![Transmembrane orientation of astaxanthin [1,9].](https://www.researchgate.net/publication/293191848/figure/fig1/AS:614216608260099@1523452059038/Transmembrane-orientation-of-astaxanthin-1-9_Q320.jpg)
Available via license: CC BY 4.0
Content may be subject to copyright.
marine drugs
Review
Potential Anti-Atherosclerotic Properties
of Astaxanthin
Yoshimi Kishimoto
1
, Hiroshi Yoshida
2,
* and Kazuo Kondo
1,3
1
Endowed Research Department “Food for Health”, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku,
Tokyo 112-8610, Japan; kishimoto.yoshimi@ocha.ac.jp (Y.K.); kondo.kazuo@ocha.ac.jp (K.K.)
2
Department of Laboratory Medicine, Jikei University Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa,
Chiba 277-8567, Japan
3
Institute of Life Innovation Studies, Toyo University, 1-1-1 Izumino, Itakura-machi, Ora-gun,
Gunma 374-0193, Japan
* Correspondence: hyoshida@jikei.ac.jp; Tel.: +81-4-7164-1111 (ext. 2270); Fax: +81-4-7164-1126
Academic Editor: Keith B. Glaser
Received: 3 December 2015; Accepted: 26 January 2016; Published: 5 February 2016
Abstract:
Astaxanthin is a naturally occurring red carotenoid pigment classified as a xanthophyll,
found in microalgae and seafood such as salmon, trout, and shrimp. This review focuses on
astaxanthin as a bioactive compound and outlines the evidence associated with its potential role in
the prevention of atherosclerosis. Astaxanthin has a unique molecular structure
that is responsible
for its powerful antioxidant activities by quenching singlet oxygen and scavenging
free radicals.
Astaxanthin has been reported to inhibit low-density lipoprotein (LDL) oxidation and to increase
high-density lipoprotein (HDL)-cholesterol and adiponectin levels in clinical studies. Accumulating
evidence suggests that astaxanthin could exert preventive actions against atherosclerotic cardiovascular
disease (CVD) via its potential to improve oxidative stress, inflammation, lipid metabolism, and
glucose metabolism. In addition to identifying mechanisms of astaxanthin bioactivity by basic
research, much more epidemiological and clinical evidence linking reduced CVD risk with dietary
astaxanthin intake is needed.
Keywords:
astaxanthin; oxidative stress; inflammation; lipid metabolism; glucose metabolism;
atherosclerosis; cardiovascular disease
1. Introduction
Astaxanthin (3,3
1
-dihydroxy-
β
,
β
1
-carotene-4,4
1
-dione), a red carotenoid pigment classified as a
xanthophyll, is known to have a powerful antioxidant ability. Oxidative stress and inflammation are
involved in the development of atherosclerotic diseases, and therefore much attention has been paid
to antioxidant foods as potential agents for preventing or treating these diseases. Astaxanthin is one
of the promising agents in the prevention of oxidative stress-related diseases, and both the basic and
clinical research on the health benefits of astaxanthin has quickly developed over the past few years.
Cardiovascular disease (CVD) is the leading cause of death worldwide. The coexistence of
dyslipidemia, impaired glucose tolerance, and hypertension with accumulated visceral fat has been
termed metabolic syndrome, which increases synergistically the risk of CVD. Metabolic syndrome
is often characterized by oxidative stress, a disturbance in the balance between the production of
reactive oxygen species (ROS) and antioxidant defenses. It has recently become clear that the effects
of astaxanthin go beyond antioxidant properties. Accumulating evidence suggests that astaxanthin
could exert cardioprotective actions by improving oxidative stress, inflammation, lipid metabolism,
and glucose metabolism. The objective of this review is to summarize the findings regarding the
bio-functions of astaxanthin in the prevention of atherosclerosis.
Mar. Drugs 2016, 14, 35; doi:10.3390/md14020035 www.mdpi.com/journal/marinedrugs
Mar. Drugs 2016, 14, 35 2 of 13
2. Food Sources and Bioavailability of Astaxanthin
Astaxanthin is biosynthesized by microalgae, bacteria, and fungi, and concentrates higher up the
food chain. Humans commonly consume astaxanthin from seafood such as salmon, trout, shrimp,
lobster, crab, and fish eggs. Astaxanthin is also fed to farmed seafood to add red color. The content
of astaxanthin was reported as 6–8 mg/kg flesh in farmed Atlantic salmon, and 6 mg/kg flesh and
25 mg/kg flesh in large trout in the European and Japanese markets, respectively [
1
]. The highest
known level of astaxanthin in nature is in the chlorophyte alga Haematococcus pluvialis, which has
become a primary source of the astaxanthin used in the food industry [
2
,
3
]. Not only the content
but also the composition of isomers of astaxanthin differ among organisms. H. pluvialis produces the
all-trans geometric form 3S, 3
1
taxanthin, and therefore this type is most largely ingested by humans [
1
].
Human cannot synthesize astaxanthin, and the ingested astaxanthin cannot be converted to vitamin A;
excessive intake of astaxanthin will thus not cause hypervitaminosis A [
4
,
5
]. In 1987, the U.S. Food and
Drug Administration (FDA) authorized astaxanthin as a feed additive for the aquaculture industry,
and in 1999 the FDA approved astaxanthin as a dietary supplement [
6
]. The use of astaxanthin as a
dietary supplement has been rapidly growing in many countries. Japan is one of the global pioneers
in astaxanthin research and production. The FDA first awarded the “generally recognized as safe”
(GRAS) status to astaxanthin extracted from H. pluvialis produced by a Japanese company in 2010.
Human clinical studies have used orally administered astaxanthin in a dose ranging from 4 mg
to 100 mg/day [
5
]. In experimental and human studies, astaxanthin seems to be well tolerated,
and no notable toxicity has been described. In a study by Coral-Hinostroza et al., male subjects
ingested a single meal containing a 10 mg dose equivalent of astaxanthin from astaxanthin diesters and
then, after four weeks, given a dose of 100 mg astaxanthin equivalents. A non-linear dose–response
relationship and selective absorption of Z-isomers were observed, and the plasma elimination half-life
was estimated as 52
˘
40 h [
7
]. The presence of dietary fat enhances the assimilation of astaxanthin
in the small intestine [
8
]. It is also noteworthy that the bioavailability of astaxanthin is decreased in
smokers by approximately 40% [8].
3. Multiple Anti-Atherosclerotic Effects of Astaxanthin
3.1. Anti-Oxidation
Carotenoids contain long conjugated double bonds in a polyene chain that are responsible for
antioxidant activities by quenching singlet oxygen and scavenging radicals to terminate the chain
reaction. Astaxanthin contains a conjugated polyene chain at the center and hydroxy and keto moieties
on each ionone ring. Owing to its unique molecular structure, astaxanthin shows better biological
activity than other antioxidants, because it can link with the cell membrane from the inside to the
outside [
1
,
9
] (Figure 1). The polyene chain in astaxanthin traps radicals in the cell membrane, while
the terminal ring of astaxanthin can scavenge radicals both at the surface and in the interior of the cell
membrane [10].
Mar.Drugs2016,14,x 3of13
Figure1.Transmembraneorientationofastaxanthin[1,9].
Astaxanthinisreportedtobemoreeffectivethanβ‐caroteneinpreventinglipidperoxidationin
solution[11]andvariousbiomembranemodelssuchaseggyolkphosphatidylcholineliposomes[12]
and rat liver microsomes [13]. Goto et al. reported in 2001 that astaxanthin was approximately
twofoldmoreeffectivethanβ‐caroteneintheinhibitionof
liposome peroxidationinducedbyADP
andFe
2+
[10].Theirreportwasthefirsttodemonstratethatastaxanthincouldtrapradicalsnotonly
at the conjugated polyene chain but also in the terminal ring moiety. The proposed molecular
interaction was as follows: (1) the two terminal rings interact with the hydrophilic polar site of
membrane phospholipids; and (2)
the hydroxyl and carbonyl groups form an intramolecular
hydrogen‐bonded five‐membered ring, increasing the hydrophobicity of astaxanthin. It is well
knownthattheactivityofcarotenoidscanbeshiftedfromantioxidanttopro‐oxidantaccordingto
theirconcentrations,highoxygentension,orinteractionswithotherco‐antioxidants[14].Martinet
al.
divided17carotenoidsintothreeclasses:(1)thosewithoutsignificantantioxidativeproperties;(2)
those with good antioxidative but also pro‐oxidative properties; and (3) those with strong
antioxidativeand without anypro‐oxidative properties. Astaxanthinwas categorized asclass(3),
whereasβ‐caroteneandlycopenewereidentifiedasclass(2)
[15].
