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Potential health‐promoting effects of astaxanthin: A high‐value carotenoid mostly from microalgae

Authors:

Abstract

The ketocarotenoid astaxanthin can be found in the microalgae Haematococcus pluvialis, Chlorella zofingiensis, and Chlorococcum sp., and the red yeast Phaffia rhodozyma. The microalga H. pluvialis has the highest capacity to accumulate astaxanthin up to 4-5% of cell dry weight. Astaxanthin has been attributed with extraordinary potential for protecting the organism against a wide range of diseases, and has considerable potential and promising applications in human health. Numerous studies have shown that astaxanthin has potential health-promoting effects in the prevention and treatment of various diseases, such as cancers, chronic inflammatory diseases, metabolic syndrome, diabetes, diabetic nephropathy, cardiovascular diseases, gastrointestinal diseases, liver diseases, neurodegenerative diseases, eye diseases, skin diseases, exercise-induced fatigue, male infertility, and HgCl₂-induced acute renal failure. In this article, the currently available scientific literature regarding the most significant activities of astaxanthin is reviewed.
REVIEW
Potential health-promoting effects of astaxanthin:
A high-value carotenoid mostly from microalgae
Jian-Ping Yuan
1
, Juan Peng
1
, Kai Yin
2
and Jiang-Hai Wang
1

1
Guangdong Provincial Key Laboratory of Marine Resources and Coastal Engineering, School of Marine Sciences,
Sun Yat-Sen University, Guangzhou, P. R. China
2
School of Life Sciences, Sun Yat-Sen University, Guangzhou, P. R. China
Received: August 30, 2010
Revised: October 13, 2010
Accepted: October 16, 2010
The ketocarotenoid astaxanthin can be found in the microalgae Haematococcus pluvialis,
Chlorella zofingiensis, and Chlorococcum sp., and the red yeast Phaffia rhodozyma. The
microalga H. pluvialis has the highest capacity to accumulate astaxanthin up to 4–5% of cell
dry weight. Astaxanthin has been attributed with extraordinary potential for protecting the
organism against a wide range of diseases, and has considerable potential and promising
applications in human health. Numerous studies have shown that astaxanthin has potential
health-promoting effects in the prevention and treatment of various diseases, such as cancers,
chronic inflammatory diseases, metabolic syndrome, diabetes, diabetic nephropathy, cardi-
ovascular diseases, gastrointestinal diseases, liver diseases, neurodegenerative diseases, eye
diseases, skin diseases, exercise-induced fatigue, male infertility, and HgCl
2
-induced acute
renal failure. In this article, the currently available scientific literature regarding the most
significant activities of astaxanthin is reviewed.
Keywords:
Astaxanthin / Carotenoid / Haematococcus pluvialis / Health-promoting effects /
Microalgae
1 Introduction
The ketocarotenoid astaxanthin, 3,30-dihydroxy-b,b-carotene-
4,40-dione, belongs to the family of xanthophylls, the
oxygenated derivatives of carotenoid. Astaxanthin is
ubiquitous in nature, especially in the marine environment
[1], and is a red pigment common to many marine animals,
such as salmonids, shrimp, lobsters, and crayfish, contri-
buting to the pinkish-red color of their flesh [2]. Astaxanthin
is biosynthesized by microalgae or phytoplankton, as the
primary production level in the marine environment.
Microalgae are consumed by zooplankton or crustaceans
which accumulate astaxanthin and, in turn are ingested by
fish which then accrue astaxanthin in the food chain [1].
Astaxanthin has been found and identified in several
microorganisms including the microalgae Haematococcus
pluvialis,Chlorella zofingiensis, and Chlorococcum sp., the red
yeast Phaffia rhodozyma, and the marine bacterium Agro-
bacterium aurantiacum [3]. Although astaxanthin can be
synthesized by plants, bacteria, a few fungi and green algae,
the green microalga H. pluvialis is considered to have the
highest capacity to accumulate astaxanthin in reported
sources [4, 5]. It has been reported that H. pluvialis could
accumulate astaxanthin up to 4–5% of dry weight [4, 6]. In
addition, Roche has begun a large-scale production of
synthetic astaxanthin, which consists of a mixture 1:2:1 of
isomers (3S, 3S0), (3R, 3S0), and (3R, 3R) respectively, since
1990 [7].
There has been growing interest in the use of astaxanthin
as a food-coloring agent, natural feed additive for the poultry
industry and for aquaculture, especially as a feed supple-
ment in the culture of salmon, trout, and shrimp. There
have also been reports concerning its application in medi-
cine due to its powerful antioxidant capacity [5]. Astaxanthin
has unique chemical properties based on its molecular
These authors have contributed equally to this work.

Additional corresponding author: Dr. Jiang-Hai Wang
E-mail: wangjhai@mail.sysu.edu.cn
Correspondence: Dr. Jian-Ping Yuan, Guangdong Provincial Key
Laboratory of Marine Resources and Coastal Engineering,
School of Marine Sciences, Sun Yat-Sen University, Guangzhou
510275, P. R. China
E-mail: yuanjp@mail.sysu.edu.cn
Fax: 186-20-39332213
&2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
150 Mol. Nutr. Food Res. 2011, 55, 150–165DOI 10.1002/mnfr.201000414
structure. Astaxanthin has two carbonyl groups, two hydroxy
groups, and eleven conjugated ethylenic double bonds
(Supporting Information Fig. S1). The polyene system gives
astaxanthin its distinctive molecular structure, chemical
properties, and light-absorption characteristics [7]. The
presence of the hydroxyl and keto moieties on each ionone
ring explains some of its unique features such as the ability
to be esterified and a higher antioxidant activity and a more
polar nature than other carotenoids [8]. Astaxanthin may act
as a strong antioxidant by donating the electrons and
reacting with free radicals to convert them to more stable
product and terminate free radical chain reaction in a wide
variety of living organisms [9, 10].
Therefore, astaxanthin has considerable potential and
promising applications in human health and nutrition [9],
and has been attributed with extraordinary potential for
protecting the organism against a wide range of diseases [7].
This article reviews the current available scientific literatures
regarding the most significant activities of astaxanthin,
including its antioxidative, anticancer, antidiabetic, and anti-
inflammatory properties, its protective effects on stomach,
liver, the heart and the blood vessels, the nervous system,
the eye, and the skin, and other activities.
2 Chemistry of astaxanthin
2.1 Astaxanthin profiles in microalgae
Free astaxanthin is particularly susceptible to oxidation [8].
Therefore, astaxanthin in nature is either conjugated with
proteins or esterified with one or two fatty acids to form
monoester and diester forms [8, 11]. In H. pluvialis, asta-
xanthins exist mainly as various astaxanthin esters formed
by combining various fatty acids with different isomers of
astaxanthin [6]. Various astaxanthin isomers have been
characterized on the basis of the configuration of the
two hydroxyl groups on the molecule [8]. Considering that
each molecule has two chiral centers in C-3 and C-30,
astaxanthin may present three configurational isomers, two
enantiomers (3R, 30R and 3S, 30S) a meso form (3R, 30S).
The 3S, 30S stereoisomer is the main form found in
H. pluvialis [7].
For different algal strains, the compositions and profile of
astaxanthin were different [6]. Peng et al. [11] showed that
the green microalga C. zofingiensis had a remarkably higher
percentage of astaxanthin diesters in comparison with
H. pluvialis with a higher percentage of astaxanthin
monoesters. The esters of astaxanthin and adonixanthin,
and free canthaxanthin were the major carotenoids in the
alga Chlorococcum cells [3]. In C. zofingiensis, the major
carotenoids were astaxanthin (about 70%) and canthax-
anthin (about 30%) [12]. On the contrsry, astaxanthin alone
was the major carotenoid in H. pluvialis [6]. Boussiba et al.
[4] showed that the esterified astaxanthin accounts for more
than 99% of the total carotenoids.
