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Astaxanthin: Sources, Extraction, Stability, Biological Activities and Its Commercial Applications—A Review

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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.
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Mar. Drugs 2014, 12, 128-152; doi:10.3390/md12010128
marine drugs
ISSN 1660-3397
www.mdpi.com/journal/marinedrugs
Review
Astaxanthin: Sources, Extraction, Stability, Biological Activities
and Its Commercial ApplicationsA Review
Ranga Rao Ambati 1,*, Siew Moi Phang 1, Sarada Ravi 2 and
Ravishankar Gokare Aswathanarayana 3
1 Institute of Ocean and Earth Sciences, University of Malaya, Kuala Lumpur 50603, Malaysia;
E-Mail: phang@um.edu.my
2 Plant Cell Biotechnology Department, Central Food Technological Research Institute, (Constituent
Laboratory of Council of Scientific & Industrial Research), Mysore-570020, Karnataka, India;
E-Mail: sarada_ravi@yahoo.com
3 C. D. Sagar Centre for Life Sciences, Dayananda Sagar Institutions, Kumaraswamy Layout,
Bangalore-560078, Karnataka, India; E-Mail: rgokare@yahoo.co.in
* Author to whom correspondence should be addressed; E-Mail: arangarao@um.edu.my;
Tel.: +603-79674610; Fax: +603-79676994.
Received: 10 October 2013; in revised form: 10 December 2013 / Accepted: 11 December 2013 /
Published: 7 January 2014
Abstract: 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.
OPEN ACCESS
Mar. Drugs 2014, 12 129
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.
Keywords: astaxanthin; sources; stability; biological activities; health
benefits; applications
1. Introduction
Astaxanthin is a xanthophyll carotenoid which is found in various microorganisms and marine
animals [1]. It is a red fat-soluble pigment which does not have pro-Vitamin A activity in the human
body, although some of the studies reported that astaxanthin has more potent biological activity than
other carotenoids. The United States Food and Drug Administration (USFDA) has approved the use of
astaxanthin as food colorant in animal and fish feed [2]. The European Commission considers natural
astaxanthin as a food dye [3]. Haematococcus pluvialis is a green microalga, which accumulates high
astaxanthin content under stress conditions such as high salinity, nitrogen deficiency, high temperature
and light [46]. Astaxanthin produced from H. pluvialis is a main source for human consumption [7].
It is used as a source of pigment in the feed for salmon, trout and shrimp [1,3]. For dietary supplement
in humans and animals, astaxanthin is obtained from seafood or extracted from H. pluvialis [8]. The
consumption of astaxanthin can prevent or reduce risk of various disorders in humans and
animals [7,8]. The effects of astaxanthin on human health nutrition have been published by various
authors [713]. In our previous reviews, we included recent findings on the potential effects of
astaxanthin and its esters on biological activities [1418]. The use of astaxanthin as a nutritional
supplement has been rapidly growing in foods, feeds, nutraceuticals and pharmaceuticals. This present
review paper provides information on astaxanthin sources, extraction methods, storage stability,
biological activities, and health benefits for the prevention of various diseases and use in
commercial applications.
2. Source of Astaxanthin
The natural sources of astaxanthin are algae, yeast, salmon, trout, krill, shrimp and crayfish.
Astaxanthin from various microorganism sources are presented in Table 1. The commercial
astaxanthin is mainly from Phaffia yeast, Haematococcus and through chemical synthesis.
Haematococcus pluvialis is one of the best sources of natural astaxanthin [1720]. Astaxanthin content
in wild and farmed salmonids are shown in Figure 1. Among the wild salmonids, the maximum
astaxanthin content in wild Oncorhynchus species was reported in the range of 2638 mg/kg flesh in
sockeye salmon whereas low astaxanthin content was reported in chum [20]. Astaxanthin content in
farmed Atlantic salmon was reported as 68 mg/kg flesh. Astaxanthin is available in the European
(6 mg/kg flesh) and Japanese market (25 mg/kg flesh) from large trout. Shrimp, crab and salmon can
serve as dietary sources of astaxanthin [20]. Wild caught salmon is a good source of astaxanthin. In
Mar. Drugs 2014, 12 130
order to get 3.6 mg of astaxanthin one can eat 165 grams of salmon per day. Astaxanthin supplement at
3.6 mg per day can be beneficial to health as reported by Iwamoto et al. [21].
Table 1. Microorganism sources of astaxanthin.
Sources
Astaxanthin (%) on the Dry Weight Basis
References
Chlorophyceae
Haematococcus pluvialis
3.8
[17,18]
Haematococcus pluvialis (K-0084)
3.8
[22]
Haematococcus pluvialis (Local isolation)
3.6
[23]
Haematococcus pluvialis (AQSE002)
3.4
[24]
Haematococcus pluvialis (K-0084)
2.7
[25]
Chlorococcum
0.2
[26,27]
Chlorella zofingiensis
0.001
[28]
Neochloris wimmeri
0.6
[29]
Ulvophyceae
Enteromorpha intestinalis
0.02
[30]
Ulva lactuca
0.01
[30]
Florideophyceae
Catenella repens
0.02
[30]
Alphaproteobacteria
Agrobacterium aurantiacum
0.01
[31]
Paracoccus carotinifaciens (NITE SD 00017)
2.2
[32]
Tremellomycetes
Xanthophyllomyces dendrorhous (JH)
0.5
[33]
Xanthophyllomyces dendrorhous (VKPM Y2476)
0.5
[34]
Labyrinthulomycetes
Thraustochytrium sp. CHN-3 (FERM P-18556)
0.2
[35]
Malacostraca
Pandalus borealis
0.12
[20]
Pandalus clarkia
0.015
[36]
Figure 1. Astaxanthin levels (mg/kg flesh) of wild and farmed (*) salmonids [20].
Mar. Drugs 2014, 12 131
3. Structure of Astaxanthin
Astaxanthin is a member of the xanthophylls, because it contains not only carbon and hydrogen but
also oxygen atoms (Figure 2). Astaxanthin consists of two terminal rings joined by a polyene chain.
This molecule has two asymmetric carbons located at the 3, 3 positions of the β-ionone ring with
hydroxyl group (-OH) on either end of the molecule. In case one, hydroxyl group reacts with a fatty
acid then it forms mono-ester, whereas when both hydroxyl groups are reacted with fatty acids the
result is termed a di-ester. Astaxanthin exists in stereoisomers, geometric isomers, free and esterified
forms [1]. All of these forms are found in natural sources. The stereoisomers (3S, 3S) and (3R 3R) are
the most abundant in nature. Haematococcus biosynthesizes the (3S, 3′S)-isomer whereas yeast
Xanthophyllomyces dendrorhous produces (3R, 3′R)-isomer [10]. Synthetic astaxanthin comprises
isomers of (3S, 3′S) (3R, 3S) and (3R, 3′R). The primary stereoisomer of astaxanthin found in the
Antarctic krill Euphausia superba is 3R, 3R which contains mainly esterified form, whereas in wild
Atlantic salmon it is 3S, 3′S which occurs as the free form [37]. The relative percentage of astaxanthin
and its esters in krill, copepod, shrimp and shell is shown in Figure 3. Astaxanthin has the molecular
formula C40H52O4. Its molar mass is 596.84 g/mol.
Figure 2. Planner structure of astaxanthin.
Figure 3. Astaxanthin and its esters from various sources [19,20].
Mar. Drugs 2014, 12 132
4. Extraction and Analysis of Astaxanthin
Astaxanthin is a lipophilic compound and can be dissolved in solvents and oils. Solvents, acids,
edible oils, microwave assisted and enzymatic methods are used for astaxanthin extraction.
Astaxanthin is accumulated in encysted cells of Haematococcus. Astaxanthin in Haematococcus was
extracted with different acid treatments, hydrochloric acid giving up to 80% recovery of the
pigment [38]. When encysted cells were treated with 40% acetone at 80 °C for 2 min followed by
kitalase, cellulose, abalone and acetone powder, 70% recovery of astaxanthin was obtained [39]. High
astaxanthin yield was observed with treatment of hydrochloric acid at various temperatures for 15 and
30 min using sonication [40]. In another study, vegetable oils (soyabean, corn, olive and grape seed)
were used to extract astaxanthin from Haematococcus. The culture was mixed with oils, and the
astaxanthin inside the cell was extracted into the oils, with the highest recovery of 93% with olive
oil [41]. Astaxanthin (1.3 mg/g) was extracted from Phaffia rhodozyma under acid conditions [42].
Microwave assisted extraction at 75 °C for 5 min resulted in 75% of astaxanthin; however, astaxanthin
content was high in acetone extract [43,44]. Astaxanthin yield from Haematococcus was 80%90%
using supercritical fluid extraction with ethanol and sunflower oil as co-solvent [4547]. Astaxanthin
was extracted repeatedly with solvents, pooled and evaporated by rotary evaporator, then re-dissolved
in solvent and absorbance of extract was measured at 476480 nm to estimate the astaxanthin
content [17]. Further the extract can be analyzed for quantification of astaxanthin using high pressure
liquid chromatography and identified by mass spectra [18].
