, respectively. The (AC) show the expression of Col1A1, bFGF, and iNOS, respectively. The asterisk represents
a signicant difference in expression (P<0.05) on the indicated day. Error bars indicate standard deviations.
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these intracellular oxidative molecules as well.5 In addition,
its anticomplement activity may also be involved in the sup-
pression of inflammation.17
The results during the proliferative and remodeling
phases also indicate the significant potential of astaxanthin
to reduce wound size throughout the closure process. This
correlates with the increased expression of bFGF due to
astaxanthin in our study. bFGF plays a significant role in
granulation tissue formation, reepithelialization, matrix
formation, and remodeling,18 which are the major events
during proliferative and remodeling phases. In vitro studies
have demonstrated that bFGF regulates the synthesis and
deposition of various EMC components, increases kerati-
nocyte motility during reepithelialization,19 promotes the
migration of fibroblasts, and stimulates them to produce
collagenase. The increased expression of bFGF mRNA
in the astaxanthin-treated group during the early phase of
wound healing may contribute to a significant acceleration
of wound closure.
As mentioned previously, a low concentration of ROS
is needed to initiate a normal repair process. Astaxanthin
was shown to preserve that physiological function by redox
regulation. For example, in host defense mechanisms,
astaxanthin suppresses ROS and inflammatory cell infiltra-
tion. At the same time, it improves the capacity and ability
of leukocytes to destroy pathogens.20 In angiogenesis, ROS
signals regulate formation of new blood vessels. Astaxanthin
may enhance the effect of ROS in activating physiological
angiogenesis, and regulate ROS at an appropriate level,
which is not harmful to endothelial cells.21 Additionally, it
may also inhibit pathological angiogenesis in vascularized
tumors by suppressing angiogenesis via the JAK2/STAT3
signaling pathway.22
Collagen is an essential component of the proliferative and
remodeling phase, as it provides strength to the wound.23,24 In
the early process of granulation tissue formation, fibroblasts
produce collagen type 3, which is later substituted with a
stronger type 1 collagen during the maturation phase. Our
data showed a significantly higher expression of Col1A1 on
day 6 after injury in the astaxanthin-treated group, compared
to the control group. This is consistent with a study on vocal
fold wound healing,25 which found that astaxanthin upregu-
lates Col1A1 expression. Wound contraction is another
important mechanism in the process of wound closure, espe-
cially in rodents.26 Astaxanthin probably accelerates wound
contraction during the proliferative and maturation phase
by enhancing the function of myofibroblasts, the cells that
are differentiated from tissue fibroblasts, which play a key
role in this process. Their smooth muscle features produce
contractile forces between the wound edges and ECM. They
also produce collagen matrix to form scar tissue, and release
cytokines and growth factors contributing to the increasing
rate of wound healing.27
However, in later stages, the myo-
fibroblasts are removed from the normally healed wound; a
persistent accumulation possibly results in hypertrophic scar
or keloid.28 In our study, there was no visible scar observed
at the end of the study in both groups. While increasing the
contraction of the wound, astaxanthin may also reduce the
chance of fibrosis by inducing apoptosis of the myofibroblast
and/or suppressing TGF-β.29,30
Conclusion
Topical treatment with astaxanthin extract appears to acceler-
ate wound healing in full-thickness dermal wounds in mice.
Future studies are likely to employ astaxanthin as a novel
redox-based strategy to treat wounds in humans.
Acknowledgment
The authors gratefully acknowledge the financial support
provided by Chulabhorn International College of Medicine,
Thammasat University, contract no 11/2558.
Disclosure
The authors report no conflicts of interest in this work.
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... Strong antiinflammatory and antioxidant activity. It regulates collagen through inhibition of MMP-1 and production of [179][180][181][182][183][184] Tomato, watermelon, red carrots, pink grapefruit, pink guava, and papaya. ...