The esterification of the hydroxyl groups of astaxanthin
increases its hydrophobicity and therefore its solubility in
globules made of triacylglycerols. The fatty acid composition
of the astaxanthin esters is very close to that of triacylgly-
cerols, consisting mostly of oleic (C
18:1
), palmitic (C
16:0
), and
linoleic acids (C
18:2
), and oleic acid constitutes 51% of the
fatty acids of astaxanthin esters [13]. Miao et al. [14] indicated
that astaxanthin C
18:1
and astaxanthin C
16:1
/C
18:1
were the
main astaxanthin monoester and diester, respectively, in
H. pluvialis. Zhekisheva et al. [13] suggested that the accu-
mulation of astaxanthin was accompanied and perhaps
preceded by that of oleate-rich triacylglycerols and the ability
to fit the composition of astaxanthin esters with that of
triacylglycerols was one of the reasons for H. pluvialis being
the richest natural source of astaxanthin.
2.2 Isomerization of trans-astaxanthin
In the astaxanthin molecule (Supporting Information
Fig. S1), each double bond from the polyene chain may exist
in two configurations as geometric isomers cis or trans [7, 15,
16]. Most carotenoids found in nature are predominantly all
trans-isomers [7]. trans-Astaxanthin is readily isomerized to
cistrans mixtures, especially the 9-cis and 13-cis unhindered
isomers for steric reasons [17]. Although astaxanthin exists
mainly as trans-astaxanthin esters of various fatty acids, cis-
astaxanthin esters are also detected in the algal pigment
extracts. A high-yielding astaxanthin ester-producing strain
of the microalga H. pluvialis, which can accumulate asta-
xanthin up 5.02% of cell dry weight, is found to contain
36.7 mg/g of trans-astaxanthin (73.1%) and 13.5 mg/g of
cis-astaxanthins (26.9%) [6].
The isomerization of trans-astaxanthin to cis-isomers in
different organic solvents has been investigated [17]. The
isomerization rate of trans-astaxanthin is dependent on the
solvent. Although the relative contents of 9-cis- and 13-cis-
astaxanthins formed during isomerization are different in
different solvents, 13-cis-astaxanthin is the main cis-isomer
from trans-astaxanthin. The results also indicate that a
higher temperature can promote markedly the isomeriza-
tion rate of trans-astaxanthin [17]. The fact that trans-asta-
xanthin cannot be isomerized completely to its cis-isomers
indicates that the isomerization reaction of trans-astaxanthin
is a reversible reaction [17, 18]. Studies have revealed that cis-
astaxanthins can also be isomerized to produce trans-asta-
xanthin and other cis-astaxanthins, and the isomerization
of trans-astaxanthin follows first-order reversible reaction
kinetics [18].
2.3 Bioavailability and safety of astaxanthin
Carotenoid absorption strongly depends on a number of
factors that are not entirely understood. Bioavailability of
carotenoids also depends on their structures; in general,
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polar carotenoids (e.g. free astaxanthin) tend to be of higher
bioavailability than apolar species (e.g. b-carotene and lyco-
pene) [19]. It has been reported that astaxanthin from
H. pluvialis shows better bioavailability than b-carotene from
Spirulina platensis and lutein from Botryococcus braunii [10].
In addition, cis-astaxanthins accumulate preferentially in
blood plasma compared with the trans-form due to apparent
shorter chain lengths [19].
Xanthophyll esters seem to be of low bioavailability, but
there is a scientific controversy [19]. Studies suggested that
xanthophyll esters were hydrolyzed in the small intestine for
absorption in humans [20]. Recently, Sugawara et al. [20]
found the enzymatic esterification of xanthophylls such as
astaxanthin in intestinal cells at a lower rate, and suggested
that the esterification of xanthophylls was mediated by
enzymatic activity after intestinal absorption. The esterified
xanthophylls were likely to be incorporated into the lipid
core in chylomicron and carried into a variety of tissues
including the skin. In addition, by esterifying xanthophylls
into highly nonpolar products, intestinal cells might be
protected from the cytotoxic effects of xanthophylls. It was
important to clarify that polar xanthophylls were suitable for
esterification in intestinal cells in order to understand the
absorption, metabolism, and biological function of carote-
noids [20]. The presence of astaxanthin esters in H. pluvialis
might be an added advantage to influence the higher bioa-
vailability of astaxanthin [10].
Few data have been found on possible toxic or harmful
effects of astaxanthin. A recent clinical study showed that a
higher dose of astaxanthin (40 mg daily) from H. pluvialis
during a 4-wk treatment period did not reveal any harmful
effects [21].
3 Potential health-promoting effects of
astaxanthin
Many earlier studies suggested that the bioactivities of
carotenoids might be due to their prior conversion to vita-
min A and focused on b-carotene. Subsequent studies
showed that some carotenoids without provitamin A activity
were as active and at times more active than b-carotene [22].
Astaxanthin, not possessing a pro-vitamin A activity, has
attracted considerable interest because of its potent bioac-
tivities including its antioxidative, anticancer, antidiabetic,
and anti-inflammatory activities, gastro-, hepato-, neuro-,
cardiovascular, ocular, and skin-protective effects, and other
activities, which are distinctly different and, at least in some
cases, more potent than that of other carotenoids [22, 23].
3.1 Antioxidant activity
Oxidative molecules with very high reactivity, such as
free radicals and reactive oxygen species, are produced by
normal aerobic metabolism in organisms for sustaining life
processes; however, excess quantities of oxidative molecules
may react with cellular components such as proteins, lipids,
and DNA, through a chain reaction, to cause protein and
lipid oxidation and DNA damage, which are associated with
various diseases [7]. These injurious actions induced by
oxidative stress can be restrained by endogenous anti-
oxidases and exogenous antioxidants such as carotenoids.
The common chemical feature of carotenoids is the polyene
chain, a long-conjugated double-bond system, which is
responsible for the antioxidant activities of carotenoids by
quenching singlet oxygen and scavenging radicals to
terminate chain reactions [24, 25]. The different chemical
anti- and pro-oxidant behavior of carotenoids is caused by
the different structure of the end groups, and the number
and position of methyl groups [26]. The biological benefits of
carotenoids may be due to their potent antioxidant proper-
ties attributed to specific physico-chemical interactions with
membranes [25].
Naguib [27] compared the antioxidant activities of various
carotenoids and showed that the relative reactivities of
astaxanthin, lutein, lycopene, a-carotene, b-carotene,
a-tocopherol, and 6-hydroxy-2,5,7,8-tetramethylchroman-2-
carboxylic acid toward peroxyl radicals were 1.3, 0.4, 0.4, 0.5,
0.2, 0.9, and 1.0, respectively, indicating that astaxanthin
had the highest antioxidant activity. The effects of astax-
anthin, zeaxanthin, lutein, b-carotene, and lycopene, on
lipid hydroperoxide generation in membranes enriched with
polyunsaturated fatty acids were evaluated by McNulty et al.
[25], who found that apolar carotenoids, such as lycopene
and b-carotene, could disorder the membrane bilayer and
showed a potent pro-oxidant effect with a 85% of increase in
lipid hydroperoxide levels, whereas astaxanthin preserved
membrane structure and exhibited significant antioxidant
activity with a 40% of decrease in lipid hydroperoxide levels,
indicating distinct effects of carotenoids on lipid peroxida-
tion due to membrane structure changes. A recent study
showed that when the micoalgal biomass (H. pluvialis,
S. platensis,orB. braunii) was fed to rats, the antioxidases
catalase, superoxide dismutase, peroxidase, and thiobarbi-
turic acid reactive substances were significantly high in
plasma at 2 h and in liver at 4 h, evidently offering protection
from free radicals in living cells, especially for astaxanthin
from H. pluvialis [10].
Guanosine is the most easily oxidized nucleoside and has
the lowest of the nucleoside one-electron reduction poten-
tials and hence internal electron transfer processes will lead
to the accumulation of guanosine radicals as a key inter-
mediate in nucleoside oxidation [28]. Edge et al. [28] recently
reported that b-carotene, lycopene, zeaxanthin, and asta-
xanthin could reduce oxidized guanosine and minimize its
formation, and the reaction of the carotenoid with the
oxidized guanosine produced the radical cation of the caro-
tenoid. It was suggested that carotenoids might offer addi-
tional protection against free radical-induced nucleoside
damage in addition to the well-established protection
afforded by direct quenching of oxidizing free radicals
152 J.-P. Yuan et al.Mol. Nutr. Food Res. 2011, 55, 150–165
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themselves. The electron transfer rate constants for the
efficient reduction of guanosine radicals are the fastest for
astaxanthin (k56.23 10
7
M
1
.s
1
) compared with
b-carotene, lycopene, and zeaxanthin (k51.67, 2.23, and
4.43 10
7
M
1
.s
1
, respectively) [28].
