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Microalgal carotenoids: beneficial effects and potential in human health Cite this: Food Funct., 2014, 5, 413

Jie Zhang,a Zheng Sun,bc Peipei Sun,ad Tianpeng Chena and Feng Chen*a Received 21st November 2013 Accepted 16th December 2013

Microalgae are huge natural sources of high-value compounds with health-promoting properties. The carotenoids derived from microalgae have significant antioxidant and anti-inflammatory effects, which allow them to provide health benefits. In this article, the bioactivities of microalgal carotenoids are

DOI: 10.1039/c3fo60607d

reviewed. Emphasis is placed on astaxanthin, a ketocarotenoid with extraordinary potential for protecting

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against a wide range of diseases.

1. Introduction Carotenoids are responsible for coloring yellow, orange and red hues in higher plants, algae, bacteria, fungi and some animals. As important non-chlorophyll accessory pigments, carotenoids are essential in light harvesting and photoprotection in all photosynthetic organisms. In recent decades, there has been convincing evidence to support the association between higher carotenoid intakes and reduced chronic disease risks. A diet rich in carotenoids may help maintain health and wellness. For this reason, the worldwide demand for carotenoids has been markedly growing. The global carotenoid market is expected to reach $1.4 billion with an annual growth rate of 2.3% by 2018.1 So far, the main part of the commercial carotenoids has been chemically synthesized. Due to safety concerns, people give preference to the carotenoids obtained from natural sources. Microalgae, a subgroup of algae, are considered as one of the best commercial sources of natural carotenoids. The term ‘microalgae’ is not a taxonomy-based concept, but refers to single cell microscopic algae.2 Some microalgae, such as Spirulina, Chlorella and Dunaliella, are well known as functional foods and have achieved great commercial success in many countries. Microalgae occupy the bottom of the food chain in aquatic ecosystems. As a dominant body of the ocean, they are responsible for consuming approximately 40% of the overall amount of carbon annually on the planet.3 Microalgae can be grown using various culturing methods. With the aid of sunlight, they convert H2O and CO2 into organic compounds a

Institute for Food & Bioresource Engineering, College of Engineering, Peking University, Beijing, 100871, P. R. China. E-mail: [email protected]; Tel: +86 (10) 62745356

b

College of Fisheries and Life Science, Shanghai Ocean University, 201306, P. R. China

c

School of Energy and Environment, City University of Hong Kong, Hong Kong, P.R. China d

College of Light Industry and Food Sciences, South China University of Technology, Guangzhou, 510640, P. R. China

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autotrophically like higher plants. Meanwhile, microalgae can be fermented heterotrophically with similar physiological features to typical microorganisms.2 Distinct evolutionary strategies and variable habitats make microalgae inherent of producing various compounds as surviving strategies with diverse structures and unique activity. These compounds include carotenoids, polyunsaturated fatty acids, polysaccharides, peptides, vitamins, enzymes, amino acids, as well as other bioactive chemicals. They offer various benecial effects on human health.4–7 Moreover, the distribution of these components varies as the cultural factors change during growth of microalgae, such as light, temperature, pH, oxygen concentration, and nutritional level. With this advantage, some high-value products could be achieved through the optimization of culture conditions. Microalgae such as D. salina, Haematococcus pluvialis, C. vulgaris, C. zongiensis and C. pyrenoidosa have been successfully developed in mass production of carotenoids (b-carotene, astaxanthin, canthaxanthin, lutein and others).2,8–11 In the present article, we review the recent advances in research and application of microalgal carotenoids in human health. Great emphasis is placed on the ketocarotenoid astaxanthin.

2.

Microalgal carotenoids

2.1. Chemical structures and distribution Carotenoids are of isoprenoid origin derived from a 40-carbon polyene chain backbone structure with cyclic groups. Carotenoids are divided into carotenes (hydrocarbons containing no oxygen) such as a-carotene, b-carotene and lycopene, and xanthophylls (hydrocarbons containing oxygen element) including lutein, zeaxanthin and violaxanthin. Primary carotenoids, such as a-carotene, b-carotene and lutein, are directly involved in photosynthesis, and they are essential for cellular survival. Secondary carotenoids, especially astaxanthin and canthaxanthin, accumulate when exposed to specic environmental stimuli (carotenogenesis).12,13

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Fig. 1 Chemical structures of carotenoids and unique cyclic end groups from microalgae.