... It has been reported to play a role in inhibiting photoaging, decreasing MMP-1 enzyme production and the inflammatory signaling pathway, and promoting keratinocyte migration in the proliferative phase of wound healing [180][181][182]. Due to these characteristics, astaxanthin is a promising molecule for accelerating the wound-healing process through migration and collagen production [183,184]. ...
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Chronic inflammation is one of the hallmarks of chronic wounds and is tightly coupled to immune regulation. The dysregulation of the immune system leads to continuing inflammation and impaired wound healing and, subsequently, to chronic skin wounds. In this review, we discuss the role of the immune system, the involvement of inflammatory mediators and reactive oxygen species, the complication of bacterial infections in chronic wound healing, and the still-underexplored potential of natural bioactive compounds in wound treatment. We focus on natural compounds with antioxidant, anti-inflammatory, and antibacterial activities and their mechanisms of action, as well as on recent wound treatments and therapeutic advancements capitalizing on nanotechnology or new biomaterial platforms.
... ASTX is also effective on prevention and treatment of DM-associated pathologies. Positive impact of ASTX has been shown on wound healing in nasal mucosa [46] and vocal fold [47], as well as impaired cutaneous regeneration [48,49]. However, the effect of the compound on chronic wound healing of the oral mucosa is unknown. ...
... Topical ASTX application reduced ROS production which prohibited inflammatory cell infiltration in epidermis. In the same study, it was stated that wounds treated with ASTX were completely epithelialized on day 9, while the control group showed only partial epithelialization, delaying complete wound closure by two days [48]. ASTX also reduced large amounts of ROS that is produced during vocal fold healing, resulting in decreased tissue contraction and hyaluronic acid deposition [47]. ...
Article
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Fibroblasts of the gingiva play a key role in oral wound healing in diabetes. In this study, effects of astaxanthin (ASTX), a xanthophyll carotenoid, were tested on gingival fibroblasts in a wound healing assay in vitro. The aim of this study was to determine whether ASTX can recover delayed wound healing or not when oxidative stress is elevated by high glucose exposure. For this purpose, human gingival fibroblasts were incubated with or without ASTX following exposure to systemic doses of low glucose (LG) and high glucose (HG) in culture media (5-and 25-, 50 mM D-glucose in DMEM Ham's F12) following 24 hours of incubation. Levels of ROS (Reactive oxygen species) were determined for each experimental group by confocal microscopy. Cell proliferation and viability were assessed by an automated cell counter with trypan blue assay. Wound healing assay was designed in 60 mm petri dishes. Cells were exposed to 5-, 25-, and 50 mM glucose for 24 hours, and a straight line free of cells was created upon full confluency. 100 μM ASTX was added to the recovery group, simultaneously. Cells were monitored with JuLI Ⓡ-Br Cell History Recorder. ROS levels were significantly increased with increasing glucose levels, while cell proliferation and viability demonstrated a negative correlation with increasing oxidative stress. ROS levels significantly decreased in the 100 μM ASTX-treated group compared to the gingival fibroblasts treated with 50 mM HG medium-only, as well as growth rate and viability. Wound healing was delayed in a dose-dependent manner following high glucose exposure, while ASTX treatment recovered wounded area by 1.16-fold in the 50 mM HG group. Our results demonstrated that ASTX enhances gingival wound healing through its antioxidative properties following high glucose induced oxidative stress. Therefore, ASTX can be suggested as a promising candidate to maintain oral health in chronic wounds of the oral tissues related to diabetes.
... With these summarized results, The AST can overcome the low bioavailability by combining with GO and RGD peptide, and maximizing their respective advantages as a nanocarrier, based on stronger antioxidant, antibacterial, and anti-inflammatory effects. It can participate in cell proliferation and inflammatory processes to help wound healing and can be used very effectively; therefore, can apply a new nanocarrier to the therapy for skin diseases including wound healing [73,74]. Furthermore, it can treat various inflammatory diseases mediated by oxidative stress; therefore, it is potential for various applications in the field of tissue engineering. ...