The above-mentioned comparison studies for various
carotenoids indicate that astaxanthin has the higher anti-
oxidant activity than other carotenoids. It has been gener-
alized that astaxanthin has an antioxidant activity, as high as
ten times more than other carotenoids such as zeaxanthin,
lutein, canthaxantin, and b-carotene, and 100 times more
than a-tocopherol, and thus has been dubbed a ‘‘super
vitamin E’’ [7]. Astaxanthin has unique chemical properties
based on its molecular structure. The presence of the
hydroxyl and keto moieties on each ionone ring is respon-
sible for its higher antioxidant activity [29]. The oxo function
is capable to resonance-stabilize carbon-centered radicals,
which may explain the powerful antioxidative properties
of astaxanthin without pro-oxidative contributions [26].
Astaxanthin catches radicals not only at the conjugated
polyene chain but also in the terminal ring moiety. Goto
et al. [30] suggested that the hydrogen atom at the C3
methine in the terminal ring was a radical trapping site.
Although the unsaturated polyene chain of astaxanthin
trapped radicals only in the membrane, the terminal ring of
astaxanthin could scavenge radicals both at the surface and
in the interior of the phospholipid membrane. The unique
properties of astaxanthin should be associated with its
potent antiperoxidation activity [30]. Recently, it was repor-
ted that astaxanthin could inhibit lipid peroxide formation
and enhance the antioxidant enzyme status in glycated
protein/iron chelate-exposed endothelial cells by suppres-
sing reactive oxygen species generation [31].
Interestingly, Liu and Osawa [32] found that cis-asta-
xanthins, especially the 9-cis isomer, might have a higher
antioxidant activity than that of the all-trans isomer in
inhibition of the generation of reactive oxygen species
induced by 6-hydroxydopamine in human neuroblastoma
SH-SY5Y cells as well as on the degradation of collagen type
II induced by docosahexaenoic acid and linoleic acid
hydroperoxides, indicating that astaxanthins, especially 9-cis-
astaxanthin, may show potential neuroprotective effect for
Parkinson’s disease and possible prophylactic effect for
arthritis.
3.2 Anti-inflammatory effects
It was reported that astaxanthin could inhibit the expression
or production of inflammatory mediators and cytokines in
both lipopolysaccharide-stimulated RAW264.7 cells and
primary macrophages by suppressing the activation of
nuclear factor-kB, which is a significant transcription factor
for inducible nitric oxide synthase, probably as a result of
scavenging intracellular reactive oxygen species [33]. Choi
et al. [34] showed that astaxanthin could exert its anti-
inflammatory actions by inhibiting the expression of indu-
cible nitric oxide synthase and cyclooxygenase-2 and the
production of nitric oxide in lipopolysaccharide-stimulated
BV2 microglial cells. This inhibitory effect of astaxanthin on
the production of nitric oxide has important implications for
the development of anti-inflammatory drugs for chronic
inflammatory diseases such as sepsis, rheumatoid arthritis,
atherosclerosis, inflammatory bowel disease, and brain
inflammatory diseases [33, 34].
Recently, Bolin et al. [35] found that astaxanthin displayed
interesting anti-inflammatory effects by preserving redox-
sensitive and essential structures of human lymphocytes,
which could be mainly deduced by the increased nitric oxide
formation, the observed reduced O_
2
/H
2
O
2
production, and
induced superoxide dismutase and catalase activities in
parallel to lower indexes of oxidative injury in lipids and
proteins. It was suggested that astaxanthin was potentially
nutritional therapeutic agent for prevention/prophylaxy
of immune-impaired diseases, such as type 2 diabetes,
sepsis, and cardiovascular disorders [35]. Macedo
et al. [36] showed that astaxanthin significantly reduced the
production of pro-inflammatory cytokines, such as tumor
necrosis factor-aand interleukin-6 in lipopolysaccharide-
stimulated neutrophils. The results also showed that asta-
xanthin improved neutrophil phagocytic and microbicidal
capacity and reduced superoxide anion and hydrogen
peroxide production, which appeared to be mediated by
calcium released from intracellular storages and nitric oxide
production, indicating a beneficial effect of astaxanthin on
human neutrophils function [36].
Immune cells are particularly sensitive to oxidative stress
due to a high percentage of polyunsaturated fatty acids in
their plasma membranes and generally produce more
oxidative products [37]. Park et al. [37] studied the possible
immune-enhancing, antioxidative, and anti-inflammatory
activity of astaxanthin in young healthy adult female human
subjects, and showed that astaxanthin could decrease a DNA
oxidative damage biomarker and inflammation, and
enhance immune response. The immunomodulatory, anti-
oxidative, and anti-inflammatory activity of astaxanthin
would likely influence the etiology of cancer and inflam-
matory diseases [37].
The anti-inflammatory activity of astaxanthin may also
have a role in the prevention or treatment of asthma. It was
reported that that ginkgolide B, astaxanthin, or their
combination could suppress activation of T cells from
asthma patients [38]. In the recent experiment, Haines et al.
[39] showed that the asthmatic animals fed astaxanthin,
Ginkgo biloba extract and vitamin C alone or in combination
exhibited significantly lower bronchoalveolar lavage fluid
inflammatory cell numbers and enhancement of lung tissue
content of cAMP and cGMP, and the efficacy was equal to or
better than ibuprofen, a widely used nonsteroidal anti-
inflammatory drug.
Sakai et al. [40] showed that astaxanthin, fucoxanthin,
zeaxanthin, and b-carotene significantly inhibited the
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antigen-induced release of b-hexosaminidase, an index of
mast cell degranulation, in rat basophilic leukemia RBL-
2H3 cells and mouse bone marrow-derived mast cells, and
antigen-induced aggregation of high-affinity IgE receptor
which was the most upstream of the degranulating signals
of mast cells.
3.3 Gastro-protective effect
3.3.1 Anti-Helicobacter pylori activity
Studies both in vivo and in vitro have shown that astaxanthin
is not only a free radical scavenger but also shows anti-
microbial activity against H. pylori [41]. It was reported that
treatment with a cell extract of the microalgae H.pluvialis
containing 2–3% of astaxanthins [42] or a Chlorococcum sp.
algal extract [43] could significantly reduce bacterial load and
gastric inflammation in H.pylori-infected mice. Wang et al.
[44] demonstrated that mice treated with H.pluvialis algal
meal showed significantly lower colonization levels and
lower inflammation scores. Nishikawa et al. [45] compared
physiologically and biochemically the effects of three kinds
of astaxanthins, including two extracts from the microalga
H. pluvialis and the red yeast P. rhodozyma, and a synthetic
astaxanthin, on stressed rats. The results indicated that rats
given astaxanthins prior to stressing were appreciably
protected against the evolution of gastric ulcerations. In
particular, ulcer indexes were smaller with the rat group fed
astaxanthin from H. pluvialis than the other two groups,
indicating that astaxanthin from H. pluviali is more
efficacious in preventing gastric ulcer evolution caused by
stress [45].
The anti-infective and anti-inflammatory effects of
astaxanthin are associated with a change in the immune
response to H. pylori by shifting the T-lymphocyte response
from a predominant Th1 response dominated by interferon-
gto a Th1:Th2 response with interferon-gand interleukin-4
[41, 42, 44], indicating that mice treated with astaxanthin
showed a significant increase in interleukin-4 release, which
was probably the result of the downregulation of Th1 cells
and upregulation of Th2 cells by astaxanthin [41]. Another
possible mechanism of action is that astaxanthin as anti-
oxidant neutralizes reactive free oxygen metabolites in the
mucosa and may have attenuated the inflammation [42]. It
was suspected that the antioxidant properties of astaxanthin
played an important role in the protection of the hydro-
phobic lining of the mucous membrane making coloniza-
tion by H. pylori much more difficult [7].
