Pharmaceutical and nutraceutical potential of natural bioactive pigment: astaxanthin

doi:10.1007/s13659-022-00347-y

摘要/Abstract

摘要： Astaxanthin (3,3'-dihydroxy-β,β-carotene-4,4'-dione) is an orange-red, lipophilic keto-carotenoid pigment. It is majorly found in marine ecosystems particularly in aquatic animals such as salmon, shrimp, trout, krill, crayfish, and so on. It is also synthesized in microalgae Heamatococcus pluvialis, Chlorococcum, Chlorella zofingiensis, red yeast Phaffia rhodozyma and bacterium Paracoccus carotinifaciens. Some aquatic and terrestrial creatures regarded as a primary and secondary sources of the astaxanthin producing and accumulating it through their metabolic pathways. Astaxanthin is the powerful antioxidant, nutritional supplement as well as promising therapeutic compound, observed to have activities against different ravaging diseases and disorders. Researchers have reported remarkable bioactivities of astaxanthin against major non-communicable chronic diseases such as cardiovascular diseases, cancer, diabetes, neurodegenerative, and immune disorders. The current review discusses some structural aspects of astaxanthin. It further elaborates its multiple potencies such as antioxidant, anti-inflammatory, anti-proliferative, anti-cancer, anti-obese, anti-diabetic, anti-ageing, anti-TB, anti-viral, anti-COVID 19, neuro-protective, nephro-protective, and fertility-enhancing properties. These potencies make it a more precious entity in the preventions as well as treatments of prevalent systematic diseases and/or disorders. Also, the review is acknowledging and documenting its powerful bioactivities in relation with the pharmaceutical as well as nutraceutical applicability.

关键词: Astaxanthin, Nutritional supplement, Therapeutic compound, Chronic diseases, Fertility enhancer

Abstract: Astaxanthin (3,3'-dihydroxy-β,β-carotene-4,4'-dione) is an orange-red, lipophilic keto-carotenoid pigment. It is majorly found in marine ecosystems particularly in aquatic animals such as salmon, shrimp, trout, krill, crayfish, and so on. It is also synthesized in microalgae Heamatococcus pluvialis, Chlorococcum, Chlorella zofingiensis, red yeast Phaffia rhodozyma and bacterium Paracoccus carotinifaciens. Some aquatic and terrestrial creatures regarded as a primary and secondary sources of the astaxanthin producing and accumulating it through their metabolic pathways. Astaxanthin is the powerful antioxidant, nutritional supplement as well as promising therapeutic compound, observed to have activities against different ravaging diseases and disorders. Researchers have reported remarkable bioactivities of astaxanthin against major non-communicable chronic diseases such as cardiovascular diseases, cancer, diabetes, neurodegenerative, and immune disorders. The current review discusses some structural aspects of astaxanthin. It further elaborates its multiple potencies such as antioxidant, anti-inflammatory, anti-proliferative, anti-cancer, anti-obese, anti-diabetic, anti-ageing, anti-TB, anti-viral, anti-COVID 19, neuro-protective, nephro-protective, and fertility-enhancing properties. These potencies make it a more precious entity in the preventions as well as treatments of prevalent systematic diseases and/or disorders. Also, the review is acknowledging and documenting its powerful bioactivities in relation with the pharmaceutical as well as nutraceutical applicability.

Key words: Astaxanthin, Nutritional supplement, Therapeutic compound, Chronic diseases, Fertility enhancer

Apurva D. Patil, Pramod J. Kasabe, Padma B. Dandge. Pharmaceutical and nutraceutical potential of natural bioactive pigment: astaxanthin[J]. 应用天然产物, 2022, 12(4): 25-25.

Apurva D. Patil, Pramod J. Kasabe, Padma B. Dandge. Pharmaceutical and nutraceutical potential of natural bioactive pigment: astaxanthin[J]. Natural Products and Bioprospecting, 2022, 12(4): 25-25.

参考文献

1. Cooper DA, Eldridge AL, Peters JC. Dietary carotenoids and certain cancers, heart disease, and age-related macular degeneration:a review of recent research. Nutr Rev. 1999;57:201-14. 2. Krinsky NI, Johnson EJ. Carotenoid actions and their relation to health and disease. Mol Asp Med. 2005;26:459-516. 3. Ye VM, Bhatia SK. Pathway engineering strategies for production of beneficial carotenoids in microbial hosts. Biotechnol Lett. 2012;34:1405-14. 4. Henke NA, Heider SA, Peters-Wendisch P, Wendisch VF. Production of the marine carotenoid astaxanthin by metabolically engineered Corynebacterium glutamicum. Mar Drugs. 2016;14:124. 5. Goodwin TW. Metabolism, nutrition, and function of carotenoids. Annu Rev Nutr. 1986;6:273-97. 6. Bendich A, Olson JA. Biological actions of carotenoids. FASEB J. 1989;3:1927-32. 7. Johnson EA, An GH. Astaxanthin from microbial sources. Crit Rev Biotechnol. 1991;11:297-326. 8. Teo CL, Chee ML, Koh KH. COVID-19 awareness, knowledge and perception towards digital health in an urban multi-ethnic Asian population. Sci Rep. 2021;11:10795. 9. Olaizola M. The production and health benefits of astaxanthin. Marine nutraceuticals and functional foods. 1st ed. Boca Raton:CRC Press; 2008. p. 321-43. 10. Pereira CPM, Souza ACR, Vasconcelos AR, Prado PS, Name JJ. Antioxidant and anti-inflammatory mechanisms of action of astaxanthin in cardiovascular diseases (Review). Int J Mol Med. 2021;247:37-48. 11. Martin HD, Ruck C, Schmidt M, Sell S, Beutner S, Mayer B, Walsh R. Chemistry of carotenoid oxidation and free radical reactions. Pure Appl Chem. 1999;71:2253-62. 12. Nishida Y, Yamashita E, Miki W. Quenching activities of common hydrophilic and lipophilic antioxidants against singlet oxygen using chemiluminescence detection system. Carotenoid Sci. 2007;11:16-20. 13. Yamashita E. Extensive bioactivity of astaxanthin from Haematococcus pluvialis in human. Carotenoids:biosynthetic and biofunctional approaches, advances in experimental medicine and biology, vol. 1261. Singapore:Springer; 2021. p. 249-60. 14. Brotosudarmo THP, Limantara L, Setiyono E. Heriyanto. Hindawi Int J Food Sci. 2020;2020(2156582):1-16. 15. National Center for Biotechnology Information. PubChem Compound Summary for CID 5281224, Astaxanthin. https://pubchem.ncbi.nlm.nih.gov/compound/Astaxanthin. Accessed 23 Sept 2021. 16. Fassett RG, Coombes JS. Astaxanthin, oxidative stress, inflammation and cardiovascular disease. Future Cardiol. 2009;5:333-42. 17. Lockwood SF, Gross GJ. Disodium disuccinate astaxanthin (CardaxTM):antioxidant and antiinflammatory cardioprotection. Cardiovasc Drug Rev. 2005;23:199-216. 18. Fassett RG, Coombes JS. Astaxanthin in cardiovascular health and disease. Molecules (Basel, Switzerland). 2012;17:2030-48. 