Article
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Background Astaxanthin (AST) is known as a powerful antioxidant that affects the removal of active oxygen and inhibits the production of lipid peroxide caused by ultraviolet light. However, it is easily decomposed by heat or light during production and storage because of the unsaturated compound nature with a structural double bond. The activity of AST can be reduced and lose its antioxidant capability. Graphene oxide (GO) is an ultrathin nanomaterial produced by oxidizing layered graphite. The chemical combination of AST with GO can improve the dispersion properties to maintain structural stability and antioxidant activity because of the tightly bonded functionalized GO surface. Methods Layered GO films were used as nanocarriers for the AST molecule, which was produced via flow-enabled self-assembly and subsequent controlled solution deposition of RGD peptide and AST molecules. Synthesis of the GO-AST complex was also carried out for the optimized concentration. The characterization of prepared materials was analyzed through transmission electron microscopy (TEM), scanning electron microscope (SEM), Fourier-transform infrared spectroscopy (FT-IR), atomic force microscope (AFM), and Raman spectroscopy. Antioxidant activity was tested by 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 2.2-diphenyl-1-picrylhydrazyl (DPPH) assays. The antibacterial effect and antioxidant effects were monitored for the ultrathin GO/RGD/AST Film. Further, reactive oxygen species (ROS) assay was used to evaluate the anti-inflammatory effects on L-929 fibroblasts. Results Cotreatment of GO-AST solution demonstrated a high antioxidant combined effect with a high ABTS and DPPH radicals scavenging activity. The GO/RGD/AST film was produced by the self-assembly process exhibited excellent antibacterial effects based on physicochemical damage against E. coli and S. aureus . In addition, the GO/RGD/AST film inhibited H 2 O 2 -induced intracellular ROS, suppressed the toxicity of lipopolysaccharide (LPS)-induced cells, and restored it, thereby exhibiting strong antioxidant and anti-inflammatory effects. Conclusion As GO nanocarrier-assisted AST exerted promising antioxidant and antibacterial reactions, presented a new concept to expand basic research into the field of tissue engineering.
... Indeed, the balance between oxidants and antioxidants is highly desirable for the wound healing process. Topical application of astaxanthin (for 15 days) resulted complete wound closure by day 9. Astaxanthin treatment significantly increased the mRNAs expression levels of wound healing markers such as collagen type1 alpha 1 (Col1A1) and basic fibroblast growth factor (bFGF) and significantly lowered expression of iNOS in the mice skin (Meephansan et al. 2017). Re-epithelialization is very essential for skin wound healing. ...
Article
Age-related diseases are associated with increased morbidity in the past few decades and the cost associated with the treatment of these age-related diseases exerts a substantial impact on social and health care expenditure. Anti-aging strategies aim to mitigate, delay and reverse aging-associated diseases, thereby improving quality of life and reducing the burden of age-related pathologies. The natural dietary antioxidant supplementation offers substantial pharmacological and therapeutic effects against various disease conditions. Astaxanthin is one such natural carotenoid with superior antioxidant activity than other carotenoids, as well as well as vitamins C and E, and additionally, it is known to exhibit a plethora of pharmacological effects. The present review summarizes the protective molecular mechanisms of actions of astaxanthin on age-related diseases of multiple organs such as Neurodegenerative diseases [Alzheimer’s disease (AD), Parkinson’s disease (PD), Stroke, Multiple Sclerosis (MS), Amyotrophic lateral sclerosis (ALS), and Status Epilepticus (SE)], Bone Related Diseases [Osteoarthritis (OA) and Osteoporosis], Cancers [Colon cancer, Prostate cancer, Breast cancer, and Lung Cancer], Cardiovascular disorders [Hypertension, Atherosclerosis and Myocardial infarction (MI)], Diabetes associated complications [Diabetic nephropathy (DN), Diabetic neuropathy, and Diabetic retinopathy (DR)], Eye disorders [Age related macular degeneration (AMD), Dry eye disease (DED), Cataract and Uveitis], Gastric Disorders [Gastritis, Colitis, and Functional dyspepsia], Kidney Disorders [Nephrolithiasis, Renal fibrosis, Renal Ischemia reperfusion (RIR), Acute kidney injury (AKI), and hyperuricemia], Liver Diseases [Nonalcoholic fatty liver disease (NAFLD), Alcoholic Liver Disease (AFLD), Liver fibrosis, and Hepatic Ischemia-Reperfusion (IR) Injury], Pulmonary Disorders [Pulmonary Fibrosis, Acute Lung injury (ALI), and Chronic obstructive pulmonary disease (COPD)], Muscle disorders (skeletal muscle atrophy), Skin diseases [Atopic dermatitis (ATD), Skin Photoaging, and Wound healing]. We have also briefly discussed astaxanthin’s protective effects on reproductive health.