In a clinical study, although no curative effect of astax-
anthin was shown in functional dyspepsia patients, signifi-
cantly greater reduction of reflux symptoms was found in
patients treated with a higher dose of astaxanthin (40 mg
daily), and the response was more pronounced in H. pylori-
infected patients compared with non-H. pylori-infected
patients, suggesting that suppression of H. pylori by asta-
xanthin led to amelioration of reflux symptoms within the
spectrum of functional dyspepsia [21].
3.3.2 Protecting against ethanol and drug toxicities
Studies had revealed that the ethanol-induced gastric
damage was mediated by the generation of free radicals [46].
Kim et al. [47] found that the oral administration of astax-
anthin had significant protection against ethanol-induced
gastric lesion in rats and could inhibit elevation of the lipid
peroxide level in gastric mucosa. The histologic examination
clearly indicated that the acute gastric mucosal lesion
induced by ethanol nearly disappeared after pretreatment
with astaxanthin [47]. Kamath et al. [46] compared the
antioxidant and anti-ulcer potency of esterified astaxanthins,
saponified astaxanthin, and total carotenoid from the
microalga H. pluvialis in ethanol-induced gastric ulcers in
rats, and showed that total carotenoids and astaxanthin
esters, especially esterified astaxanthin exerted a dose-
dependent gastroprotective effect on acute, ethanol-induced
gastric lesions in rats. The anti-ulcerogenic potency of
astaxanthin might be due to inhibition of H
1
,K
1
-ATPase,
upregulation of mucin content, and increase of antioxidant
status [46].
The production of oxygen-free radicals and lipid perox-
idation plays a crucial role in the development of the gastric
mucosal lesions induced by nonsteroidal anti-inflammatory
drugs indomethacin or naproxen, which are used clinically
as anti-inflammatory and analgesic agents [48, 49]. Studies
showed that astaxanthin had the in vivo protective effect on
indomethacin- or naproxen-induced gastric lesions in rats in
a dose-dependent manner, indicating that astaxanthin may
offer an attractive new treatment strategy for curing gastric
lesions in humans [48, 49].
3.4 Hepatoprotective effect
Astaxanthin was transferred to the liver with lipid and
accumulated in the microsomal and the mitochondrial
fractions of the liver tissue [50]. Astaxanthin may protect the
liver against chemicals such as CCl
4
. A study showed that
astaxanthin could obstruct the increase of glutamate-oxala-
cetate transaminase and glutamate-pyruvate transaminase
activities and thiobarbituric acid reactive substances in
response to CCl
4
while causing an increase in glutathione
levels and superoxide dismutase activities in the CCl
4
-trea-
ted rat liver [51]. A recent study also showed that astaxanthin
could attenuate the adverse effect of CCl
4
and protect
hepatocytes [52]. These studies suggested that astaxanthin
protected liver damage induced by CCl
4
by inhibiting lipid
peroxidation, stimulating the cellular antioxidant system
[51, 52], and modulating the inflammatory process. More-
over, an early study investigated the preventive effects of
b-carotene, b-apo-80-carotenal, astaxanthin, canthaxanthin,
154 J.-P. Yuan et al.Mol. Nutr. Food Res. 2011, 55, 150–165
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lycopene, and vitamin A on the initiation of liver carcino-
genesis by aflatoxin B1 in male weanling rats, and showed
that astaxanthin, b-carotene, b-apo-80-carotenal, and
canthaxanthin were very efficient in reducing the number
and the size of liver preneoplastic foci [53]. In particular,
astaxanthin, b-apo-80-carotenal, and canthaxanthin exerted
their protective effect through the deviation of aflatoxin B1
metabolism to aflatoxin M1, and thus protected aflatoxin B1
from genotoxicity and initiating actions [53].
Oval cells can differentiate into hepatocytes and biliary
epithelial cells, leading to liver regeneration when mature
hepatocytes are injured. However, oval cells can trigger
hepatic cancer, especially when an irreversible block of the
process of normal differentiation is disturbed [54]. Wo
´jcik
et al. [54] showed that both astaxanthin and b-carotene could
inhibit the proliferative activity of oval cells and intensify the
differentiation process of oval cells obtained especially from
the neoplastic liver, indicating their hepatoprotective prop-
erties. In addition, liver ischemia-reperfusion injury is an
important clinical problem in many clinical conditions such
as liver transplantation, hepatic surgery for tumor excision,
and trauma and hepatic failure after hemorrhagic shock
[55]. Recently, Curek et al. [55] found that total histopatho-
logical scoring of cellular damage was significantly
decreased in hepatic ischemia-reperfusion injury following
astaxanthin treatment, and parenchymal cell damage,
swelling of mitochondria, and disarrangement of rough
endoplasmatic reticulum were also partially reduced. It was
concluded that astaxanthin could offer protection in liver
ischemia-reperfusion injury by reducing oxidant-induced
protein carbonyl formation and conversion of xanthine
dehygrogenase to xanthine oxidase [55].
Current recommended therapy for previously untreated
and relapsed hepatitis C patients is a combination of pegy-
lated interferon and ribavirin. Moreover, a large number of
supplements are used by patients universally to maintain
their health condition. Resveratrol and astaxanthin might be
good candidates for an antioxidative as well as an anti-
hepatitis C virus agent [56]. Nakamura et al. [56] investigated
the effect of the two antioxidants on hepatitis C virus
replication, and found that pegylated interferon and riba-
virin significantly reduced hepatitis C virus RNA replication,
but these effects were dose dependently hampered and
attenuated by the addition of resveratrol, which significantly
enhanced hepatitis C virus RNA replication. On the
contrary, astaxanthin did not affect antiviral effects of
pegylated interferon or ribavirin, and was suitable as an
antioxidant therapy for chronic hepatitis C.
The effects of astaxanthin supplementation in obese mice
fed a high-fat diet had been investigated by Ikeuchi et al.
[57], who found that astaxanthin could inhibit the increases
in body weight and weight of adipose tissue with a high-fat
diet and reduce liver weight, liver triglyceride, plasma
triglyceride, and total cholesterol. One of the mechanisms
may be through ameliorating impaired lipid metabolism by
increasing adiponectin level and improving insulin sensi-
tivity [58]. Recently, Bhuvaneswari et al. [59] also evaluated
the effects of astaxanthin in obese mice fed a high fat plus
high fructose diet, and showed that astaxanthin restricted
weight gain, promoted insulin sensitivity, and prevented
liver injury by decreasing cytochrome P 4502E1, myeloper-
oxidase, and nitro-oxidative stress, and improving the anti-
oxidant status. In addition, lipid deposition and increased
transforming growth factor-bexpression induced by the
high calorie diet were also abolished by astaxanthin [59].
These studies indicated that astaxanthin might be of value
in preventing obesity, metabolic syndrome, and liver disease
arising from insulin resistance/obesity in affluent societies
[57, 59].
3.5 Antidiabetic activity
3.5.1 Diabetes
Diabetes mellitus is strongly associated with oxidative stress,
which can be a consequence of increased free radical
production, reduced antioxidant defenses, or both [60].
Oxidative stress induced by hyperglycemia possibly causes
the dysfunction of pancreatic b-cells and various forms of
tissue damage in patients with diabetes mellitus [61]. It was
found that astaxanthin could diminish the oxidative stress
caused by hyperglycemia in the pancreatic bcells, signifi-
cantly improve glucose tolerance, increase serum insulin
levels, and decrease blood glucose levels, indicating that
astaxanthin might exert beneficial effects on pancreatic
b-cell function and could protect pancreatic b-cells against
glucose toxicity by preventing the progressive destruction of
these cells [61].
Based on the strong correlation between oxidative stress
and immune dysfunction in diabetic patients, Otton et al.
[62] recently studied the antioxidant effects of astaxanthin in
the reactive oxygen/nitrogen species metabolism of
lymphocytes isolated from alloxan-induced diabetic rats. The
results showed that astaxanthin could be a good adjuvant in
prophylaxis or recovery of lymphocyte dysfunctions asso-
ciated with diabetic patients, especially when focusing on
the re-establishment of the redox balance and a hypothetical
antiapoptotic effect in lymphocytes [62].