19. Khan SK, Malinski T, Mason RP, Kubant R, Jacob RF, Fujioka K, Denstaedt SJ, King TJ, Jackson HL, Hieber AD, et al. Novel astaxanthin prodrug (CDX-085) attenuates thrombosis in a mouse model. Thromb Res. 2010;126:299-305. 20. Lead Compound CDX-085. https://ir.cardaxpharma.com/press-releases/detail/124/cardax-to-be-granted-chinese-patent-protection-for-lead. Accessed 24 Oct 2021. 21. Stachowiak B, Szulc P. Astaxanthin for the food industry. Molecules. 2021;26:2666. 22. Pleissner D, Lin CSK. Valorisation of food waste in biotechnological processes. Sustain Chem Process. 2013;1:21. 23. Oslan SNH, Shoparwe NF, Yusoff AH, Rahim AA, Chang CS, Tan JS, Oslan SN, Arumugam K, Ariff AB, Sulaiman AZ, Mohamed MS. A review on Haematococcus pluvialis bioprocess optimization of green and red stage culture conditions for the production of natural astaxanthin. Biomolecules. 2021;11:256. 24. Johnson EA, Lewis MJ. Astaxanthin Formation by the Yeast Phaffia Rhodozyma. J Gen Microbiol. 1979;115:173-83. 25. Andersson M, Nieuwerburgh L, Snoeijs P. Pigment transfer from phytoplankton to zooplankton with emphasis on astaxanthin production in the Baltic Sea food web. Mar Ecol Prog Ser. 2003;254:213-24. 26. Cunningham FX, Gantt EA. Elucidation of the pathway to astaxanthin in the flowers of Adonis aestivalis. Plant Cell. 2011;23:3055-69. 27. Mawson R. U.S. Patent 5453565A. Accessed 23 Sept 2021. 28. Cunningham FX, Gantt EA. Portfolio of plasmids for identification and analysis of carotenoid pathway enzymes:Adonis Aestivalis as a case study. Photosynth Res. 2007;92:245-59. 29. Renstrøm B, Berger H, Liaaen-Jensen S. Esterified, optical pure (3S,3'S) astaxanthin from flowers of Adonis annua. Syst Ecol. 1981;9:249-50. 30. Li Y, Gong F, Guo S, Yu W, Liu J. Adonis amurensis is a promising alternative to Haematococcus as a resource for natural esterified (3S,3'S)-astaxanthin production. Plants. 2021;10:1059. 31. Czeczuga B. Investigations on carotenoids in Embryophyta. 1. Bryophyta. The Bryologist. 1980;83:21-8. 32. Takemura M, Misawa N. Carotenoid biosynthesis in liverworts. Carotenoids:biosynthetic and biofunctional approaches, advances in experimental medicine and biology, vol. 1261. Singapore:Springer; 2021. p. 115-20. 33. Misawa N, Takemura M, Maoka T. Carotenoid biosynthesis in animals:case of arthropods. Carotenoids:biosynthetic and biofunctional approaches, advances in experimental medicine and biology, vol. 1261. Singapore:Springer; 2021. p. 217-20. 34. Eom H, Lee CG, Jin E. Gene profile analysis in astaxanthin-induced Haematococcus pluvialis using a c-DNA microarray. Planta. 2006;223:1231-42. 35. Lee YK, Ding SY. Cell cycle and accumulation of astaxanthin in Haematococcus lacustris(Chlorophyta). J Phycol. 1994;30:445-9. 36. 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;98:300-5. 37. Rao AR, Raghunath Reddy RL, Baskaran V, Sarada R, Ravishankar GA. Characterization of microalgal carotenoids by mass spectrometry and their bioavailability and antioxidant properties elucidated in rat model. J Agric Food Chem. 2010;58:8553-9. 38. Lim KC, Yusoff FM, Shariff M, Kamarudin MS. Astaxanthin as feed supplement in aquatic animals. Rev Aquac. 2018;10:738-73. 39. Yuan JP, Chen F. Purification of trans-astaxanthin from a high-yielding astaxanthin ester-producing strain of the microalga Haematococcus pluvialis. Food Chem. 2000;68:443-8. 40. Chekanov K, Lobakova E, Selyakh I, Semenova L, Sidorov R, Solovchenko A. Accumulation of astaxanthin by a new Haematococcus pluvialis strain BM1 from the white sea coastal rocks (Russia). Mar Drugs. 2014;12:4504-20. 41. Khoo KS, Chew KW, Ooi CW, Ong HC, Ling TC, Show PL. Extraction of natural astaxanthin from Haematococcus pluvialis using liquid biphasic flotation system. Bioresour Technol. 2019;290:121794. 42. Jannel S, Caro Y, Bermudes M, Petit T. Novel Insights into the biotechnological production of Haematococcus pluvialis-derived astaxanthin:advances and key challenges to allow its industrial use as novel food ingredient. J Mar Sci Eng. 2020;8:789. 43. Lorenz RT, Cysewski GR. Commercial potential for Haematococcus microalgae as a natural source of astaxanthin. Trends Biotechnol. 2000;18:160-7. 44. GRAS Notice (GRN) No 700(U. S. Food and Drug Administration, 2017). https://www.fda.gov/downloads/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/ucm584383.pdf. Accessed 23 Sept 2021. 45. Davinelli S, Nielsen ME, Scapagnini G. Astaxanthin in skin health, repair, and disease:a comprehensive review. Nutrients. 2018;10:522. 46. Sifuentes LR, Marszalek JE, Carbajal GH, Hernández CC. Importance of downstream processing of natural astaxanthin for pharmaceutical application. Front Chem Eng. 2021;2:601483. 47. Johnson EA. Phaffia rhodozyma:colorful odyssey. Int Microbiol. 2003;6:169-74. 48. Kim JH, Kang SW, Kim SW, Chang HI. High-level production of astaxanthin by Xanthophyllomyces dendrorhous mutant JH1 using statistical experimental designs. Biosci Biotechnol Biochem. 2005;69:1743-8. 49. de la Fuente JL, Rodriguez-Saiz M, Schleissner C, Diez B, Peiro E, Barredo JL. High-titer production of astaxanthin by the semi-industrial fermentation of Xanthophyllomyces dendrorhous. J Biotechnol. 2010;148:144-6. 50. Kucsera J, Pfeiffer I, Takeo K. Biology of the red yeast Xanthophyllomyces dendrorhous(Phaffia rhodozyma). Mycoscience. 2000;41:195-9. 51. Barredo JL, García-Estrada C, Kosalkova K, Barreiro C. Biosynthesis of astaxanthin as a main carotenoid in the heterobasidiomycetous yeast Xanthophyllomyces dendrorhous. J Fungi. 2017;3:44. 52. Tran TN, Tran QV, Huynh HT, Hoang NS, Nguyen HC, Ngo DN. Astaxanthin production by newly isolated Rhodosporidium toruloides:optimization of medium compositions by response surface methodology. Not Bot Horti Agrobot Cluj-Napoca. 2019;47:320-7. 53. Tsubokura A, Yoneda H, Mizuta H. Paracoccus carotinifaciens sp. nov., a new aerobic Gram-negative astaxanthin-producing bacterium. Int J Syst Evol Microbiol. 1999;49:277-82. 54. Scientific Opinion of the Panel.(European Food Safety Authority, 2007). The EFSA Journal. 2007; 546:1-30. 55. Katsumata T, Ishibashi T, Kyle D. A sub-chronic toxicity evaluation of a natural astaxanthin-rich carotenoid extract of Paracoccus carotinifaciens in rats. Toxicol Reports. 2014;1:582-8. 56. Giannaccare G, Pellegrini M, Senni C, Bernabei F, Scorcia V, Cicero AFG. Clinical applications of astaxanthin in the treatment of ocular diseases:emerging insights. Mar Drugs. 2020;18:239. 57. Shah MM, Liang Y, Cheng JJ, Daroch M. Astaxanthin producing green microalga Haematococcus pluvialis:from single cell to high value commercial products. Front Plant Sci. 2016;7:531. 58. Yokoyama A, Miki W, Izumida H, Shizuri Y. New trihydroxy-keto-carotenoids isolated from an astaxanthin-producing marine bacterium. Biosci Biotechnol Biochem. 