Theincreaseinthesusceptibilityoflow‐densitylipoprotein(LDL)andcellmembranelipidsto
oxidativeprocessescontributestoatherosclerosisandthrombusformation.Ourgroupwasthefirst
to report that astaxanthin protected human LDL against oxidative attack [16]. Compared to
α‐tocopherol and lutein, astaxanthin showed a greater antioxidative
effect on LDL oxidation
inducedbyAMVN‐CH
3
O(2,2‐azobis‐4‐methoxy‐2,4‐dimethylvaleronitrile) in vitro.Toconfirmthe
antioxidant effect of astaxanthin ex vivo, we recruited 24 healthyadults to consume astaxanthin
purifiedfromkrillat0,1.8,3.6,14.4,and21.6mg/dayfor14daysandthenmeasuredthechangesin
LDLoxidizability.Atthe
endofthestudy,astaxanthinconsumptionsignificantlyprolongedthelag
time,amarkerofthesusceptibilityofLDLtooxidation,atthedoselevelsof3.6mg/dayandhigher.
Importantly,anintakeof3.6mgastaxanthinisequivalenttoapproximately165gofsalmonflesh.
Nakagawa et al. reported the
efficacy of astaxanthin supplementation (6 and 12 mg/day) on
phospholipidhydroperoxides(PLOOH)levelsinerythrocytesin30healthysubjects.After12weeks
of administration, decreased PLOOH levels and increased astaxanthin in erythrocytes were
observed[17].Karppietal.alsoreportedthatsupplementationofastaxanthinfor12weeksreduced
therevelsof
plasma12‐and15‐hydroxyfattyacidsinhealthymales[18].Inobeseandoverweight
adults, supplemental astaxanthin (5 and 20 mg/day) reduced biomarkers of oxidative stress
including malondialdehyde (MDA) and isoprostane, and increased superoxide dismutase (SOD)
andtotalantioxidantcapacity(TAC)[19].Thesefindingssuggestthatastaxanthinmaydecrease
in
vivolipidperoxidation.
Figure 1. Transmembrane orientation of astaxanthin [1,9].
Mar. Drugs 2016, 14, 35 3 of 13
Astaxanthin is reported to be more effective than
β
-carotene in preventing lipid peroxidation in
solution [
11
] and various biomembrane models such as egg yolk phosphatidylcholine liposomes [
12
]
and rat liver microsomes [
13
]. Goto et al. reported in 2001 that astaxanthin was approximately
twofold more effective than
β
-carotene in the inhibition of liposome peroxidation induced by ADP
and Fe
2+
[
10
]. Their report was the first to demonstrate that astaxanthin could trap radicals not only at
the conjugated polyene chain but also in the terminal ring moiety. The proposed molecular interaction
was as follows: (1) the two terminal rings interact with the hydrophilic polar site of membrane
phospholipids; and (2) the hydroxyl and carbonyl groups form an intramolecular hydrogen-bonded
five-membered ring, increasing the hydrophobicity of astaxanthin. It is well known that the activity
of carotenoids can be shifted from antioxidant to pro-oxidant according to their concentrations, high
oxygen tension, or interactions with other co-antioxidants [
14
]. Martin et al. divided 17 carotenoids into
three classes: (1) those without significant antioxidative properties; (2) those with good antioxidative
but also pro-oxidative properties; and (3) those with strong antioxidative and without any pro-oxidative
properties. Astaxanthin was categorized as class (3), whereas
β
-carotene and lycopene were identified
as class (2) [15].
The increase in the susceptibility of low-density lipoprotein (LDL) and cell membrane lipids
to oxidative processes contributes to atherosclerosis and thrombus formation. Our group was the
first to report that astaxanthin protected human LDL against oxidative attack [
16
]. Compared to
α
-tocopherol and lutein, astaxanthin showed a greater antioxidative effect on LDL oxidation induced
by AMVN-CH
3
O (2,2-azobis-4-methoxy-2,4-dimethylvaleronitrile)
in vitro
. To confirm the antioxidant
effect of astaxanthin ex vivo, we recruited 24 healthy adults to consume astaxanthin purified from krill
at 0, 1.8, 3.6, 14.4, and 21.6 mg/day for 14 days and then measured the changes in LDL oxidizability.
At the end of the study, astaxanthin consumption significantly prolonged the lag time, a marker of the
susceptibility of LDL to oxidation, at the dose levels of 3.6 mg/day and higher. Importantly, an intake
of 3.6 mg astaxanthin is equivalent to approximately 165 g of salmon flesh. Nakagawa et al. reported
the efficacy of astaxanthin supplementation (6 and 12 mg/day) on phospholipid hydroperoxides
(PLOOH) levels in erythrocytes in 30 healthy subjects. After 12 weeks of administration, decreased
PLOOH levels and increased astaxanthin in erythrocytes were observed [
17
]. Karppi et al. also
reported that supplementation of astaxanthin for 12 weeks reduced the revels of plasma 12- and
15-hydroxy fatty acids in healthy males [
18
]. In obese and overweight adults, supplemental astaxanthin
(
5 and 20 mg/day
) reduced biomarkers of oxidative stress including malondialdehyde (MDA) and
isoprostane, and increased superoxide dismutase (SOD) and total antioxidant capacity (TAC) [
19
].
These findings suggest that astaxanthin may decrease in vivo lipid peroxidation.
There are several antioxidant enzymes that catalyze reactions to counteract free radicals and ROS.
Nuclear factor erythroid-related factor 2 (Nrf2) is a master regulator of the antioxidant response
and xenobiotic metabolism through the regulation of a wide range of antioxidant and Phase II
detoxification genes [
20
,
21
]. Tripathi et al. demonstrated that astaxanthin treatment attenuated
cyclophosphamide-induced oxidative stress, DNA damage, and cell death in rat hepatocytes through
an Nrf2-antioxidant response element (ARE) pathway [
22
]. It was further observed that the levels of
Nrf2 and the targeted phase-II enzymes, i.e., NAD(P)H dehydrogenase, quinone 1 (NQO1) and heme
oxygenase 1 (HO-1) were increased with astaxanthin treatment. Interestingly, astaxanthin showed
synergistic effects on the induction of the cellular glutathione level and the mRNA expression of Nrf2
and its target genes (NQO1, HO-1, and glutathione S-transferase mu 2 [GSTM2]) when combined with
docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) in a human hepatoma cell line [23].
Paraoxonase 1 (PON1), which is mainly responsible for the breakdown of lipid peroxides
before they can accumulate in LDL, is an enzyme located on circulating high-density lipoprotein
(HDL) particles, but the enzymatic activity of PON1 is readily inactivated by oxidants [
24
]. In
hypercholesterolemic rabbits, astaxanthin prevented protein oxidation and changes in PON1 and
thioredoxin reductase (TrxR-1) activities [
25
]. TrxR-1 is a redox-active protein that efficiently regenerates
oxidized thioredoxin. These effects were not related to a direct effect of astaxanthin on these enzymes,
Mar. Drugs 2016, 14, 35 4 of 13
because astaxanthin enhanced TrxR-1 and had no effect on PON1 activity
in vitro
[
25
]. It was reported
that regular physical activity might increase PON1 activity [
26
]. Astaxanthin supplementation
(4 mg/day) for 90 days showed a beneficial effect in improving PON1 activity as well as the total
sulphydryl group content in young soccer players [
27
]. The same researchers also reported that
post-exercise creatine kinase (CK) and aspartate aminotransferase (AST) levels were significantly lower
in their astaxanthin group compared to a placebo group [
28
]. Astaxanthin might be of special interest
for athletes who are more susceptible to oxidative stress.