Nakano et al. [63] compared the effect of astaxanthin in
combination with other antioxidants such as ascorbic acid
and a-tocopherol against oxidative damage in streptozotocin-
induced diabetic rats, and indicated that astaxanthin in
combination with a-tocopherol could ameliorate oxidative
injury through the suppression of oxidative stress induced by
diabetes. On the contrary, a high dose of ascorbic acid intake
was found to increase lipid peroxidation in diabetic rats [63].
Nishigaki et al. [31] recently found that astaxanthin could
inhibit the nonenzymatic glycation and glycated protein/iron
chelate-induced cytotoxicity in human umbilical-vein endo-
thelial cells by preventing lipid and protein oxidation and
increasing the activity of antioxidant enzymes in vitro.
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In addition, Hussein et al. [58] investigated the effects of
astaxanthin in a metabolic syndrome animal model of
spontaneously hypertensive corpulent rat, and found that
astaxanthin significantly lowered the levels of blood glucose,
nonesterified fatty acids and triglycerides, and significantly
increased the levels of high-density lipoprotein cholesterol
and adiponectin, indicating that astaxanthin ameliorates
insulin resistance and improve insulin sensitivity by
mechanisms involving the increase of glucose uptake, and
by modulating the levels of circulating adiponectin and
blood lipids [58]. Recently, Bhuvaneswari et al. [59] showed
that significant elevation in both glucose and insulin levels
induced by a high fat plus high fructose diet in mice
was abolished by astaxanthin supplementation, also indi-
cating that astaxanthin could substantially improve insulin
sensitivity.
3.5.2 Diabetic nephropathy
Uchiyama et al. [61] evaluated the renal damage by
measuring urinary albumin level, and found that this
parameter was significantly lower in astaxanthin-treated db/
db mice than in untreated mice. However, it was uncertain
whether the antioxidant activity of astaxanthin was directly
responsible for the lessened glomerular damage because the
blood glucose level of astaxanthin-treated mice was also
significantly lower [61]. Naito et al. [64] examined whether
chronic administration of astaxanthin could prevent the
progression of diabetic nephropathy induced by oxidative
stress in mice, and showed that astaxanthin could exert
beneficial effects on renal mesangial cells and ameliorate
the progression of diabetic nephropathy in the rodent model
of type 2 diabetes. Kim et al. [65] examined the protective
action of astaxanthin against high-glucose-induced oxidative
stress, inflammation, and apoptosis in proximal tubular
epithelial cells. The results demonstrated that astaxanthin
had a protective efficacy against several deleterious effects
caused by high glucose exposure in proximal tubular
epithelial cells. Manabe et al. [66] investigated the protective
mechanism of astaxanthin on the progression of diabetic
nephropathy using an in vitro model of hyperglycemia,
focusing on normal human mesangial cells, and found that
astaxanthin significantly suppressed high glucose-induced
reactive oxygen species production, the activation of tran-
scription factors, and cytokine expression or production by
mesangial cells. These studies suggested that astaxanthin
might prevent the progression of diabetic nephropathy
mainly through the reduction of the oxidative stress on the
kidneys and the prevention of renal cell damage [64], the
modulation of oxidative stress, inflammation, and apoptosis
in high-glucose-treated proximal tubular epithelial cells [65],
or reactive oxygen species scavenging effect in mitochondria
of mesangial cells [66].
In addition, the importance of the transforming growth
factor-bsignaling in the pathophysiology of diabetic
nephropathy was confirmed by Naito et al. [67], who deter-
mined the gene expression patterns in the glomerular cells
of the diabetic mouse kidney and investigated the effects of
astaxanthin on the expression of these genes, and found
that long-term treatment with astaxanthin significantly
decreased the expression of upregulated probes, including
those genes associated with oxidative phosphorylation,
oxidative stress, and the transforming growth factor-b-
collagen synthesis system.
3.5.3 Dental pulp and salivary gland
Leite et al. [60] evaluated the effect of astaxanthin on anti-
oxidant enzymes of dental pulp from alloxan-induced
diabetic rats. The results showed that although having no
effect on superoxide dismutase and catalase activities,
astaxanthin could stimulate glutathione peroxidase in
control and diabetic rats and partially improved the diabetic
complications [60]. In addition, Leite et al. [68] also evaluated
the effect of astaxanthin on the antioxidant enzymes of
salivary gland from alloxan-induced diabetic rats, and
showed that astaxanthin restored the enzymatic activities in
the salivary gland.
3.6 Cardiovascular protective effect
Carotenoids are believed to have therapeutic benefit in
treating cardiovascular disease because of their antioxidant
properties [24]. However, clinical trials with several well-
known agents such as b-carotene have been disappointing
[69], and fail to demonstrate a consistent benefit in patients
at risk for cardiovascular disease. This may be attributed to
the distinct antioxidant properties of various carotenoids
resulting from their structure-dependent physicochemical
interactions with biologic membranes [24].
The antioxidant activity of several carotenoids has been
investigated by Palozza et al. [70] during spontaneous and
peroxyl radical-induced cholesterol oxidation. The results
showed that these carotenoids exhibited significant anti-
oxidant activity by inhibiting spontaneous and free radical-
induced formation of 7-keto-cholesterol and the overall order
of efficacy of these carotenoids was astaxanthin4cantha-
xanthin4lutein 5b-carotene. The finding might have
important beneficial effects on human health by limiting the
formation of atheroma [70]. Iwamoto et al. [71] found a
dose–response relationship between astaxanthin and low-
density lipoprotein oxidation time both in vitro and in vivo,
indicating that astaxanthin could inhibit low-density lipo-
protein oxidation and possibly therefore contributed to the
prevention of atherosclerosis.
Lipid and macrophage infiltration is closely associated
with early plaque development [72]. It was found that
astaxanthin significantly reduced the macrophage
infiltration in the lesions, and lowered the occurrence of
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macrophage apoptosis and plaque ruptures, indicating that
astaxanthin might improve plaque stability in the athero-
sclerotic setting [72] by increasing adiponectin. Another
study showed that astaxanthin could suppress the scavenger
receptors upregulation, matrix metalloproteinases activa-
tion, and pro-inflammatory cytokines expression in macro-
phages, indicating that astaxanthin is effective to regulate
the macrophage atherogenesis-related functions [29].
Hussein et al. [73] found that oral administration of
astaxanthin for 14 days significantly lowered the arterial
blood pressure in spontaneously hypertensive rats but not in
normotensive Wistar Kyoto strain, and the long-term
administration of astaxanthin for 5 wk could also delay the
incidence of stroke in the stroke prone spontaneously
hypertensive rats. Subsequently, Hussein et al. [74] showed
that astaxanthin might modulate the blood fluidity in
hypertension, and the antihypertensive effects of asta-
xanthin might be exerted through mechanisms including
normalization of the sensitivity of the adrenoceptor
sympathetic pathway, particularly a-adrenoceptors, and by
restoration of the vascular tone through attenuation of the
angiotensin II- and reactive oxygen species-induced vaso-
constriction. In the succedent experiment, Hussein et al. [8]
further found that astaxanthin significantly reduced the
plasma level of NO
2and NO
3, an indicator of the endo-
genous formation of NO, and definitive structural altera-
tions in the coronary artery and aorta of spontaneously
hypertensive rats were ameliorated by astaxanthin,
suggesting that astaxanthin could modulate the oxidative
condition and might improve vascular elastin and arterial
wall thickness in hypertension. These results indicated that
astaxanthin could exert beneficial effects in protection
against hypertension and stroke [8, 73, 74]. In addition, it
was shown that astaxanthin lowered blood pressure and
lessened the activity of the renin-angiotensin system in
Zucker Fatty Rats, indicating that the renin-angiotensin
system was involved in the ability of astaxanthin to lower
blood pressure [75].
A recent study showed that astaxanthin could increase
heart mitochondrial membrane potential and contractility
index dose dependently and tend to decrease plasma inter-
leukin-1a, tumor necrosis factor-a, and serum amyloid A
concentrations in BALB/c mice, supporting the possible
effect of astaxanthin for cardiac protection [76]. Pashkow et al.
