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Potential Anti-Atherosclerotic Properties of Astaxanthin


Abstract and Figures

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.
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marine drugs
Potential Anti-Atherosclerotic Properties
of Astaxanthin
Yoshimi Kishimoto
, Hiroshi Yoshida
* and Kazuo Kondo
Endowed Research Department “Food for Health”, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku,
Tokyo 112-8610, Japan; (Y.K.); (K.K.)
Department of Laboratory Medicine, Jikei University Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa,
Chiba 277-8567, Japan
Institute of Life Innovation Studies, Toyo University, 1-1-1 Izumino, Itakura-machi, Ora-gun,
Gunma 374-0193, Japan
* Correspondence:; 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
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.
astaxanthin; oxidative stress; inflammation; lipid metabolism; glucose metabolism;
atherosclerosis; cardiovascular disease
1. Introduction
Astaxanthin (3,3
-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
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 [
]. 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 [
]. 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
taxanthin, and therefore this type is most largely ingested by humans [
Human cannot synthesize astaxanthin, and the ingested astaxanthin cannot be converted to vitamin A;
excessive intake of astaxanthin will thus not cause hypervitaminosis A [
]. 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 [
]. 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 [
]. 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 [
]. The presence of dietary fat enhances the assimilation of astaxanthin
in the small intestine [
]. 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 [
] (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
and rat liver microsomes [13]. Goto et al. reported in 2001 that astaxanthin was approximately
liposome peroxidationinducedbyADP
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
hydrogenbonded fivemembered ring, increasing the hydrophobicity of astaxanthin. It is well
those with good antioxidative but also prooxidative properties; and (3) those with strong
antioxidativeand without anyprooxidative properties. Astaxanthinwas categorized asclass(3),
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
O(2,2azobis4methoxy2,4dimethylvaleronitrile) in vitro.Toconfirmthe
antioxidant effect of astaxanthin ex vivo, we recruited 24 healthyadults to consume astaxanthin
Nakagawa et al. reported the
efficacy of astaxanthin supplementation (6 and 12 mg/day) on
of administration, decreased PLOOH levels and increased astaxanthin in erythrocytes were
adults, supplemental astaxanthin (5 and 20 mg/day) reduced biomarkers of oxidative stress
including malondialdehyde (MDA) and isoprostane, and increased superoxide dismutase (SOD)
Figure 1. Transmembrane orientation of astaxanthin [1,9].
Mar. Drugs 2016, 14, 35 3 of 13
Astaxanthin is reported to be more effective than
-carotene in preventing lipid peroxidation in
solution [
] and various biomembrane models such as egg yolk phosphatidylcholine liposomes [
and rat liver microsomes [
]. Goto et al. reported in 2001 that astaxanthin was approximately
twofold more effective than
-carotene in the inhibition of liposome peroxidation induced by ADP
and Fe
]. 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 [
]. 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
-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 [
]. Compared to
-tocopherol and lutein, astaxanthin showed a greater antioxidative effect on LDL oxidation induced
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 [
]. 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 [
]. 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) [
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 [
]. 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 [
]. 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 [
]. In
hypercholesterolemic rabbits, astaxanthin prevented protein oxidation and changes in PON1 and
thioredoxin reductase (TrxR-1) activities [
]. 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
]. It was reported
that regular physical activity might increase PON1 activity [
]. 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 [
]. 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 [
]. 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 [
]. Additionally,
in inflammation states, macrophages produce excess amounts of matrix-degrading enzymes,
pro-inflammatory cytokines/chemokines, nitric oxide (NO), and cyclooxygenase-2 (COX-2) [
Matrix metalloproteinases (MMPs), a family of Zn
-dependent endopeptidases, are responsible for
the degradation of most extracellular matrix proteins, and they mediate tissue remodeling in various
pathologic conditions [
]. 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 [3335].
Mar.Drugs2016,14,x 5of13
In our previous study, astaxanthin remarkably suppressed the expression of the scavenger
receptorsSRAandCD36)theactivityandtheexpressionofMMPs,andthe mRNAexpression of
various inflammatory mediators, i.e., tumor necrosis factor (TNF)‐α, interleukin (IL)1β, IL6,
the antioxidant property of astaxanthin might account for its inhibitory effects on macrophage
inflammation through the inhibition of nuclear factorkappa B (NF‐κB) activation. The
proinflammatory cytokines, prostaglandins, and NO produced by activated macrophages play
critical roles in atherogenesis.