5. Storage and Stability of Astaxanthin
Astaxanthin stability was assessed in various carriers and storage conditions. Astaxanthin derived
from Haematococcus and its stability in various edible oils was determined [48]. Astaxanthin was
stable at 7090 °C in ricebran, gingelly and palm oils with 84%90% of retention of astaxanthin
content which can be used in food, pharmaceutical and nutraceutical applications, whereas astaxanthin
content was reduced at 120 and 150 °C [48]. Astaxanthin nanodispersions stability was evaluated in
skimmed milk, orange juice and deionized water was used as a control [49]. It was found that
degradation of astaxanthin was significantly higher in skimmed milk than orange juice. In another
study, stability of astaxanthin biomass was examined after drying and storage at various conditions for
nine weeks [50]. The results showed that degradation of astaxanthin was as low as 10% in biomass
dried at 180/110 °C and stored at 21 °C under nitrogen after nine weeks of storage. The stability of
astaxanthin from Phaffia rhodozyma was studied and it was found that stability was high at pH 4.0 and
at a lower temperature [51]. The storage stability of astaxanthin was enhanced at 4 °C and 25 °C in a
complex mixture of hydroxyproply-β-cyclodextrin and water [52]. Astaxanthin stability was
investigated using microencapsulation with chitosan, polymeric nanospheres, emulsions and
β-cyclodextrin as reported by various authors [5356].
6. Biochemistry of Astaxanthin
Astaxanthin contains conjugated double bonds, hydroxyl and keto groups. It has both lipophilic and
hydrophilic properties [1]. The red color is due to the conjugated double bonds at the center of the
Mar. Drugs 2014, 12 133
compound. This type of conjugated double bond acts as a strong antioxidant by donating the electrons
and reacting with free radicals to convert them to be more stable product and terminate free radical
chain reaction in a wide variety of living organisms [8]. Astaxanthin showed better biological activity
than other antioxidants [11], because it could link with cell membrane from inside to outside
(Figure 4).
Figure 4. Superior position of astaxanthin in the cell membrane [12].
7. Bioavailability and Pharmacokinetics of Astaxanthin
7.1. Bioavailability
Dietary oils may enhance the absorption of astaxanthin. Astaxanthin with combination of fish oil
promoted hypolipidemic/hypocholesterolemic effects in plasma and its increased phagocytic activity
of activated neutrophils when compared with astaxanthin and fish oil alone [57]. Astaxanthin was
superior to fish oil in particular by improving immune response and lowering the risk of vascular and
infectious diseases. The proliferation activity of T- and B-lymphocytes was diminished followed by
lower levels of O2, H2O2 and NO production, increased antioxidant enzymes superoxide dismutase,
catalase and glutathione peroxidase (GPx), and calcium release in cytosol after administration of
astaxanthin with fish oil [58]. Bioavailability and antioxidant properties of astaxanthin were enhanced
in rat plasma and liver tissues after administration of Haematococcus biomass dispersed in olive
oil [14,15,17].
Astaxanthin is a fat soluble compound, with increased absorption when consumed with dietary oils.
Astaxanthin was shown to significantly influence immune function in several in vitro and in vivo
assays [14,15,17]. Lipophilic compounds such as astaxanthin are usually transformed metabolically
before they are excreted, and metabolites of astaxanthin have been detected in various rat tissues [59].
Astaxanthin bioavailability in human plasma was confirmed with single dosage of 100 mg [60]. Its
Mar. Drugs 2014, 12 134
accumulation in humans was found after administration of Haematococcus biomass as source of
astaxanthin [61]. Astaxanthin bioavailability in humans was enhanced by lipid based formulations;
high amounts of carotenes solubilized into the oil phase of the food matrix can lead to greater
bioavailability [62]. A recent study reported that astaxanthin accumulation in rat plasma and liver was
observed after feeding of Haematococcus biomass as source of astaxanthin [14,15,17].
7.2. Pharmacokinetics
Carotenoids are absorbed into the body like lipids and transported via the lymphatic system into the
liver. The absorption of carotenoids is dependent on the accompanying dietary components. A high
cholesterol diet may increase carotenoid absorption while a low fat diet reduces its absorption.
Astaxanthin mixes with bile acid after ingestion and make micelles in the intestinum tenue. The
micelles with astaxanthin are partially absorbed by intestinal mucosal cells. Intestinal mucosal cells
incorporate astaxanthin into chylomicra. Chylomicra with astaxanthin are digested by lipoprotein
lipase after releasing into the lymph within the systemic circulation, and chylomicron remnants are
rapidly removed by the liver and other tissues. Astaxanthin is assimilated with lipoproteins and
transported into the tissues [62]. Of several naturally occurring carotenoids, astaxanthin is considered
one of the best carotenoids being able to protect cells, lipids and membrane lipoproteins against
oxidative damage.
8. Biological Activities of Astaxanthin and Its Health Benefits
8.1. Antioxidant Effects
An antioxidant is a molecule which can inhibit oxidation. Oxidative damage is initiated by free
radicals and reactive oxygen species (ROS). These molecules have very high reactivity and are
produced by normal aerobic metabolism in organisms. Excess oxidative molecules may react with
proteins, lipids and DNA through chain reaction, to cause protein and lipid oxidation and DNA
damage which are associated with various disorders. This type of oxidative molecules can be inhibited
by endogenous and exogenous antioxidants such as carotenoids. Carotenoids contain polyene chain,
long conjugated double bonds, which carry out antioxidant activities by quenching singlet oxygen and
scavenging radicals to terminate chain reactions. The biological benefits of carotenoids may be due to
their antioxidant properties attributed to their physical and chemical interactions with cell membranes.
Astaxanthin had higher antioxidant activity when compared to various carotenoids such as lutein,
lycopene, α-carotene and β-carotene reported by Naguib et al. [63]. The antioxidant enzymes catalase,
superoxide dismutase, peroxidase and thiobarbituric acid reactive substances (TBARS) were high in
rat plasma and liver after feeding Haematococcus biomass as source of astaxanthin [17]. Astaxanthin
in H. pluvialis offered the best protection from free radicals in rats followed by β-carotene and
lutein [15,17]. Astaxanthin contains a unique molecular structure in the presence of hydroxyl and keto
moieties on each ionone ring, which are responsible for the high antioxidant properties [10,64].
Antioxidant activity of astaxanthin was 10 times more than zeaxanthin, lutein, canthaxanthin,
β-carotene and 100 times higher than α-tocopherol [65]. The oxo functional group in carotenoids has
higher antioxidant activity without pro-oxidative contribution [66]. The polyene chain in astaxanthin
Mar. Drugs 2014, 12 135
traps radicals in the cell membrane, while the terminal ring of astaxanthin could scavenge radicals at
the outer and inner parts of cell membrane (Figure 4). Antioxidant enzyme activities were evaluated in
the serum after astaxanthin was supplemented in the diet of rabbits, showing enhanced activity of
superoxide dismutase and thioredoxin reductase whereas paraoxonase was inhibited in the
oxidative-induced rabbits [67]. Antioxidant enzyme levels were increased when astaxanthin fed to
ethanol-induced gastric ulcer rats [68].
8.2. Anti-Lipid Peroxidation Activity
Astaxanthin has a unique molecular structure which enables it to stay both in and outside the cell
membrane. It gives better protection than β-carotene and Vitamin C which can be positioned inside the
lipid bilayer. It serves as a safeguard against oxidative damage by various mechanisms, like quenching
of singlet oxygen; scavenging of radicals to prevent chain reactions; preservation of membrane
structure by inhibiting lipid peroxidation; enhancement of immune system function and regulation of
gene expression. Astaxanthin and its esters showed 80% anti-lipid peroxidation activity in ethanol
induced gastric ulcer rats and skin cancer rats [14,68]. Astaxanthin inhibited lipid peroxidation in
biological samples reported by various authors [14,15,17,18,68,69].
8.3. Anti-Inflammation
Astaxanthin is a potent antioxidant to terminate the induction of inflammation in biological
systems. Astaxanthin acts against inflammation. Algal cell extracts of Haematococcus and
Chlorococcum significantly reduced bacterial load and gastric inflammation in H. pylori-infected
mice [16,70,71]. Park et al. [72] reported astaxanthin reduced the DNA oxidative damage biomarker
inflammation, thus enhancing immune response in young healthy adult female human subjects.
Haines et al. [73] reported lowered bronchoalveolar lavage fluid inflammatory cell numbers, and
enhanced cAMP, cGMP levels in lung tissues after feeding astaxanthin with Ginkgo biloba extract and
Vitamin C. Another study showed astaxanthin esters and total carotenoids from Haematococcus
exerted a dose-dependent gastroprotective effect on acute, gastric lesions in ethanol-induced gastric
ulcers in rats. This may be due to inhibition of H1, K1 ATPase, upregulation of mucin content and an
increase in antioxidant activities [68]. Astaxanthin showed protective effect on high glucose induced
oxidative stress, inflammation and apoptosis in proximal tubular epithelial cells. Astaxanthin is a
promising molecule for the treatment of ocular inflammation in eyes as reported by the Japanese
researchers [74,75]. Astaxanthin can prevent skin thickening and reduce collagen reduction against UV
induced skin damage [14,76,77].
8.4. Anti-Diabetic Activity
Generally, oxidative stress levels are very high in diabetes mellitus patients. It is induced by
hyperglycemia, due to the dysfunction of pancreatic β-cells and tissue damage in patients. Astaxanthin
could reduce the oxidative stress caused by hyperglycemia in pancreatic β-cells and also improve
glucose and serum insulin levels [78]. Astaxanthin can protect pancreatic β-cells against glucose
toxicity. It was also shown to be a good immunological agent in the recovery of lymphocyte
Mar. Drugs 2014, 12 136
dysfunctions associated with diabetic rats [79]. In another study, ameliorate oxidative stress in
streptozotocin-diabetes rats were inhibited by the combination of astaxanthin with α-tocopherol [80]. It
is also inhibited glycation and glycated protein induced cytotoxicity in human umbilical vein
endothelial cells by preventing lipid/protein oxidation [81]. Improved insulin sensitivity in both
spontaneously hypertensive corpulent rats and mice on high fat plus high fructose diets was observed
after feeding with astaxanthin [8284]. The urinary albumin level in astaxanthin treated diabetic mice
was significantly lower than the control group [78]. Some of the studies demonstrated that astaxanthin
prevents diabetic nephropathy by reduction of the oxidative stress and renal cell damage [8587].