3.2. Anti-Inflammation
Chronic inflammation is the main pathophysiological factor in many diseases, such as diabetes,
hypertension and atherosclerosis. Inhibiting the production of intracellular ROS is a general way
to suppress the pro-inflammatory signals, and thus modulators of redox balance are considered the
key regulators of inflammatory responses. Macrophages play a central role in inflammation and
atherosclerosis progression (Figure 2). The scavenger receptor-mediated uptake of oxidized-LDL by
macrophages leads to the formation of foam cells and the development of atherosclerotic plaque.
The class A scavenger receptor (SR-A) and CD36 are responsible for the major part of oxidized LDL
uptake by macrophages, suggesting pro-atherogenic roles of SR-A and CD36 [
29
,
30
]. Additionally,
in inflammation states, macrophages produce excess amounts of matrix-degrading enzymes,
pro-inflammatory cytokines/chemokines, nitric oxide (NO), and cyclooxygenase-2 (COX-2) [
31
].
Matrix metalloproteinases (MMPs), a family of Zn
2+
-dependent endopeptidases, are responsible for
the degradation of most extracellular matrix proteins, and they mediate tissue remodeling in various
pathologic conditions [
32
]. The expression of MMPs is increased in atherosclerotic lesions and is linked
to weakening of the vascular wall due to degradation of the extracellular matrix [33–35].
Mar.Drugs2016,14,x 5of13
Figure2.Roleofmacrophagesinthedevelopmentofatherosclerosis.
In our previous study, astaxanthin remarkably suppressed the expression of the scavenger
receptorsSR‐AandCD36)theactivityandtheexpressionofMMPs,andthe mRNAexpression of
various inflammatory mediators, i.e., tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β, IL‐6,
induciblenitricoxidesynthase(iNOS),and
COX‐2,inTHP‐1macrophages[36].Wespeculatedthat
the antioxidant property of astaxanthin might account for its inhibitory effects on macrophage
inflammation through the inhibition of nuclear factor‐kappa B (NF‐κB) activation. The
pro‐inflammatory cytokines, prostaglandins, and NO produced by activated macrophages play
critical roles in atherogenesis.
The inhibition of pro‐inflammatory cytokine secretion from
macrophagesmight be oneofthemechanisms mediatingthebeneficialeffects ofantioxidantson
atherosclerosisdevelopment.Anotherstudyreportedthatastaxanthindecreasedtheexpressionof
pro‐inflammatory mediators such as prostaglandin E2, TNF‐α, and IL‐1β by suppressing
IκB‐dependent
NF‐κBactivationinbothlipopolysaccharide (LPS)‐stimulatedRAW264.7cellsand
primarymacrophages[37].
Macedo et al. showed that asta xanthin significantly reduced the production of
pro‐inflammatorycytokines(TNF‐αandIL‐6)inLPS‐stimulatedneutrophils[38].Theirstudyalso
revealed that astaxanthin enhanced neutrophil phagocytic and microbicidal capacity and
suppressed
superoxide anion and hydrogen peroxide production, which might be mediated by
calciumreleasedfromintracellularstorageandNOproduction[38].Thesestudiesindicatedthatthe
anti‐inflammatoryeffectsofastaxanthinthroughitssuppressionofNF‐κBactivationmaybebased
on its antioxidant activity. In addition, astaxanthin treatment reduced the secretion of
pro‐inflammatorycytokines (IL‐1β, IL‐6 and TNF‐α) in H
2
O
2
‐stimulated U937 mononuclearcells,
and this property was elicited by a restoration of the basal SHP‐1 protein expression level and
reducedNF‐κB(p65)nuclearexpression[39].SHP‐1isaproteintyrosinephosphatasethatactsasa
negative regulator of inflammatory cytokine signaling, and SHP‐1 deficiency in mice causes
spontaneous inflammation and autoimmunity [40]; the authors of that study proposed that
astaxanthinmostlikelyinhibitstheROS‐inducedproductionofNF‐κBtranscriptionfactorthrough
therestorationofphysiologica llevelsofSHP‐1[39].
Figure 2. Role of macrophages in the development of atherosclerosis.
In our previous study, astaxanthin remarkably suppressed the expression of the scavenger
receptors SR-A and CD36) the activity and the expression of MMPs, and the mRNA expression
of various inflammatory mediators, i.e., tumor necrosis factor (TNF)-
α
, interleukin (IL)-1
β
, IL-6,
inducible nitric oxide synthase (iNOS), and COX-2, in THP-1 macrophages [
36
]. We speculated
that the antioxidant property of astaxanthin might account for its inhibitory effects on macrophage
Mar. Drugs 2016, 14, 35 5 of 13
inflammation through the inhibition of nuclear factor-kappa B (NF-
κ
B) activation. The pro-inflammatory
cytokines, prostaglandins, and NO produced by activated macrophages play critical roles in
atherogenesis. The inhibition of pro-inflammatory cytokine secretion from macrophages might be one
of the mechanisms mediating the beneficial effects of antioxidants on atherosclerosis development.
Another study reported that astaxanthin decreased the expression of pro-inflammatory mediators
such as prostaglandin E2, TNF-
α
, and IL-1
β
by suppressing I
κ
B-dependent NF-
κ
B activation in both
lipopolysaccharide (LPS)-stimulated RAW264.7 cells and primary macrophages [37].
Macedo et al. showed that astaxanthin significantly reduced the production of pro-inflammatory
cytokines (TNF-
α
and IL-6) in LPS-stimulated neutrophils [
38
]. Their study also revealed that
astaxanthin enhanced neutrophil phagocytic and microbicidal capacity and suppressed superoxide
anion and hydrogen peroxide production, which might be mediated by calcium released from
intracellular storage and NO production [
38
]. These studies indicated that the anti-inflammatory
effects of astaxanthin through its suppression of NF-
κ
B activation may be based on its antioxidant
activity. In addition, astaxanthin treatment reduced the secretion of pro-inflammatory cytokines (IL-1
β
,
IL-6 and TNF-
α
) in H
2
O
2
-stimulated U937 mononuclear cells, and this property was elicited by a
restoration of the basal SHP-1 protein expression level and reduced NF-
κ
B (p65) nuclear expression [
39
].
SHP-1 is a protein tyrosine phosphatase that acts as a negative regulator of inflammatory cytokine
signaling, and SHP-1 deficiency in mice causes spontaneous inflammation and autoimmunity [
40
];
the authors of that study proposed that astaxanthin most likely inhibits the ROS-induced production
of NF-κB transcription factor through the restoration of physiological levels of SHP-1 [39].
Ischemia-reperfusion (IR) is a complex inflammatory process that includes major oxidative stress
induced by ischemia and hypoxia [
41
]. Curek et al. found that astaxanthin treatment significantly
decreased the conversion of xanthine dehydrogenase (XDH) to xanthine oxidase (XO), which reduced
the level of oxidative stress in hepatocellular injury following IR in rats [
42
]. Another study showed
that apoptosis and autophagy caused by hepatic IR injury were attenuated by astaxanthin pretreatment
following a reduction in the release of ROS and inflammatory cytokines via the mitogen-activated
protein kinase (MAPK) pathway in mice [
43
]. With respect to IR, some studies reported the protective
effects of astaxanthin on brain and myocardial injury following IR [44–46].
In a clinical study, Park et al. studied the possible immune-enhancing, anti-oxidative, and
anti-inflammatory activity of astaxanthin in healthy adult females, and their results showed that
astaxanthin supplementation (2 and 8 mg/day) for eight weeks could decrease both the level of a
DNA oxidative damage biomarker and inflammation, and enhance the immune response [
47
]. The
enhancement of the immune response was also observed in dogs fed astaxanthin [
48
],
β
-carotene [
49
],
and lutein [50].