Structures of some common carotenoids are shown in Fig. 1. Carotenoids in algae are species-specic and therefore can be used as important chemotaxonomic markers.14 The distribution of principle carotenoids in various microalgae is summarized in Table 1. Ketocarotenoids such as astaxanthin and canthaxanthin are abundantly present in algae, whereas they rarely occur in higher plants. Some species in Adonis are the only higher plants which can produce ketocarotenoids.15 The acetylene (C^C) is also only found in algae such as alloxanthin and diadinoxanthin.14 Allene (C]C]C) is a unique structure in natural products, and fucoxanthin is the rst found allenic carotenoid, which was obtained from brown algae.16 Epoxy carotenoids are also abundant in algae, such as antheraxanthin, violaxanthin and fucoxanthin. These diverse and unique structures allow carotenoids to exert a wide range of physiological effects.

cell-signaling molecules. The moderate level of oxidative stress is important in the regulation of many life processes, such as mediating the oxygen deprivation-induced stress responses, defending against infectious agents, modulating cellular signaling pathways and inducing cellular proliferation.17 However, once the redox homeostasis is in disorder, they can trigger a chain reaction to destroy the cellular function molecules or skeleton to cause aberrant cell death, which sequentially contributes to the development of a number of diseases.18 These injuries induced by oxidative damage may be restrained by endogenous antioxidases and exogenous antioxidants such as carotenoids.18,19 Benecial roles of carotenoids in the prevention and treatment of various diseases have been deeply investigated (Table 2). The common chemical backbone of carotenoids is the polyene chain with a long conjugated double bond system. This chain may be terminated by cyclic end groups containing oxygen-bearing substitutes. The electron-rich conjugated system of the polyene and functional cyclic end groups determine the antioxidant activities of carotenoids together.20 Carotenoids can scavenge harmful radicals through 3 ways: electron transfer, radical adduct formation and hydrogen atom transfer.21–24 Car + Rc / Carc+ + R (electron transfer) Car + Rc / [Car/R]c (radical adduct formation) Car + Rc / Car( H)c + RH (hydrogen atom transfer)

There are a number of methods for testing the antioxidant activity of carotenoids, and they may lead to different or even contrary outcomes,25 which make an accurate evaluation difficult. Liposomes are considered as good mimic systems of membranes to evaluate the antioxidant capacity of bioactive

2.2. Bioactivity and disease prevention 2.2.1. Antioxidant effects. Oxidative molecules such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) are well recognized as potentially harmful or benecial

Table 1

Distribution of principle carotenoids in various microalgae

Carotenoids

Microalgae

Quantitya (mg g 1)

a-Carotene b-Carotene Lutein

D. salina D. salina C. protothecoides D. salina Scenedesmus almeriensis Galdieria sulphuraria H. pluvialis C. zongiensis G. sulphuraria D. salina

2.7  0.5123 138.3  10.0123 4.6,124 5.4125 6.6  0.9123 5.3126 0.4  0.1127 22.7,128 40.0,57 98.0129 0.9,130 1.0,10,131 2.2,132 6.8,128 0.6  0.1127 11.3  1.6123

Astaxanthin

Zeaxanthin a

Different quantities of carotenoids correspond to different culturing modes for the same microalgae.

414 | Food Funct., 2014, 5, 413–425

The antioxidant carotenoids responsible for the prevention of chronic diseases

Table 2

Chronic diseases

Carotenoids

Neurodegenerative diseases Stroke Alzheimer's disease Parkinson's disease

Lutein,51 astaxanthin63 Astaxanthin,133 b-carotene133 b-Carotene134

Cardiovascular diseases Atherosclerosis Hypertension

Lutein,135,136 astaxanthin137 Astaxanthin62,29

Diabetes Diabetic retinopathy Diabetic nephropathy

Lutein,138 zeaxanthin139 Astaxanthin105,107

Ocular protective Cancer Osteoporosis Male infertility Hepatoprotective effect

Lutein140 Fucoxanthin,73 astaxanthin73 b-Cryptoxanthin141 Astaxanthin142 Astaxanthin143