8.5. Cardiovascular Disease Prevention
Astaxanthin is a potent antioxidant with anti-inflammatory activity and its effect examined in both
experimental animals and human subjects. Oxidative stress and inflammation are pathophysiological
features of atherosclerotic cardiovascular disease. Astaxanthin is a potential therapeutic agent against
atherosclerotic cardiovascular disease [88]. The efficacy of disodium disuccinate astaxanthin (DDA) in
protecting mycocardium using mycocardial ischemia reperfusion model in animals was evaluated.
Myocardial infarct size was reduced in Sprague Dawley rats, and improved in myocardial salvage in
rabbits after four days of pre-treatment with DDA at 25, 50 and 75 mg/kg body weight [89,90].
Astaxanthin was found in rat mycocardial tissues after pretreatment with DDA at dosage of 150 and
500 mg/kg/day for seven days [91]. Astaxanthin effects on blood pressure in spontaneously
hypertensive rats (SHR), normotensive Wistar Kyoto rats (NWKR) and stroke prone spontaneously
hypertensive rats (SPSHR) were reported [92]. Astaxanthin was found in the plasma, heart, liver,
platelets, and increased basal arterial blood flow in mice fed with astaxanthin derivative [93]. Human
umbilical vien endothelial cells and platelets treated with the astaxanthin showed increased nitric oxide
levels and decrease in peroxynitrite levels [93]. Mice fed 0.08% astaxanthin had higher heart
mitochondrial membrane potential and contractility index compared to the control group [94].
Astaxanthin effects on paraoxonase, thioredoxin reductase activities, oxidative stress parameters and
lipid profile in hypercholesterolemic rabbits were evaluated. Astaxanthin prevented the activities of
those enzymes from hypercholesterolemia induced protein oxidation at the dosages of 100 mg and
500 mg/100 g [67].
8.6. Anticancer Activity
The specific antioxidant dose may be helpful for the early detection of various degenerative
disorders. Reactive oxygen species such as superoxide, hydrogen peroxide and hydroxyl radical are
generated in normal aerobic metabolism. Singlet oxygen is generated by photochemical events
whereas peroxyl radicals are produced by lipid peroxidation. These oxidants contribute to aging and
degenerative diseases such as cancer and atherosclerosis through oxidation of DNA, proteins and
lipids [95]. Antioxidant compounds decrease mutagenesis and carcinogenesis by inhibiting oxidative
damage to cells. Cellcell communication through gap junctions is lacking in human tumors and its
restoration tends to decrease tumor cell proliferation. Gap junctional communication occurs due to an
increase in the connexin-43 protein via upregulation of the connexin-43 gene. Gap junctional
communication was improved in between the cells by natural carotenoids and retinoids [96].
Mar. Drugs 2014, 12 137
Canthaxanthin and astaxanthin derivatives enhanced gap junctional communication between mouse
embryo fibroblasts [9799]. Increased connexin-43 expression in murine fibroblast cells by β-carotene
was reported [100,101]. Astaxanthin showed significant antitumor activity when compared to other
carotenoids like canthaxanthin and β-carotene [102,103]. It also inhibited the growth of fibrosarcoma,
breast, and prostate cancer cells and embryonic fibroblasts [104]. Increased gap junctional intercellular
communication in primary human skin fibroblasts cells were observed when treated with
astaxanthin [99]. Astaxanthin inhibited cell death, cell proliferation and mammary tumors in
chemically induced male/female rats and mice [105109]. H. pluvialis extract inhibited the growth of
human colon cancer cells by arresting cell cycle progression and promoting apoptosis reported by
Palozza et al. [104]. Nitroastaxanthin and 15-nitroastaxanthin are the products of astaxanthin with
peroxynitrite, 15-nitroastaxanthin anticancer properties were evaluated in a mouse model. Epstein-Barr
virus and carcinogenesis in mouse skin papillomas were significantly inhibited by astaxanthin
treatment [110].
8.7. Immuno-Modulation
Immune system cells are very sensitive to free radical damage. The cell membrane contains poly
unsaturated fatty acids (PUFA). Antioxidants in particular astaxanthin offer protection against free
radical damage to preserve immune-system defenses. There are reports on astaxanthin and its effect on
immunity in animals under laboratory conditions however clinical research is lacking in humans.
Astaxanthin showed higher immuno-modulating effects in mouse model when compared to
β-carotene [111]. Enhanced antibody production and decreased humoral immune response in older
animals after dietary supplementation of astaxanthin was reported [111,112]. Astaxanthin produced
immunoglobulins in human cells in a laboratory study [113]. Eight week-supplementation of
astaxanthin in humans [72] resulted in increased blood levels of astaxanthin and improved activity of
natural killer cells which targeted and destroyed cells infected with viruses. In this study, T and B cells
were increased, DNA damage was low, and C-reactive protein (CRP) was significantly lower in the
astaxanthin supplemented group [67,102,114]. Recent reports on astaxanthin biological activities are
presented in Table 2.
Table 2. Astaxanthin biological activities in in vitro and in vivo models.
References
[14,15,17,115120]
[14]
[14,110,121]
[84,122125]
[68,71]
[126]
[90,127,128]
[94,122,129,130]
[72,114]
[131,132]
Mar. Drugs 2014, 12 138
9. Safety and Dose of Astaxanthin
Astaxanthin is safe, with no side effects when it is consumed with food. It is lipid soluble,
accumulates in animal tissues after feeding of astaxanthin to rats and no toxic effects were
found [15,17,133]. Excessive astaxanthin consumption leads to yellow to reddish pigmentation of the
skin in animals. Astaxanthin is incorporated into fish feed, resulting in the fish skin becoming reddish
in color. Antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase
levels significantly increased in rats after oral dosage of astaxanthin [14,15]. A study reported that
blood pressure (bp) was reduced in stroke prone rats and in hypertensive rats by feeding 50 mg/kg
astaxanthin for five weeks and 14 days, respectively [134]. Astaxanthin was also shown significant
protection against naproxen induced gastric, antral ulcer and inhibited lipid peroxidation levels in
gastric mucosa [67,135]. Astaxanthin accumulation in eyes was observed when astaxanthin was fed to
rats [136]. Astaxanthin extracted from Paracoccus carotinifaciens showed potential antioxidant and
also anti-ulcer properties in murine models as reported by Murata et al. [137]. Astaxanthin
bioavailability was increased with supplement of lipid based formulations [14,15,17,138].
Supratherapeutic concentrations of astaxanthin had no adverse effects on platelet, coagulation and
fibrinolytic function [139]. Research has so far reported no significant side effects of astaxanthin
consumption in animals and humans. These results support the safety of astaxanthin for future
clinical studies.
It is recommended to administer astaxanthin with omega-3 rich seed oils such as chia, flaxseed,
fish, nutella, walnuts and almonds. The combination of astaxanthin (48 mg) with foods, soft gels and
capsules and cream is available in the market. Recommended dose of astaxanthin is 24 mg/day. A
study reported that no adverse effects were found with the administration of astaxanthin (6 mg/day) in
adult human subjects [140]. Astaxanthin effects on human blood rheology were investigated in adult
men subjects with a single-blind method after administration of astaxanthin at 6 mg/day for
10 days [141]. Recent studies on astaxanthin dosage effects on human health benefits were presented
in Table 3.
Table 3. Health benefits of astaxanthin in human subjects.
Duration of Experiment
Subjects in Humans
Dosage (mg/day)
Benefits of Astaxanthin
References
2 weeks
Volunteers
1.8, 3.6, 14.4 and 21.6
Reduction of LDL oxidation
[21]
Single dose
Middle aged male
volunteers
100
Astaxanthin take up by VLDL
chylomicrons
[60]
8 weeks
Healthy females
0.2 and 8
Decreased plasma
8-hydoxy-2-deoxyguanosine and
lowered in CRP levels
[72]
8 weeks
Healthy adults
6
Assessed by blood pressure
[140]
10 days
Healthy males
6
Improved blood rheology
[141]
12 weeks
Healthy non-smoking
finnish males
8
Decreased oxidation of fatty acids
[142]
12 months
Age related macular
degeneration
4
Improved central retinal
dysfunction in age related macular
degeneration
[143]
Mar. Drugs 2014, 12 139
Table 3. Cont.
12 weeks
Middle aged/elderly
12
Improved Cog health battery scores
[144]
12 weeks
Middle aged/elderly
6
Improved groton maze learning
test scores
[144]
8 or 6 weeks
Healthy female or male
6
Improved skin winkle, corneocyte
layer, epidermis and dermis
[145]
2 weeks
Disease (bilateral
cataract)
6
Improved superoxide scavenging
activity and lowered hydroperoxides
in the human aqueous humor
[146]
LDL, Low-density lipoproteins, VLDL, Very low-density lipoprotein, CRP, C-reactive protein.