... It has been shown that astaxanthin can decrease the oxidative stress and reduce damage caused by oxidative metabolism to skin and delay skin aging [56]. At the same time, Astaxanthin can also help repair damaged skin [57] and accelerate wound healing in mice [58]. Therefore, β-carotene and other antioxidants play important roles to maintain skin health. ...
Article
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β-carotene, a member of the carotenoid family, is a provitamin A, and can be converted into vitamin A (retinol), which plays essential roles in the regulation of physiological functions in animal bodies. Microalgae synthesize a variety of carotenoids including β-carotene and are a rich source of natural β-carotene. This has attracted the attention of researchers in academia and the biotech industry. Methods to enrich or purify β-carotene from microalgae have been investigated, and experiments to understand the biological functions of microalgae products containing β-carotene have been conducted. To better understand the use of microalgae to produce β-carotene and other carotenoids, we have searched PubMed in August 2021 for the recent studies that are focused on microalgae carotenoid content, the extraction methods to produce β-carotene from microalgae, and the bioactivities of β-carotene from microalgae. Articles published in peer-reviewed scientific journals were identified, screened, and summarized here. So far, various types and amounts of carotenoids have been identified and extracted in different types of microalgae. Diverse methods have been developed overtime to extract β-carotene efficiently and practically from microalgae for mass production. It appears that methods have been developed to simplify the steps and extract β-carotene directly and efficiently. Multiple studies have shown that extracts or whole organism of microalgae containing β-carotene have activities to promote lifespan in lab animals and reduce oxidative stress in culture cells, etc. Nevertheless, more studies are warranted to study the health benefits and functional mechanisms of β-carotene in these microalgae extracts, which may benefit human and animal health in the future.
... Its protective effects against oxidative stress (Al-Bulish et al., 2017) and inflammation are also observed (Chew et al., 2013). Additionally, AST accelerates wound healing and prevents scab formation (Meephansan et al., 2017), and also protects against the development of burn wounds (Fang et al., 2017). ...
Article
Full-text available
In the work, the antioxidant activity of astaxanthin (AST) and the influence of the base formulation on the kinetics of AST release were studied. Three stable O/W AST-loaded emulsions, differing in droplet size (12.7 µm (E1), 3.8 µm (E2), 3.2 µm (E3)) and a nanoemulsion (0.13 µm, NE) were prepared. The results confirmed very strong antioxidant activity of AST. The emulsion internal phase droplet size did not significantly affect the AST release. The amount of released AST was respectively: 13.60% (E1), 11.42% (E2), 9.45% (E3), 9.71% (NE). The best fit to experimental data was obtained using the Higuchi model for emulsions and the Korsmeyer-Peppas model for NE. The results show that the AST release process is limited by the diffusion through carriers and the prepared O/W emulsions can be applied as vehicles for delivery of astaxanthin to the skin, ensuring effective anti-aging action of the cosmetics.