The inhibition of proinflammatory cytokine secretion from
macrophagesmight be oneofthemechanisms mediatingthebeneficialeffects ofantioxidantson
proinflammatory mediators such as prostaglandin E2, TNF‐α, and IL1β by suppressing
NF‐κBactivationinbothlipopolysaccharide (LPS)stimulatedRAW264.7cellsand
Macedo et al. showed that asta xanthin significantly reduced the production of
revealed that astaxanthin enhanced neutrophil phagocytic and microbicidal capacity and
superoxide anion and hydrogen peroxide production, which might be mediated by
on its antioxidant activity. In addition, astaxanthin treatment reduced the secretion of
proinflammatorycytokines (IL1β, IL6 and TNF‐α) in H
stimulated U937 mononuclearcells,
and this property was elicited by a restoration of the basal SHP1 protein expression level and
negative regulator of inflammatory cytokine signaling, and SHP1 deficiency in mice causes
spontaneous inflammation and autoimmunity [40]; the authors of that study proposed that
therestorationofphysiologica llevelsofSHP1[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)-
, interleukin (IL)-1
, IL-6,
inducible nitric oxide synthase (iNOS), and COX-2, in THP-1 macrophages [
]. 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-
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-
, and IL-1
by suppressing I
B-dependent NF-
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-
and IL-6) in LPS-stimulated neutrophils [
]. 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 [
]. These studies indicated that the anti-inflammatory
effects of astaxanthin through its suppression of NF-
B activation may be based on its antioxidant
activity. In addition, astaxanthin treatment reduced the secretion of pro-inflammatory cytokines (IL-1
IL-6 and TNF-
) in H
-stimulated U937 mononuclear cells, and this property was elicited by a
restoration of the basal SHP-1 protein expression level and reduced NF-
B (p65) nuclear expression [
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 [
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 [
]. 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 [
]. 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 [
]. With respect to IR, some studies reported the protective
effects of astaxanthin on brain and myocardial injury following IR [4446].
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 [
]. The
enhancement of the immune response was also observed in dogs fed astaxanthin [
-carotene [
and lutein [50].
3.3. Lipid Metabolism
Astaxanthin has been reported to improve dyslipidemia and metabolic syndrome in animal
models [
]. 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 [
]. In the same experiment, the expressions
of carnitine palmitoyl transferase 1 (CPT1), acetyl-CoA carboxylase
(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
-oxidation in the
liver [
]. 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)-
or liver X receptor (LXR)-
and -
levels, but it increased the expression of
ATP-binding cassette transporters (ABC) A1 and G1, thereby enhancing the cholesterol efflux from
macrophages [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
], and that adiponectin may directly regulate HDL
metabolism through a dual effect on the very-low-density lipoprotein (VLDL)-triglyceride pool and
hepatic lipase [
]. 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 [
]. In contrast,
a recent meta-analysis of seven randomized controlled trials (including our trial [
]) failed to identify
a significant effect of astaxanthin on the plasma lipid profile, but a slight glucose-lowering effect was
observed [
]. 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 [
]. 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 [
and affected the regulation of hepatic lipid synthesis [
]. 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 [
]. 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 [
]. 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 [
]. 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
-cells [
]. 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 [
]. 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 [
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 [
], 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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
B-mediated inflammation in HFFD-fed mice [
]. 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 [
]. Another study reported that astaxanthin beneficially affected
both sucrose-induced elevations of blood pressure and insulin resistance at relatively high doses in
rats [
]. 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)
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 [
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 [
]. 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.
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
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
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
deoxyguanosine, CRP
Lipid Metabolism-Modulating
Yoshida et al.
(2010) [57]
Non-obese subjects with
mild hypertriglycemia
(n = 61)
placebo-controlled study;
12 weeks; 0, 6, 12 or
18 mg/day
Ó serum TG, Ò HDL-C,
Ursoniu et al.
(2015) [64]
Meta-analysis of
seven randomized
controlled studies
No significant effect on
plasma lipid profile
Glucose Lowering
Ursoniu et al.
(2015) [64]
Meta-analysis of
seven randomized
controlled studies
Slight lowering effect on
plasma glucose
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.
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... Xanthophylls, one major category of carotenoids (the other group is carotenes), is a class of oxygen-containing pigments widely present in nature [23]. Mounting evidence suggested the antioxidant and anti-inflammatory properties of xanthophylls, and the potential to regulate lipid metabolism and mediate endothelial dysfunction [24][25][26]. In this regard, xanthophylls have been proposed as adjunct therapies to prevent and slow the progression of atherosclerosis. ...