10. Commercial Applications of Astaxanthin
In the present scenario, production of astaxanthin from natural sources has become one of the most
successful activities in biotechnology. Astaxanthin has great demand in food, feed, nutraceutical and
pharmaceutical applications. This has promoted major efforts to improve astaxanthin production from
biological sources instead of synthetic ones. According to the current literature, astaxanthin is used in
various commercial applications in the market. Astaxanthin products are available in the form of
capsule, soft gel, tablet, powder, biomass, cream, energy drink, oil and extract in the market (Table 4).
Some of the astaxanthin products were made with combination of other carotenoids, multivitamins,
herbal extracts and omega-3, 6 fatty acids. Patent applications are available on astaxanthin for
preventing bacterial infection, inflammation, vascular failure, cancer, cardiovascular diseases,
inhibiting lipid peroxidation, reducing cell damage and body fat, and improving brain function and
skin thickness (Table 5). Astaxanthin containing microorganisms or animals find many applications in
a wide range of commercial activities, the reason for which astaxanthin enriched microalgae
production can provide more attractive benefits.
Table 4. Astaxanthin products from various companies and its use for various purposes.
Brand Name
Dosage form
Ingredients
Company Name
Purpose
Physician Formulas
Soft gel/Tablets
2 mg/4 mg-AX
Physician formulas vitamin
company
Antioxidant
Eyesight Rx
Tablet
AX, vitamin-C, plant
extracts
Physician formulas Vitamin
company
Vision function
KriaXanthin
Soft gel
1.5 mg-AX, EPA, DHA
Physician formulas vitamin
company
Antioxidant
Astaxanthin Ultra
Soft gel
4 mg-AX
AOR
Cardiovascular
health/gastrointestinal
Astaxanthin Gold
Soft gel
4 mg-AX
Nutrigold
Eye/joint/skin/immune
health
Best Astaxanthin
Soft gel
6 mg-AX, CX
Bioastin
Cell membrane/blood
flow
Dr.Mercola
Capsules
4 mg AX, 325 mg
Omega-3 ALA
Dr. Mercola premium
supplements
Aging/muscle
Solgar
Soft gel
5 mg-AX
Solgar global manufacture
Healthy skin
Astaxanthin
Cream
AX, herbal extracts
True botanica
Face moisturizing
Mar. Drugs 2014, 12 140
Table 4. Cont.
astavita ex
Capsules
8 mg AX, T3
Fuji Chemical Industry
Agingcare
astavita SPORT
Capsules
9 mg AX, T3 and zinc
Fuji Chemical Industry
Sports nutrition
AstaREAL
Oil, powder, water
soluble, biomass
AX, AX-esters
Fuji Chemical Industry
Soft gel, tablet,
beverages, animal
feed, capsules
AstaTROL
Oil
AX
Fuji Chemical Industry
Cosmetics
AstaFX
Capsules
AX
Purity and products evidence
based nutritional supplements
Skin/cardiovascular
function
Pure Encapsulations
Capsules
AX
Synergistic nutrition
Antioxidant
Zanthin Xp-3
Soft gel capsules
2 mg, 4 mg-AX
Valensa
Human body
Micro Algae Super
Food
Soft gel
4 mg AX
Anumed intel biomed
company
heart/eye/joint
(Information obtained from the respective company websites); AX, astaxanthin, AXE, astaxanthin esters, CX,
canthaxanthin, DHA, docosahexaenoic acid, EPA, eicosapentaenoic acid, ALA, alpha linolenic acid, T3, tocotrienol.
Table 5. Recent patent applications for astaxanthin.
Patent No.
Title
Purpose
References
US20060217445
Natural astaxanthin extract reduces DNA oxidation
Reduce endogenous oxidative
damage
[147]
US20070293568
Neurocyte protective agent
Neuroprotection
[148]
US20080234521
Crystal forms of astaxanthin
Nutritional dosage
[149]
US20080293679
Use of carotenoids and carotenoid derivatives analogs
for reduction/ inhibition of certain negative effects of
COX inhibitors
Inhibit of lipid peroxidation
[150]
US20090047304
Composition for body fat reduction
Inhibits body fat
[151]
US20090069417
Carotenoid oxidation products as chemopreventive and
chemotherapeutic agents
Cancer prevention
[152]
US20090136469
Formulation for oral administration with beneficial
effects on the cardiovascular system
Cardiovascular protection
[153]
US20090142431
Algal and algal extract dietary supplement composition
Dietary supplement
[154]
US20090297492
Method for improving cognitive performance
Improving brain function
[155]
US20100158984
Encapsulates
Capsules
[156]
US20100204523
Method of preventing discoloration of carotenoid
pigment and container used therefor
Prevention of discoloration
[157]
US20100267838
Pulverulent carotenoid preparation for colouring drinks
Drinks
[158]
US20100291053
Inflammatory disease treatment
Preventing inflammatory disease
[159]
US20120004297
Agent for alleviating vascular failure
Preventing vascular failure
[160]
US20120114823
Feed additive for improved pigment retention
Fish feed
[161]
US20120238522
Carotenoid containing compositions and methods
Preventing bacterial infections
[162]
US20120253078
Agent for improving carcass performance in
finishing hogs
Food supplements
[163]
US20130004582
Composition and method to alleviate joint pain
Reduced joint pain and
symptoms of osteoarthritis
[164]
US20130108764
Baked food produced from astaxanthin containing dough
Astaxanthin used in baked food
[165]
Mar. Drugs 2014, 12 141
11. Conclusion
The current research data on astaxanthin is encouraging and have resulted from well controlled
trials in in vitro and in vivo models. Astaxanthin showed potential effects on various diseases including
cancers, hypertension, diabetes, cardiovascular, gastrointestinal, liver, neurodegenerative, and skin
diseases. Its antioxidant properties are used against oxidative damage in diseased cells. Recently, our
laboratory isolated and characterized astaxanthin and its esters from Haematococcus and checked their
biological activities in in vitro and in vivo models, confirming that astaxanthin and its esters show
potential biological activities in animal models. However, there is a lack of research on astaxanthin
esters (mono-di) and their metabolic pathways in biological systems. Future research should focus on
effects of astaxanthin esters on various biological activities and their uses in nutraceutical and
pharmaceutical applications. Astaxanthin mono-diesters may increase biological activities better than
the free form which can be easily absorbed into the metabolism. Further research requires to be
investigated on their metabolic pathways and also molecular studies in in vitro and in vivo models for
their use in commercial purposes.
Acknowledgments
The first author thanks the University of Malaya Research Grant (UMRG RP001i-13SUS),
University of Malaya, Kuala Lumpur, Malaysia for providing financial support for this project.
Conflicts of Interest
The authors declare no conflict of interest.
References
1. Higuera-Ciapara, I.; Felix-Valenzuela, L.; Goycoolea, F.M. Astaxanthin: A review of its
chemistry and applications. Crit. Rev. Food Sci. Nutr. 2006, 46, 185196.
2. 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,
58D68D.
3. Roche, F. Astaxanthin: Human food safety summary. In Astaxanthin As a Pigmenter in Salmon
Feed, Color Additive Petition 7C02 1 1, United States Food and Drug Administration;
Hoffman-La Roche Ltd.: Basel, Switzerland, 1987; p. 43.
4. Sarada, R.; Tripathi, U.; Ravishankar, G.A. Influence of stress on astaxanthin production in
Haematococcus pluvialis grown under different culture conditions. Process Biochem. 2002, 37,
623627.
5. Ranga Rao, A. Production of astaxanthin from cultured green alga Haematococcus pluvialis and
its biological activities. Ph.D. Thesis, University of Mysore, Mysore, India, 15 May 2011.
6. Sarada, R.; Ranga Rao, A.; Sandesh, B.K.; Dayananda, C.; Anila, N.; Chauhan, V.S.;
Ravishankar, G.A. Influence of different culture conditions on yield of biomass and value added
products in microalgae. Dyn. Biochem. Proc. Biotechnol. Mol. Biol. 2012, 6, 7785.
Mar. Drugs 2014, 12 142
7. Kidd, P. Astaxanthin, cell membrane nutrient with diverse clinical benefits and anti-aging
potential. Altern. Med. Rev. 2011, 16, 355364.
8. Guerin, M.; Huntley, M.E.; Olaizola, M. Haematococcus astaxanthin: Applications for human
health and nutrition. Trends Biotechnol. 2003, 21, 210216.
9. Yang, Y.; Kim, B.; Lee, J.Y. Astaxanthin structure, metabolism, and health benefits. J. Hum.
Nutr. Food Sci. 2013, 1, 1003:11003:11.
10. 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, 443449.
11. 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, 150165.
12. Yamashita, E. Astaxanthin as a medical food. Funct. Foods Health Dis. 2013, 3, 254258.
13. Dhankhar, J.; Kadian, S.S.; Sharma, A. Astaxanthin: A potential carotenoid. Int. J. Pharm. Sci.
Res. 2012, 3, 12461259.
14. Ranga Rao, A.; Sindhuja, H.N.; Dharmesh, S.M.; Sankar, K.U.; Sarada, R.; Ravishankar, G.A.
Effective inhibition of skin cancer, tyrosinase, and antioxidative properties by astaxanthin and
astaxanthin esters from the green alga Haematococcus pluvialis. J. Agric. Food Chem. 2013, 61,
38423851.
15. Ranga Rao, A.; Baskaran, V.; Sarada, R.; Ravishankar, G.A. In vivo bioavailability and
antioxidant activity of carotenoids from micro algal biomassA repeated dose study. Food Res.
Int. 2013, 54, 711717.