... Topical AST application has been reported to have several skin health benefits, including antioxidant and anti-aging effects [13,[15][16][17][18][19], protection against UV irradiation [16,20], anti-wrinkle [14,16,21], hydration [21], wound healing [22,23], anti-cancer properties [17], and anti-eczema effects [13,24]. However, the low bioavailability and solubility of AST limit its use in topical formulations. ...
Article
Full-text available
Astaxanthin (AST) is a biomolecule known for its powerful antioxidant effect, which is considered of great importance in biochemical research and has great potential for application in cosmetics, as well as food products that are beneficial to human health and medicines. Unfortunately, its poor solubility in water, chemical instability, and low oral bioavailability make its applications in the cosmetic and pharmaceutical field a major challenge for the development of new products. To favor the search for alternatives to enhance and make possible the use of AST in formulations, this article aimed to review the scientific data on its application in delivery systems. The search was made in databases without time restriction, using keywords such as astaxanthin, delivery systems, skin, cosmetic, topical, and dermal. All delivery systems found, such as liposomes, particulate systems, inclusion complexes, emulsions, and films, presented peculiar advantages able to enhance AST properties, among which are stability, antioxidant potential, biological activities, and drug release. This survey showed that further studies are needed for the industrial development of new AST-containing cosmetics and topical formulations.
... Antioxidante (Chintong et al., 2019;Eren et al., 2019) Despigmentante (Chintong et al., 2019) Estimulador de colágeno (Chou et al., 2016) Estimulador de fibroblastos (Chou et al., 2016) Cicatrizante (Meephansan et al., 2017;Ritto et al., 2017) Antiinflamatória (Park et al., 2018) Hidratante (Ikarashi et al., 2020) Entre as diversas atividades biológicas encontradas e avaliadas para a molécula de astaxantina, a atividade antioxidante se destaca por ser uma característica intrínseca à essa molécula (Alves et al., 2020). Chintong e colaboradores ( Ritto et al. (2017), via inibição de RhoA e ativação de Rac1. ...
Article
The present study aimed to design and optimize, a nanoconjugate of gabapentin (GPN)-melittin (MLT) and to evaluate its healing activity in rat diabetic wounds. To explore the wound healing potency of GPN-MLT nanoconjugate, an in vivo study was carried out. Diabetic rats were subjected to excision wounds and received daily topical treatment with conventional formulations of GPN, MLT, GPN-MLT nanoconjugate and a marketed formula. The outcome of the in vivo study showed an expedited wound contraction in GPN-MLT-treated animals. This was confirmed histologically. The nanoconjugate formula exhibited antioxidant activities as evidenced by preventing malondialdehyde (MDA) accumulation and superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzymatic exhaustion. Further, the nanoconjugate showed superior anti-inflammatory activity as it inhibited the expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). This is in addition to enhancement of proliferation as indicated by increased expression of transforming growth factor-β (TGF- β), vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor receptor-β (PDGFRB). Also, nanoconjugate enhanced hydroxyproline concentration and mRNA expression of collagen type 1 alpha 1 (Col 1A1). In conclusion, a GPN-MLT nanoconjugate was optimized with respect to particle size. Analysis of pharmacokinetic attributes showed the mean particle size of optimized nanoconjugate as 156.9 nm. The nanoconjugate exhibited potent wound healing activities in diabetic rats. This, at least partly, involve enhanced antioxidant, anti-inflammatory, proliferative and pro-collagen activities. This may help to develop novel formulae that could accelerate wound healing in diabetes. © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Article
Background The wide range of health benefits and variety of biological activities of carotenoids have made them the focal point of industrial as well as academic research on a global scale. Astaxanthin which is a keto-carotenoid is found in a few varieties of bacteria, fungi, yeast, algae, crustaceans, and fishes. Due to its potent biological activity specifically its ability to protect from reactive oxygen species in the living system, it is proven to be the most effective anti-oxidant with a range of bioactivities. Scope and approach The present review is focused on the recent advances in the biomedical advantages of natural astaxanthin viz its anti-oxidant, anti-inflammatory, wound healing, cardioprotective, hepatoprotective, anti-diabetic, neuroprotective, anti-carcinogenic and osteoprotective. An overview of bioavailability and future perspectives of astaxanthin is also highlighted. Key findings and conclusions Important sources of natural astaxanthin as a potent nutraceutical have been explored. The natural form of astaxanthin is found to be more biologically active than its synthetic counterpart. Several research initiatives are in vogue worldwide on astaxanthin viz its natural sources, efficient methods of extraction and various biological activities that are helpful to use it in food and pharmaceutical industries.