1996;60:200-3. 59. Matsuno T. Aquatic animal carotenoids. Fish Sci. 2001;67:771-89. 60. Maoka T. Carotenoid metabolism in aquatic animals. Carotenoids:biosynthetic and biofunctional approaches, advances in experimental medicine and biology, vol. 1261. Singapore:Springer; 2021. p. 29-50. 61. Tsushima M, Katsuyama M, Matsuno T. Metabolism of carotenoids in the apple snail, Pomacea canaliculata. Comp Biochem Physiol. 1997;118B:431-6. 62. Schiedt K, Bischof S, Glinz E. Recent progress on carotenoid metabolism in animals. Pure Apple Chem. 1991;63:89-100. 63. Manunta C. Astaxanthin in insects and other terrestrial arthropoda. Nature. 1948;162:298. 64. Harashima K, Ohno T, Sawachika T, Hidaka T, Ohnishi E. Carotenoids in orange pupae of the swallowtail, Papilio xuthus. Insect Biochem. 1972;2:29-48. 65. Maoka T, Kawase N, Ueda T, Nishida R. Carotenoids of dragonflies, from the perspective of comparative biochemical and chemical ecological studies. Biochem Syst Ecol. 2020;89:104001. 66. Veerman A. Carotenoid metabolism in Tetranychus urticae koch (Acari:Tetranychidae). Comp Biochem Physiol. 1974;47:101-16. 67. Wybouw N, Kurlos AH, Greenhalgh R, Bryon A, Kosterlitz O, Manabe Y, Osakabe M, et al. Convergent evolution of cytochrome P450s underlies independent origins of keto-carotenoid pigmentation in animals. Proc R Soc B Biol Sci. 2019;286:20191039. 68. Liaaen-Jensen S. Carotenoids in food chain. In:Britton G, Liaaen-Jensen S, Pfander H, editors. Carotenoids:biosynthesis and metabolism, vol. 3. Basel Switzerland:Birkhäuser; 1998. p. 359-71. 69. Maoka T, Akimoto N, Tsushima M, Komemushi S, Mezaki T, Iwase F, Takahashi Y, Sameshima N, Mori M, Sakagami Y. Carotenoids in marine invertebrates living along the Kuroshio current coast. Mar Drugs. 2011;9:1419-27. 70. Maoka T, Nakachi S, Kobayashi R, Mori M, Sakagami Y. A new carotenoid, 9Z,9'Z-tetrahydroastaxanthin, from the sea cucumber Plesiocolochirus minutus. Tetrahedron Lett. 2015;56:5954-5. 71. McGraw KJ. Colorful songbirds metabolize carotenoids at the integument. J Avian Biol. 2004;35:471-6. 72. Fox DL. Astaxanthin in the American Flamingo. Nature. 1955;175:942-3. 73. LaFountain AM, Pacheco CO, Prum RO, Frank HA. Nuclear magnetic resonance analysis of carotenoids from the burgundy plumage of the Pompadour Cotinga (Xipholena punicea) Arch. Biochem Biophys. 2013;539:133-41. 74. Maoka T. Carotenoid metabolism in terrestrial animals. Carotenoids:Biosynthetic and biofunctional approaches, advances in experimental medicine and biology, vol. 1261. Singapore:Springer; 2021. p. 51-66. 75. Yong YYR, Lee YK. Do carotenoids play a photoprotective role in the cytoplasm of Haematococcus lacustris(Chlorophyta)?J Phycol. 1991;30:257-61. 76. Hagen C, Bornman G, Braune W. Reversible lowering of modulated chlorophyll fluorescence after saturating flashes in Haematococcus lacustris(Volvocales) at room temperature. Physiol Plant. 1992;86:593-9. 77. Zlotnik IS, Sukenik A, Dubinsky Z. Physiological and photosynthetic changes during the formation of red aplanospores in the chlorophyte Haematococcus pluvialis. J Phycol. 1993;29:463-9. 78. Boussiba S, Bing W, Zarka A, Yuan JP, Chen F. Changes in pigment profiles of Haematococcus pluvialis during exposure to environmental stresses. Biotechnol Lett. 1999;21:601-4. 79. Lu F, Vonshak A, Boussiba S. Effect of temperature and irradiance on growth of Haematococcus plulialis(Chlorophyceae). J Phycol. 2004;30:829-33. 80. Tan S, Cunningham FX, Youmans M, Grabowski B, Sun Z, Gantt E. Cytochrome-f loss in astaxanthin accumulating red cells of Haematococcus pluvialis(Chlorophyceae):comparison of photosynthetic activity, photosynthetic enzymes and thylakoid membrane polypeptides in red and green cells. J Phycol. 1995;31:897-905. 81. Mehler AH. Studies on reaction of illuminated chloroplast. I. Mechanisms of the reduction of oxygen and other Hill reagents. Arch Biochem Biophys. 1951;33:65-77. 82. Elstner EF. Oxygen activation and oxygen toxicity. Annu Rev Plant Physiol. 1982;33:73-96. 83. Krinsky NI. Carotenoid protection against oxidation. Pure Appl Chem. 1979;51:649-60. 84. Allen RD. Dissection of oxidative stress tolerance using transgenic plants. Plant Physiol. 1995;107:1049-54. 85. Ye ZW, Jiang JG, Wu GH. Biosynthesis and regulation of carotenoids in Dunaliella:progresses and prospects. Biotechnol Adv. 2008;26:352-60. 86. Kobayashi M, Kakizono T, Nagai S. Enhanced carotenoid biosynthesis by oxidative stress in acetate-induced cyst cells of a green unicellular alga, Haematococcus pluvialis. Appl Environ Microbiol. 1993;59:867-73. 87. Fan L, Vonshak A, Zarka A, Boussiba S. Does astaxanthin protect Haematococcus against light damage?Zeitschrift für Naturforschung C. 1998;53:93-100. 88. Bouvier F, Backhaus RA, Camara B. Induction and control of chromoplast-specific carotenoid genes by oxidative stress. J Biol Chem. 1998;273:30651-9. 89. Rajesh K, Rohit MV, Mohan SV. Chapter-7:microalgae-based carotenoids production. In:Rastogi RP, Madamwar D, Pandey A, editors. Algal green chemistry. Elsevier; 2017. p. 139-47. 90. M.I.M. Mosquera, M.J. Galan, D.H. Mendez, Carotenoids extraction using CO2 in supercritical state, from kale (Brassica oleracea, Lin. var. acephala). Proceedings of International Congress on Pigments in Food Technology.(Sevilla, Spain, 1999), pp. 65-69 91. Vidhyavathi R, Venkatachalam L, Sarada R, Aswanthanrayana G, Ravishankar GA. Regulation of carotenoid biosynthetic genes and carotenoid accumulation in the green alga Haematococcus pluvialis under nutrient stress conditions. J Exp Bot. 2008;59:1409-18. 92. Hussein G, Sankawa U, Goto H, Matsumoto K, Watanabe H. Astaxanthin, a carotenoid with potential in human health and nutrition. J Nat Prod. 2006;69:443-9. 93. Hix LM, Frey DA, Mclaws MD, Osterlie M, Lockwood SF, Bertram JS. Inhibition of chemically-induced neoplastic transformation by a novel tetrasodium diphosphate astaxanthin derivative. Carcinogenesis. 2005;26:1634-41. 94. Kurihara H, Koda H, Asami S, Kiso Y, Tanaka T. Contribution of the antioxidative property of astaxanthin to its protective effect on the promotion of cancer metastasis in mice treated with restraint stress. Life Sci. 2002;70:2509-20. 95. Parisi V, Edeschi M, Gallinaro G, Varano M, Saviano S, Piermarocchi S. Carotenoids and antioxidants in age-related maculopathy Italian study. Ophthalmology. 2008;115:324-333.e2. 96. Seabra LMJ, Pedrosa LFC. Astaxanthin:structural and functional aspects. Rev Nutr. 2010;23:1041-50. 97. WHO Fact sheets (World Health Organization, 2021) https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds). Accessed 24 April 2022. 98. Puddu P, Puddu GM, Galletti L, Cravero E, Muscari A. Mitochondrial dysfunction as an initiating event in atherogenesis:a plausible hypothesis. Cardiology. 