[69] suggested that there might be a potential therapeutic role
for astaxanthin in the management of myocardial injury,
oxidized low-density lipoprotein, and rethrombosis after
thrombolysis, as well as other cardiac diseases such as atrial
fibrillation. Augusti et al. [77] indicated that although astax-
anthin did not prevent hypercholesterolemia or athero-
sclerotic lesions caused by the atherogenic diet in rabbits, it
could play a beneficial role by preventing lipid peroxidation
and changes in antioxidant enzyme activities.
Moreover, Lauver et al. [78] reported that disodium
disuccinate astaxanthin, a water-dispersible synthetic asta-
xanthin derivative, reduced myocardial damage in a rabbit
model of ischemia/reperfusion and suggested that the
mechanisms of action might include both antioxidant and
anticomplement components.
In a human study, Yoshida et al. [79] recently indicated
that astaxanthin increased adiponectin and ameliorated
triglyceride and high-density lipoprotein cholesterol in
humans, and the changes of adiponectin correlated posi-
tively with high-density lipoprotein cholesterol changes
independent of age and body mass index. In addition,
Miyawaki et al. [80] studied healthy adult male volunteers
with a blood transit time of 45–70 s to evaluate the
effect on blood rheology from continuous ingestion of
astaxanthin 6 mg/day for a 10-day period, and showed a
shortening of blood transit time from 52.874.9 to
47.674.2 s, indicating an improvement of human blood
rheology by astaxanthin.
3.7 Anticancer activity
A case-control study with a large cohort involving ten
countries showed that higher plasma concentrations of
some individual carotenoids, retinol, and a-tocopherol were
associated with reduced risk of gastric cancer [81]. There are
two different classes of chemopreventive agents, retinoids/
provitamin A carotenoids and the nonprovitamin carote-
noids, which may act through separate mechanisms [82].
Increasing evidence has shown that carotenoids possess
potent cancer chemopreventive properties independent of
their antioxidant activity or their potential for conversion to
retinoids [23]. Some of carotenoids showed more potent
anticarcinogenic activity than b-carotene and might be more
useful for cancer prevention [83]. It had been reported that
in individuals at high risk for developing lung cancer as a
consequence of smoking and/or asbestos exposure, b-caro-
tene failed to demonstrate protection, and even was found to
induce lung pathology [84], suggesting that the use of
carotenoids without pro-vitamin A activity such as asta-
xanthin might provide protection and avoid the toxicity
associated with retinoids [82]. Chew and Park [22] had
suggested that although astaxanthin, canthaxanthin, and
b-carotene inhibited tumor growth, astaxanthin showed the
highest anti-tumor activity. Growth-inhibitory effects of
astaxanthin have been reported in different tumor cells,
including colon, oral fibrosarcoma, breast, prostate cancer
cells, and embryonic fibroblasts [23].
Daubrawa et al. [85] compared the effects of cantha-
xanthin and astaxanthin on gap junctional intercellular
communication, which is important for homeostasis,
growth control, and development of cells, in primary human
skin fibroblasts, and found that astaxanthin was a strong
suppressor of gap junctional intercellular communication
and affected channel function by changing the phosphor-
ylation pattern of connexin43. However, in contrast to
astaxanthin, canthaxanthin and other carotenoids could
stimulate gap junctional intercellular communication and
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enhance connexin43 expression in cell culture. Briviba et al.
[86] compared the subcellular localization of astaxanthin and
b-carotene in cultured HT29 human colon adenocarcinoma
cells. The results showed that astaxanthin was effectively
taken up by the cells and localized mostly in the cytoplasm,
and cells incubated with b-carotene showed about a 50-fold
lower cellular amount of b-carotene. The difference of
astaxanthin and b-carotene distribution in cells of intestinal
origin suggested that the possible defense against reactive
molecules by carotenoids in these cells might also be
different [86].
Astaxanthin was found to have considerable preventive
activities on azoxymethane-induced large bowel carcino-
genesis and 4-nitroquinoline-1-oxide-induced tongue carci-
nogenesis in rats [87]. Tanaka et al. [88, 89] found that
astaxanthin was possible chemopreventive agent for N-butyl-
N-(4-hydroxybutyl)-nitrosamine-induced bladder carcino-
genesis in male ICR mice and 4-nitroquinoline-1-oxide-
induced oral carcinogenesis in male F344 rats, partly due to
suppression of cell proliferation. Jyonouchi et al. [90] showed
that astaxanthin could suppress fibrosarcoma cell growth
and stimulated immunity against tumor antigen, suggesting
that astaxanthin might exert antitumor activity through the
enhancement of immune responses.
Kozuki et al. [91] found that astaxanthin could inhibit the
invasion of rat ascites hepatoma AH109A cells in a coculture
system with rat mesentery-derived mesothelial cells in a
dose-dependent manner. AH109A cells cultured with
hypoxanthine and xanthine oxidase showed a highly inva-
sive activity and astaxanthin could suppress this reactive
oxygen species-potentiated invasive capacity [91]. Kurihara
et al. [92] showed that astaxanthin could inhibit stress-
induced impairment to the antitumor activity of natural
killer cells via its antioxidative property, and thus inhibit the
stress-induced promotion of hepatic metastasis in mice.
Moreover, astaxanthin could improve stress-induced
immune dysfunction better potently than a-tocopherol
and b-carotene [92]. Tripathi and Jena [93] found that
astaxanthin could attenuate oxidative stress, DNA damage,
cell death as well as induction of early hepatocarcinogenesis
in rat induced by cyclophosphamide. It was suggested that
the protective effect of astaxanthin was mediated through
the upregulation of nuclear factor E
2
-related factor
2 – antioxidant-response element pathway [93].
It has been reported that astaxanthin could inhibit the
growth of mammary tumors in female BALB/c mice [94].
Recently, Nakao et al. [95] reported that astaxanthin fed prior
to tumor initiation could suppress mammary tumor growth,
and increase the natural killer cell populations and plasma
interferon-gconcentration in BALB/c mice injected with a
mammary tumor cell line. However, astaxanthin supple-
mentation after tumor initiation might be contraindicated
and would result in more rapid tumor growth and elevate
palsma inflammatory cytokines interleukin-6 and tumor
necrosis factor-a, emphasizing the importance of anti-
oxidant status prior to disease initiation [95].
The inhibitory effect of astaxanthin against chemically
induced colonic pre-neoplastic progression was found by
Prabhu et al. [96], who showed that the decreased levels of
colon enzymic and nonenzymic antioxidants and increased
levels of lipid peroxidation marker levels in a dimethylhy-
drazine-induced rat colon carcinogenesis model were
significantly reversed on astaxanthin administration.
Palozza et al. [23] demonstrated that H. pluvialis extract
could inhibit the growth of HCT-116, HT-29, LS-174, WiDr,
and SW-480 human colon cancer cells by arresting cell-cycle
progression and promoting apoptosis. Moreover, it was also
found that the effects of H. pluvialis extract on cell growth
and apoptosis were more pronounced than those of purified
astaxanthin at the same astaxanthin concentration [23].
Adult T-cell leukemia is a fatal malignancy of
T lymphocytes caused by human T-cell leukemia virus type
1 infection and remains incurable [97]. Ishikawa et al. [97]
found that b-carotene and astaxanthin had mild inhibitory
effects on human T-cell leukemia virus type 1-infected T-cell
lines, and the inhibitory activities of fucoxanthin and its
deacetylated metabolite fucoxanthinol were stronger than
those of b-carotene and astaxanthin.
3.8 Neuroprotective effect
Ikeda et al. [98] found that astaxanthin markedly suppressed
6-hydroxydopamine-induced apoptosis in human neuro-
blastoma SH-SY5Y cells by inhibiting intracellular reactive
oxygen species generation, thereby attenuating p38 MAPK
activation and mitochondrial dysfunction. Liu et al. [99]
demonstrated that astaxanthin could prevent docosahex-
aenoic acid hydroperoxide- or 6-hydroxydopamine-induced
neuronal apoptosis, mitochondrial abnormalities, and
intracellular reactive oxygen species generation in SH-SY5Y
cells. Chan et al. [100] also showed that astaxanthin likely
enhanced cell and mitochondrial membrane stability. These
studies suggested that astaxanthin had the protective effects
on a neurodegenerative disease, dependent on its anti-
oxidant potential and mitochondria protection, and might be
a promising neuroprotective therapeutic agent for oxidative
stress-associated neurodegeneration such as Parkinson’s
disease [98–100].