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compounds, because of the structural similarity between liposomes and cell membranes.26,27 The scavenging capacity of marine carotenoids against reactive species was investigated based on the uorescence loss of a uorescent lipid (C11-BODIPY581/591) in liposomes (Table 3).27 Astaxanthin exhibited the most powerful effects among all carotenoids. Its scavenging function against peroxyl radicals (ROOc) and peroxynitrite anions (ONOO ) was stronger than a-tocopherol. Its overall antioxidant activity was also stronger than quercetin, a well-known bioactive avone. In another study, the in vitro antioxidant action of astaxanthin was found to be 10 times stronger than zeaxanthin, lutein, tunaxanthin, canthaxanthin and b-carotene, and 100 times stronger than a-tocopherol.28 Astaxanthin may also convert free radicals into more stable products by donating the electrons, and this resonance-stabilized carbon centered radicals can prevent the peroxidation of astaxanthin in a wide variety of living organisms.20,29,30 Such potent antioxidant action may be attributed to the unique structure of astaxanthin, i.e. the presence of the oxo (carbonyl and hydroxyl) groups on each ionone ring.29 The membrane–carotenoid interaction is also a vital factor. Astaxanthin has polar hydroxyl groups in each of two terminal rings, and these terminal rings could be located either in the membrane or on the membrane surface via intermolecular and intramolecular hydrogen bonds, which is favorable to scavenge radicals both at the surface and in the interior of the phospholipid membrane.31 On the other hand, apolar carotenoids, such as lycopene and b-carotene, located inside the hydrophobic core, lack exible interactions with phospholipid acyl chains. Accordingly, only the polyene chain could trap the active oxygen species near the membrane surface and in the membrane. Also, they could disorder the membrane bilayer, and exert potent pro-oxidant effects by disrupting the intermolecular packing of the phospholipid molecules.31,32 Researchers detected ve carotenoids and they found that only

astaxanthin showed a considerable reduction in lipid peroxidation of 41%, while others disturbed the membrane bilayer with pro-oxidant activities. Lycopene, b-carotene, zeaxanthin and lutein increased the lipid hydroperoxide (LOOH) level by 119%, 87%, 21% and 18%, respectively.32 The orientation and location within the membrane of carotenoids may inuence their differential effects on lipid peroxidation rates.32 These contrasting effects of carotenoids may explain the different even contrary results observed in clinical and experimental studies.33 2.2.2. Anti-inammatory effects. Innate inammation can be regarded as a defending and self-healing process. It eliminates the foreign pathogens to resolve infection and repair injured tissues by releasing inammatory chemicals.34 On the other hand, the aberrant inammation can cause more serious damage to a host tissue. Inammation chemicals attack normal tissues surrounding the infected tissue, and then lead to oxidative damage and extensive tissue inammation. Inammation is reported to be associated with a wide range of progressive diseases, including cancer, cardiovascular disease, neurodegeneration and metabolic disorders.35,36 Extensive studies showed that the elimination of chronic inammation could be an effective way to prevent various chronic diseases.36,37 Inammation involves the production of various inammatory chemicals, such as nitric oxide (NO), prostaglandin E2 (PGE2), interleukin (IL) family cytokines, ROS, and RNS. NO and PGE2 are synthesized by inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2), respectively. Nuclear factor-kB (NFkB) is a key transcription factor involved in the regulation of these proinammatory cytokines and mediators.38 The abnormal and constitutive activation of NF-kB is related to a number of chronic inammatory diseases. The inhibition of the NF-kB to suppress the expression of inammation-associated genes is a major way to exert anti-inammation activity. Dexamethasone, a commonly used anti-inammatory drug, is a good example.39 The classic pathway of NF-kB activation is shown in Fig. 2. Under normal conditions, NF-kB dimers, consisting of p65 and

Table 3 Peroxyl radical (ROOc), hydroxyl radical (HOc), hypochlorous acid (HOCl) and peroxynitrite anion (ONOO ) scavenging capacity of carotenoids27

Scavenging capacitya Carotenoids

ROOc

HOCl

ONOO

HOc

b-Carotene Zeaxanthin Lutein Lycopene Fucoxanthin Canthaxanthin Astaxanthin a-Tocopherol Quercetin Trolox Ascorbic acid Cysteine