... Basically, the underlying principles for antioxidant defense in atherosclerosis involve three levels 1) prevention, a first line of defense against ROS formation via quenching singlet oxygen or scavenging radicals; 2) interception, the process of deactivation via radical chain-breaking, or via transferring the attacking species into less harmful products, as well as via transporting oxidizing equivalents away from the sensitive target sites, e.g. from the membrane to cytosol; 3) repair, a restitution or replenishment for various phospholipid oxidation substances and injured DNA, etc. [95,96]. The long conjugated double bonds in a polyene chain allows xanthophylls to quench singlet oxygen and clear radicals so that the chain reaction could be interrupted [24]. Besides, its unique molecular structure with the hydroxy group or epoxides on the terminal ring enables them to interact with water-soluble radicals and deliver them away from highly sensitive sites, normally from the hydrophobic membrane, facilitating the antioxidant effects both at surface and interior part of cell [24,95]. ...
... The long conjugated double bonds in a polyene chain allows xanthophylls to quench singlet oxygen and clear radicals so that the chain reaction could be interrupted [24]. Besides, its unique molecular structure with the hydroxy group or epoxides on the terminal ring enables them to interact with water-soluble radicals and deliver them away from highly sensitive sites, normally from the hydrophobic membrane, facilitating the antioxidant effects both at surface and interior part of cell [24,95]. ...
... not reported NF-κB  TNF-, IL-6, IL-1 prostaglandin E, inducible nitric oxide synthase (iNOS), and COX-2, in macrophages and neutrophils,  inflammation in vivo [88]. ...
... Several trials with dietary AST Preventive effects against atherosclerosis [88]; neuroprotective against cognitive impairment [91]; improved visual acuity and retinal blood flow [92]; reduced the signs of skin aging [93]. AST can neither be converted into vitamin A nor synthesized de novo by animals; 269 therefore, it must be consumed in the diet [94]. ...
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Carotenoids are natural products regulated by the food sector, currently used as feed dyes and as antioxidants in dietary supplements and composing functional foods for human consumption. Of the nearly one thousand carotenoids described to date, only retinoids, derived from beta carotene, have the status of drug and are regulated by the pharmaceutical sector. In this review, we address a novel field: the transformation of xanthophylls-particularly the highly marketed astaxanthin and the practically unknown bacterioruberin-in therapeutic agents by altering their pharmacokinetics, biodistribution, and pharmacodynamics through their formulation as nanomedicines. The antioxidant activity of xanthophylls is mediated by routes different from those of the classical oral anti-inflammatory drugs such as corticosteroids and non-steroidal anti-inflammatory 19 drugs (NSAIDs): remarkably, xanthophylls lack therapeutic activity but also lack toxicity. Formulated as nanomedicines, xanthophylls gain therapeutic activity, by mechanisms other than increased bioavailability. Loaded into ad-hoc tailored nanoparticles to protect their structure throughout storage and during gastrointestinal transit or skin penetration, xanthophylls can be targeted and delivered to selected inflamed cell groups, achieving a massive intracellular concentration after endocytosis of small doses of the formulation. Most first reports showing the activities of oral and topical anti-inflammatories xanthophyll-based nanomedicines against chronic diseases such as inflammatory bowel disease, psoriasis, atopic dermatitis, and dry eye disease emerged between 2020 and 2023. Here we discuss in detail their preclinical performance-mostly targeted vesicular and polymeric nanoparticles-on cellular models and in vivo. The results, although preliminary, are auspicious enough to speculate their potential use upon oral or topical administration in the treatment of chronic inflammatory diseases.
... The biological activity of Asta is usually related to the reduction of oxidative damage markers, and the production of inflammation is strongly related to oxidative stress. More and more studies have proven that Asta has sound anti-inflammatory effects [13]. Relevant studies have shown that F-Asta could effectively treat enteritis [14]. ...
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This paper aims to explore the effect and mechanism of water-soluble astaxanthin succinate diester (Asta-SD) on ulcerative colitis (UC) induced by dextran sodium sulfate in zebrafish and C57BL/6J mice. Asta-SD was synthesized with hydrophilic fatty acid succinic anhydride and the hydroxyl groups at the ends of F-Asta were synthesized by esterifying. Through the construction of a zebrafish intestinal inflammation model, it was found that Asta-SD could effectively reduce the levels of ROS and increase the number of healthy intestinal lysosomes in zebrafish. After continuous gavage of Asta-SD for seven days, the body weight, disease activity index, colonic length, colonic histopathology, expression of inflammatory factors, and intestinal flora of the mice were measured. The results showed that Asta-SD could significantly alleviate weight loss and colonic shrinkage, as well as reducing pro-inflammatory cytokines and recess injury in UC mice. The 16S rRNA gene sequencing showed that Asta-SD significantly increased the beneficial bacteria (Lactobacillus, Anaerotruncus) and decreased the relative abundance of pathogenic bacteria, effectively maintaining intestinal microbiota homeostasis in mice. Based on Pearson analysis, Bacteroides, Parabacteroides, and Butyrimionas were expected to be associated with the significant difference in the expression of inflammatory factors between the UC and the corresponding host. Thus, Asta-SD significantly improves UC and maintains intestinal microbiota homeostasis.