2005;103:137-41. 99. Spahis S, Borys JM, Levy E. Metabolic syndrome as a multifaceted risk factor for oxidative stress. Antioxid Redox Signal. 2017;26:445-61. 100 Vona R, Gambardella L, Cittadini C, Straface E, Pietraforte D. Biomarkers of oxidative stress in metabolic syndrome and associated diseases. Oxid Med Cell Longev. 2019;2019:8267234. 101 Guerin M, Huntley ME, Olaizola M. Haematococcus astaxanthin:applications for human health and nutrition. Trends Biotechnol. 2003;21:210-6. 102 Hussein G, Goto H, Oda S, Sankawa U, Matsumoto K, Watanabe H. Antihypertensive potential and mechanism of action of astaxanthin:III. Antioxidant and histopathological effects in spontaneously hypertensive rats. Biol Pharm Bull. 2006;29:684-8. 103 Maoka T, Etoh H. Some biological functions of carotenoids in Japanese food. Functional Foods of the East. Boca Raton:CRC Press; 2010. p. 85-97. 104 Zhang L, Wang H. Multiple mechanisms of anti-cancer effects exerted by astaxanthin. Mar Drugs. 2015;13:4310-30. 105 Kishimoto Y, Yoshida H, Kondo K. Potential anti-atherosclerotic properties of astaxanthin. Mar Drugs. 2016;14:35. 106 Yoshida H, Yanai H, Ito K, Tomono Y, Koikeda T, Tsukahara H, Tada N. Administration of natural astaxanthin increases serum HDL-cholesterol and adiponectin in subjects with mild hyperlipidemia. Atherosclerosis. 2010;209:520-3. 107 Miyawaki H, Takahashi J, Tsukahara H, Takehara I. Effects of astaxanthin on human blood rheology. J Clin Biochem Nutr. 2008;43:69-74. 108 Chen Y, Li S, Guo Y, Yu H, Bao Y, Xin X, Yang H, Ni X, Wu N, Jia D. Astaxanthin attenuates hypertensive vascular remodeling by protecting vascular smooth muscle cells from oxidative stress induced mitochondrial dysfunction. Oxid Med Cell Longev. 2020;2020:4629189. 109 Pashkow FJ, Watumull DG, Campbell CL. Astaxanthin:a novel potential treatment for oxidative stress and inflammation in cardiovascular disease. Am J Cardiol. 2008;101:59D-68D. 110 Ramesh C, Vinithkumar NV, Kirubagaran R, Venil CK, Dufossé L. Multifaceted applications of microbial pigments:current knowledge, challenges and future directions for public health implications. Microorg. 2019;7:186. 111 Preuss HG, Echard B, Yamashita E, Perricone NV. High dose astaxanthin lowers blood pressure and increases insulin sensitivity in rats:Are these effects interdependent?Int J Med Sci. 2011;8:126-38. 112 Hussein G, Nakamura M, Zhao Q, Iguchi T, Goto H, Sankawa U, Watanabe H. Antihypertensive and neuroprotective effects of astaxanthin in experimental animals. Biol Pharm Bull. 2005;28:47-52. 113 Yanai H, Ito K, Yoshida H, Tada N. Antihypertensive effects of astaxanthin. Integr Blood Press Control. 2008;1:1-3. 114 Mashhadi NS, Zakerkish M, Mohammadiasl J, Zarei M, Mohammadshahi M, Haghighizadeh MH. Astaxanthin improves glucose metabolism and reduces blood pressure in patients with type 2 diabetes mellitus. Asia Pac J Clin Nutr. 2018;27:341-6. 115 Becker RC. The role of blood viscosity in the development and progression of coronary artery disease. Cleve Clin J Med. 1993;60:353-8. 116 Monroy-Ruiz J, Sevilla MÁ, Carrón R, Montero MJ. Astaxanthin-enriched-diet reduces blood pressure and improves cardiovascular parameters in spontaneously hypertensive rats. Pharmacol Res. 2011;63:44-50. 117 Sasaki Y, Kobara N, Higashino S, Giddings JC, Yamamoto J. Astaxanthin inhibits thrombosis in cerebral vessels of stroke-prone spontaneously hypertensive rats. Nutr Res. 2011;31:784-9. 118 Hu R, Saw CL-L, Yu R, Kong A-NT. Regulation of NF-E2-related factor 2 signaling for cancer chemoprevention:antioxidant coupled with anti-inflammatory. Antioxid Redox Signal. 2010;13:1679-98. 119 Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394-424. 120 Patridge E, Gareiss P, Kinch MS, Hoyer D. An analysis of FDA-approved drugs:natural products and their derivatives. Drug Discov Today. 2016;21:204-7. 121 Faraone I, Sinisgalli C, Ostuni A, Armentano MF, Carmosino M, Milella L, Russo D, Labanca F, Khan H. Astaxanthin anticancer effects are mediated through multiple molecular mechanisms:a systematic review. Pharmacol Res. 2020;155:104689. 122 Gradelet S, Astorg P, Le Bon A-M, Bergès R, Suschetet M. Modulation of aflatoxin B1 carcinogenicity, genotoxicity and metabolism in rat liver by dietary carotenoids:evidence for a protective effect of CYP1A inducers. Cancer Lett. 1997;114:221-3. 123 Mortensen A, Skibsted LH, Sampson J, Rice-Evans C, Everett SA. Comparative mechanisms and rates of free radical scavenging by carotenoid antioxidants. FEBS Lett. 1997;418:91-7. 124 Murakami A, Nakashima M, Koshiba T, Maoka T, Nishino H, Yano M, Sumida T, Kim OK, Koshimizu K, Ohigashi H. Modifying effects of carotenoids on superoxide and nitric oxide generation from stimulated leukocytes. Cancer Lett. 2000;149:115-23. 125 Santocono M, Zurria M, Berrettini M, Fedeli D, Falcioni G. Influence of astaxanthin, zeaxanthin and lutein on DNA damage and repair in UVA-irradiated cells. J Photochem Photobiol B Biol. 2006;85:205-15. 126 Yang Y, Yang I, Cao M, Z-y S, Wu R, Guo Y, Fang M, Kong A-N. Fucoxanthin elicits epigenetic modifications, Nrf2 activation and blocking transformation in mouse skin JB6 P+cells. AAPS J. 2018;20:32. 127 Chen Y-T, Kao C-J, Huang H-Y, Huang S-Y, Chen C-Y, Lin Y-S, Wen Z-H, Wang H-MD. Astaxanthin reduces MMP s, suppresses cancer cell migrations, and triggers apoptotic caspases of in vitro and in vivo models in melanoma. J Funct Food. 2017;31:20-31. 128 X-d S, J-j Z, M-r W, W-b L, X-b G, Lv C. Astaxanthin induces mitochondria mediated apoptosis in rat hepatocellular carcinoma CBRH-7919 cells. Biol Pharm Bull. 2011;34:839-44. 129 Shao Y, Ni Y, Yang J, Lin X, Li J, Zhang L. Astaxanthin inhibits proliferation and induces apoptosis and cell cycle arrest of mice H22 hepatoma cells. Med Sci Monit. 2016;22:2152-60. 130 Sowmya PR, Arathi BP, Vijay K, Baskaran V, Lakshminarayana R. Astaxanthin from shrimp efficiently modulates oxidative stress and allied cell death progression in MCF-7 cells treated synergistically with β-carotene and lutein from greens. Food Chem Toxicol. 2017;106(Pt A):58-69. 131 Koklesova L, Liskova A, Samec M, Buhrmann C, Samuel SM, Varghese E, Ashrafizadeh M, Najafi M, Shakibaei M, Büsselberg D, Giordano FA, Golubnitschaja O, Kubatka P. Carotenoids in cancer apoptosis-the road from bench to bedside and back. Cancers. 2020;12:2425. 132 Ko JC, Chen JC, Wang TJ, Zheng HY, Chen WC, Chang PY, Lin YW. Astaxanthin down-regulates Rad51 via inactivation of AKT kinase to enhance mitomycin C-induced cytotoxicity in human non-small cell lung cancer cells. Biochem Pharmacol. 2016;105:91-100. 