16. Ranga Rao, A.; Harshvardhan Reddy, A.; Aradhya, S.M. Antibacterial properties of Spirulina
platensis, Haematococcus pluvialis, Botryococcus braunii micro algal extracts. Curr. Trends
Biotechnol. Pharm. 2010, 4, 809819.
17. Ranga Rao, A.; Raghunath Reddy, R.L.; Baskaran, V.; Sarada, R.; Ravishankar, G.A.
Characterization of microalgal carotenoids by mass spectrometry and their bioavailability and
antioxidant properties elucidated in rat model. J. Agric. Food Chem. 2010, 58, 85538559.
18. Ranga Rao, A.; Sarada, R.; Baskaran, V.; Ravishankar, G.A. Identification of carotenoids from
green alga Haematococcus pluvialis by HPLC and LC-MS (APCI) and their antioxidant
properties. J. Microbiol. Biotechnol. 2009, 19, 13331341.
19. Lorenz, R.T. A Technical Review of Haematococcus Algae; NatuRose Technical Bulletin
#060; Cyanotech Corporation: Kailua-Kona, HI, USA, 1999; pp. 112.
20. EFSA (European Food Safety Authority). Opinion of the scientific panel on additives and
products or substances used in animal feed on the request from the European commission on the
safety of use of colouring agents in animal human nutrition. EFSA J. 2005, 291, 140.
21. 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, 216222.
22. Aflalo, C.; Meshulam, Y.; Zarka, A.; Boussiba, S. On the relative efficiency of two- vs. one-stage
production of astaxanthin by the green alga Haematococcus pluvialis. Biotechnol. Bioeng. 2007,
98, 300305.
Mar. Drugs 2014, 12 143
23. Torzillo, G.; Goksan, T.; Faraloni, C.; Kopecky, J.; Masojídek, J. Interplay between
photochemical activities and pigment composition in an outdoor culture of Haematococcus
pluvialis during the shift from the green to red stage. J. Appl. Phycol. 2003, 15, 127136.
24. Olaizola, M. Commercial production of astaxanthin from Haematococcus pluvialis using
25,000-liter outdoor photobioreactors. J. Appl. Phycol. 2000, 12, 499506.
25. Wang, J.; Han, D.; Sommerfeld, M.R.; Lu, C.; Hu, Q. Effect of initial biomass density on growth
and astaxanthin production of Haematococcus pluvialis in an outdoor photobioreactor.
J. Appl. Phycol. 2013, 25, 253260.
26. Zhang, D.H.; Lee, Y.K. Enhanced accumulation of secondary carotenoids in a mutant of the
green alga, Chlorococcum sp. J. Appl. Phycol. 1997, 9, 459463.
27. Zhang, D.H.; Ng, M.L.; Phang, S.M. Composition and accumulation of secondary carotenoids in
Chlorococcum sp. J. Appl. Phycol. 1997, 9, 147155.
28. Wang, Y.; Peng, J. Growth associated biosynthesis of astaxanthin in heterotrophic Chlorella
zofingiensis (Chlorophyta). World J. Microbiol. Biotechnol. 2008, 24, 19151922.
29. Orosa, M.; Torres, E.; Fidalgo, P.; Abalde, J. Production and analysis of secondary carotenoids in
green algae. J. Appl. Phycol. 2000, 12, 553556.
30. Banerjee, K.; Ghosh, R.; Homechaudhuri, S.; Mitra, A. Biochemical composition of marine
macroalgae from gangetic delta at the apex of Bay of Bengal. Afr. J. Basic Appl. Sci. 2009, 1,
96104.
31. Yokoyama, A.; Adachi, K.; Shizuri, Y. New carotenoid glucosides, astaxanthin glucoside and
adonimxanthin glucoside, isolated from the astaxanthin producing marine bacterium,
Agrobacterium aurantiacum. J. Nat. Prod. 1995, 58, 19291933.
32. EFSA (European Food Safety Authority). Safety and efficacy of panaferd-AX(red carotenoid
rich bacterium Paracoccus carotinifaciens as feed additive for salmon and trout. EFSA J. 2007,
546, 130.
33. Kim, J.H.; Kang, S.W.; Kim, S.W.; Chang, H.I. High-level production of astaxanthin by
Xanthophyllomyces dendrorhous mutant JH1 using statistical experimental designs. Biosci.
Biotechnol. Biochem. 2005, 69, 17431748.
34. De la Fuente, J.L.; Rodríguez-Sáiz, M.; Schleissner, C.; ez, B.; Peiro, E.; Barredo, J.L.
High-titer production of astaxanthin by the semi-industrial fermentation of Xanthophyllomyces
dendrorhous. J. Biotechnol. 2010, 148, 144146.
35. Yamaoka, Y. Microorganism and production of carotenoid compounds. U.S. Patent 7,374,908
B2, 20 May 2008.
36. Meyers, S.P.; Bligh, D. Characterization of astaxanthin pigments from heat processed crawfish
waste. J. Agric. Food Chem. 1981, 3, 505508.
37. Foss, P.; Renstrøm, B.; Liaaen-Jensen, S. Natural occurrence of enantiomeric and meso
astaxanthin. 7-crustaceans including zooplankton. Comp. Biochem. Physiol. B 1987, 86B,
313314.
38. Sarada, R.; Vidhyavathi, R.; Usha, D.; Ravishankar, G.A. An efficient method for extraction of
astaxanthin from green alga Haematococcus pluvialis. J. Agric. Food Chem. 2006, 54,
75857588.
Mar. Drugs 2014, 12 144
39. Kobayashi, M.; Kurimura, Y.; Sakamoto, Y.; Tsuji, Y. Selective extraction of astaxanthin and
chlorophyll from the green alga Haematococcus pluvialis. Biotechnol. Tech. 1997, 11, 657660.
40. Mendes-Pinto, M.M.; Raposo, M.F.J.; Bowen, J.; Young, A.J.; Morais, R. Evaluation of different
cell disruption processes on encysted cells of Haematococcus pluvialis: Effects on astaxanthin
recovery and implications for bio-availability. J. Appl. Phycol. 2001, 13, 1924.
41. Kang, C.D.; Sim, S.J. Direct extraction of astaxanthin from Haematococcus culture using
vegetable oils. Biotechnol. Lett. 2008, 30, 441444.
42. Ni, H.; Chen, Q.H.; He, G.Q.; Wu, G.B.; Yang, Y.F. Optimization of acidic extraction of
astaxanthin from Phaffia rhodozyma. J. Zhejiang Univ. Sci. B 2008, 9, 5159.
43. Ruen-ngam, D.; Shotipruk, A.; Pavasant, P. Comparison of extraction methods for recovery of
astaxanthin from Haematococcus pluvialis. Sep. Sci. Technol. 2010, 46, 6470.
44. Storebakken, T.; Sørensen, M.; Bjerkeng, B.; Harris, J.; Monahan, P.; Hiu, S. Stability of
astaxanthin from the red yeast, Xanthophyllomyces dendrorhous, during feed processing: Effects
of enzymatic cell wall disruption and extrusion temperature. Aquaculture 2004, 231, 489500.
45. Machmudah, S.; Shotipruk, A.; Goto, M.; Sasaki, M.; Hirose, T. Extraction of astaxanthin from
Haematococcus pluvialis using supercritical CO2 and ethanol as entrainer. Ind. Eng. Chem. Res.
2006, 45, 36523657.
46. Nobre, B.; Marcelo, F.; Passos, R.; Beiro, L.; Palavra, A.; Gouveia, L.; Mendes, R. Supercritical
carbon dioxide extraction of astaxanthin and other carotenoids from the microalga
Haematococcus pluvialis. Eur. Food Res. Technol. 2006, 223, 787790.
47. Wang, L.; Yang, B.; Yan, B.; Yao, X. Supercritical fluid extraction of astaxanthin from
Haematococcus pluvialis and its antioxidant potential in sunflower oil. Innov. Food Sci. Emerg.
Technol. 2012, 13, 120127.
48. Ranga Rao, A.; Sarada, R.; Ravishankar, G.A. Stabilization of astaxanthin in edible oils and its
use as an antioxidant. J. Sci. Food Agric. 2007, 87, 957965.
49. Anarjan, N.; Tan, C.P. Chemical stability of astaxanthin nanodispersions in orange juice and
skimmed milk as model food systems. Food Chem. 2013, 139, 527531.
50. Raposo, M.F.J.; Morais, A.M.M.B.; Morais, R.S.C. Effects of spray drying and storage on
astaxanthin content of Haematococcus pluvialis biomass. World J. Microbiol. Biotechnol. 2012,
28, 12531257.
51. Villalobos-Castillejos, F.; Cerezal-Mezquita, P.; Hemandez-De Jesus, M.L.; Barragan-Huerta,
B.E. Production and stability of water-dispersible astaxanthin oleoresin from Phaffia rhodozyma.
Int. J. Food Sci. Technol. 2013, 48, 12431251.
52. Yuan, C.; Du, L.; Jin, Z.; Xu, X. Storage stability and antioxidant activity of complex of
astaxanthin with hydroxypropyl-β-cyclodextrin. Carbohydr. Polym. 2013, 91, 385389.
53. Higuera-Ciapara, I.; Felix-Valenzuela, L.; Goycoolea, F.M.; Arguelles-Monal, W.
Microencapsulation of astaxanthin in a chitosan matrix. Carbohydr. Polym. 2004, 56, 4145.
54. Tachaprutinun, A.; Udomsup, T.; Luadthong, C.; Wanichwecharungruang, S. Preventing the
thermal degradation of astaxanthin through nanoencapsulation. Int. J. Pharm. 2009, 374,
119124.