... ASX is a premium, safe, and effective feed additive with multiple biological functions such as anti-oxidation, anti-inflammation, and coloration, and thus has been used in aquaculture and livestock breeding (Kumar et al. 2021;Stachowiak and Szulc 2021). ASX is a left-handed trans structure (3S,3'S), in which a longer conjugated double bond possesses a more active electronic effect and is more prone to neutralizing free radicals, exhibiting stronger antioxidant activity (Brotosudarmo et al. 2020;Higuera-Ciapara et al. 2006;Kishimoto et al. 2016). In this study, we compared high-ASX and low-ASX effects on feeding anguillarum. ...
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Astaxanthin (ASX) shows strong antioxidant property and is widely used as a fish feed additive. However, the underlying molecular mechanism of how ASX improves the ability of fish to resist bacterial infection remains largely unknown. To investigate the effects of dietary ASX from Haematococcus pluvialis on pearl gentian grouper, transcriptome combined with intestinal microbe analysis was conducted. The results of RNA-Seq analysis demonstrated that compared with the control group, the differently expressed genes of ASX-treated group were enriched in AMPK, autophagy, HIF-1, and PI3K-Akt signaling pathway. 16 s rDNA of intestinal microbiota analysis revealed that the dominant bacteria in the intestine of fish fed with ASX were Proteobacteria and Bacteroidetes. Moreover, ASX-fed significantly reduced the level of reactive oxygen species (ROS) and NF-κb mRNA expression in fish with bacterial infection. ASX treatment also prolonged the survival time of fish in the infection condition. Our work reveals that ASX systematically improves the antibacterial ability of grouper by regulating AMPK, autophagy, HIF-1, and PI3K-Akt signaling pathway and assisting in the colonization of intestinal dominant flora.
... Astaxanthin is a keto-carotenoid derived from Hematococcus pluvialis, which is used as a health binder with Sirtuin1 (SIRT1) supplements for improving muscle strength and also has therapeutic effects on atherosclerosis and macular degeneration [227][228][229][230]. Mingming et al. reported that Astaxanthin binds with SIRT1, inhibits Nrf2-modulated oxidative stress, and regulates NF-κB-related inflammatory responses in CS-induced emphysema mouse models and human bronchial epithelial cells [231]. ...
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Cigarette smoke (CS) poses a significant risk factor for respiratory, vascular, and organ diseases owing to its high content of harmful chemicals and reactive oxygen species (ROS). These substances are known to induce oxidative stress, inflammation, apoptosis, and senescence due to their exposure to environmental pollutants and the presence of oxidative enzymes. The lung is particularly susceptible to oxidative stress. Persistent oxidative stress caused by chronic exposure to CS can lead to respiratory diseases such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (PF), and lung cancer. Avoiding exposure to environmental pollutants, like cigarette smoke and air pollution, can help mitigate oxidative stress. A comprehensive understanding of oxidative stress and its impact on the lungs requires future research. This includes identifying strategies for preventing and treating lung diseases as well as investigating the underlying mechanisms behind oxidative stress. Thus, this review aims to investigate the cellular processes induced by CS, specifically inflammation, apoptosis, senescence, and their associated biomarkers. Furthermore, this review will delve into the alveolar response provoked by CS, emphasizing the roles of potential therapeutic target markers and strategies in inflammation and oxidative stress.
Ferroptosis is a form of regulated cell death closely associated with oxidative stress and mitochondrial dysfunction and is characterised by the accumulation of reactive oxygen species (ROS) and lipid species and iron overload. Damage to human lens epithelial cells (LECs) is associated with age-related cataract progression. Astaxanthin (ATX), a carotenoid with natural antioxidant properties, counteracts ferroptosis in the treatment of various degenerative diseases. However, this mechanism has not been reported with respect to cataract treatment. In this study, the differential expression levels of glutathione peroxidase 4 (GPX4) in the lens of young and aged mice were analysed. Continuous ATX supplementation for 8 months upregulated GPX4 expression in the mouse LECs and delayed the progression of ferroptosis. Upon treatment with erastin, ROS and malondialdehyde accumulated and the mitochondrial membrane potential decreased. At the same time, the expressions of GPX4, SLC7A11, and ferritin were suppressed in human LECs. All of these phenomena were partially reversed by ATX and Fer-1, a ferroptosis inhibitor. This study confirmed that the ATX-mediated targeting of GPX4 might alleviate human LECs damage by inhibiting ferroptosis and ameliorating oxidative stress and that this could represent a promising therapeutic approach for age-related cataract.