3.3. Lipid Metabolism
Astaxanthin has been reported to improve dyslipidemia and metabolic syndrome in animal
models [
51
–
53
]. In apoE knockout mice fed a high-fat and high-cholesterol diet, astaxanthin increased
the levels of LDL receptor (LDLR), 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase and
sterol regulatory element binding protein 2 (SREBP-2) in the liver, which might be responsible
for the hypocholesterolemic effect of astaxanthin [
53
]. In the same experiment, the expressions
of carnitine palmitoyl transferase 1 (CPT1), acetyl-CoA carboxylase
β
(ACACB) and acyl-CoA oxidase
(ACOX) mRNA were significantly increased by astaxanthin supplementation, suggesting that the
triglyceride-lowering effect of astaxanthin might be due to increased fatty acid
β
-oxidation in the
liver [
53
]. Iizuka et al. investigated the effects of astaxanthin on key molecules in cholesterol efflux from
macrophages. Their study revealed that astaxanthin did not modify peroxisome proliferator-activated
receptor (PPAR)-
γ
or liver X receptor (LXR)-
α
and -
β
levels, but it increased the expression of
ATP-binding cassette transporters (ABC) A1 and G1, thereby enhancing the cholesterol efflux from
macrophages [
54
]. In diet-induced obesity in mice, astaxanthin significantly lowered the plasma
triglyceride, alanine transaminase (ALT) and AST levels and increased the mRNA expression of
Mar. Drugs 2016, 14, 35 6 of 13
antioxidant genes regulated by Nrf2 in the liver [
55
]. In addition, astaxanthin decreased macrophage
infiltration and apoptosis of vascular cells in atherosclerotic plaques and provided stabilization of the
plaques in hyperlipidemic rabbits [56].
To determine the lipid metabolism-modulating effect of astaxanthin in humans, we conducted
a placebo-controlled study of astaxanthin administration at doses of 0, 6, 12, and 18 mg/day for
12 weeks with 61 non-obese subjects with mild hypertriglycemia. Multiple comparison tests showed
that 12 and 18 mg/day of astaxanthin significantly reduced the subjects’ triglyceride levels, and the
6- and 12-mg doses significantly increased HDL-cholesterol. The serum adiponectin level was also
increased by astaxanthin (12 or 18 mg/day), and the changes of adiponectin positively correlated
with the HDL-cholesterol changes [
57
]. The HDL-increasing effect of astaxanthin is thus of significant
interest, because a very limited number of dietary factors were suggested to increase HDL-cholesterol
concentrations [
58
]. Our study showed a markedly positive correlation between the percentage change
of adiponectin and that of the HDL-cholesterol level.
Although the mechanisms of astaxanthin-mediated adiponectin elevation are still poorly
understood, several investigations have shown that there is a significant and independent association
between serum adiponectin and HDL-cholesterol [
59
], and that adiponectin may directly regulate HDL
metabolism through a dual effect on the very-low-density lipoprotein (VLDL)-triglyceride pool and
hepatic lipase [
60
–
62
]. Another mechanism of the astaxanthin-induced increase in HDL-cholesterol may
be considered, albeit by an implicit action, due to the increased ABCA1 expression and cholesterol efflux
from macrophages through the actions of adiponectin increased by astaxanthin [
54
,
63
]. In contrast,
a recent meta-analysis of seven randomized controlled trials (including our trial [
57
]) failed to identify
a significant effect of astaxanthin on the plasma lipid profile, but a slight glucose-lowering effect was
observed [
64
]. The review’s authors mentioned that the study interpretation had limitations regarding
the heterogeneous populations, the varying concepts of the studies, and the different quantities of
astaxanthin used.
For the improvement of astaxanthin’s oral bioavailability, a novel prodrug of astaxanthin
(CDX-085) was developed (approximately 10-fold more potent compared to pure astaxanthin). The oral
administration of CDX-085 effectively lowered the total cholesterol and aortic arch atherosclerosis
in LDL receptor-deficient mice and the triglyceride levels in ApoE-deficient mice [
65
]. Khan et al.
reported that CDX-085 reduced thrombi and increased blood flow in a mouse model of oxidative
stress-induced thrombus, which appeared to be partially mediated by increased NO and decreased
peroxynitrite in endothelial cells and platelets [66].
Several studies have indicated that changes in the intracellular redox balance can modify lipid
metabolism. Indeed, oxidative stress was associated with lipid accumulation in adipose tissue [
67
,
68
]
and affected the regulation of hepatic lipid synthesis [
69
]. During exercise, ROS generation in skeletal
muscle increases along with the elevation of energy expenditure, and such ROS may also affect the
utilization of energy substrates in muscle, which leads to a disorder in the lipid metabolism.
Aoi et al.
reported that astaxanthin accelerated lipid utilization during exercise, leading to improved endurance
and an efficient reduction of body fat with training in mice [
70
]. An increase of fatty acyl-CoA
uptake into the mitochondria via CPT1 during exercise may be involved in the promotion of lipid
metabolism by the antioxidant activity of astaxanthin. According to these findings, astaxanthin is
expected to improve aerobic performance and body weight control by the modification of muscle
energy metabolism via its antioxidant effect.
3.4. Glucose Metabolism and Blood Pressure Control
Growing evidence suggests that diabetes and other disorders of glucose metabolism, such as
impaired glucose tolerance (IGT), needs to be taken into consideration as independent risk factors
for CVD [
71
–
73
]. Since oxidative stress promotes insulin resistance in obesity and type 2 diabetes,
it is crucial to find effective antioxidants for decreasing this threat. As mentioned above, a recent
meta-analysis of randomized controlled trials showed that astaxanthin supplementation slightly
Mar. Drugs 2016, 14, 35 7 of 13
lowered glucose levels [
64
]. Antidiabetic effects of astaxanthin could be explained by means of several
proposed mechanisms. In db/db mice, astaxanthin showed a protective effect against oxidative stress
and cytotoxicity in pancreatic
β
-cells [
74
]. Arunkumar et al. reported that astaxanthin activated the
hepatic IRS-PI3K-Akt signaling pathway and improved glucose metabolism in liver of high-fructose
and high-fat diet (HFFD)-fed mice [
75
]. Another study reported that astaxanthin treatment normalized
the activities of hexokinase, pyruvate kinase, glucose-6-phosphatase, fructose-1,6-bisphosphatase
and glycogen phosphorylase and increased the glycogen reserves in the liver of HFFD-fed mice [
76
].
In addition, astaxanthin decreased the HFFD-induced activation of serine kinases (JNK and ERK).
The anti-obesity effect of astaxanthin has been reported in high fat-fed mice; astaxanthin was shown
to increase fatty acid utilization [
52
], which can be responsible for its anti-diabetic effect. It is known
that fucoxanthin, a xanthophyll carotenoid present in brown seaweeds, induces uncoupling protein 1
(UCP1) in mitochondria, leading to the oxidation of fatty acids and heat production in white adipose
tissue [
77
]. Fucoxanthin supplementation was also tested in humans: a 16 week supplementation with
4 mg/day promoted weight loss, reduced body and liver fat content, and improved liver function
tests in obese non-diabetic women [
78
]. The mechanisms of anti-diabetic and anti-obesity effect of
astaxanthin remain unclear and has yet to be studied in clinical condition.
Studies in animal models of insulin resistance and fatty liver have demonstrated that hepatic
steatosis and endoplasmic reticulum (ER) stress are linked to each other [
79
]. A recent study showed
that disruption of ER homeostasis led to chronic unfolded protein response (UPR) and induced
inflammation and insulin resistance in the liver [
80
]. Hepatic ER stress can promote de novo lipogenesis,
while lipids can exacerbate ER stress, a situation that creates a vicious cycle. Bhuvaneswari et al.
reported that astaxanthin reduced hepatic ER stress, ROS production, phosphorylation of JNK, and
NF-
κ
B-mediated inflammation in HFFD-fed mice [
81
]. Astaxanthin may also have prevented the
progression of diabetic nephropathy by decreasing renal oxidative stress and by preventing renal
cell damage in db/db mice [
82
]. Another study reported that astaxanthin beneficially affected
both sucrose-induced elevations of blood pressure and insulin resistance at relatively high doses in
rats [
83
]. Astaxanthin may have an innate antihypertensive effect, because astaxanthin administration
lowered the blood pressure and delayed the incidence of stroke in spontaneously hypertensive
rats (SHRs)
[84,85];
however, this effect is not well-defined, and further studies to elucidate the
antihypertensive effect of astaxanthin should be performed.