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The singlet oxygen quenching activities among common hydrophilic and lipophilic antioxidants such as polyphenols, tocopherols, carotenoids, ascorbic acid, coenzyme Q10 and α-lipoic acid were recorded under the same test condition: the chemiluminescence detection system for direct 1O2 counting using the thermodissociable endoperoxides of 1,4-dimethylnaphthalene as 1O2 generator in DMF : CDCl3 (9 : 1). Carotenoids exhibited larger total quenching rate constants than other antioxidants, with astaxanthin showing the strongest activity. α-Tocopherol and α-lipoic acid showed considerable activities, whereas the activities of ascorbic acid, CoQ10 and polyphenols were only slight; these included capsaicin, probucol, edaravon, BHT and Trolox. This system has the potential of being a powerful tool to evaluate the quenching activity against singlet oxygen for various hydrophilic and lipophilic compounds.
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Identifying agents that inhibit STAT-3, a cytosolic transcription factor involved in the activation of various genes implicated in tumour progression is a promising strategy for cancer chemoprevention. In the present study, we investigated the effect of dietary astaxanthin on JAK-2/STAT-3 signaling in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model by examining the mRNA and protein expression of JAK/STAT-3 and its target genes. Quantitative RT-PCR, immunoblotting and immunohistochemical analyses revealed that astaxanthin supplementation inhibits key events in JAK/STAT signaling especially STAT-3 phosphorylation and subsequent nuclear translocation of STAT-3. Furthermore, astaxanthin downregulated the expression of STAT-3 target genes involved in cell proliferation, invasion and angiogenesis, and reduced microvascular density, thereby preventing tumour progression. Molecular docking analysis confirmed inhibitory effects of astaxanthin on STAT signaling and angiogenesis. Cell culture experiments with the endothelial cell line ECV304 substantiated the role of astaxanthin in suppressing angiogenesis. Taken together, our data provide substantial evidence that dietary astaxanthin prevents the development and progression of HBP carcinomas through the inhibition of JAK-2/STAT-3 signaling and its downstream events. Thus, astaxanthin that functions as a potent inhibitor of tumour development and progression by targeting JAK/STAT signaling may be an ideal candidate for cancer chemoprevention.
Article
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Liver fibrosis is a common pathway leading to cirrhosis and a worldwide clinical issue. Astaxanthin is a red carotenoid pigment with antioxidant, anticancer, and anti-inflammatory properties. The aim of this study was to investigate the effect of astaxanthin on liver fibrosis and its potential protective mechanisms. Liver fibrosis was induced in a mouse model using CCL4 (intraperitoneal injection, three times a week for 8 weeks), and astaxanthin was administered everyday at three doses (20, 40, and 80 mg/kg). Pathological results indicated that astaxanthin significantly improved the pathological lesions of liver fibrosis. The levels of alanine aminotransferase aspartate aminotransferase and hydroxyproline were also significantly decreased by astaxanthin. The same results were confirmed in bile duct liagtion, (BDL) model. In addition, astaxanthin inhibited hepatic stellate cells (HSCs) activation and formation of extracellular matrix (ECM) by decreasing the expression of NF- κ B and TGF- β 1 and maintaining the balance between MMP2 and TIMP1. In addition, astaxanthin reduced energy production in HSCs by downregulating the level of autophagy. These results were simultaneously confirmed in vivo and in vitro. In conclusion, our study showed that 80 mg/kg astaxanthin had a significant protective effect on liver fibrosis by suppressing multiple profibrogenic factors.