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The growth, immune response, and reproductive performance of broodstock of Nile tilapia ( Oreochromis niloticus ) under winter stress conditions were investigated the effects of supplementary diets with astaxanthin-enriched bacterium, Paracoccus carotinifaciens . Throughout an eight-week period in the winter season, male and female tilapia were fed with diets containing different levels of P. carotinifaciens dietary supplementation: 0 g/kg (T1; control), 5 g/kg (T2), 10 g/kg (T3), and 20 g/kg (T4). Subsequently, a four-week mating system was implemented during the winter stress period. The results revealed that there were no significant differences observed in growth, hematological indices, and blood chemical profiles among all treatment groups for both male and female tilapia. However, a significant increase in cholesterol content was noted in both male and female tilapia fed with the T4 diet (p<0.05). The total carotenoid content in the muscle was evaluated, and significantly higher values were found in both male and female tilapia that fed T4 supplementation (p<0.05). Moreover, immunological parameters such as myeloperoxidase and antioxidant parameters in the liver including superoxide dismutase activity and catalase enzyme activity showed significant increases in tilapia fed with the T4 diet. The impact of P. carotinifaciens supplementation on broodstock tilapia indicated a significant increase in spermatozoa concentration in males and increased egg production in females after consumption of the T4 diet (p<0.05). Thus, this study highlighted that the presence of astaxanthin-enriched bacterium P. carotinifaciens in the diet of broodstock Nile tilapia can lead to the accumulation of carotenoids in their muscle tissue, improvement in antioxidant status, enhancement of immune function, and potential enhancement of reproductive capabilities, even under overwintering conditions.
Apatinib, a small-molecule VEGFR2-tyrosine kinase inhibitor, has shown potent anticancer activity in various clinical cancer treatments, but also different adverse reactions. Therefore, it is necessary to study its potential toxicity and working mechanism. We used zebrafish to investigate the effects of apatinib on the development of embryos. Zebrafish exposed to 2.5, 5, and 10 μM apatinib showed adverse effects such as decreased liver area, pericardial oedema, slow yolk absorption, bladder atrophy, and body length shortening. At the same time, it leads to abnormal liver tissue structure, liver function and related gene expression. Furthermore, after exposure to apatinib, oxidative stress levels were significantly elevated but liver developmental toxicity was effectively ameliorated with oxidative stress inhibitor treatment. Apatinib induces down-regulation of key target genes of Wnt signaling pathway in zebrafish, and it is found that Wnt activator can significantly rescue liver developmental defects. These results suggest that apatinib may induce zebrafish hepatotoxicity by inhibiting the Wnt signaling pathway and up-regulating oxidative stress, helping to strengthen our understanding of rational clinical application of apatinib.
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This study set out to evaluate the wound healing properties of brittle star extracts in vitro and in vivo. Due to the great arm regeneration potential of the brittle star, Ophiocoma cynthiae, the present study aimed to evaluate the wound healing effect of hydroalcoholic extracts of brittle star undergoing arm regeneration in wound healing models. The brittle star samples were collected from Nayband Bay, Bushehr, Iran. After wound induction in the arm of brittle stars, hydroalcoholic extracts relating to different times of arm regeneration were prepared. The GC-MS analysis, in vitro MTT cell viability and cell migration, Western blot, and computational analysis tests were performed. Based on the in vitro findings, two BSEs were chosen for in vivo testing. Macroscopic, histopathological and biochemical evaluations were performed after treatments. The results showed positive proliferative effects of BSEs. Specifically, forty-two compounds were detected in all groups of BSEs using GC-MS analysis, and their biological activities were assessed. The MTT assay showed that the 14 d BSE had a higher proliferative effect on HFF cells than 7 d BSE. The cell migration assay showed that the wound area in 7 d and 14 d BSEs was significantly lower than in the control group. Western blot analysis demonstrated an increase in the expression of proliferation-related proteins. Upon the computational analysis, a strong affinity of some compounds with proteins was observed. The in vivo analysis showed that the evaluation of wound changes and the percentage of wound healing in cell migration assay in the 7 d BSE group was better than in the other groups. Histopathological scores of the 7 d BSE and 14 d BSE groups were significantly higher than in the other groups. In conclusion, the hydroalcoholic extract of O. cynthiae undergoing arm regeneration after 7 and 14 days promoted the wound healing process in the cell and rat skin wound healing model due to their proliferative and migratory biological activity.