55. Ribeiro, H.S.; Rico, L.G.; Badolato, G.G.; Schubert, H. Production of O/W emulsions containing
astaxanthin by repeated premix membrane emulsification. J. Food Sci. 2005, 70, E117E123.
Mar. Drugs 2014, 12 145
56. Chen, X.; Chen, R.; Guo, Z.; Li, C.; Li, P. The preparation and stability of the inclusion complex
of astaxanthin with β-cyclodextrin. Food Chem. 2007, 101, 15801584.
57. Barros, M.P.; Marin, D.P.; Bolin, A.P.; de ssia Santos Macedo, R.; Campoio, T.R.;
Fineto, C., Jr.; Guerra, B.A.; Polotow, T.G.; Vardaris, C.; Mattei, R.; et al. Combined astaxanthin
and fish oil supplementation improves glutathione-based redox balance in rat plasma and
neutrophils. Chem. Biol. Interact. 2012, 197, 5867.
58. Otton, R.; Marin, D.P.; Bolin, A.P.; de ssia Santos Macedo, R.; Campoio, T.R.; Fineto, C.J.;
Guerra, B.A.; Leite, J.R.; Barros, M.P.; Mattei, R. Combined fish oil and astaxanthin
supplementation modulates rat lymphocyte function. Eur. J. Nutr. 2012, 51, 707718.
59. Page, G.I.; Davies, S.J. Astaxanthin and canthaxanthin do not induce liver or kidney
xenobiotic-metabolizing enzymes in rainbow trout (Oncorhynchus mykiss Walbaum). Comp.
Biochem. Physiol. C Toxicol. Pharmacol. 2002, 133C, 443451.
60. Osterlie, M.; Bjerkeng, B.; Liaaen-Jensen, S. Plasma appearance and distribution of astaxanthin
E/Z isomers in plasma lipoproteins of after single dose administration of astaxanthin. J. Nutr.
Biochem. 2000, 11, 482492.
61. 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,
19281932.
62. Olson, J.A. Carotenoids: absorption, transport, and metabolism of carotenoids in humans. Pure
Appl. Chem. 2004, 66, 10111016.
63. Naguib, Y.M.A. Antioxidant activities of astaxanthin and related carotenoids. J. Agric. Food
Chem. 2000, 48, 11501154.
64. Liu, X.; Osawa, T. Cis astaxanthin and especially 9-cis astaxanthin exhibits a higher antioxidant
activity in vitro compared to the all trans isomer. Biochem. Biophys. Res. Commun. 2007, 357,
187193.
65. Miki, W. Biological functions and activities of animal carotenoids. Pure Appl. Chem. 1991, 63
141146.
66. Martin, H.D.; Jager, C.; Ruck, C.; Schmidt, M. Anti and pro-oxidant properties of carotenoids.
J. Prakt. Chem. 1999, 341, 302308.
67. Augusti, P.R.; Quatrin, A.; Somacal, S.; Conterato, G.M.; Sobieskim, 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, 4249.
68. Kamath, B.S.; Srikanta, B.M.; Dharmesh, S.M.; Sarada, R.; Ravishankar, G.A. Ulcer preventive
and antioxidative properties of astaxanthin from Haematococcus pluvialis. Eur. J. Pharmacol.
2008, 590, 387395.
69. Goto, S.; Kogure, K.; Abe, K.; Kimata, Y.; 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,
251258.
70. Liu, B.H.; Lee, Y.K. Effect of total secondary carotenoids extracts from Chlorococcum sp. on
Helicobacter pylori infected BALB/c mice. Int. Immunopharmacol. 2003, 3, 979986.
Mar. Drugs 2014, 12 146
71. Bennedsen, M.; Wang, X.; Willen, R.; Wadstrom, T.; Andersen, L.P. Treatment of H. pylori
infected mice with antioxidant astaxanthin reduces gastric inflammation, bacterial load and
modulates cytokine release by splenocytes. Immunol. Lett. 1999, 70, 185189.
72. 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. 2010, 7, 110.
73. Haines, D.D.; Varga, B.; Bak, I.; Juhasz, B.; Mahmoud, F.F; Kalantari, H.; Gesztelyi, R.; Lekli,
I.; Czompa, A.; Tosaki, A. Summative interaction between astaxanthin, Ginkgo biloba extract
(EGb761) and vitamin C in suppression of respiratory inflammation: A comparison with
ibuprofen. Phytother. Res. 2011, 25, 128136.
74. Ohgami, K.; Shiratori, K.; Kotake, S.; Nishida, T.; Mizuki, N.; Yazawa, K.; Ohno, S. Effects of
astaxanthin on lipopolysaccharide-induced inflammation in vitro and in vivo. Invest. Ophthalmol.
Vis. Sci. 2003, 44, 26942701.
75. Suzuki, Y.; Ohgami, K.; Shiratori, K.; Jin, X.H.; Llieva, I.; Koyama, Y.; Yazawa, K.; Yoshidia,
K.; Kase, S.; Ohno, S. Suppressive effects of astaxanthin against rat endotoxin induced uveitis by
inhibiting the NF-kB signaling pathway. Exp. Eye Res. 2006, 82, 275281.
76. Hama, S.; Takahashi, K.; Inai, Y.; Shiota, K.; Sakamoto, R.; Yamada, A.; Tsuchiya, H.;
Kanamura, K.; Yamashita, E.; Kogure, K. Protective effects of topical application of a poorly
soluble antioxidant astaxanthin liposomal formulation on ultraviolet-induced skin damage.
J. Pharm. Sci. 2012, 101, 29092916.
77. Santos, S.D.; Cahú, T.B.; Firmino, G.O.; de Castro, C.C.; Carvalho, L.B.J.; Bezerra, R.S.; Filho,
J.L. Shrimp waste extract and astaxanthin: Rat alveolar macrophage, oxidative stress and
inflammation. J. Food Sci. 2012, 77, 141146.
78. Uchiyama, K.; Naito, Y.; Hasegawa, G.; Nakamura, N.; Takahashi, J.; Yoshikawa, T.
Astaxanthin protects β-cells against glucose toxicity in diabetic db/db mice. Redox Rep. 2002, 7,
290293.
79. Otton, R.; Marin, D.P.; Bolin, A.P.; Santos, R.C.; Polotow, T.G.; Sampaio, S.C.; De Barros, M.P.
Astaxanthin ameliorates the redox imbalance in lymphocytes of experimental diabetic rats.
Chem. Biol. Interact. 2010, 186, 306315.
80. Nakano, M.; Onodera, A.; Saito, E.; Tanabe, M.; Yajima, K.; Takahashi, J.; Nguyen, V.C. Effect
of astaxanthin in combination with α-tocopherol or ascorbic acid against oxidative damage in
diabetic ODS rats. J. Nutr. Sci. Vitaminol. 2008, 54, 329334.
81. Nishigaki, I.; Rajendran, P.; Venugopal, R.; Ekambaram, G.; Sakthisekaran, D.; Nishigaki, Y.
Cytoprotective role of astaxanthin against glycated protein/iron chelate-induced toxicity in
human umbilical vein endothelial cells. Phytother. Res. 2010, 24, 5459.
82. 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,
522529.
83. Bhuvaneswari, S.; Arunkumar, E.; Viswanathan, P.; Anuradha, C.V. Astaxanthin restricts weight
gain, promotes insulin sensitivity and curtails fatty liver disease in mice fed an
obesity-promoting diet. Process Biochem. 2010, 45, 14061414.
Mar. Drugs 2014, 12 147
84. Bhuvaneswari, S.; Yogalakshmi, B.; Sreeja, S.; Anuradha, C.V. Astaxanthin reduces hepatic
endoplasmic reticulum stress and nuclear factor-κB-mediated inflammation in high fructose and
high fat diet-fed mice. Cell Stress Chaperones 2013, in press.
85. 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, 4959.
86. Kim, Y.J.; Kim, Y.A.; Yokozawa, T. Protection against oxidative stress, inflammation, and
apoptosis of high glucose- exposed proximal tubular epithelial cells by astaxanthin. J. Agric.
Food Chem. 2009, 57, 87938797.
87. Manabe, E.; Handa, O.; Naito, Y.; Mizushima, K.; Akagiri, S.; Adachi, S.; Takagi, T.; Kokura,
S.; Maoka, T.; Yoshikawa, T. Astaxanthin protects mesangial cells from hyperglycemia induced
oxidative signaling. J. Cell Biochem. 2008, 103, 19251937.
88. Fassett, R.G.; Combes, J.S. Astaxanthin: A potential therapeutic agent in cardiovascular disease.
Mar. Drugs 2011, 9, 447465.
89. 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, 686692.
90. Gross, G.J.; Lockwood, S.F. Acute and chronic administration of disodium disuccinate
astaxanthin (Cardax) produces marked cardioprotection in dog hearts. Mol. Cell. Biochem. 2005,
272, 221227.
91. Gross, G.J.; Hazen, S.L.; Lockwood, S.F. Seven day oral supplementation with Cardax
(disodium disuccinate astaxanthin) provides significant cardioprotection and reduces oxidative
stress in rats. Mol. Cell. Biochem. 2006, 283, 2330.
92. Monroy-Ruiz, J.; Sevilla, M.Á.; Carrón, R.; Montero, M.J. Astaxanthin-enriched-diet reduces
blood pressure and improves cardiovascular parameters in spontaneously hypertensive rats.