0.14 0.56 0.6 0.08 0.43 0.04 0.64 0.48 0.84 1.00 NA 0.04

0.71 1.41 0.97 0.35 1.18 0.28 1.66 1.77 1.42 1.00 NA NA

NAb 3.87 4.81 0.4 6.26 0.1 9.4 NA 5.63 NA 0.41 1.00

1.02 0.77 0.78 0.31 NA NA 0.73 0.37 0.97 NA 1.00 0.02

a

The scavenging capacity was calculated considering as a reference: trolox for ROOc and HOc, cysteine for HOCl and ascorbic acid for ONOO . b NA: no activity was found for the tested concentrations.

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Schematic NF-kB pathway (modified from ref. 40). NF-kB dimers: composed of p65 and p50 subunits; IkBs: NF-kB inhibitors; IKK: IkB kinase.

Fig. 2

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p50 subunits, are bound to inhibitory kBs (IkBs) and retained within the cytoplasm. When the cells are stimulated with proinammatory factors, IkBs are rapidly phosphorylated by IkB kinase (IKK) and then degraded via proteasomal degradation. The free NF-kB is translocated into the nucleus, wherein it binds to target sites and induces the transcriptions of proinammatory mediators.40,41 Carotenoids are natural inhibitors of NF-kB signaling with anti-inammatory activity.42 Some microalgal carotenoids as inhibitors of NF-kB signaling are shown in Table 4. The effect of astaxanthin against various proinammatory diseases was investigated, which was associated with the suppression of proinammatory mediators and cytokines in vivo and ex vitro.39,43 Equipped with the scavenging effect against intracellular ROS, astaxanthin blocked the nuclear translocation of the NF-kB p65 subunit through the inhibition of IkB-a degradation and IKK activity in LPS-stimulated macrophages.39 Reports showed that the astaxanthin treatment inhibited the expression of inammation-related molecules, including VEGF, IL-6, ICAM-1, MCP-1, VEGFR-1, and VEGFR-2, and led to a signicant inhibition of macrophage inltration into choroidal neovascularization.43 The mechanism was related to the suppression of the NF-kB pathway, which included the IkB-a degradation and p65 nuclear translocation inhibition.43 These results suggested the possibility of taking astaxanthin supplementation as a therapeutic strategy to manage the choroidal neovascularization (CNV) associated with age-related macular degeneration.43

There are a number of studies investigating the antiinammatory role of lutein. They were conducted in human trials44 and animal models including pigs,45 turkeys,46 chickens47,48 and as murine.49–52 Lutein suppressed IkB-a degradation and NF-kB p65 nuclear translocation both in vivo and in vitro, suggesting its positive effects on the control of CNV development.53 It was reported that lutein has anti-inammation property against endotoxin-induced uveitis (EIU) by inhibiting IkB-a degradation as well as the subsequent production of proinammatory mediators such as NO, TNF-a, IL-6, PGE2, MCP-1, and MIP-2.54 Fucoxanthin inhibited the NF-kB activation by suppressing IkB-a degradation and the nuclear translocation of p50 and p65 proteins in lipopolysaccharide-induced RAW264.7 macrophages. The phosphorylation of mitogen-activated protein kinases (MAPKs) was also inhibited dose-dependently by fucoxanthin.41 Moreover, b-carotene blocked the nuclear translocation of the NF-kB p65 protein subunit and inhibited IkBa phosphorylation and degradation to inhibit the inammatory cytokines in vivo and in vitro.55 Violaxanthin extracted from microalgae C. ellipsoidea showed anti-inammatory effects based on the suppression of the NF-kB and MAPK pathways, suggesting that C. ellipsoidea has great potential as a candidate for the treatment of inammatory diseases.38 Alloxanthin and diatoxanthin showed remarkable suppression in the overexpression of COX-2 and iNOS in RAW264.7 cells induced by LPS.56 Also, oral administration of zeaxanthin was effective in the management of acute inammatory responses induced by ultraviolet B irradiation.52

Table 4 Inhibition of NF-kB signaling and some examples of therapeutic indications for carotenoidsa