Chang et al. [101] recently found that astaxanthin showed
an amazingly potent protective effect against the damaging
effects elicited by b-amyloid peptide 25–35 in PC12 cells,
and might be used as a very potential neuron protectant and
a potent anti-Alzheimer’s disease adjuvant therapy, parti-
cularly in its early stage.
It was found that astaxanthin could reduce ischemia-
induced free radical damage, apoptosis, neurodegeneration,
and cerebral infarction in brain tissue through the inhibi-
tion of oxidative stress, reduction of glutamate release, and
antiapoptosis, and might be clinically useful for patients
vulnerable or prone to ischemic events [102]. Recently, Lin
et al. [103] used isolated nerve terminals (synaptosomes)
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purified from the rat cerebral cortex to investigate the effect
of astaxanthin on endogenous glutamate release, and
showed that astaxanthin exhibited a dose-dependent inhi-
bition of 4-aminopyridine-elicited release of glutamate,
presenting an additional explanation for the neuroprotective
effect of astaxanthin besides antioxidant and anti-inflam-
matory properties. Kim et al. [104] found that astaxanthin
could inhibit H
2
O
2
-mediated apoptotic death via modulation
of p38 and MEK signaling pathways. These results high-
lighted the therapeutic potential of astaxanthin in the
prevention and treatment of a wide range of neurological
and neurodegenerative disorders [102, 104].
Recently, Kim et al. [105] demonstrated that astaxanthin
as an extracellular factor enhanced stem cell potency via an
increase of the proliferative capacity in neural stem cells,
and improved the osteogenic and adipogenic differentiation
potential of neural stem cells. In addition, Abadie-Guedes
et al. [106] demonstrated that astaxanthin could antagonize
the ethanol-induced facilitation of cortical spreading
depression propagation in the young adult rat brain and its
antioxidant properties might be involved in such effects.
3.9 Ocular protective effect
It had been reported that, after ingestion of astaxanthin for
consecutive 28 days, the uncorrected far visual acuity was
significantly improved and the accommodation time was
significantly shortened in healthy volunteers over 40 years of
age receiving 4 or 12 mg once a day, and there was no
change in refraction, flicker fusion frequency, or pupillary
reflex [107]. In another experiment, it was found that
astaxanthin extracted from the microalga H. pluvialis
significantly improved the deep vision and the critical flicker
fusion of healthy adult male volunteers, and no effects on
static and kinetic visual acuity were observed [108]. Nagaki
et al. [109] found that 6 mg of astaxanthin from H. pluvialis
per day could improve eye fatigue in visual display terminal
workers. It was shown that astaxanthin might increase
retinal capillary blood flow in both eyes in normal volunteers
and intraocular pressures remained unchanged during the
supplementation period [110]. In addition, Izumi-Nagai
et al. [111] concluded that astaxanthin treatment, together
with inflammatory processes including NF-kB activation,
subsequent upregulation of inflammatory molecules, and
macrophage infiltration, significantly suppressed the devel-
opment of choroidal neovascularization capable of leading to
severe vision loss and blindness.
Ohgami et al. [112] indicated that astaxanthin had a dose-
dependent ocular anti-inflammatory effect on endotoxin-
induced uveitis through suppressing the production of nitric
oxide, prostaglandin E2, and tumor necrosis factor-aby
directly blocking nitric oxide synthase activity. In their
succedent study, Suzuki et al. [113] showed that astaxanthin
could reduce ocular inflammation in eyes with endotoxin-
induced uveitis by downregulating proinflammatory factors
and inhibiting the nuclear factor-kB-dependent signaling
pathway, suggesting that astaxanthin might be a promising
agent for the treatment of ocular inflammation [112, 113].
Astaxanthin was found to be capable of providing
appreciable protection for vulnerable tryptophan residues
and b
high
-crystallin against oxidative stress, and thus capable
of protecting porcine lens crystallins against oxidative
damage and degradation by calcium-induced calpain [114].
Liao et al. [115] reported that astaxanthin could interact with
selenite, whose accumulation in the lens might cause
cataract formation directly, and thus could delay selenite-
induced lens crystalline precipitation and attenuate selenite-
induced cataractogenesis in rats. Nakajima et al. [116] found
that astaxanthin had neuroprotective effects against retinal
ganglion cell damage. Recently, Cort et al. [117] showed that
astaxanthin significantly decreased the percent of apoptotic
cells on the retina in rats with elevated intraocular pressure.
This study confirmed the role of oxidative injury in elevated
intraocular pressure and highlighted the protective effect of
astaxanthin in ocular hypertension [117].
3.10 Skin-protective effect
It was reported that preincubation with synthetic asta-
xanthin or an algal extract containing 14% of astaxanthin
could prevent ultraviolet A-induced alterations in cellular
superoxide dismutase activity and decrease in cellular
glutathione content [118]. Camera et al. [119] compared the
modulation of ultraviolet A-related injury by astaxanthin,
canthaxanthin, and b-carotene for systemic photoprotection
in human dermal fibroblasts, and found that astaxanthin
exhibited a pronounced photoprotective effect and counter-
acted ultraviolet A-induced alterations to a significant extent,
and uptake of astaxanthin by fibroblasts was higher than
that of canthaxanthin and b-carotene, indicating that asta-
xanthin had a superior preventive effect toward photo-
oxidative changes. Recently, Suganuma et al. [120] examined
the effects of astaxanthin on the induction of matrix-
metalloproteinase-1 and skin fibroblast elastase by ultravio-
let A treatment of cultured human dermal fibroblasts, and
showed that astaxanthin could interfere with ultraviolet
A-induced matrix-metalloproteinase-1 and skin fibroblast
elastase/neutral endopeptidase expression. These studies
suggest that topical or oral administration of astaxanthin
might prevent or minimize the effects of ultraviolet A
radiation such as skin sagging or wrinkling [118, 120].
3.11 Effect on exercise endurance
It has been shown that astaxanthin from H. pluvialis could
significantly lower serum lactic acid concentration in adult
male volunteers at 2 min after 1200 m running and no other
effects were observed, suggesting that astaxanthin is effec-
tive for the improvement of muscle fatigue that might lead
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to sports performance benefits [108]. Another study showed
that astaxanthin might preferentially attenuate sensations of
delayed-onset muscular soreness, which is one of the
symptoms of exercise induced muscle damage, in weight
trained individuals with a high percentage area for fiber
types IIA and IIAB/B [121].
Aoi et al. [122] found that astaxanthin could attenuate
exercise-induced damage in mouse skeletal muscle and
heart, including an associated neutrophil infiltration that
induced further damage. In the succedent experiments, Aoi
et al. [123] showed that astaxanthin promoted lipid meta-
bolism rather than glucose utilization during exercise via
carnitine palmitoyltransferase I activation, which led to the
improvement of endurance and efficient reduction of
adipose tissue with training. In another study, Ikeuchi et al.
[124] also showed that astaxanthin could cause a decrease in
glucose utilization and an increase in fatty acid utilization as
an energy source during exercise. The glycogen thus saved
could become an available energy source for the later stages
of exercise, and thus slower utilization of glycogen resulted
in improved endurance exercise performance and delaying
the onset of fatigue [124].
3.12 Effect on fertility
Eskenazi et al. [125] suggested that a healthy diet with
high intake of antioxidants might be an inexpensive
and safe way to improve semen quality and fertility.
Comhaire et al. [126] evaluated the effects of astaxanthin as
complementary treatment to improve the outcome of the
World Health Organization male infertility treatment
guidelines in a pilot double-blind randomized trial. Sixteen
milligrams per day of astaxanthin was given to the male
partners of 20 infertile couples, whose semen characteristics
were below the World Health Organization recommended
reference values. The results showed that astaxanthin
significantly decreased reactive oxygen species and the
secretion of inhibin B by the Sertoli cells, indicating a
positive effect of astaxanthin on sperm parameters and
fertility [126]. In addition, Tripathi and Jena [127] showed
that astaxanthin treatment significantly improved the testes
weight, sperm count, and sperm head morphology as
compared with only cyclophosphamide-treated animals,
indicating the chemoprotective potential of astaxanthin
against cyclophosphamide induced germ cell toxicity in
mice.