Pharmacol. Res. 2011, 63, 4450.
93. 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, 299305.
94. Nakao, R.; Nelson, O.L.; Park, J.S.; Mathison, B.D.; Thompson, P.A.; Chew, B.P. Effect of
astaxanthin supplementation on inflammation and cardiac function in BALB/c mice. Anticancer
Res. 2010, 30, 27212725.
95. 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
LDLR and ApoE mice. Atherosclerosis 2012, 222, 99105.
96. Wolf, G. Retinoids and carotenoids as inhibitors of carcinogenesis and inducers of cell-cell
communication. Nutr. Rev. 1992, 50, 270274.
97. Hanusch, M.; Stahl, W.; Schulz, W.A.; Sies, H. Induction of gap junctional communication by
4-oxoretinoic acid generated from its precursor canthaxanthin. Arch. Biochem. Biophys. 1995,
317, 423428.
Mar. Drugs 2014, 12 148
98. Hix, L.M.; Lockwood, S.F.; Bertram, J.S. Upregulation of connexin 43 protein expression and
increased gap junctional communication by water soluble disodium disuccinate astaxanthin
derivatives. Cancer Lett. 2006, 211, 2537.
99. Daubrawa, F.; Sies, H.; Stahl, W. Astaxanthin diminishes gap junctional intercellular
communication in primary human fibroblasts. J. Nutr. 2005, 135, 25072511.
100. Zhang, L.X.; Cooney, R.V.; Bertram, J.S. Carotenoids enhance gap junctional communication
and inhibit lipid peroxidation in C3H/10T1/2 cells: relationship to their cancer chemopreventive
action. Carcinogenesis 1991, 12, 21092114.
101. Zhang, L.X.; Cooney, R.V.; Bertram, J.S. Carotenoids up-regulate connexin-43 gene expression
independent of their provitamin A or antioxidant properties. Cancer Res. 1992, 52, 57075712.
102. Chew, B.P.; Park, J.S. Carotenoid action on the immune response. J. Nutr. 2004, 134,
257S261S.
103. Chew, B.P.; Park, J.S.; Wong, M.W.; Wong, T.S. A comparison of the anticancer activities of
dietary β-carotene, canthaxanthin and astaxanthin in mice in vivo. Anticancer Res. 1999, 19,
18491853.
104. Palozza, P.; Torelli, C.; Boninsegna, A.; Simone, R.; Catalano, A.; Mele, M.C.; Picci, N.
Growth-inhibitory effects of the astaxanthin-rich alga Haematococcus pluvialis in human colon
cancer cells. Cancer Lett. 2009, 283, 108117.
105. Tanaka, T.; Makita, H.; Ohnishi, M.; Mori, H.; Satoh, K.; Hara, A. Chemoprevention of rat oral
carcinogenesis by naturally occurring xanthophyll’s, astaxanthin and canthaxanthin. Cancer Res.
1995, 55, 40594064.
106. Tanaka, T.; Morishita, Y.; Suzui, M.; Kojima, T.; Okumura, A.; Mori, H. Chemoprevention of
mouse urinary bladder carcinogenesis by the naturally occurring carotenoid astaxanthin.
Carcinogenesis 1994, 15, 1519.
107. Jyonouchi, H.; Sun, S.; Iijima, K.; Gross, M.D. Antitumor activity of astaxanthin and its mode of
action. Nutr. Cancer 2000, 36, 5965.
108. Prabhu, P.N.; Ashokkumar, P.; Sudhandiran, G. Antioxidative and anti-proliferative effects of
astaxanthin during the initiation stages of 1,2-dimethyl hydrazineinduced experimental colon
carcinogenesis. Fund. Clin. Pharmacol. 2009, 23, 225234.
109. Nakao, R.; Nelson, O.L.; Park, J.S.; Mathison, B.D.; Thompson, P.A.; Chew, B.P. Effect of
dietary astaxanthin at different stages of mammary tumor initiation in BALB/c mice. Anticancer
Res. 2010, 30, 21712175.
110. Maoka, T.; Tokuda, H.; Suzuki, N.; Kato, H.; Etoh, H. Anti-oxidative, anti-tumor-promoting, and
anti-carcinogenesis activities of nitroastaxanthin and nitrolutein, the reaction products of
astaxanthin and lutein with peroxynitrite. Mar. Drugs 2012, 10, 13911399.
111. Jyonouchi, H.; Hill, R.; Tomita, Y.; Good, R. Studies of immunomodulating actions of
carotenoids. I. Effects of β-carotene and astaxanthin on murine lymphocyte functions and cell
surface marker expression in in vitro culture system. Nutr. Cancer 1991, 16, 93105.
112. Jyonouchi, H.; Zhang, L.; Gross, M.; Tomita, Y. Immunomodulating actions of carotenoids:
Enhancement of in vivo and in vitro antibody production to T-dependent antigens. Nutr. Cancer
1994, 21, 4758.
Mar. Drugs 2014, 12 149
113. Jyonouchi, H.; Sun, S.; Gross, M. Effect of carotenoids on in vitro immunoglobulin production
by human peripheral blood mononuclear cells: astaxanthin, a carotenoid without vitamin A
activity, enhances in vitro immunoglobulin production in response to a T-dependent stimulant
and antigen. Nutr. Cancer 1995, 23, 171183.
114. Park, J.S.; Mathison, B.D.; Hayek, M.G.; Massimino, S.; Reinhart, G.A.; Chew, B.P.
Astaxanthin stimulates cell-mediated and humoral immune responses in cats. Vet. Immunol.
Immunopathol. 2011, 144, 455461.
115. Choi, H.D.; Kang, H.E.; Yang, S.H.; Lee, M.G.; Shin, W.G. Pharmacokinetics and first-pass
metabolism of astaxanthin in rats. Br. J. Nutr. 2011, 105, 220227.
116. Sila, A.; Ayed-Ajmi, Y.; Sayari, N.; Nasri, M.; Martinez-Alvarez, O.; Bougatef, A. Antioxidant
and anti-proliferative activities of astaxanthin extracted from the shell waste of deep-water pink
shrimp (Parapenaeus longirostris). Nat. Prod. J. 2013, 3, 8289.
117. Kim, J.H.; Chang, M.J.; Choi, H.D.; Youn, Y.K.; Kim, J.T.; Oh, J.M.; Shin, W.G. Protective
effects of Haematococcus astaxanthin on oxidative stress in healthy smokers. J. Med. Food 2011,
14, 14691475.
118. 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, 15631571.
119. 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, 16111617.
120. Ishiki, M.; Nishida, Y.; Ishibashi, H.; Wada, T.; Fujisaka, S.; Takikawa, A.; Urakaze, M.;
Sasaoka, T.; Usui, I.; Tobe, K. Impact of divergent effects of astaxanthin on insulin signaling in
l6 cells. Endocrinology 2013, 154, 26002612.
121. Huangfu, J.; Liu, J.; Sun, Z.; Wang, M.; Jiang, Y.; Chen, Z.Y.; Chen, F. Anti-ageing effects of
astaxanthin-rich alga Haematococcus pluvialis on fruit flies under oxidative stress. J. Agric.
Food Chem. 2013, 6, 78007804.
122. Chew, W.; Mathison, B.D.; Kimble, L.L.; Mixter, P.F.; Chew, B.P. Astaxanthin decreases
inflammatory biomarkers associated with cardiovascular disease in human umbilical vein
endothelial cells. Am. J. Adv. Food Sci. Technol. 2013, 1, 117.
123. Park, J.S.; Mathison, B.D.; Hayek, M.G.; Zhang, J.; Reinhart, G.A.; Chew, B.P. Astaxanthin
modulates age-associated mitochondrial dysfunction in healthy dogs. J. Animal Sci. 2013, 91,
268275.
124. Gal, A.F.; Andrei, S.; Cernea, C.; Taulescu, M.; Catoi, C. Effects of astaxanthin supplementation
on chemically induced tumorigenesis in Wistar rats. Acta Vet. Scand. 2012, 54, 16.
125. Wibrand, K.; Berge, K.; Messaoudi, M.; Duffaud, A.; Panja, D.; Bramham, C.R.; Burri, L.
Enhanced cognitive function and antidepressant-like effects after krill oil supplementation in rats.
Lipids Health Dis. 2013, 12, 113.
126. Turkez, H.; Geyikoglu, F.; Yousef, M.I. Beneficial effect of astaxanthin on
2,3,7,8-tetrachlorodibenzo-p-dioxin-induced liver injury in rats. Toxicol. Ind. Health 2012, 29,
591599.
Mar. Drugs 2014, 12 150
127. Chan, K.C.; Pen, P.J.; Yin, M.C. Anti-coagulatory and anti-inflammatory effects of astaxanthin
in diabetic rats. J. Food Sci. 2012, 77, H76H80.
128. Dong, L.Y.; Jin, J.; Lu, G.; Kang, X.L. Astaxanthin attenuates the apoptosis of retinal ganglion
cells in db/db mice by inhibition of oxidative stress. Mar. Drugs 2013, 11, 960974.
129. 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, 96104.
130. 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, 520523.
131. Chang, C.H.; Chen, C.Y.; Chiou, J.Y.; Peng, R.Y.; Peng, C.H. Astaxanthin secured apoptic death
of PC12 cells induced by β-amyloid peptide 2535: Its molecular action targets. J. Med. Food
2010, 13, 548556.
132. Lu, Y.P.; Liu, S.Y.; Sun, H.; Wu, X.M.; Li, J.J.; Zhu, L. Neuroprotective effect of astaxanthin on
H2O2-induced neurotoxicity in vitro and on focal cerebral ischemia in vivo. Brain Res. 2010,
1360, 4048.