133 Nagaraj S, Rajaram MG, Arulmurugan P, Baskaraboopathy A, Karuppasamy K, Jayappriyan KR, Sundararaj R, Rengasamy R. Antiproliferative potential of astaxanthin-rich alga Haematococcus pluvialis Flotow on human hepatic cancer (HepG2) cell line. Biomed Prev Nutr. 2012;2:149-53. 134 Hormozi M, Ghoreishi S, Baharvand P. Astaxanthin induces apoptosis and increases activity of antioxidant enzymes in LS-180 cells. Artif Cells Nanomed Biotechnol. 2019;47:891-5. 135 Lung Diseases, Environmental Health Topics (National Institute of Environmental Health Sciences, 2022), https://www.niehs.nih.gov/health/topics/conditions/lung-disease/index.cfm. Accessed 24 April 2022. 136 Kim JH, Chang MJ, Choi HD, Youn YK, Kim JT, Oh JM, Shin WG. Protective effects of Haematococcus astaxanthin on oxidative stress in healthy smokers. J Med Food. 2011;14:1469-75. 137 Cheng J, Eroglu A. The promising effects of astaxanthin on lung diseases. Adv Nutr. 2021;12:850-64. 138 IDF Diabetes Atlas, 9th edn.(International Diabetes Federation:Brussels, Belgium, 2019) ISBN 978-2-930229-87-4. 139 Newsholme P, Cruzat VF, Keane KN, Carlessi R, de Bittencourt PIH. Molecular mechanisms of ROS production and oxidative stress in diabetes. Biochem J. 2016;473:4527-50. 140 Luc K, Schramm-Luc A, Guzik TJ, Mikolajcyk TP, Sangiovanni E, Martinelli G, Bossi L, Carpentier-Maguire E, Tchamgoue AD, Agbor G, et al. Oxidative stress and inflammatory markers in prediabetes and diabetes. J Physiol Pharmacol. 2019;70:809-24. 141 Landon R, Gueguen V, Petite H, Letourneur D, Pavon-Djavid G, Anagnostou F. Impact of astaxanthin on diabetes pathogenesis and chronic complications. Mar Drugs. 2020;18:357. 142 Roohbakhsh A, Karimi G, Iranshahi M. Carotenoids in the treatment of diabetes mellitus and its complications:a mechanistic review. Biomed Pharmacother. 2017;91:31-42. 143 Wang J-J, Chen Z-Q, Lu W-Q. Hypoglycemic effect of astaxanthin from shrimp waste in alloxan-induced diabetic mice. Med Chem Res. 2012;21:2363-7. 144 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;7:290-3. 145 Sayahi M, Shirali S. The antidiabetic and antioxidant effects of carotenoids:a review. Asian J Pharm Res Health Care. 2017;9:186-91. 146 Asayama K, Hayashibe H, Dobashi K, Uchida N, Nakane T, Kodera K, Shirahata A, Taniyama M. Decrease in serum adiponectin level due to obesity and visceral fat accumulation in children. Obesity. 2003;11:1072-9. 147 Ibrahim MM. Subcutaneous and visceral adipose tissue:structural and functional differences. Obes Rev. 2010;11:11-8. 148 Ishiki M, Nishida Y, Ishibashi H, Wada T, Fujisaka S, Takikawa A, et al. Impact of divergent effects of astaxanthin on insulin signaling in L6 cells. Endocrinology. 2013;154:2600-12. 149 Bhuvaneswari S, Anuradha CV. Astaxanthin prevents loss of insulin signaling and improves glucose metabolism in liver of insulin resistant mice. Can J Physiol Pharmacol. 2012;90:1544-52. 150 Hussein G, Nakagawa T, Goto H, Shimada Y, Matsumoto K, Sankawa U, Watanabe H. Astaxanthin ameliorates features of metabolic syndrome in SHR/NDmcr-cp. Life Sci. 2007;80:522-9. 151 Belalcazar LM, Lang W, Haffner SM, Hoogeveen RC, Pi-Sunyer FX, Schwenke DC, et al. Adiponectin and the mediation of HDL-cholesterol change with improved lifestyle:the Look AHEAD Study. J Lipid Res. 2012;53:2726-33. 152 Kitahara A, Takahashi K, Morita N, Murashima T, Onuma H, Sumitani Y, Tanaka T, Kondo T, Hosaka T, Ishida H. The novel mechanisms concerning the inhibitions of palmitate-induced proinflammatory factor releases and endogenous cellular stress with astaxanthin on MIN6β-cells. Mar Drugs. 2017;15:185. 153 Arunkumar E, Bhuvaneswari S, Anuradha CV. An intervention study in obese mice with astaxanthin, a marine carotenoid-effects on insulin signaling and pro-inflammatory cytokines. Food Funct. 2012;3:120-6. 154 Nishida Y, Nawaz A, Kado T, Takikawa A, Igarashi Y, Onogi Y, Wada T, Sasaoka T, Yamamoto S, Sasahara M, et al. Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway. J Cachexia Sarcopenia Muscle. 2020;11:241-58. 155 Chan K, Pen P-J, Yin M. Anti-coagulatory and anti-inflammatory effects of astaxanthin in diabetic rats. J Food Sci. 2012;77:H76-80. 156 Bhuvaneswari S, Arunkumar E, Viswanathan P, Anuradha CV. Astaxanthin restricts weight gain, promotes insulin sensitivity and curtails fatty liver disease in mice fed a obesity-promoting diet. Process Biochem. 2010;45:1406-14. 157 Aoi W, Naito Y, Takanami Y, Ishii T, Kawai Y, Akagiri S, Kato Y, Osawa T, Yoshikawa T. Astaxanthin improves muscle lipid metabolism in exercise via inhibitory effect of oxidative CPT I modification. Biochem Biophys Res Commun. 2008;366:892-7. 158 Xia W, Tang N, Kord-Varkaneh H, Low TY, Tan SC, Wu X, Zhu Y. The effects of astaxanthin supplementation on obesity, blood pressure, CRP, glycemic biomarkers, and lipid profile:a meta-analysis of randomized controlled trials. Pharmacol Res. 2020;161:105113. 159 Choi HD, Kim JH, Chang MJ, Kyu-Youn Y, Shin WG. Effects of astaxanthin on oxidative stress in overweight and obese adults. Phytother Res. 2011;25:1813-8. 160 Choi HD, Youn YK, Shin WG. Positive effects of astaxanthin on lipid profiles and oxidative stress in overweight subjects. Plant Foods Hum Nutr. 2011;66:363-9. 161 Gao LJ, Zhu YQ, Xu L. Mechanisms of protective effects of astaxanthin in nonalcoholic fatty liver disease. Hepatoma Res. 2021;7:30. 162 Wu L, Mo W, Feng J, Li J, Yu Q, Li S, Zhang J, Chen K, Ji J, Dai W, Wu J, Xu X, Mao Y, Guo C. Astaxanthin attenuates hepatic damage and mitochondrial dysfunction in non-alcoholic fatty liver disease by up-regulating the FGF21/PGC-1α pathway. Br J Pharmacol. 2020;177:3760-77. 163 Han JH, Ju JH, Lee YS, et al. Astaxanthin alleviated ethanol-induced liver injury by inhibition of oxidative stress and inflammatory responses via blocking of STAT3 activity. Sci Rep. 2018;8:14090. 164 Liu H, Liu M, Fu X, Zhang Z, Zhu L, Zheng X, Liu J. Astaxanthin prevents alcoholic fatty liver disease by modulating mouse gut microbiota. Nutrients. 2018;10:1298. 165 Jia Y, Wu C, Kim J, Kim B, Lee SJ. Astaxanthin reduces hepatic lipid accumulations in high-fat-fed C57BL/6J mice via activation of peroxisome proliferatoractivated receptor (PPAR) alpha and inhibition of PPAR gamma and Akt. J Nutr Biochem. 2016;28:9-18. 166 Yang Y, Seo JM, Nguyen A, Pham TX, Park HJ, Park Y, Kim B, Bruno RS, Lee J. Astaxanthin-rich extract from the green alga Haematococcus pluvialis lowers plasma lipid concentrations and enhances antioxidant defense in apolipoprotein E knockout mice. J Nutr. 2011;141:1611-7. 167 Ursoniu S, Sahebkar A, Serban MC, Banach M. Lipid profile and glucose changes after supplementation with astaxanthin:a systematic review and meta-analysis of randomized controlled trials. Arch Med Sci. 2015;11:253-66. 