3.13 Effect on kidney function impairment
Inorganic mercury is accumulated mainly in kidneys after
absorption and causes acute renal failure. Reactive oxygen
species are implicated as mediators of tissue damage in the
acute renal failure induced by inorganic mercury [128].
Augusti et al. [128] investigated the possible protective effect
of astaxanthin against nephrotoxicity induced by mercuric
chloride, and indicated that astaxanthin could have a bene-
ficial role against HgCl
2
toxicity by preventing lipid and
protein oxidation, changes in the activity of antioxidant
enzymes, and histopathological changes.
4 Concluding remarks
Growing evidence from tissue culture, animal, and clinical
studies (Supporting Information Tables S1, S2, and S3)
suggests that astaxanthin has potential health-promoting
effects in the prevention and treatment of various diseases,
such as cancers (gastric, colon, breast, prostate, oral, tongue,
bladder, liver cancers, fibrosarcoma, and leukemia), chronic
inflammatory diseases (asthma, sepsis, rheumatoid arthri-
tis, atherosclerosis, inflammatory bowel disease, and brain
inflammatory diseases), metabolic syndrome (obesity,
dyslipidemia, hypertension, and insulin resistance),
diabetes, diabetic nephropathy, cardiovascular disease
(hypertension, atherosclerosis, stroke, atrial fibrillation,
rethrombosis after thrombolysis, and myocardial injury),
gastrointestinal diseases (gastritis, gastric ulcer, duodenal
ulcer, and ethanol- or drug-induced gastric lesions), liver
disease (fatty liver, hepatitis, liver ischemia-reperfusion
injury, and chemicals-induced liver damages), neurodegen-
erative diseases (ischemia/reperfusion-induced neurode-
generation, Parkinson’s disease, Alzheimer’s disease, and
other neurodegenerative disorders), eye disease (cataract,
glaucoma, ocular inflammatory such as uveitis, choroidal
neovascularization, and eye fatigue from visual display
terminals), skin diseases (ultraviolet A-induced skin
damage, skin cancer, and skin sagging or wrinkling), exer-
cise-induced fatigue (muscle fatigue, delayed-onset muscu-
lar soreness), male infertility, and HgCl
2
-induced acute
renal failure.
These protections against various diseases by astaxanthin
are likely to involve antioxidant mechanisms including
prevention of oxidative damage and cellular necrosis or
apoptosis induced by oxidative stress; other potential
mechanisms include decreased expression or production of
inflammatory mediators and cytokines by suppressing the
activation of nuclear factor-kB, decreased expression or
production of transforming growth factor-b1, increased
levels of circulating adiponectin and insulin sensitivity,
decreased activity of the renin-angiotensin system, and
antimicrobial activity against H. pylori,etc. Although the
currently available data and recent findings are very
encouraging, more extensive, well-controlled clinical trials,
especially for 9-cis-astaxanthin, are suggested for each of
these categories.
This work is supported by Science and Technology Planning
Project of Guangdong Province, China (2007B020708003).
The authors have declared no conflict of interest.
160 J.-P. Yuan et al.Mol. Nutr. Food Res. 2011, 55, 150–165
&2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
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... As a ketocarotenoid, ASX with the structural formula C40H52O4 has a molar mass of 596.84 g/mol [29]. This compound has two terminal rings joined by a polyene chain with either single or double bonds. ...
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We evaluated the effect of astaxanthin on visual function in 49 eyes of 49 healthy volunteers. They were over 40 years of age. They were divided into 4 groups matched for age and gender. Each group was given peroral astaxanthin once a day. The dosage was 0 mg, 2 mg, 4 mg, or 12 mg for each group. After ingestion of astaxanthin for consecutive 28 days, the uncorrected far visual acuity significantly improved in groups receiving 4 mg or 12 mg. The accommodation time significantly shortened in groups receiving 4 mg or 12 mg. There was no change in refraction, flicker fusion frequency, or pupillary reflex.
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Nonsteroidal anti-inflammatory drugs such as indomethacin induce severe gastric mucosal damage in humans and rodents. In the present study, the in vivo protective effect of astaxanthin on indomethacin-induced gastric lesions in rats was investigated. The test groups were injected with indomethacin (25 mg/kg) after the oral administration of astaxanthin (25 mg/kg) for 1, 2, and 3 days, while the control group was treated only with indomethacin. Thiobarbituric acid reactive substances in the gastric mucosa, as an index of lipid peroxidation, increased significantly after indomethacin administration and this increase was inhibited by oral administration of astaxanthin. In addition, pretreatment with astaxanthin resulted in a significant increase of the activities of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH-px). Histologic examination clearly revealed acute gastric mucosal lesions induced by indomethacin in the stomach of the control group, but were not observed in that of the test group. These results indicate that astaxanthin activates SOD, catalase, and GSH-px, and removes the lipid peroxides and free radicals induced by indomethacin. It is evident that astaxanthin acts as a free radical quencher and antioxidant, and is an effective molecule in the remedy of gastric mucosal lesion.
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AIM: To elucidate the effect of antioxidants, resveratrol (RVT) and astaxanthin (AXN), on hepatitis C virus (HCV) replication. METHODS: We investigated the effect of recent popular antioxidant supplements on replication of the HCV replicon system OR6. RVT is a strong antioxidant and a kind of polyphenol that inhibits replication of various viruses. AXN is also a strong antioxidant. The replication of HCV RNA was assessed by the luciferase reporter assay. An additive effect of antioxidants on antiviral effects of interferon (IFN) and ribavirin (RBV) was investigated. RESULTS: This is the first report to investigate the effect of RVT and AXN on HCV replication. In contrast to other reported viruses, RVT significantly enhanced HCV RNA replication. Vitamin E also enhanced HCV RNA replication as reported previously, although AXN didnot affect replication. IFN and RBV significantly reduced HCV RNA replication, but these effects were dose-dependently hampered and attenuated by the addition of RVT. AXN didnot affect antiviral effects of IFN or RBV. CONCLUSION: These results suggested that RVT is not suitable as an antioxidant therapy for chronic hepatitis C.
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Hepatocyte protection by astaxanthin (100 mg/kg feed for 4 wk with rats) was tested with CCl4 (0.2 mL/100 g weight). The liver catalase and the lipid peroxide contents of the control, CCl4 treated, and CCl4 + astaxanthin treated rats were 17.1, 30.1, and 26.1 mmol/mg protein/min and 1.23, 1.74, and 1.51 μmol/g liver, respectively. These data indicated that astaxanthin attenuated the adverse effect of CCl4. The effect of astaxanthin [300 mg/kg in normal feed for 44 weeks and high-fat feed (10% lard oil, w/w) for the next 26 weeks] on the weight gain was investigated. With the feed of chemically synthesized astaxanthin, the weight increase was significantly slow in the male mice, but not in the females. Chemical astaxanthin decreased the levels of blood glucose, cholesterol, and triglyceride in mice by 4–21%, suggesting astaxanthin can be used to protect hepatocytes and cardiovascular system, and to limit weight gain caused by a high lipid consumption.
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We have previously found that in Chlorella emersonii, grown under synergistic conditions of high irradiance and low nitrogen, chlorophyll and primary carotenoids were degraded, whereas secondary carotenoids were produced. In this study Chlorella zofingiensis was cultivated under similar conditions. Maximal growth was achieved in a culture growing under light irradiance of 150 μmol quanta m-2 s-1 and a nitrogen concentration of 0.5 mg/mL of KNO3. Higher nitrogen concentrations or higher irradiance inhibited cell division. The secondary carotenoids produced were identified as canthaxanthin (about 30 %) and astaxanthin (about 70 %) in the form of mono- and diesters. Maximal accumulation occurred in cells starved of nitrogen and grown at a light irradiance of 300 μLmol m-2 s-1. Exposure of a thin layer of algal cells to sunlight resulted in de-esterification of the astaxanthin esters. It is suggested that secondary carotenoids have a photo-protective role, that is, under high light conditions they protect chlorophyll and other photosynthetic pigments against damage.