Diabetes-induced cognitive deficit is a prevalent disease with substantial morbidity and mortality,
presenting a global health problem with serious economic burdens. Xu et al. performed Morris
water maze tests to test whether astaxanthin would affect the cognitive function of diabetic rats, and
their findings demonstrated that astaxanthin improved the escape latency, mean path length, mean
percentage of time spent in the target quadrant, and the number of times of crossing platform [
86
].
Xu et al. also demonstrated that astaxanthin ameliorated the caspase-3/9 expression and promoted
the expression of PI3K/Akt in the rat cerebral cortex and hippocampus [
86
]. Importantly, Japanese
researchers demonstrated that astaxanthin-rich H. pluvialis extract (6 mg or 12 mg/day for 12 weeks)
improved cognitive function in healthy aged humans [87].
4. Conclusions
Beyond the antioxidant ability of astaxanthin, many studies have established that astaxanthin
can exert preventive actions against atherosclerosis via its potential to improve inflammation, lipid
metabolism, and glucose metabolism. Table 1 shows the summary of above-mentioned investigations
into the anti-atherosclerotic effects of astaxanthin.
The current data may be promising in clinical conditions, but the therapeutic potential of this
natural compound in humans remains to be established. In addition to identifying the mechanisms
underlying astaxanthin’s bioactivity by basic research, much more epidemiological and clinical
evidence is needed. This review provides new insight into the use of astaxanthin as a preventive or
therapeutic strategy for atherosclerotic diseases.
Mar. Drugs 2016, 14, 35 8 of 13
Table 1.
Clinical studies and a meta-analysis investigating the potential anti-atherosclerotic effects
of astaxanthin.
Anti-Oxidation
Iwamoto et al.
(2000) [16]
Healthy volunteers
(n = 24)
Open labeled; 2 weeks;
1.8, 3.6, 14.4 or 21.6 mg/day
Ó LDL oxidation
Nakagawa et al.
(2011) [17]
Middle-aged and senior
subjects (n = 30)
Randomized, double-blind,
placebo controlled; 12 weeks;
6 or 12 mg/day
Ó phospholipid
peroxidation in
erythrocytes
Karppi et al.
(2007) [18]
Healthy non-smoking
males (n = 40)
Randomized, double-blind,
placebo controlled; 12 weeks;
8 mg/day
Ó plasma 12- and
15-hydroxy fatty acids
Choi et al.
(2011) [19]
Obese and overweight
adults (n = 23)
Randomized, double-blind;
3 weeks; 5 or 20 mg/day
Ó plasma MDA,
isoprastane Ò SOD, TAC
Anti-Inflammation
Park et al.
(2010) [47]
Healthy female college
students (n = 42)
Randomized, double-blind,
placebo controlled; 8 weeks;
0, 2 or 8 mg/day
Ó plasma 8-hydroxy-2
1
-
deoxyguanosine, CRP
Lipid Metabolism-Modulating
Yoshida et al.
(2010) [57]
Non-obese subjects with
mild hypertriglycemia
(n = 61)
Randomized,
placebo-controlled study;
12 weeks; 0, 6, 12 or
18 mg/day
Ó serum TG, Ò HDL-C,
adiponectin
Ursoniu et al.
(2015) [64]
Meta-analysis of
seven randomized
controlled studies
No significant effect on
plasma lipid profile
(LDL-C, HDL-C, TG)
Glucose Lowering
Ursoniu et al.
(2015) [64]
Meta-analysis of
seven randomized
controlled studies
Slight lowering effect on
plasma glucose
Acknowledgments:
This review work was supported in part by a Grant-in-Aid for Scientific Research (26461116)
from Japan’s Ministry of Education, Culture, Sports, Science and Technology (to H. Yoshida).
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
Ambati, R.R.; Phang, S.M.; Ravi, S.; Aswathanarayana, R.G. Astaxanthin: Sources, extraction, stability,
biological activities and its commercial applications–A review. Mar. Drugs 2014, 12, 128–152. [PubMed]
2.
Lorenz, R.T.; Cysewski, G.R. Commercial potential for haematococcus microalgae as a natural source of
astaxanthin. Trends Biotechnol. 2000, 18, 160–167. [CrossRef]
3.
Yuan, J.P.; Peng, J.; Yin, K.; Wang, J.H. Potential health-promoting effects of astaxanthin: A high-value
carotenoid mostly from microalgae. Mol. Nutr. Food Res. 2011, 55, 150–165. [CrossRef] [PubMed]
4.
Hussein, G.; Sankawa, U.; Goto, H.; Matsumoto, K.; Watanabe, H. Astaxanthin, a carotenoid with potential
in human health and nutrition. J. Nat. Prod. 2006, 69, 443–449. [CrossRef] [PubMed]
5.
Fassett, R.G.; Coombes, J.S. Astaxanthin in cardiovascular health and disease. Molecules
2012
, 17, 2030–2048.
[CrossRef] [PubMed]
6.
Guerin, M.; Huntley, M.E.; Olaizola, M. Haematococcus astaxanthin: Applications for human health and
nutrition. Trends Biotechnol. 2003, 21, 210–216. [CrossRef]
7.
Coral-Hinostroza, G.N.; Ytrestoyl, T.; Ruyter, B.; Bjerkeng, B. Plasma appearance of unesterified astaxanthin
geometrical E/Z and optical R/S isomers in men given single doses of a mixture of optical 3 and 3
1
R/S isomers
of astaxanthin fatty acyl diesters. Comp. Biochem. Physiol. C Toxicol. Pharmacol.
2004
, 139, 99–110. [CrossRef]
[PubMed]
Mar. Drugs 2016, 14, 35 9 of 13
8.
Okada, Y.; Ishikura, M.; Maoka, T. Bioavailability of astaxanthin in haematococcus algal extract: The effects
of timing of diet and smoking habits. Biosci. Biotechnol. Biochem. 2009, 73, 1928–1932. [CrossRef] [PubMed]
9.
Pashkow, F.J.; Watumull, D.G.; Campbell, C.L. Astaxanthin: A novel potential treatment for oxidative stress
and inflammation in cardiovascular disease. Am. J. Cardiol. 2008, 101, 58D–68D. [CrossRef] [PubMed]
10.
Goto, S.; Kogure, K.; Abe, K.; Kimata, Y.; Kitahama, K.; Yamashita, E.; Terada, H. Efficient radical trapping at
the surface and inside the phospholipid membrane is responsible for highly potent antiperoxidative activity
of the carotenoid astaxanthin. Biochim. Biophys. Acta 2001, 1512, 251–258. [CrossRef]
11.
Terao, J. Antioxidant activity of beta-carotene-related carotenoids in solution. Lipids
1989
, 24, 659–661.
[CrossRef] [PubMed]
12.
Lim, B.P.; Nagao, A.; Terao, J.; Tanaka, K.; Suzuki, T.; Takama, K. Antioxidant activity of xanthophylls on
peroxyl radical-mediated phospholipid peroxidation. Biochim. Biophys. Acta
1992
, 1126, 178–184. [PubMed]
13.
Palozza, P.; Krinsky, N.I. Astaxanthin and canthaxanthin are potent antioxidants in a membrane model.
Arch. Biochem. Biophys. 1992, 297, 291–295. [CrossRef]
14.
Ciccone, M.M.; Cortese, F.; Gesualdo, M.; Carbonara, S.; Zito, A.; Ricci, G.; De Pascalis, F.; Scicchitano, P.;
Riccioni, G. Dietary intake of carotenoids and their antioxidant and anti-inflammatory effects in
cardiovascular care. Mediators Inflamm. 2013, 2013. [CrossRef]
15.
Martin, H.D.; Ruck, C.; Schmidt, M.; Sell, S.; Beutner, S.; Mayer, B.; Walsh, R. Chemistry of carotenoid
oxidation and free radical reactions. Pure Appl. Chem. 1999, 71, 2253–2262. [CrossRef]
16.