168 Li J, Xia Y, Liu T, Wang J, Dai W, Wang F, Zheng Y, Chen K, Li S, et al. Protective effects of astaxanthin on ConA-induced autoimmune hepatitis by the JNK/p-JNK pathway-mediated inhibition of autophagy and apoptosis. PLoS ONE. 2015;10:e0120440. 169 Dhinaut J, Balourdet A, Teixeira M, et al. A dietary carotenoid reduces immunopathology and enhances longevity through an immune depressive effect in an insect model. Sci Rep. 2017;7:12429. 170. 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 in in vitro culture system. Nutr Cancer. 1991;16:93-105. 171. 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;21:47-58. 172. 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;23:171-83. 173. Park JS, Chyun JH, Kim YK, Line LL, Chew BP. Astaxanthin decreased oxidative stress and inflammation and enhanced immune response in humans. Nutr Metab. 2010;7:18. 174. Augusti PR, Quatrin A, Somacal S, Conterato GM, Sobieskim R, Ruviaro AR, Maurer LH, Duarte MM, Roehrs M, Emanuelli T. Astaxanthin prevents changes in the activities of thioredoxin reductase and paraoxonase in hypercholesterolemic rabbits. J Clin Biochem Nutr. 2012;51:42-9. 175. Chew BP, Park JS. Carotenoid action on the immune response. J Nutr. 2004;134:257S-261S. 176. Park JS, Mathison BD, Hayek MG, Massimino S, Reinhart GA, Chew BP. Astaxanthin stimulates cell-mediated and humoral immune responses in cats. Vet Immunol Immunopathol. 2011;144:455-61. 177. Ambati RR, Phang SM, Ravi S, Aswathanarayana RG. Astaxanthin:sources, extraction, stability, biological activities and its commercial applications-a review. Mar Drugs. 2014;12:128-52. 178. Hwang E, Lee DG, Park SH, Oh MS, Kim SY. Coriander leaf extract exerts antioxidant activity and protects against UVB-induced photo-aging of skin by regulation of pro-collagen type I and MMP-1 . J Med Food. 2014;17:985-95. 179. Valavanidis A, Vlachogianni T, Fiotakis C. 8-hydroxy- 2' -deoxyguanosine (8-OHdG):a critical biomarker of oxidative stress and carcinogenesis. J Environ Sci Health. 2009;27:120-39. 180. Tominaga K, Hongo N, Karato M, Yamashita E. Cosmetic benefits of astaxanthin on humans subjects. Acta Biochim Pol. 2012;59:43-7. 181. Suganuma K, Nakajima H, Ohtsuki M, Imokawa G. Astaxanthin attenuates the UVA-induced up-regulation of matrix-metalloproteinase-1 and skin fibroblast elastase in human dermal fibroblasts. J Dermatol Sci. 2010;58:136-42. 182. Yoon HS, Cho HH, Cho S, Lee SR, Shin MH, Chung JH. Supplementing with dietary astaxanthin combined with collagen hydrolysate improves facial elasticity and decreases matrix metalloproteinase-1 and -12 :a comparative study with placebo. J Med Food. 2014;17:810-6. 183. Phetcharat L, Wongsuphasawat K, Winther K. The effectiveness of a standardized rose hip powder, containing seeds and shells of Rosa canina, on cell longevity, skin wrinkles, moisture, and elasticity. Clin Interv Aging. 2015;10:1849-56. 184. Sztretye M, Dienes B, Gönczi M, Czirják T, Csernoch L, Dux L, Szentesi P, Keller-Pintér A. Astaxanthin:a potential mitochondrial-targeted antioxidant treatment in diseases and with aging. Oxid Med Cell Longev. 2019;2019:3849692. 185. Rzajew J, Radzik T, Rebas E. Calcium-involved action of phytochemicals:carotenoids and monoterpenes in the brain. Int J Mol Sci. 2020;21:1428. 186. Kowsalya K, Vidya N, Vijayalakshmi V, Arun M. Super nutritive marine astaxanthin, an effectual dietary carotenoid for neurodegenerative diseases. Int Res J Multidiscipl Tech Maple Tree J. 2019;1:115-24. 187. Bhatt T, Patel K. Carotenoids:potent to prevent diseases review. Nat Prod Bioprospect. 2020;10:109-17. 188. Correa DD, Ahles TA. Neurocognitive changes in cancer survivors. Cancer J. 2008;14:396-400. 189. Galasso C, Orefice I, Pellone P, Cirino P, Miele R, Ianora A, Brunet C, Sansone C. On the neuroprotective role of astaxanthin:new perspectives? Mar Drugs. 2018;16:247. 190. Petri D, Lundebye AK. Tissue distribution of astaxanthin in rats following exposure to graded levels in the feed. Comp Comp Biochem Physiol C. 2007;145:202-9. 191. Manabe Y, Komatsu T, Seki S, Sugawara T. Dietary astaxanthin can accumulate in the brain of rats. Biosci Biotechnol Biochem. 2018;82:1433-6. 192. El-Agamy SA, Abdel-Aziz AK, Wahdan S, Esmat A, Azab S. Astaxanthin ameliorates doxorubicin-induced cognitive impairment (chemobrain) in experimental rat model:impact on oxidative, inflammatory, and apoptotic machineries. Mol Neurobiol. 2018;55:5727-40. 193. Nakagawa K, Kiko T, Miyazawa T, Kimura GCF, Satoh A, Miyazawa T. Antioxidant effect of astaxanthin on phospholipid peroxidation in human erythrocytes. Br J Nutr. 2011;105:1563-71. 194. Ajmani RS, Metter EJ, Jaykumar R, Ingram DK, Spangler EL, Abugo OO, Rifkind JM. Hemodynamic changes during aging associated with cerebral blood flow and impaired cognitive function. Neurobiol Aging. 2000;21:257-69. 195. Mohanty JG, Eckley DM, Williamson JD, Launer LJ, Rifkind JM. Do red blood cell-b-amyloid interactions alter oxygen delivery in Alzheimer's disease? Adv Exp Med Biol. 2008;614:29-35. 196. Leijenaara JF, van Maurik IS, Kuijer JPA, van der Flier WM, Scheltens P, Barkhof F, Prins ND. Lower cerebral blood flow in subjects with Alzheimer's dementia, mild cognitive impairment, and subjective cognitive decline using two-dimensional phase-contrast magnetic resonance imaging. Alzheimers Dement. 2017;9:76-83. 197. Cunnane SC, Plourde M, Pifferi F, Bégin M, Féart C, Barberger-Gateau P. Fish, docosahexaenoic acid and Alzheimer's disease. Prog Lipid Res. 2009;48:239-56. 198. Gorjão R, Azevedo-Martins AK, Rodrigues HG, Abdulkader F, Arcisio-Miranda M, Procopio J, Curi R. Comparative effects of DHA and EPA on cell function. Pharmacol Ther. 2009;122:56-64. 199. Mattei R, Polotow TG, Vardaris CV, Guerra BA, Leite JR, Otton R, Barros MP. Astaxanthin limits fish oil-related oxidative insult in the anterior forebrain of Wistar rats:putative anxiolytic effects? Pharmacol Biochem Behav. 2011;99:349-55. 200. Nolan JM, Mulcahy R, Power R, Moran R, Howard AN. Nutritional intervention to prevent Alzheimer's Disease:potential benefits of xanthophyll carotenoids and Omega-3 Fatty acids combined. J Alzheimers Dis. 2018;64:367-78. 201. Damodara Gowda KM, Suchetha Kumari N, Ullal H. Role of astaxanthin in the modulation of brain-derived neurotrophic factor and spatial learning behavior in perinatally undernourished Wistar rats. Nutr Neurosci. 2020;23:422-31. 202. Xue Y, Qu Z, Fu J, Zhen J, Wang W, Cai Y, Wang W. The protective effect of astaxanthin on learning and memory deficits and oxidative stress in a mouse model of repeated cerebral ischemia/reperfusion. Brain Res Bull. 2017;131:221-8. 