Carotenoids

Therapeutic indications

Model

NF-kB inhibition

b-Carotene

Liver brosis,144 Crohn's disease,145 renal damage146 and CVD147

LPS-stimulated RAW264.7 cell, primary macrophages and LPS-administrated mice55

Lutein

AMD,53,148 atherosclerosis,44,45 retinal neural damage50,51 and ultraviolet radiation52,49

EIU in lewis rats54

IkB-a degradation and phosphorylation, p65 nuclear translocation, IKK activation, intracellular ROSY IkB-a degradation

CNV in C57BL/6J mice induced by laser photocoagulation and b-End3, RAW264.7 and ARPE-19 cell lines53 LPS-stimulated RAW264.7 cells41

IkB-a degradation, nuclear translocation of the p65 subunit

IkB-a degradation, p65 nuclear translocation

Fucoxanthin

Inammation

Astaxanthin

Colitis and colitis-associated colon carcinogenesis,149 cardiac function,150 diabetes90,108 and EIU151

CNV in C57BL/6J mice induced by laser photocoagulation43 LPS-stimulated RAW264.7 cells and primary macrophages39

Inammation

LPS-stimulated mouse RAW264.7 cells38

Violaxanthin

IkB-a degradation, p50 and p65 nuclear translocation

IkB-a degradation, IKK activity inhibition, p65 nuclear translocation inhibition p65 nuclear translocation, IkBa phosphorylation

Modulation expression of inammatory chemicals NOY, PGE2Y, iNOSY, COX2Y, TNF-aY, IL-1bY, NADPH oxidaseY

NOY, PGE2Y, iNOSY, COX2Y, TNF-aY, IL-6Y, MCP-1Y, MIP-2Y ICAM-1Y, MCP-1Y, VEGFY, macrophage inltrationY

NOY, PGE2Y, IL-1bY, TNFaY, IL-6Y, MAPK phosphorylationY VEGFY, IL-6Y, ICAM-1Y, MCP-1Y, VEGFR-1Y, VEGFR-2Y NOY, PGE2Y, TNF-aY, IL-1bY, iNOSY, COX-2Y

NOY, PGE2Y, iNOSY, COX-2Y

a

LPS, lipopolysaccharide; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; MCP-1, monocyte chemotactic protein -1; ICAM-1, intercellular adhesion molecule-1; CNV, choroidal neovascularization; EIU, endotoxin-induced uveitis; AMD, age-related macular degeneration.

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3.

Astaxanthin

As a powerful free-radical scavenger without any pro-oxidant effect, astaxanthin has attracted the most attention among carotenoids. The green microalga H. pluvialis accumulates the highest level of astaxanthin in nature, achieving up to 4–5% of dry weight.2,57 The use of astaxanthin as a nutraceutical was approved by the United States Food and Drug Administration in 1999, followed by as a feed additive for aquaculture in 1987.58 There is a growing body of evidence to support the role of astaxanthin in the prevention and treatment of many chronic diseases, such as cardiovascular disorders, cancer, diabetes and neurodegeneration.

3.1. Cardiovascular protection Cardiovascular diseases (CVDs) are a group of disorders of the heart and blood vessels, accounting for up to one third of all deaths worldwide.59 Smoking, obesity, heavy drinking, and elevated cholesterol are all potential risk factors for CVDs, which usually occur with other metabolic abnormalities including glucose intolerance, dyslipidemia, and diabetes.17 Atherosclerosis and hypertension are the most common causes of CVDs.60 Inammation and oxidative stress are implicated in the manifestations of CVDs. NF-kB plays important roles in CVDs. NF-kB activation has been identied in smooth muscle cells, macrophages, and endothelial cells of human atherosclerotic lesions.17 As mentioned earlier, astaxanthin is an excellent antiinammation agent via the inhibition of NF-kB activation. Astaxanthin is also effective in lowering density lipoprotein (LDL). The elevated oxidized LDL can induce macrophages to become foam cells, which subsequently forms the fatty streaks, and this is the feature of early atherogenesis. Results showed that in both in vivo and ex vitro experiments, astaxanthin suppressed the LDL oxidation dose-dependently.61 NO synthesized by the vascular endothelium plays an essential role in the regulation of blood pressure (BP). Astaxanthin showed antihypertensive effects in spontaneously hypertensive rats (SHR) via supplementation of 50 mg kg 1 astaxanthin for 5 weeks due to a NO-related mechanism.29,62 Also, astaxanthin showed antithrombotic and antihypertensive effects through the increase of NO bioavailability against ROS in cerebral vessels of stroke-prone SHR.63 Astaxanthin exerted BP lowering effects, which was associated with the improved endothelium-dependent vasodilatation in resistance vessels as well as the decrease of cO2 production stimulated by NAD(P)H oxidase.64 Some studies also investigated the relationship between astaxanthin supplementation and CVD relevant risks in human trials.65 A randomized and placebo-controlled human study for 12 weeks showed that astaxanthin supplementation ameliorated triglyceride (12 and 18 mg per day doses) and high-density lipoprotein (HDL) cholesterol (6 and 12 mg per day doses) and the increased adiponectin was correlated positively with HDL-cholesterol changes independent of the age and body mass index (BMI).66 The effects of astaxanthin derived from