Iwamoto, T.; Hosoda, K.; Hirano, R.; Kurata, H.; Matsumoto, A.; Miki, W.; Kamiyama, M.; Itakura, H.;
Yamamoto, S.; Kondo, K. Inhibition of low-density lipoprotein oxidation by astaxanthin. J. Atheroscler.
Thromb. 2000, 7, 216–222. [CrossRef] [PubMed]
17.
Nakagawa, K.; Kiko, T.; Miyazawa, T.; Carpentero Burdeos, G.; Kimura, F.; Satoh, A.; Miyazawa, T.
Antioxidant effect of astaxanthin on phospholipid peroxidation in human erythrocytes. Br. J. Nutr.
2011
, 105,
1563–1571. [CrossRef] [PubMed]
18.
Karppi, J.; Rissanen, T.H.; Nyyssonen, K.; Kaikkonen, J.; Olsson, A.G.; Voutilainen, S.; Salonen, J.T. Effects
of astaxanthin supplementation on lipid peroxidation. Int. J. Vitam. Nutr. Res.
2007
, 77, 3–11. [CrossRef]
[PubMed]
19.
Choi, H.D.; Kim, J.H.; Chang, M.J.; Kyu-Youn, Y.; Shin, W.G. Effects of astaxanthin on oxidative stress in
overweight and obese adults. Phytother. Res. 2011, 25, 1813–1818. [CrossRef] [PubMed]
20.
Itoh, K.; Chiba, T.; Takahashi, S.; Ishii, T.; Igarashi, K.; Katoh, Y.; Oyake, T.; Hayashi, N.; Satoh, K.;
Hatayama, I.; et al. An NRF2/small maf heterodimer mediates the induction of phase II detoxifying
enzyme genes through antioxidant response elements. Biochem. Biophys. Res. Commun.
1997
, 236, 313–322.
[CrossRef] [PubMed]
21.
Huang, Y.; Li, W.; Su, Z.Y.; Kong, A.T. The complexity of the NRF2 pathway: Beyond the antioxidant
response. J. Nutr. Biochem. 2015, 26, 1401–1413. [CrossRef] [PubMed]
22.
Tripathi, D.N.; Jena, G.B. Astaxanthin intervention ameliorates cyclophosphamide-induced oxidative stress,
DNA damage and early hepatocarcinogenesis in rat: Role of Nrf2, p53, p38 and phase-II enzymes. Mutat. Res.
2010, 696, 69–80. [CrossRef] [PubMed]
23.
Saw, C.L.; Yang, A.Y.; Guo, Y.; Kong, A.N. Astaxanthin and omega-3 fatty acids individually and in
combination protect against oxidative stress via the Nrf2-are pathway. Food Chem. Toxicol.
2013
, 62,
869–875. [CrossRef] [PubMed]
24.
Aviram, M. Introduction to the serial review on paraoxonases, oxidative stress, and cardiovascular diseases.
Free Radic. Biol. Med. 2004, 37, 1301–1303. [CrossRef] [PubMed]
25.
Augusti, P.R.; Quatrin, A.; Somacal, S.; Conterato, G.M.; Sobieski, R.; Ruviaro, A.R.; Maurer, L.H.;
Duarte, M.M.; Roehrs, M.; Emanuelli, T. Astaxanthin prevents changes in the activities of thioredoxin
reductase and paraoxonase in hypercholesterolemic rabbits. J. Clin. Biochem. Nutr.
2012
, 51, 42–49. [CrossRef]
[PubMed]
26.
Senti, M.; Tomas, M.; Anglada, R.; Elosua, R.; Marrugat, J.; Covas, M.I.; Fito, M. Interrelationship of smoking,
paraoxonase activity, and leisure time physical activity: A population-based study. Eur. J. Intern. Med.
2003
,
14, 178–184. [CrossRef]
27.
Baralic, I.; Djordjevic, B.; Dikic, N.; Kotur-Stevuljevic, J.; Spasic, S.; Jelic-Ivanovic, Z.; Radivojevic, N.;
Andjelkovic, M.; Pejic, S. Effect of astaxanthin supplementation on paraoxonase 1 activities and oxidative
stress status in young soccer players. Phytother. Res. 2013, 27, 1536–1542. [CrossRef] [PubMed]
Mar. Drugs 2016, 14, 35 10 of 13
28.
Djordjevic, B.; Baralic, I.; Kotur-Stevuljevic, J.; Stefanovic, A.; Ivanisevic, J.; Radivojevic, N.; Andjelkovic, M.;
Dikic, N. Effect of astaxanthin supplementation on muscle damage and oxidative stress markers in elite
young soccer players. J. Sports Med. Phys. Fit. 2012, 52, 382–392. [PubMed]
29.
Miller, Y.I.; Chang, M.K.; Binder, C.J.; Shaw, P.X.; Witztum, J.L. Oxidized low density lipoprotein and innate
immune receptors. Curr. Opin. Lipidol. 2003, 14, 437–445. [CrossRef] [PubMed]
30.
Kunjathoor, V.V.; Febbraio, M.; Podrez, E.A.; Moore, K.J.; Andersson, L.; Koehn, S.; Rhee, J.S.; Silverstein, R.;
Hoff, H.F.; Freeman, M.W. Scavenger receptors class A-I/II and cd36 are the principal receptors responsible
for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J. Biol. Chem.
2002, 277, 49982–49988. [CrossRef] [PubMed]
31. Ross, R. Atherosclerosis is an inflammatory disease. Am. Heart J. 1999, 138, S419–S420. [CrossRef]
32.
Chakraborti, S.; Mandal, M.; Das, S.; Mandal, A.; Chakraborti, T. Regulation of matrix metalloproteinases:
An overview. Mol. Cell. Biochem. 2003, 253, 269–285. [CrossRef] [PubMed]
33.
Watanabe, N.; Ikeda, U. Matrix metalloproteinases and atherosclerosis. Curr. Atheroscler. Rep.
2004
, 6,
112–120. [CrossRef] [PubMed]
34.
Chen, F.; Eriksson, P.; Hansson, G.K.; Herzfeld, I.; Klein, M.; Hansson, L.O.; Valen, G. Expression of matrix
metalloproteinase 9 and its regulators in the unstable coronary atherosclerotic plaque. Int. J. Mol. Med.
2005
,
15, 57–65. [CrossRef] [PubMed]
35.
Zeng, B.; Prasan, A.; Fung, K.C.; Solanki, V.; Bruce, D.; Freedman, S.B.; Brieger, D. Elevated circulating levels
of matrix metalloproteinase-9 and -2 in patients with symptomatic coronary artery disease. Intern. Med. J.
2005, 35, 331–335. [CrossRef] [PubMed]
36.
Kishimoto, Y.; Tani, M.; Uto-Kondo, H.; Iizuka, M.; Saita, E.; Sone, H.; Kurata, H.; Kondo, K. Astaxanthin
suppresses scavenger receptor expression and matrix metalloproteinase activity in macrophages.
Eur. J. Nutr.
2010, 49, 119–126. [CrossRef] [PubMed]
37.
Lee, S.J.; Bai, S.K.; Lee, K.S.; Namkoong, S.; Na, H.J.; Ha, K.S.; Han, J.A.; Yim, S.V.; Chang, K.; Kwon, Y.G.; et al.
Astaxanthin inhibits nitric oxide production and inflammatory gene expression by suppressing I-kappaB
kinase-dependent NF-kappaB activation. Mol. Cells 2003, 16, 97–105. [PubMed]
38.
Macedo, R.C.; Bolin, A.P.; Marin, D.P.; Otton, R. Astaxanthin addition improves human neutrophils function:
In vitro study. Eur. J. Nutr. 2010, 49, 447–457. [CrossRef] [PubMed]
39.
Speranza, L.; Pesce, M.; Patruno, A.; Franceschelli, S.; de Lutiis, M.A.; Grilli, A.; Felaco, M. Astaxanthin
treatment reduced oxidative induced pro-inflammatory cytokines secretion in U937: SHP-1 as a novel
biological target. Mar. Drugs 2012, 10, 890–899. [CrossRef] [PubMed]
40.