203. Pan L, Zhou Y, Li XF, Wan QJ, Yu LH. Preventive treatment of astaxanthin provides neuroprotection through suppression of reactive oxygen species and activation of antioxidant defense pathway after stroke in rats. Brain Res Bull. 2017;130:211-20. 204. Cakir E, Cakir U, Tayman C, Turkmenoglu TT, Gonel A, Turan IO. Favorable effects of astaxanthin on brain damage due to ischemia- reperfusion injury. Comb Chem High Throughput Screen. 2020;23:214-24. 205. Sharma K, Sharma D, Sharma M, Sharma N, Bidve P, Prajapati N, Kalia K, Tiwari V. Astaxanthin ameliorates behavioral and biochemical alterations in in-vitro and in-vivo model of neuropathic pain. Neurosci Lett. 2018;674:162-70. 206. Fakhri S, Dargahi L, Abbaszadeh F, Jorjani M. Effects of astaxanthin on sensory-motor function in a compression model of spinal cord injury:involvement of ERK and AKT signaling pathway. Eur J Pain. 2019;23:750-64. 207. Chang MX, Xiong F. Astaxanthin and its effects in inflammatory responses and inflammation-associated diseases:recent advances and future directions. Molecules (Basel, Switzerland). 2020;25:5342. 208. Dion PA, Daoud H, Rouleau GA. Genetics of motor neuron disorders:new insights into pathogenic mechanisms. Nat Rev Genet. 2009;10:769-82. 209. Strong MJ, Kesavapany S, Pant HC. The pathobiology of amyotrophic lateral sclerosis:a proteinopathy? J Neuropathol Exp Neurol. 2005;64:649-64. 210. Isonaka R, Hiruma H, Katakura T, Kawakami T. Inhibition of superoxide dismutase selectively suppresses growth of rat spinal motor neurons:comparison with phosphorylated neurofilament-containing spinal neurons. Brain Res. 2011;1425:13-9. 211. O'Donnell E, Lynch MA. Dietary antioxidant supplementation reverses age-related neuronal changes. Neurobiol Aging. 1998;19:461-7. 212. Taksima T, Chonpathompikunlert P, Sroyraya M, Hutamekalin P, Limpawattana M, Klaypradit W. Effects of astaxanthin from shrimp shell on oxidative stress and behavior in animal model of Alzheimer's disease. Mar Drugs. 2019;17:628. 213. Che H, Li Q, Zhang T, Wang D, Yang L, Xu J, Yanagita T, Xue C, Chang Y, Wang Y. Effects of astaxanthin and docosahexaenoic-acid-acylated astaxanthin on Alzheimer's disease in APP/PS1 double-transgenic mice. J Agric Food Chem. 2018;66:4948-57. 214. Grimmig B, Kim SH, Nash K, Bickford PC, Douglas Shytle R. Neuroprotective mechanisms of astaxanthin:a potential therapeutic role in preserving cognitive function in age and neurodegeneration. GeroScience. 2017;39:19-32. 215. Yook JS, Okamoto M, Rakwal R, Shibato J, Lee MC, Matsui T, Chang H, Cho JY, Soya H. Astaxanthin supplementation enhances adult hippocampal neurogenesis and spatial memory in mice. Mol Nutr Food Res. 2016;60:589-99. 216. Galasso C, Corinaldesi C, Sansone C. Carotenoids from marine organisms:biological functions and industrial applications. Antioxidants (Basel, Switzerland). 2017;6:96. 217. Grimmig B, Daly L, Subbarayan M, Hudson C, Williamson R, Nash K, Bickford PC. Astaxanthin attenuates neurotoxicity in a mouse model of Parkinson's disease. Funct Foods Health Dis. 2017;7:562-76. 218. Liu X, Shibata T, Hisaka S, Osawa T. Astaxanthin inhibits reactive oxygen species-mediated cellular toxicity in dopaminergic SH-SY5Y cells via mitochondria-targeted protective mechanism. Brain Res. 2009;1254:18-27. 219. Ikeda Y, Tsuji S, Satoh A, Ishikura M, Shirasawa T, Shimizu T. Protective effects of astaxanthin on 6-hydroxydopamine-induced apoptosis in human neuroblastoma SH-SY5Y cells. J Neurochem. 2008;107:1730-40. 220. Fakhri S, Aneva IY, Farzaei MH, Sobarzo-Sánchez E. The neuroprotective effects of astaxanthin:therapeutic targets and clinical perspective. Molecules. 2019;24:2640. 221. Wang XJ, Chen W, Fu XT, Ma JK, Wang MH, Hou YJ, Tian DC, Fu XY, Fan CD. Reversal of homocysteine-induced neurotoxicity in rat hippocampal neurons by astaxanthin:evidences for mitochondrial dysfunction and signaling crosstalk. Cell Death Dis. 2019;5:70. 222. Ye Q, Zhang X, Huang B, Zhu Y, Chen X. Astaxanthin suppresses MPP+-induced oxidative damage in PC12 cells through a Sp1/NR1 signaling pathway. Mar Drugs. 2013;11:1019-34. 223. Ye Q, Huang B, Zhang X, Zhu Y, Chen X. Astaxanthin protects against MPP+-induced oxidative stress in PC12 cells via the HO-1/NOX2 axis. BMC Neurosci. 2012;13:156. 224. Cort A, Ozturk N, Akpinar D, et al. Suppressive effect of astaxanthin on retinal injury induced by elevated intraocular pressure. Regul Toxicol Pharmacol. 2010;58:121-30. 225. Kikuchi K, Dong Z, Shinmei Y, Murata M, Kanda A, Noda K, Harada T, Ishida S. Hindawi, cytoprotective effect of astaxanthin in a model of normal intraocular pressure glaucoma. J Ophthalmol. 2020;2020:9539681. 226. Lin WN, Kapupara K, Wen YT, Chen YH, Pan IH, Tsai RK. Haematococcus pluvialis-derived astaxanthin is a potential neuroprotective agent against optic nerve ischemia. Mar Drugs. 2020;18:85. 227. Otsuka T, Shimazawa M, Inoue Y, et al. Astaxanthin protects against retinal damage:evidence from in vivo and in vitro retinal ischemia and reperfusion models. Curr Eye Res. 2016;41:1465-72. 228. Stevens JC, Sun S, Beard CM, et al. Carpal tunnel syndrome in Rochester, Minnesota, 1961 to 1980. Neurology. 1988;38:134-8. 229. Falkenburg SA. Choosing hand splints to aid carpal tunnel syndrome recovery. Occup Health Saf. 1987;56:63-4. 230. Weiss ND, Gordon L, Bloom T, So Y, Rempel DM. Position of the wrist associated with the lowest carpal-tunnel pressure:implications for splint design. J Bone Joint Surg Am. 1995;77:1695-9. 231. O'Connor D, Marshall SC, Massy-Westropp N, Pitt V. Non-surgical treatment (other than steroid injection) for carpal tunnel syndrome. Cochrane Database Syst Rev. 2003;2003:CD003219. 232. Shi Q, Macdermid JC. Is surgical intervention more effective than non-surgical treatment for carpal tunnel syndrome? A systematic review. J Orthop Surg Res. 2011;6:17. 233. Wilson JK, Sevier TL. A review of treatment for carpal tunnel syndrome. Disabil Rehabil. 2003;25:113-9. 234. Kaplan SJ, Glickel SZ, Eaton RG. Predictive factors in the nonsurgical treatment of carpal tunnel syndrome. J Hand Surg J Br Soc Surg Hand. 1990;15:106-8. 235. MacDermid JC, Evenhuis W, Louzon M. Inter-instrument reliability of pinch strength scores. J Hand Ther. 2001;14:36-42. 236. Phalen GS. The carpal-tunnel syndrome:clinical evaluation of 598 hands. Clin Orthop. 1972;83:29-40. 237. Macdermid JC, Vincent JI, Gan BS, Grewal RA. A blinded placebo-controlled randomized trial on the use of astaxanthin as an adjunct to splinting in the treatment of carpal tunnel syndrome. Hand (N Y). 2012;7:1-9. 238. Ikeuchi M, Koyama T, Takahashi J, Yazawa K. Effects of astaxanthin supplementation on exercise-induced fatigue in mice. Biol Pharm Bull. 2006;29:2106-10. 