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Background: Hepatic ischemia reperfusion (IR) is an important issue in complex liver resection and liver transplantation. The aim of the present study was to determine the protective effect of astaxanthin (ASX), an antioxidant, on hepatic IR injury via the reactive oxygen species/mitogen-activated protein kinase (ROS/MAPK) pathway. Methods: Mice were randomized into a sham, IR, ASX or IR + ASX group. The mice received ASX at different doses (30 mg/kg or 60 mg/kg) for 14 days. Serum and tissue samples at 2 h, 8 h and 24 h after abdominal surgery were collected to assess alanine aminotransferase (ALT), aspartate aminotransferase (AST), inflammation factors, ROS, and key proteins in the MAPK family. Results: ASX reduced the release of ROS and cytokines leading to inhibition of apoptosis and autophagy via down-regulation of the activated phosphorylation of related proteins in the MAPK family, such as P38 MAPK, JNK and ERK in this model of hepatic IR injury. Conclusion: Apoptosis and autophagy caused by hepatic IR injury were inhibited by ASX following a reduction in the release of ROS and inflammatory cytokines, and the relationship between the two may be associated with the inactivation of the MAPK family.
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Nowadays the global tendency towards physical activity reduction and an augmented dietary intake of fats, sugars and calories is leading to a growing propagation of overweight, obesity and lifestyle-related diseases, such diabetes, hypertension, dyslipidemia and metabolic syndrome. In particular, obesity, characterized as a state of low-level inflammation, is a powerful determinant both in the development of insulin resistance and in the progression to type 2 diabetes. A few molecular targets offer hope for anti-obesity therapeutics. One of the keys to success could be the induction of uncoupling protein 1 (UCP1) in abdominal white adipose tissue (WAT) and the regulation of cytokine secretions from both abdominal adipose cells and macrophage cells infiltrated into adipose tissue. Anti-obesity effects of fucoxanthin, a characteristic carotenoid, exactly belonging to xanthophylls, have been reported. Nutrigenomic studies reveal that fucoxanthin induces UCP1 in abdominal WAT mitochondria, leading to the oxidation of fatty acids and heat production in WAT. Fucoxanthin improves insulin resistance and decreases blood glucose levels through the regulation of cytokine secretions from WAT. The key structure of anti-obesity effect is suggested to be the carotenoid end of the polyene chromophore, which contains an allenic bond and two hydroxyl groups. Fucoxanthin, which can be isolated from edible brown seaweeds, recently displayed its many physiological functions and biological properties. We reviewed recent studies and this article aims to explain essential background of fucoxanthin, focusing on its promising potential anti-obesity effects. In this respect, fucoxanthin can be developed into promising marine drugs and nutritional products, in order to become a helpful functional food.
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Introduction: Many studies have shown that oral supplementation with astaxanthin may be a novel potential treatment for inflammation and oxidative stress in cardiovascular diseases, but evidence of the effects on lipid profile and glucose is still inconclusive. Therefore, we performed a meta-analysis to evaluate the efficacy of astaxanthin supplementation on plasma lipid and glucose concentrations. Material and methods: The search included PubMed, Cochrane Library, Scopus, and EMBASE (up to November 27, 2014) to identify randomized controlled trials (RCTs) investigating the effects of astaxanthin supplementation on lipid profile and glucose levels. Two independent reviewers extracted data on study characteristics, methods and outcomes. Results: Seven studies meeting inclusion criteria with 280 participants were selected for this meta-analysis; 163 participants were allocated to the astaxanthin supplementation group and 117 to the control group. A random-effect meta-analysis of data from 7 RCTs (10 treatment arms) did not show any significant effect of supplementation with astaxanthin on plasma concentrations of total cholesterol (weighted mean difference (WMD): –1.52 mg/dl, 95% CI: –8.69 to –5.66, p = 0.679), LDL-C (WMD: +1.25 mg/dl, 95% CI: –6.70 to +9.21, p = 0.758), HDL-C (WMD: +1.75 mg/dl, 95% CI: –0.92 to +4.42, p = 0.199), triglycerides (WMD: –4.76 mg/dl, 95% CI: –21.52 to +12.00, p = 0.578), or glucose (WMD: –2.65 mg/dl, 95% CI: –5.84 to +0.54, p = 0.103). All these effect sizes were robust, and omission of any of the included studies did not significantly change the overall estimate. Conclusions: This meta-analysis of data from 10 RCT arms did not indicate a significant effect of supplementation with astaxanthin on plasma lipid profile, but a slight glucose-lowering effect was observed. Further, well-designed trials are necessary to validate these results.