Tsui, H.W.; Hasselblatt, K.; Martin, A.; Mok, S.C.; Tsui, F.W. Molecular mechanisms underlying SHP-1 gene
expression. Eur. J. Biochem. 2002, 269, 3057–3064. [CrossRef] [PubMed]
41.
Sanderson, T.H.; Reynolds, C.A.; Kumar, R.; Przyklenk, K.; Huttemann, M. Molecular mechanisms of
ischemia-reperfusion injury in brain: Pivotal role of the mitochondrial membrane potential in reactive
oxygen species generation. Mol. Neurobiol. 2013, 47, 9–23. [CrossRef] [PubMed]
42.
Curek, G.D.; Cort, A.; Yucel, G.; Demir, N.; Ozturk, S.; Elpek, G.O.; Savas, B.; Aslan, M. Effect of astaxanthin
on hepatocellular injury following ischemia/reperfusion. Toxicology
2010
, 267, 147–153. [CrossRef] [PubMed]
43.
Li, J.; Wang, F.; Xia, Y.; Dai, W.; Chen, K.; Li, S.; Liu, T.; Zheng, Y.; Wang, J.; Lu, W.; et al. Astaxanthin
pretreatment attenuates hepatic ischemia reperfusion-induced apoptosis and autophagy via the ROS/MAPK
pathway in mice. Mar. Drugs 2015, 13, 3368–3387. [CrossRef] [PubMed]
44.
Lu, Y.P.; Liu, S.Y.; Sun, H.; Wu, X.M.; Li, J.J.; Zhu, L. Neuroprotective effect of astaxanthin on H
2
O
2
-induced
neurotoxicity
in vitro
and on focal cerebral ischemia
in vivo
. Brain Res.
2010
, 1360, 40–48. [CrossRef] [PubMed]
45.
Shen, H.; Kuo, C.C.; Chou, J.; Delvolve, A.; Jackson, S.N.; Post, J.; Woods, A.S.; Hoffer, B.J.; Wang, Y.;
Harvey, B.K. Astaxanthin reduces ischemic brain injury in adult rats. FASEB J.
2009
, 23, 1958–1968. [CrossRef]
[PubMed]
46.
Lauver, D.A.; Lockwood, S.F.; Lucchesi, B.R. Disodium disuccinate astaxanthin (cardax) attenuates
complement activation and reduces myocardial injury following ischemia/reperfusion. J. Pharmacol.
Exp. Ther. 2005, 314, 686–692. [CrossRef] [PubMed]
47.
Park, J.S.; Chyun, J.H.; Kim, Y.K.; Line, L.L.; Chew, B.P. Astaxanthin decreased oxidative stress and
inflammation and enhanced immune response in humans. Nutr. Metab. (Lond.)
2010
, 7, 18. [CrossRef]
[PubMed]
Mar. Drugs 2016, 14, 35 11 of 13
48.
Chew, B.P.; Mathison, B.D.; Hayek, M.G.; Massimino, S.; Reinhart, G.A.; Park, J.S. Dietary astaxanthin
enhances immune response in dogs. Vet. Immunol. Immunopathol. 2011, 140, 199–206. [CrossRef] [PubMed]
49.
Chew, B.P.; Park, J.S.; Wong, T.S.; Kim, H.W.; Weng, B.B.; Byrne, K.M.; Hayek, M.G.; Reinhart, G.A. Dietary
beta-carotene stimulates cell-mediated and humoral immune response in dogs. J. Nutr.
2000
, 130, 1910–1913.
[PubMed]
50.
Kim, H.W.; Chew, B.P.; Wong, T.S.; Park, J.S.; Weng, B.B.; Byrne, K.M.; Hayek, M.G.; Reinhart, G.A. Dietary
lutein stimulates immune response in the canine. Vet. Immunol. Immunopathol.
2000
, 74, 315–327. [CrossRef]
51.
Hussein, G.; Nakagawa, T.; Goto, H.; Shimada, Y.; Matsumoto, K.; Sankawa, U.; Watanabe, H. Astaxanthin
ameliorates features of metabolic syndrome in SHR/NDmcr-cp. Life Sci.
2007
, 80, 522–529. [CrossRef]
[PubMed]
52.
Ikeuchi, M.; Koyama, T.; Takahashi, J.; Yazawa, K. Effects of astaxanthin in obese mice fed a high-fat diet.
Biosci. Biotechnol. Biochem. 2007, 71, 893–899. [CrossRef] [PubMed]
53.
Yang, Y.; Seo, J.M.; Nguyen, A.; Pham, T.X.; Park, H.J.; Park, Y.; Kim, B.; Bruno, R.S.; Lee, J. Astaxanthin-rich
extract from the green alga haematococcus pluvialis lowers plasma lipid concentrations and enhances
antioxidant defense in apolipoprotein E knockout mice. J. Nutr.
2011
, 141, 1611–1617. [CrossRef] [PubMed]
54.
Iizuka, M.; Ayaori, M.; Uto-Kondo, H.; Yakushiji, E.; Takiguchi, S.; Nakaya, K.; Hisada, T.; Sasaki, M.;
Komatsu, T.; Yogo, M.; et al. Astaxanthin enhances ATP-binding cassette transporter A1/G1 expressions and
cholesterol efflux from macrophages. J. Nutr. Sci. Vitaminol. (Tokyo) 2012, 58, 96–104. [CrossRef] [PubMed]
55.
Yang, Y.; Pham, T.X.; Wegner, C.J.; Kim, B.; Ku, C.S.; Park, Y.K.; Lee, J.Y. Astaxanthin lowers plasma tag
concentrations and increases hepatic antioxidant gene expression in diet-induced obesity mice. Br. J. Nutr.
2014, 112, 1797–1804. [CrossRef] [PubMed]
56.
Li, W.; Hellsten, A.; Jacobsson, L.S.; Blomqvist, H.M.; Olsson, A.G.; Yuan, X.M. Alpha-tocopherol and
astaxanthin decrease macrophage infiltration, apoptosis and vulnerability in atheroma of hyperlipidaemic
rabbits. J. Mol. Cell. Cardiol. 2004, 37, 969–978. [CrossRef] [PubMed]
57.
Yoshida, H.; Yanai, H.; Ito, K.; Tomono, Y.; Koikeda, T.; Tsukahara, H.; Tada, N. Administration of
natural astaxanthin increases serum HDl-cholesterol and adiponectin in subjects with mild hyperlipidemia.
Atherosclerosis 2010, 209, 520–523. [CrossRef] [PubMed]
58.
Siri-Tarino, P.W. Effects of diet on high-density lipoprotein cholesterol. Curr. Atheroscler. Rep.
2011
, 13,
453–460. [CrossRef] [PubMed]
59.
Cnop, M.; Havel, P.J.; Utzschneider, K.M.; Carr, D.B.; Sinha, M.K.; Boyko, E.J.; Retzlaff, B.M.; Knopp, R.H.;
Brunzell, J.D.; Kahn, S.E. Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma
lipoproteins: Evidence for independent roles of age and sex. Diabetologia 2003, 46, 459–469. [PubMed]
60.
Ng, T.W.; Watts, G.F.; Farvid, M.S.; Chan, D.C.; Barrett, P.H. Adipocytokines and VLDL metabolism:
Independent regulatory effects of adiponectin, insulin resistance, and fat compartments on VLDL
apolipoprotein B-100 kinetics? Diabetes 2005, 54, 795–802. [CrossRef] [PubMed]
61.
Chan, D.C.; Barrett, P.H.; Ooi, E.M.; Ji, J.; Chan, D.T.; Watts, G.F. Very low density lipoprotein metabolism
and plasma adiponectin as predictors of high-density lipoprotein apolipoprotein AI kinetics in obese and
nonobese men. J. Clin. Endocrinol. Metab. 2009, 94, 989–997. [CrossRef] [PubMed]
62.
Schneider, J.G.; von Eynatten, M.; Schiekofer, S.; Nawroth, P.P.; Dugi, K.A. Low plasma adiponectin levels
are associated with increased hepatic lipase activity in vivo. Diabetes Care 2005, 28, 2181–2186. [PubMed]
63.