239. Imai A, Oda Y, Ito N, Seki S, Nakagawa K, Miyazawa T, Ueda F. Effects of dietary supplementation of astaxanthin and sesamin on daily fatigue:a randomized, double-blind, placebo-controlled, two-way crossover study. Nutrients. 2018;10:281. 240. Kim SH, Kim H. Inhibitory effect of astaxanthin on oxidative stress-induced mitochondrial dysfunction-a mini-review. Nutrients. 2018;10:1137. 241. Hayashi M, Kawamura M, Kawashima Y, Uemura T, Maoka T. Effect of astaxanthin-rich extract derived from Paracoccus carotinifaciens on the status of stress and sleep in adults. J Clin Biochem Nutr. 2020;66:92-102. 242. Tripathi DN, Jena GB. Astaxanthin inhibits cytotoxic and genotoxic effects of cyclophosphamide in mice germ cells. Toxicology. 2008;248:96-103. 243. Comhaire FH, Mahmoud A. The role of food supplements in the treatment of the infertile man. Reprod Biomed Online. 2003;7:385-91. 244. Wang JY, Lee YJ, Chou MC, Chang R, Chiu CH, et al. Astaxanthin protects steroidogenesis from hydrogen peroxide-induced oxidative stress in mouse Leydig cells. Mar Drugs. 2015;13:1375-88. 245. Vahidinia A, Rahbar AR, Shakoori Mahmoodabadi MM. Effect of astaxanthin, vitamin E, and vitamin C in combination with calorie restriction on sperm quality and quantity in male rats. J Diet Suppl. 2017;14:252-63. 246. Donà G, Kožuh I, Brunati AM, Andrisani A, Ambrosini G, Bonanni G, Ragazzi E, Armanini D, Clari G, Bordin L. Effect of astaxanthin on human sperm capacitation. Mar Drugs. 2013;11:1909-19. 247. Clinical Trial Report (National Institute of Health, USA 2019), https://clinicaltrials.gov/ct2/show/NCT02310087. Accessed 24 April 2022. 248. Yang YX, Kim YJ, Jin Z, Lohakare JD, Kim CH, Ohh SH, Lee SH, Choi JY, Chae BJ. Effects of dietary supplementation of astaxanthin on production performance, egg quality in layers and meat quality in finishing pigs. Asian-Australas J Anim Sci. 2006;19:1019-25. 249. Hansen KB, Tauson AH, Inborr J. Effect of supplementation with the antioxidant astaxanthin on reproduction, pre-weaning growth performance of kits and daily milk intake in mink. J Reprod Fertil Suppl. 2001;57:331-4. 250. Abdel-Ghani MA, Yanagawa Y, Balboula AZ, Sakaguchi K, Kanno C, Katagiri S, Takahashi M, Nagano M. Astaxanthin improves the developmental competence of in vitro-grown oocytes and modifies the steroidogenesis of granulosa cells derived from bovine early antral follicles. Reprod Fertil Dev. 2019;31:272-81. 251. Iwabayashi M, Fujioka N, Nomoto K, Miyazaki R, Takahashi H, Hibino S, Takahashi Y, Nishikawa K, Nishida M, Yonei Y. Efficacy and safety of eight-week treatment with astaxanthin in individuals screened for increased oxidative stress burden. Anti Aging Med. 2009;6:15-21. 252. Clinical Trial Report (National Institute of Health, USA, 2021), https://clinicaltrials.gov/ct2/show/study/NCT03991286. Accessed 24 April 2022. 253. Moravkova M, Slany M, Trcka I, Havelkova M, Svobodova J, Skoric M. Human-to-human and human-to-dog Mycobacterium tuberculosis transmission studied by IS6110 RFLP analysis:a case report. Vet Med. 2011;56:314-7. 254. Alix E, Godreuil S, Blanc-Potard AB. Identification of a Haarlem genotype-specific single nucleotide polymorphism in the mgt C virulence gene of Mycobacterium tuberculosis. J Clin Microbiol. 2006;44:2093-8. 255. Global tuberculosis control:WHO report (World Health Organization, 2010). https://apps.who.int/iris/handle/10665/44425. Accessed 24 April 2022. 256. Vasudevan S, Venkatraman A, Yahoob SAM, Jojula M, Sundaram R, Boomi P. Biochemical evaluation and molecular docking studies on encapsulated astaxanthin for the growth inhibition of Mycobacterium tuberculosis. J Appl Biol Biotechnol. 2021;9:31-9. 257. Donà G, Andrisani A, Tibaldi E, Brunati AM, Sabbadin C, Armanini D, Ambrosini G, Ragazzi E, Bordin L. Astaxanthin prevents human papillomavirus L1 protein binding in human sperm membranes. Mar Drugs. 2018;16:427. 258. Ahmadi AR, Nasrabadi RA. Astaxanthin protective barrier and its ability to improve the health in patients with COVID-19. Iran J Microbiol. 2021;13:434-41. 259. Talukdar J, Bhadra B, Dattaroy T, Nagle V, Dasgupta S. Potential of natural astaxanthin in alleviating the risk of cytokine storm in COVID-19. Biomed Pharmacother. 2020;132:110886. 260. Chia WY, Kok H, Chew KW, Low SS, Show PL. Can algae contribute to the war with COVID-19? Bioengineered. 2021;12:1226-37. 261. Fakhri S, Nouri Z, Moradi SZ, Farzaei MH. Astaxanthin, COVID-19 and immune response:focus on oxidative stress, apoptosis and autophagy. Phytother Res. 2020;34:2790-2. 262. Brendler T, Williamson EM. Astaxanthin:how much is too much? A safety review. Phytother Res. 2019;33:3090-111. 263. Naidu AS, Pressman P, Roger A, Clemens RA. Coronavirus and nutrition:what is the evidence for dietary supplements usage for COVID-19 control and management? Nutr Today. 2021;56:19-25. 264. Zhu C, Farré G, Díaz-Gómez J, Capell T, Nogareda C, Sandmann G, Christou P. Engineered maize hybrids with diverse carotenoid profiles and potential applications in animal feeding. Carotenoids:biosynthetic and biofunctional approaches, advances in experimental medicine and biology, vol. 1261. Singapore:Springer; 2021. p. 95-114. 265. Cysewski GR, Lorenz RT. Industrial production of microalgal cell mass and secondary products-species of high potential Haematococcus. Handbook of Microalgal Culture:biotechnology and applied phycology. Oxford:Blackwell Science; 2004. p. 281-8. 266. Li J, Zhu D, Niu J, Shen S, Wang G. An economic assessment of astaxanthin production by large scale cultivation of Haematococcus pluvialis. Biotechnol Adv. 2011;29:568-74. 267. Begum H, Yusoff FM, Banerjee S, Khatoon H, Shariff M. Availability and utilization of pigments from microalgae. Crit Rev Food Sci Nutr. 2016;56:2209-22. 268. Sheikhzadeh N, Tayefi-Nasrabadi H, Oushani AK, Enferadi MH. Effects of Haematococcus pluvialis supplementation on antioxidant system and metabolism in rainbow trout (Oncorhynchus mykiss). Fish Physiol Biochem. 2012;38:413-9. 269. Rao AR, Baskaran V, Sarada R, Ravishankar GA. In vivo bioavailability and antioxidant activity of carotenoids from micro algal biomass-a repeated dose study. Food Res Int. 2013;54:711-7. 270. Rao AR, Sindhuja HN, Dharmesh SM, Sankar KU, Sarada R, Ravishankar GA. 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;61:3842-51. 271. Stewart JS, Lignell A, Pettersson A, Elfving E, Soni MG. Safety assessment of astaxanthin rich microalgae biomass:acute and subchronic toxicity studies in rats. Food Chem Toxicol. 2008;46:3030-6. 272. Odeberg MJ, 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;19:299-304. 273. 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;17:125-32. 274. Spiller GA, Dewell A. Safety of an astaxanthin rich Haemaotoccus pluvialis algal extract:a randomized clinical trial. J Med Food. 2003;6:51-6.