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H. pluvialis were evaluated on the human blood rheology in 20 adult men using a single-blind method. It was found that the administration of astaxanthin (6 mg per day) for 10 days signicantly decreased the transit time for blood from 52.8 s to 47.6 s, which suggested the improvement of blood rheology.67 3.2. Anticancer effects Cancer is a severe health menace to human being. Global cases of cancer are predicted to reach 15 million new cases by 2020.68 Diets occupy approximately one-third of the overall risk of cancer, and they contribute up to 50% of the cancerization of some specic cells and tissues in the endometrium, breast, colorectum, pancreas, prostate and gall bladder.69 Thus, the adjustment in food nutritional components is one of the most important approaches for prophylaxis of oncological diseases. Astaxanthin has been demonstrated to possess potent cancer chemopreventive properties.70,71 The proposed antitumor mechanism of astaxanthin is shown in Fig. 3. Anti-proliferation is an important action. The supplementation of astaxanthin signicantly decreased the cell proliferation of colon,72,73 breast,74 urinary bladder,75 prostate76 and oral tumors.77 One feature of carcinogenesis is the loss of gap junctional communication (GJC). It is a cell-to-cell channel that enables the exchange of low-molecular weight compounds like nutrients and signaling molecules. GJC is important for homeostasis, growth control and development of cells.78 Connexin (Cx) proteins are major components responsible for intercellular communication in GJC and Cx43 is the most widely expressed connexin. Carotenoids and retinoids can induce the intercellular communication via activating gap junctions, which is correlated with the growth inhibition of chemically transformed cells.29,79,80 Disodium disuccinate astaxanthin, a water soluble synthetic astaxanthin derivative, functionally increased GJC through upregulating the Cx43 expression as well as increasing the size and number of Cx43 immunoreactive gap junctional plaques.81 However, astaxanthin strongly diminished the intercellular communication in primary human broblasts through changing the phosphorylation pattern of connexin43 to lower phosphorylation states.78

Fig. 3

Anticancer mechanism of astaxanthin and its derivatives (ASX).

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Dietary astaxanthin may help decrease a DNA damage biomarker and acute phase protein, and enhance the immune response in young healthy females by decreasing oxidative stress and inammation.82 Astaxanthin also improved antitumor immune responses to markedly attenuate the cancer metastasis. Such activities were associated with the inhibition of stress-induced lipid peroxidation. The effect of astaxanthin to improve the stress-induced immune dysfunction was much better than some well-known antioxidants such as a-tocopherol and b-carotene.83 Astaxanthin could protect against chemically induced colonic pre-neoplastic progression in rats via increasing the enzymic and non-enzymic antioxidants as well as inhibiting the lipid peroxidation.84 Moreover, astaxanthin may also induce the apoptosis of CBRH-7919 cells via the JAK1/STAT3 signaling pathway and changing the cell ultrastructure.85 The astaxanthin-rich alga H. pluvialis inhibited cell growth dose- and time-dependently by promoting apoptosis and cell cycle arrest in several colon cancer cell lines. The effects of the H. pluvialis extract on cell growth and apoptosis were more signicant than puried astaxanthin, which strongly supported the potential benets of this algal extract for cancer chemoprotection.73