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Cardiovascular disease related to atherosclerosis represents nowadays the largest cause of morbidity and mortality in developed countries. Due to inflammatory nature of atherosclerosis, several studies had been conducted in order to search for substances with anti-inflammatory activity on arterial walls, able to exert beneficial roles on health. Researches investigated the role of dietary carotenoids supplementation on cardiovascular disease, due to their free radicals scavenger properties and their skills in improving low-density lipoprotein cholesterol resistance to oxidation. Nevertheless, literature data are conflicting: although some studies found a positive relationship between carotenoids supplementation and cardiovascular risk reduction, others did not find any positive effects or even prooxidant actions. This paper aimed at defining the role of carotenoids supplementation on cardiovascular risk profile by reviewing literature data, paying attention to those carotenoids more present in our diet ( β -carotene, α -carotene, β -cryptoxanthin, lycopene, lutein, zeaxanthin, and astaxanthin).
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There is currently much interest in biological active compounds derived from natural resources, especially compounds that can efficiently act on molecular targets, which are involved in various diseases. Astaxanthin (3,3'-dihydroxy-β, β'-carotene-4,4'-dione) is a xanthophyll carotenoid, contained in Haematococcus pluvialis, Chlorella zofingiensis, Chlorococcum, and Phaffia rhodozyma. It accumulates up to 3.8% on the dry weight basis in H. pluvialis. Our recent published data on astaxanthin extraction, analysis, stability studies, and its biological activities results were added to this review paper. Based on our results and current literature, astaxanthin showed potential biological activity in in vitro and in vivo models. These studies emphasize the influence of astaxanthin and its beneficial effects on the metabolism in animals and humans. Bioavailability of astaxanthin in animals was enhanced after feeding Haematococcus biomass as a source of astaxanthin. Astaxanthin, used as a nutritional supplement, antioxidant and anticancer agent, prevents diabetes, cardiovascular diseases, and neurodegenerative disorders, and also stimulates immunization. Astaxanthin products are used for commercial applications in the dosage forms as tablets, capsules, syrups, oils, soft gels, creams, biomass and granulated powders. Astaxanthin patent applications are available in food, feed and nutraceutical applications. The current review provides up-to-date information on astaxanthin sources, extraction, analysis, stability, biological activities, health benefits and special attention paid to its commercial applications.
The role of beta-carotene on immune response in domestic dogs is not known. Female Beagle dogs were fed 0, 2, 20 or 50 mg beta-carotene/d; blood was sampled at wk 0, 1, 2, 4 and 8 for analysis of the following: lymphoproliferation, leukocyte subpopulations and concentrations of interleukin-2 (IL-2), immunoglobulin (Ig)G and IgM. Delayed-type hypersensitivity (DTH) response was assessed at wk 0, 3 and 7. beta-Carotene supplementation increased plasma beta-carotene concentrations in a dose-dependent manner. Compared with unsupplemented dogs, those fed 20 or 50 mg of beta-carotene had higher CD4+ cell numbers and CD4:CD8 ratio, However, there was no treatment difference in CD8+, CD21+ and major histocompatability complex (MHC) class II+ cells. Plasma IgG, but not IgM concentration was higher in dogs fed beta-carotene throughout the study period. The DTH response to phytohemagglutinin (PHA) and vaccine was heightened in beta-carotene-supplemented doss. beta-Carotene feeding did not influence mitogen-induced lymphocyte proliferation or IL-2 production. Immune response was impaired in dogs classified as low beta-carotene absorbers compared with similar dogs fed the same amount of beta-carotene. Therefore, dietary beta-carotene heightened cell-mediated and humoral immune responses in dogs.