133. Stewart, J.S.; Lignell, A.; Pettersson, A.; Elfving, E.; Soni, M.G. Safety assessment of
astaxanthin rich microalgae biomass: acute and subchronic toxicity studies in rats. Food Chem.
Toxicol. 2008, 46, 30303036.
134. 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, 4752.
135. Kim, J.H.; Kim, Y.S.; Song, G.G.; Park, J.J.; Chang, H.I. Protective effect of astaxanthin on
naproxen-induced gastric antral ulceration in rats. Eur. J. Pharmacol. 2005, 514, 5359.
136. Petri, D.; Lundebye, A.K. Tissue distribution of astaxanthin in rats following exposure to graded
levels in the feed. Comp. Biochem. Physiol. C Toxicol. Pharmacol. 2007, 145, 202209.
137. Murata, K.; Oyagi, A.; Takahira, D.; Tsuruma, K.; Shimazawa, M.; Ishibashi, T.; Hara, H.
Protective effects of astaxanthin from paracoccus carotinifaciens on murine gastric ulcer models.
Phytother. Res. 2012, 26, 11261132.
138. Odeberg, M.J.; Lignell, A.; Pettersson, A.; Hoglund, P. Oral bioavailability of the antioxidant
astaxanthin in humans is enhanced by incorporation of lipid based formulations. Eur. J. Pharm.
Sci. 2003, 19, 299304.
139. Serebruany, V.; Malinin, A.; Goodin, T.; Pashkow, F. The in vitro effects of xancor, a synthetic
astaxanthine derivative, on hemostatic biomarkers in aspirin-naive and aspirin-treated subjects
with multiple risk factors for vascular disease. Am. J. Ther. 2010, 17, 125132.
140. Spiller, G.A.; Dewell, A. Safety of an astaxanthin rich Haemaotoccu pluvialis algal extract: A
randomized clinical trial. J. Med. Food 2003, 6, 5156.
141. Miyawaki, H.; Takahashi, J.; Tsukahara, H.; Takehara, I. Effects of astaxanthin on human blood
rheology. J. Clin. Biochem. Nutr. 2008, 43, 6974.
Mar. Drugs 2014, 12 151
142. 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, 311.
143. Parisi, V.; Tedeschi, M.; Gallinaro, G.; Varano, M.; Saviano, S.; Piermarocchi, S. Carotenoids
and antioxidants in age-related maculopathy italian study: multifocal electroretinogram
modifications after one year. Ophthalmology 2008, 115, 324333.
144. Katagiri, M.; Satoh, A.; Tsuji, S.; Shirasawa, T. Effects of astaxanthin rich Haematococcus
pluvialis extact on cognitive function: Arandomised double blind, placebo-controlled study.
J. Clin. Biochem. Nutr. 2012, 51, 102107.
145. Tominaga, K.; Hongo, N.; Karato, M.; Yamashita, E. Cosmetic benefits of astaxanthin on
humans subjects. Acta Biochim. Pol. 2012, 59, 4347.
146. Hashimoto, H.; Arai, K.; Hayashi, S.; Okamoto, H.; Takahashi, J.; Chikuda, M.; Obara, Y.
Effects of astaxanthin on antioxidation in human aqueous humor. J. Clin. Biochem. Nutr. 2013,
53, 17.
147. Chew, B.P.; Park, J.S. Natural astaxanthin extract reduces DNA oxidation. Patent
US20060217445, 28 September 2006.
148. Tsuji, S.; Shirasawa, T.; Shimizu, T. Neurocyte protective agent. Patent US20070293568,
23 December 2007.
149. Leigh, S.; Steven Leight, M.L.; Hogevest, P.V. Crystal forms of astaxanthin. Patent
US20080234521, 25 September 2007.
150. Lockwood, S.F.; Preston, M. Use of carotenoids and or carotenoid derivatives analogs for
reduction/inhibition of certain negative effects of COX inhibitors. Patent US20080293679,
27 November 2008.
151. Takahashi, J.; Yamashita, E.; Fukamauchi, M.; Tanka, I. Composition for body fat reduction.
Patent US20090047304, 8 June 2009.
152. Sharoni, Y.; Levy, J.; Sela, Y.; Nir, Z. Carotenoid oxidation products as chemo preventive and
chemotherapeutic agents. Patent US20090069417, 12 March 2009.
153. Senin, P.; Setnikar, I.; Rovati, A. Formulation for oral administration with beneficial effects on
the cardiovascular system. U.S. Patent 20090136469, 28 May 2009.
154. David, A.E.; Melchior, R. Algal and algal extract dietary supplement composition. Patent
US20090142431, 4 June 2009.
155. Satoh, A.; Tsuji, S. Method for improving cognitive performance. Patent US20090297492,
3 December 2009.
156. Qvyjt, F. Encapsulates. Patent US20100158984, 24 June 2010.
157. Tominaga, K.; Karato, M.; Hongo, N.; Yamashita, E. Method of preventing discoloration of
carotenoid pigment and container used therefor. Patent US20100204523, 12 August 2010.
158. Kopsel, C. Pulverulent carotenoid preparation for colouring drinks. Patent US20100267838,
21 October 2010.
159. Clayton, D.; Rutter, R. Inflammatory disease treatment. Patent US20100291053,
18 November 2010.
160. Higashi, N.; Takahashi, J. Agent for alleviating vascular failure. Patent US20120004297,
5 January 2012.
Mar. Drugs 2014, 12 152
161. Koppe, W.M.; Moeller, N.P.; Baardsen, G.K.L. Feed additive for improved pigment retention.
Patent US20120114823, 10 May 2012.
162. Jouni, Z.; Makhoul, Z. Carotenoid containing compositions and methods. Patent
US20120238522, 20 September 2012.
163. Monahan, P.; Hiu, S. Agent for improving carcass performance in finishing hogs. Patent
US20120253078, 4 October 2012.
164. Minatelli, J.A.; Thomas, S.; Rajendran, L.; Moerck, E. Composition and method to alleviate joint
pain. Patent US20130004582, 3 January 2013.
165. Ooi, Y.; Kitamura, A.; Yamashita, E. Baked food produced from astaxanthin containing dough.
Patent US 20130108764, 2 May 2013.
© 2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).
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... B-carotene takes 5-7 days, while lycopene takes 2-3 days to be eliminated. Astaxanthin's half-life (t 1 2 ) is 16 h [168]. Carotenoids are well tolerated with minimal side effects [168]; carotenoids are also non-toxic. ...
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Astaxanthin is a red pigment that belongs to the carotenoid family like β-carotene. And it’s found in seafood such as crustaceans: shrimp and crabs and fish: salmon and sea bream. Recently, astaxanthin has been reported to have antioxidant activity up to 100 times more potent than that of vitamin E against lipid peroxidation and about 40 times more potent than that of β-carotene on singlet oxygen quenching. Astaxanthin does not show any pro-oxidant activity and its main sight of action is on/in the cell membrane. Various important benefits to date have suggested for human health such as immunomodulation, anti-stress, anti-inflammation, LDL cholesterol oxidation suppression, enhanced skin health, improved semen quality, attenuating eye fatigue, sport performance and endurance, limiting exercised induced muscle damage, suppressing the development of life-style related diseases such as obesity, atherosclerosis, diabetes, hyperlipidemia and hypertension. Nowadays, the research and demand for natural astaxanthin in human health application are explosively growing worldwide. Especially, the clinicians use the astaxanthin extracted from the microalgae, Haematotoccus pluvialis as an add-on supplementation for the patients who are unsatisfied with the current medications or who can’t receive any medications because of their serious symptom. For example, the treatment enhances their daily activity levels or QOL in heart failure or benign prostatic hypertrophy/lower urinary tract symptom patients Other studies and trials are under way on chronic diseases such as non-alcoholic steatohepatitis, diabetes and CVD. We may call astaxanthin “a medical food” in the near future.Keywords: astaxanthin, medical food, Haematococcus, add-on supplementation
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Micro algae Spirulina platensis, Haematococcus pluvialis and Botryococcus braunii are cultured commercially and their productions are established in different parts of the world. In the present investigation the antibacterial properties of different solvent extracts of these three micro algae were evaluated. The maximum phenolic contents (128, 131, 110 μg/mg) was recorded in chloroform extracts of S. platensis, H. pluvialis and ethyl acetate extract of B. braunii. Hexane, chloroform, ethylacetate, acetone and methanol extracts of S. platensis, B. braunii and H. pluvialis were tested against important clinical bacterial isolates such as Bacillus subtilus, Bacillus cereus, Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, Listeria monocytogenes, Micrococcus luteus, Proteus mirabilis, Pseudomonas aeruginosa, Salmonella typhi, Staphylococcus aureus, Streptococcus fecalis and Yersinia enterocolitica. The antibacterial activity was determined by agar-well diffusion assay and minimum inhibitory concentration (MIC). Chloroform and ethlyacetate extracts of S. platensis showed highest inhibition against B. subtilus (18.12 mm and MIC at 200 ppm), while chloroform extract of H. pluvialis recorded highest inhibition against B. subtilus (17.32 mm and MIC at 150 ppm). In B. braunii, ethlyacetate extract exhibited maximum inhibition against E. aerogenes (15.11 mm and MIC at 300 ppm). We conclude that, S. platensis, H. pluvialis and B. braunii extracts can be used as bacteriostatic agents for suitable applications.