Article
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Introduction: It is known that the wound-healing process can be aided by the presence of antioxidants. Many plants have been reported to possess wound-healing and antioxidant properties. This review aims to appraise published literature and evaluate whether wound-healing and antioxidant properties co-exist in plants. Methods: Web of knowledge, Google Scholar and PubMed were primarily used to search for published reports on wound-healing and antioxidant properties of plants. Other relevant publications, e.g., books and journal articles, were also consulted. Results: Literature search has revealed that several wound-healing plants also possess considerable antioxidant properties as evident from the results of various in vitro and in vivo assays. It has appeared that the wound-healing properties of plants, in most cases, are associated with their antioxidant activities. Conclusions: The wound-healing property and antioxidant activity co-exist in many plant species from a variety of families.
Article
In the present study, we sought to elucidate whether astaxanthin contributes to induce angiogenesis and its mechanisms. To this end, we examined the role of astaxanthin on human brain microvascular endothelial cell line (HBMEC) and rat aortic smooth muscle cell (RASMC) proliferation, invasion and tube formation in vitro. For study of mechanism, the Wnt/β-catenin signaling pathway inhibitor IWR-1-endo was used. HMBECs and RASMCs proliferation were tested by cell counting. Scratch adhesion test was used to assess the ability of invasion. A matrigel tube formation assay was performed to test capillary tube formation ability. The Wnt/β-catenin pathway activation in HMBECs and RASMCs were tested by Western blot. Our data suggested that astaxanthin induces angiogenesis by increasing proliferation, invasion and tube formation in vitro. Wnt and β-catenin expression were increased by astaxanthin and counteracted by IWR-1-endo in HMBECs and RASMCs. Tube formation was increased by astaxanthin and counteracted by IWR-1-endo. It may be suggested that astaxanthin induces angiogenesis in vitro via a programmed Wnt/β-catenin signaling pathway. Copyright © 2015 Elsevier GmbH. All rights reserved.
Article
The murine dorsum dermal excisional wound model has been widely utilized with or without splint application. However, variations in experimental methods create challenges for direct comparison of results provided in the literature and for design of new wound healing studies. Here we investigated the effects of wound location and size, number of wounds, type of adhesive used for splint fixation on wound healing using splinted or unsplinted dorsum excisional full thickness wound models. One or two 6- or 8-mm full thickness wounds were made with or without splinting in genetically diabetic but heterozygous mice (Dock7(m) +/+ Lepr(db) ). Two different adhesives: tissue adhesive (TA) and an over the counter cyanoacrylate adhesive "Krazy glue(®) " (OTCA) were used to fix splints. Wound contraction, wound closure, and histopathological parameters including reepithelialization, collagen deposition and inflammation were compared between groups. No significant effect of wound number (1 vs 2), side (left vs right, cranial vs caudal) or size on wound healing was observed. The OTCA group had a significantly higher splint success compared to the TA group that resulted in significantly higher reepithelialization and collagen deposition in the OTCA group. Understanding the outcomes and effects of the variables will help investigators choose appropriate experimental conditions for the study purpose and interpret data. This article is protected by copyright. All rights reserved. © 2015 by the Wound Healing Society.
Article
Oxidative stress refers to elevated intracellular levels of reactive oxygen species (ROS) that cause damage to lipids, proteins and DNA. Oxidative stress has been linked to a myriad of pathologies. However, elevated ROS also act as signaling molecules in the maintenance of physiological functions - a process termed redox biology. In this review we discuss the two faces of ROS - redox biology and oxidative stress - and their contribution to both physiological and pathological conditions. Redox biology involves a small increase in ROS levels that activates signaling pathways to initiate biological processes, while oxidative stress denotes high levels of ROS that result in damage to DNA, protein or lipids. Thus, the response to ROS displays hormesis, given that the opposite effect is observed at low levels compared with that seen at high levels. Here, we argue that redox biology, rather than oxidative stress, underlies physiological and pathological conditions.