Oxidative stress is implicated as an important mechanism by which diabetes causes nephropathy. Astaxanthin, which is found as a common pigment in algae, fish, and birds, is a carotenoid with significant potential for antioxidative activity. In this study, we examined whether chronic administration of astaxanthin could prevent the progression of diabetic nephropathy induced by oxidative stress in mice. We used female db/db mice, a rodent model of type 2 diabetes, and their non-diabetic db/m littermates. The mice were divided into three groups as follows: non-diabetic db/m, diabetic db/db, and diabetic db/db treated with astaxanthin. Blood glucose level, body weight, urinary albumin, and urinary 8-hydroxydeoxyguanosine (8-OHdG) were measured during the experiments. Histological and 8-OHdG immunohistochemical studies were performed for 12 weeks from the beginning of treatment. After 12 weeks of treatment, the astaxanthin-treated group showed a lower level of blood glucose compared with the non-treated db/db group; however, both groups had a significantly high level compared with the db/m mice. The relative mesangial area calculated by the mesangial area/total glomerular area ratio was significantly ameliorated in the astaxanthin-treated group compared with the non-treated db/db group. The increases in urinary albumin and 8-OHdG at 12 weeks of treatment were significantly inhibited by chronic treatment with astaxanthin. The 8-OHdG immunoreactive cells in glomeruli of non-treated db/db mice were more numerous than in the astaxanthin-treated db/db mice. In this study, treatment with astaxanthin ameliorated the progression and acceleration of diabetic nephropathy in the rodent model of type 2 diabetes. The results suggested that the antioxidative activity of astaxanthin reduced the oxidative stress on the kidneys and prevented renal cell damage. In conclusion, administration of astaxanthin might be a novel approach for the prevention of diabetes nephropathy.
Diabetes-induced cognitive deficit (DICD) is a prevalent disease with substantial morbidity and mortality and as a global health problem with serious economic burdens. Astaxanthin (AST) has a good prospect in production of nutritional, medical, and particularly functional health drug. The present study was aimed to study the effect of AST on DICD in diabetes mellitus (DM) rat through suppression of oxidative stress, nitric oxide synthase (NOS) pathway, inflammatory reaction and upregulation of PI3K/Akt. In the study, Morris water maze teat was used to detect the cognitive function of DM rat. Afterwards, we measured the body weight and blood glucose levels of DM rats. Then, oxidative stress, the activities of eNOS and iNOS, and inflammatory factors were analyzed using a commercial kit in cerebral cortex and hippocampus. Finally, the caspase-3/9 and phosphoinositide 3-kinase (PI3K)/Akt expressions were also checkout with Real Time PCR and immunoblotting, respectively. In this experiment, AST could availably enhance the body weight and reduce blood glucose levels of DM rats. Moreover, AST could observably perfect cognitive function of DM rat. Next, the activities of oxidative stress, nitric oxide synthase and inflammation were distinctly diminution in DM rat, after the treatment of AST. Furthermore, our present results demonstrated that AST had the protective effect on the brain cell of DM rat, decreased the caspase-3/9 expression and promoted the expression of PI3K/Akt in cerebral cortex and hippocampus.
Non-alcoholic fatty liver disease (NAFLD) is significantly associated with hyperlipidaemia and oxidative stress. We have previously reported that astaxanthin (ASTX), a xanthophyll carotenoid, lowers plasma total cholesterol and TAG concentrations in apoE knockout mice. To investigate whether ASTX supplementation can prevent the development of NAFLD in obesity, male C57BL/6J mice (n 8 per group) were fed a high-fat diet (35 %, w/w) supplemented with 0, 0·003, 0·01 or 0·03 % of ASTX (w/w) for 12 weeks. The 0·03 % ASTX-supplemented group, but not the other groups, exhibited a significant decrease in plasma TAG concentrations, suggesting that ASTX at a 0·03 % supplementation dosage exerts a hypotriacylglycerolaemic effect. Although there was an increase in the mRNA expression of fatty acid synthase and diglyceride acyltransferase 2, the mRNA levels of acyl-CoA oxidase 1, a critical enzyme in peroxisomal fatty acid β-oxidation, exhibited an increase in the 0·03 % ASTX-supplemented group. There was a decrease in plasma alanine transaminase (ALT) and aspartate transaminase (AST) concentrations in the 0·03 % ASTX-supplemented group. There was a significant increase in the hepatic mRNA expression of nuclear factor erythroid 2-related factor 2 and its downstream genes, which are critical for endogenous antioxidant mechanism, in the 0·03 % ASTX-supplemented group. Furthermore, there was a significant decrease in the mRNA abundance of IL-6 in the primary splenocytes isolated from the 0·03 % ASTX-supplemented group upon lipopolysaccharide (LPS) stimulation when compared with that in the splenocytes isolated from the control group. In conclusion, ASTX supplementation lowered the plasma concentrations of TAG, ALT and AST, increased the hepatic expression of endogenous antioxidant genes, and rendered splenocytes less sensitive to LPS stimulation. Therefore, ASTX may prevent obesity-associated metabolic disturbances and inflammation.