3.3. Neuroprotective effects Neurons are hardly to regenerate. Non-reversible damage of nervous tissue causes the onset and development of degeneration disease. It was estimated that neurodegenerative diseases will surpass cancer to be the second biggest cause of death among the elderly by the 2040s.86 So far, the understanding of pathogenesis of neurodegenerative diseases remains incomplete, but oxidative stress is considered to be a common mediator existing in most neurodegenerative disorders, such as in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease.87 Antioxidants may function as the potential agents for the prevention and remission of neuron diseases. Astaxanthin is one of the very few compounds which could cross the blood-brain-barrier in addition to scavenging free radicals and quenching singlet oxygen. Astaxanthin was found to prevent the human neuroblastoma (SH-SY5Y) cells from the oxidative stress induced by docosahexaenoic acid hydroperoxides (DHA-OOH),88 6-hydroxydopamine (6-OHDA),89,90 and oxygen glucose deprivation.89 It also protected against the oxidative stress induced by 1-methyl-4phenylpyridinium in a rat pheochromocytoma (PC12) cell line.90,91 Astaxanthin inhibited the H2O2-mediated apoptotic cell death in mouse neural progenitor cells and abolished the 6-OHDA-induced reactive oxygen species generation via modulation of p38 and MEK signaling pathways and blocking of p38 MAPK activation and apoptosis, respectively.87,92 Additionally, astaxanthin suppressed the b-amyloid (Ab25-35)-induced cytotoxicity in SH-SY5Y and PC12 cells, indicating the potential of astaxanthin as a neuroprotectant as well as an adjuvant against Alzheimer's disease at the early stage.93,94 Astaxanthin also exhibited noticeable neuroprotective effects in vivo. It attenuated the brain damage induced by ischemiareperfusion in a dose-dependent manner,95,96 which suggested

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that astaxanthin may be useful for patients who are vulnerable or prone to ischemic events in clinical trials. Additionally, astaxanthin protected against the hypertension and stroke, and improved memory in vascular dementia, because it shortened the latency of escaping onto the platform and increased the time for crossing the former platform quadrant in the Morris water maze learning performance.29,62 Moreover, astaxanthin was found to have therapeutic potential for spinal cord injury with signicant improvement of neurotrophin-3 expression.97 Astaxanthin also antagonized the impairing effect induced by acute ethanol on propagation of cortical spreading depression independent of the age of experimental animals.98

3.4. Antidiabetic effects Diabetes mellitus is a very serious public health problem affecting millions of people around the world. Individuals affected by diabetes are prone to many long-term complications such as retinopathy, cataract, neuropathy and nephropathy.99 Some of these complications can even lead to death or permanent disability. A possible mechanism of diabetes is the formation and accumulation of advanced glycation end products (AGEs). They are generated in the late stage of Maillard reaction (or nonenzymatic glycation).99 In this reaction, a protein or lipid molecule is covalently bonded to a sugar without the controlling action of an enzyme. Once AGEs are formed in living organisms, they can generate cross-links between key molecules such as DNA, proteins and some enzymes, causing structural modication and functional impairments.100,101 Therefore, to nd AGE inhibitors, especially from the natural source, is a promising strategy for the prevention or treatment of diabetes. The AGE inhibitory potential of microalgae was studied. Results showed that the ethyl acetate extracts of several algae signicantly suppressed the formation of AGEs at the concentration of 500 ppm.102 Through screening of 20 species, the green alga Chlorella and diatom Nitzschia laevis were found to exhibit the strongest effects. The inhibition rates were 81.76– 88.02% and 91.68%, higher than that of aminoguanidine (1 mM, inhibition rate: 80.51%), a commonly used glycation inhibitor. Bio-guided experiments identied that astaxanthin is a major component responsible for the antiglycoxidative properties of C. zongiensis.103 Astaxanthin also showed benets in cell-based and animal studies. The effects of astaxanthin in human-derived retinal pigment epithelial cells were examined.104 Results showed that the generation of both endogenous and exogenous AGEs were signicantly suppressed, suggesting the positive roles of astaxanthin in controlling the progression of diabetic retinopathy. In another study, the astaxanthin supplementation remarkably contributed to the amelioration of diabetic nephropathy in diabetic db/db mice through inhibiting oxidative stress.105–107 Diabetic nephropathy is a leading cause of diabetes deaths. In addition to antioxidant activities, astaxanthin may also work through other ways. In high-glucose treated proximal tubular epithelial cells, the treatment of astaxanthin signicantly lowered the expression of