Tsubakio-Yamamoto, K.; Matsuura, F.; Koseki, M.; Oku, H.; Sandoval, J.C.; Inagaki, M.; Nakatani, K.;
Nakaoka, H.; Kawase, R.; Yuasa-Kawase, M.; et al. Adiponectin prevents atherosclerosis by increasing
cholesterol efflux from macrophages. Biochem. Biophys. Res. Commun.
2008
, 375, 390–394. [CrossRef]
[PubMed]
64.
Ursoniu, S.; Sahebkar, A.; Serban, M.C.; Banach, M. Lipid profile and glucose changes after supplementation
with astaxanthin: A systematic review and meta-analysis of randomized controlled trials. Arch. Med. Sci.
2015, 11, 253–266. [CrossRef] [PubMed]
65.
Ryu, S.K.; King, T.J.; Fujioka, K.; Pattison, J.; Pashkow, F.J.; Tsimikas, S. Effect of an oral astaxanthin prodrug
(CDX-085) on lipoprotein levels and progression of atherosclerosis in IDIR (
´
/
´
) and ApoE (
´
/
´
) mice.
Atherosclerosis 2012, 222, 99–105. [CrossRef] [PubMed]
66.
Khan, S.K.; Malinski, T.; Mason, R.P.; Kubant, R.; Jacob, R.F.; Fujioka, K.; Denstaedt, S.J.; King, T.J.;
Jackson, H.L.; Hieber, A.D.; et al. Novel astaxanthin prodrug (CDX-085) attenuates thrombosis in a mouse
model. Thromb. Res. 2010, 126, 299–305. [CrossRef] [PubMed]
Mar. Drugs 2016, 14, 35 12 of 13
67.
Furukawa, S.; Fujita, T.; Shimabukuro, M.; Iwaki, M.; Yamada, Y.; Nakajima, Y.; Nakayama, O.;
Makishima, M.; Matsuda, M.; Shimomura, I. Increased oxidative stress in obesity and its impact on metabolic
syndrome. J. Clin. Investig. 2004, 114, 1752–1761. [CrossRef] [PubMed]
68.
Fujita, K.; Nishizawa, H.; Funahashi, T.; Shimomura, I.; Shimabukuro, M. Systemic oxidative stress is
associated with visceral fat accumulation and the metabolic syndrome. Circ. J.
2006
, 70, 1437–1442. [CrossRef]
[PubMed]
69.
Napolitano, M.; Rivabene, R.; Avella, M.; Amicone, L.; Tripodi, M.; Botham, K.M.; Bravo, E. Oxidation affects
the regulation of hepatic lipid synthesis by chylomicron remnants. Free Radic. Biol. Med.
2001
, 30, 506–515.
[CrossRef]
70.
Aoi, W.; Naito, Y.; Takanami, Y.; Ishii, T.; Kawai, Y.; Akagiri, S.; Kato, Y.; Osawa, T.; Yoshikawa, T. Astaxanthin
improves muscle lipid metabolism in exercise via inhibitory effect of oxidative CPT I modification.
Biochem. Biophys. Res. Commun. 2008, 366, 892–897. [CrossRef] [PubMed]
71.
The DECODE study group on behalf of the Europe an Diabetes Epidemiology Group. Glucose tolerance
and mortality: comparison of WHO and American Diabetic Association diagnostic criteria. Lancet
1999
, 354,
617–621.
72.
Saydah, S.H.; Loria, C.M.; Eberhardt, M.S.; Brancati, F.L. Subclinical states of glucose intolerance and risk of
death in the U.S. Diabetes Care 2001, 24, 447–453. [CrossRef] [PubMed]
73.
Ning, F.; Tuomilehto, J.; Pyorala, K.; Onat, A.; Soderberg, S.; Qiao, Q.; Group, D.S. Cardiovascular disease
mortality in europeans in relation to fasting and 2-h plasma glucose levels within a normoglycemic range.
Diabetes Care 2010, 33, 2211–2216. [CrossRef] [PubMed]
74.
Uchiyama, K.; Naito, Y.; Hasegawa, G.; Nakamura, N.; Takahashi, J.; Yoshikawa, T. Astaxanthin protects
beta-cells against glucose toxicity in diabetic db/db mice. Redox. Rep.
2002
, 7, 290–293. [CrossRef] [PubMed]
75.
Arunkumar, E.; Bhuvaneswari, S.; Anuradha, C.V. An intervention study in obese mice with astaxanthin,
a marine carotenoid–effects on insulin signaling and pro-inflammatory cytokines. Food Funct.
2012
, 3,
120–126. [CrossRef] [PubMed]
76.
Bhuvaneswari, S.; Anuradha, C.V. Astaxanthin prevents loss of insulin signaling and improves glucose
metabolism in liver of insulin resistant mice. Can. J. Physiol. Pharmacol.
2012
, 90, 1544–1552. [CrossRef]
[PubMed]
77.
Gammone, M.A.; D’Orazio, N. Anti-obesity activity of the marine carotenoid fucoxanthin. Mar. Drugs
2015
,
13, 2196–2214. [CrossRef] [PubMed]
78.
Abidov, M.; Ramazanov, Z.; Seifulla, R.; Grachev, S. The effects of Xanthigen in the weight management of
obese premenopausal women with non-alcoholic fatty liver disease and normal liver fat. Diabetes Obes. Metab.
2010, 12, 72–81. [CrossRef] [PubMed]
79.
Boden, G.; Duan, X.; Homko, C.; Molina, E.J.; Song, W.; Perez, O.; Cheung, P.; Merali, S. Increase in
endoplasmic reticulum stress-related proteins and genes in adipose tissue of obese, insulin-resistant
individuals. Diabetes 2008, 57, 2438–2444. [CrossRef] [PubMed]
80.
Yalcin, A.; Hotamisligil, G.S. Impact of ER protein homeostasis on metabolism. Diabetes
2013
, 62, 691–693.
[CrossRef] [PubMed]
81.
Bhuvaneswari, S.; Yogalakshmi, B.; Sreeja, S.; Anuradha, C.V. Astaxanthin reduces hepatic endoplasmic
reticulum stress and nuclear factor-kappab-mediated inflammation in high fructose and high fat diet-fed
mice. Cell. Stress Chaperones 2014, 19, 183–191. [CrossRef] [PubMed]
82.
Naito, Y.; Uchiyama, K.; Aoi, W.; Hasegawa, G.; Nakamura, N.; Yoshida, N.; Maoka, T.; Takahashi, J.;
Yoshikawa, T. Prevention of diabetic nephropathy by treatment with astaxanthin in diabetic db/db mice.
Biofactors 2004, 20, 49–59. [CrossRef] [PubMed]
83.
Preuss, H.G.; Echard, B.; Yamashita, E.; Perricone, N.V. High dose astaxanthin lowers blood pressure and
increases insulin sensitivity in rats: Are these effects interdependent? Int. J. Med. Sci.
2011
, 8, 126–138.
[CrossRef] [PubMed]
84.
Hussein, G.; Nakamura, M.; Zhao, Q.; Iguchi, T.; Goto, H.; Sankawa, U.; Watanabe, H. Antihypertensive and
neuroprotective effects of astaxanthin in experimental animals. Biol. Pharm. Bull.
2005
, 28, 47–52. [CrossRef]
[PubMed]
85.
Yanai, H.; Ito, K.; Yoshida, H.; Tada, N. Antihypertensive effects of astaxanthin. Integr. Blood Press. Control
2008, 1, 1–3. [PubMed]
Mar. Drugs 2016, 14, 35 13 of 13
86.
Xu, L.; Zhu, J.; Yin, W.; Ding, X. Astaxanthin improves cognitive deficits from oxidative stress, nitric oxide
synthase and inflammation through upregulation of PI3K/Akt in diabetes rat. Int. J. Clin. Exp. Pathol.
2015
,
8, 6083–6094. [PubMed]
87.
Katagiri, M.; Satoh, A.; Tsuji, S.; Shirasawa, T. Effects of astaxanthin-rich haematococcus pluvialis extract on
cognitive function: A randomised, double-blind, placebo-controlled study. J. Clin. Biochem. Nutr.
2012
, 51,
102–107. [CrossRef] [PubMed]
©
2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons by Attribution
(CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