Article
Objectives/HypothesisOur previous study demonstrated that a large amount of reactive oxygen species (ROS) is produced during the early phase of vocal fold wound healing. In the current study, we investigated the effect of astaxanthin, which is a strong antioxidant, on the regulation of oxidative stress and scarring during vocal fold wound healing. Study DesignProspective animal experiment with control. Methods Sprague-Dawley rats were dosed with astaxanthin (Ast-treated group, 100 mg/kg/day) or olive oil (sham-treated group) by oral gavage daily from preinjury day 1 to postinjury day 4. After vocal folds were injured under the endoscope, larynges were harvested for histological and immunohistochemical examinations on postinjury days 1, 3, 5, and 56, and quantitative real time polymerase chain reaction (PCR) on postinjury days 1 and 3. ResultsThe expression of 4-hydroxy-2-nonenal, which is an oxidative stress marker, was reduced significantly in the lamina propria of the Ast-treated group as compared to the sham-treated group. Histological examination showed significantly less tissue contraction with favorable deposition of hyaluronic acid in the lamina propria of the Ast-treated group compared to the sham-treated group. Real time PCR revealed significantly upregulated mRNA expression of basic fibroblast growth factor on postinjury day 1 and procollagen type I in the Ast-treated group compared to the sham-treated group. Conclusions These findings suggest that astaxanthin has the potential to prevent vocal fold scarring by regulating oxidative stress during the early phase of vocal fold wound healing.
Article
Astaxanthin, a member of the carotenoid family, is the only known ketocarotenoid transported into the brain by transcytosis through the blood-brain barrier. However, whether astaxanthin has antifibrotic functions is unknown. In this study, we investigated the effects of astaxanthin on transforming growth factor 1-mediated and bleomycin-induced pulmonary fibrosis in vitro and in vivo. The results showed that astaxanthin significantly improved the structure of the alveoli and alleviated collagen deposition in vivo. Compared with the control group, the astaxanthin-treated groups exhibited downregulated protein expressions of -smooth muscle actin, vimentin, hydroxyproline, and B cell lymphoma/leukemia-2 as well as upregulated protein expressions of E-cadherin and p53 in vitro and in vivo. Astaxanthin also inhibited the proliferation of activated A549 and MRC-5 cells at median inhibitory concentrations of 40 and 30 M, respectively. In conclusion, astaxanthin could relieve the symptoms and halt the progression of pulmonary fibrosis, partly by preventing transdifferentiation, inhibiting proliferation, and promoting apoptosis of activated cells.
Article
Previous studies have indicated that although normal wound healing requires low levels of reactive oxygen species (ROS), excessive amounts of ROS impair wound healing. In injured vocal folds, this excess may result in dysphonia due to scarring that is difficult to treat. However, the expression of ROS during vocal fold wound healing has yet to be investigated. In this study, we assessed the expression and localization of ROS in injured vocal folds by immunohistochemical analysis. Vocal folds of Sprague-Dawley rats were unilaterally injured by stripping the mucosa under transoral endoscopy. The larynges were harvested at specific time points after injury and were immunohistochemically examined for 4-hydroxy-2-nonenal (4-HNE), an ROS marker, and for the presence of inflammatory cells. We found that 4-HNE-immunopositive cells were significantly increased in the lamina propria of the injured vocal folds as compared to the normal vocal folds on postinjury days 1 and 3. More than half of the 4-HNE-immunopositive cells were also immunopositive for a macrophage- and granulocyte-specific antibody. This study suggests that a large amount of ROS is produced during early-phase wound healing, until postinjury day 3, and that this period may be crucial for regulating ROS levels. The results also suggest that inflammatory cells may contribute to ROS generation.