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iNOS, COX-2, inhibited the NF-kB nuclear translocation, and decreased the ratio of Bax/Bcl-2. These results indicated that anti-apoptosis and anti-inammatory activities of astaxanthin are also important mechanisms for the prevention of diabetic nephropathy.108 Additionally, the astaxanthin administration elevated antithrombin-III and protein C activities, which subsequently inhibited the activity of several proteases and inactivated coagulation factors. These results suggested the potential of astaxanthin to reduce the risk of diabetes-associated atherogenesis and thrombosis.109 Astaxanthin also improved the condition of diabetic complications associated with endothelial dysfunction via inhibiting the ox-LDL-LOX1-eNOS pathway.110 Moreover, astaxanthin may have the potential to be a good adjuvant in prophylaxis/recovery of lymphocyte dysfunctions associated with diabetic patients, especially when focusing on the re-establishment of the redox balance and a hypothetical antiapoptotic effect in lymphocytes. However, how to conrm the balance between efficient antioxidant protection and suitable proliferative capacities of diabetic lymphocytes is still an open question for exploring the biological activity of astaxanthin for the chronic disease treatment.111

3.5. Anti-obesity effects Obesity has been recognized by WHO as a global epidemic since 1997. Obese people are also prone to develop a number of chronic diseases such as cardiovascular disease, cancer, diabetes, hyperlipidemia, and hypertension. Hence, screening of anti-obesity agents, especially from natural sources, is of great importance.112,113 According to recent 53 publications found in PubMed (1990– 2013), astaxanthin as well as other 7 natural products stood out as the most promising anti-obesity agents, which were proved to be effective and safe for body weight management.112 Animal studies showed that the administration of astaxanthin at 6 mg kg 1 or 30 mg kg 1 signicantly reduced the body weight and adipose tissue weight gain induced by a high-fat diet, and also reduced the liver weight, liver triglyceride, plasma triglyceride and total cholesterol.114 Astaxanthin could not affect the energy intake but may have benecial effects on the endurance capacity and stimulate an increase in fatty acid utilization.114,115 Korean researchers conducted a randomized and double-blind trial involving overweight and obese young adults. They found that the daily administration of astaxanthin (5 mg and 20 mg) for 3 weeks effectively protected against the obesity-induced oxidative stress. The observed activities were due to the lowering plasma MDA and ISP levels as well as the increasing plasma TAC and SOD levels in overweight and obese groups.116 Another study showed that astaxanthin can prevent mitochondrial damage and alleviate the oxidative stress that is associated with nonalcoholic fatty liver disease.117 Insulin is an important hormone to maintain glucose homeostasis, and type 2 diabetes is associated with insulin resistance. There are some pieces of evidence suggesting the connection between type 2 diabetes and obesity: fat cells are more resistant to insulin than muscle cells, and it makes glucose accumulate in the blood.118 Astaxanthin has been

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reported to ameliorate the insulin resistance in mice.119,120 It may protect cells from oxidative stress generated by various stimuli including TNFa and palmitate to ameliorate insulin resistance in vitro.121 The treatment of astaxanthin (6 mg kg 1) was also reported to improve insulin signaling by activating the post-receptor insulin signaling and reducing oxidative stress, lipid accumulation and proinammatory cytokines in obese mice.118 Besides possessing antioxidant activities, astaxanthin was found to have antagonistic effects on adipocytes and agonistic effects on peritoneal macrophages as a novel selective peroxisome proliferator-activated receptor (PPAR) g modulator.122

4. Conclusions Microalgal carotenoids possess diverse biological functions and may have great impact on human health. In addition to carotenoids, microalgae are also rich in a wide range of high-value products with benecial health potential. Currently, a major limitation for the commercialization of these microalgaederived ingredients is their high cost, as the yield of microalgae is still too low to meet the requirements of industrial-scale application. Therefore, the development of cost-efficient modes of mass cultivation could be a vital direction for microalgal biotechnology.

Acknowledgements The present study was supported by the State Oceanic Administration of China, the 973 project (2011CB200904) and the 863 project (2012AA02A707) of the Ministry of Science and Technology of China.

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