Sains Malaysiana 50(3)(2021): 803-819

http://doi.org/10.17576/jsm-2021-5003-21

Health Beneficial Properties of Spirulina in Preventing Non-Communicable Diseases - The Green Metabolic Regulator from the Sea

(Manfaat Kesihatan Spirulina dalam Mencegah Penyakit Tidak Berjangkit - Pengatur Metabolik Hijau dari Laut)

SOPHIA OGECHI EKEUKU¹, IMA-NIRWANA SOELAIMAN¹, KOK-YONG CHIN^1,2*

¹Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur, Federal Territory, Malaysia

²State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

Diserahkan 8 April 2020/Diterima: 12 Ogos 2020

ABSTRACT

Spirulina is a type of cyanobacteria containing various micro- and macronutrients and has been used as a functional food. Due to its nutritional components, spirulina possesses antioxidant and anti-inflammatory properties, which can potentially prevent non-communicable diseases (NCDs) triggered by inflammation and oxidative stress. This review aims to provide an overview of the effects of spirulina supplementation on NCDs derived from cellular, animals, and human studies. The current literature generally showed that spirulina could protect against NCDs, such as metabolic disorders, osteoporosis, gastric ulcer, hepatic, renal, and neurological disorders. These beneficial effects were mediated through the antioxidant and anti-inflammatory effects of spirulina and seem to be dependent on dose and duration of treatment. Despite the abundance of preclinical studies, human clinical trials validating the effects of spirulina on NCDs are lacking. These preclinical findings warrant a proper clinical trial to evaluate the efficacy and safety of spirulina supplementation in protecting human against NCDs.

Keywords: Blue-green algae; cyanobacteria; energy metabolism; inflammation; non-communicable diseases; oxidative stress  

ABSTRAK

Spirulina ialah sejenis sianobakteria yang mengandungi pelbagai nutrisi mikro serta makro dan telah digunakan sebagai makanan fungsian. Disebabkan oleh komponen nutrisinya, spirulina mempunyai ciri-ciri antioksidan dan anti-keradangan yang berpotensi untuk mencegah penyakit tidak berjangkit yang diaruh oleh keradangan dan tekanan oksidatif. Ulasan ini bertujuan memberi gambaran tentang kesan suplementasi spirulina ke atas penyakit tidak berjangkit yang diterbitkan daripada kajian sel, haiwan dan manusia. Kajian kepustakaan menunjukkan spirulina boleh mencegah penyakit tidak berjangkit seperti ketidak-normalan metabolik, osteoporosis, ulser gastrik, penyakit hati, ginjal dan neurologi. Manfaat ini dijana melalui kesan antioksidan dan anti-keradangan spirulina. Walaupun terdapat banyak kajian praklinikal, kajian manusia secara klinikal masih tidak mencukupi. Keputusan kajian praklinikal ini perlu disahkan melalui percubaan klinikal yang wajar untuk menguji keberkesanan dan keselamatan supplemen spirulina dalam melindungi manusia daripada penyakit tidak berjangkit. 

Kata kunci: Alga biru-hijau; keradangan; metabolisme tenaga; penyakit tidak berjangkit; sianobakteria; tekanan oksidatif

RUJUKAN

Ahmad, M., Saleem, S. & Ahmad, A.S. 2005. Ginkgo biloba affords dose-dependent protection against 6-hydroxydopamine-induced Parkinsonism in rats: Neurochemical and immunohistochemical evidences. Journal of Neurochemistry 93(1): 94-104.

Aissaoui, O., Amiali, M., Bouzid, N., Belkacemi, K. & Bitam, A. 2017. Effect of Spirulina platensis ingestion on the abnormal biochemical and oxidative stress parameters in the pancreas and liver of alloxan-induced diabetic rats. Pharmaceutical Biology 55(1): 1304-1312.

Akbal, A., Tutkun, E. & Yılmaz, H.  2014. Lead exposure is a risk for worsening bone mineral density in middle-aged male workers. Aging Male 17(3): 189-193.

Alam, A., Siddiqui, M.A., Quamri, A., Fatima, S., Roqaiya, M. & Ahmad, Z. 2016. Efficacy of Spirulina (tahlab) in patients of type 2 diabetes mellitus (Ziabetus shakri) - A randomized controlled trial. Journal of Diabetes and Metabolism 7(10): 1-5.

Alberti, G., Zimmet, P. & Shaw, J. 2006. The IDF Consensus Worldwide Definition of the Metabolic Syndrome. Brussels: International Diabetes Federation. pp. 1-24.

Al-Qahtani, W.H. & Binobead, M.A. 2019. Anti-inflammatory, antioxidant and antihepatotoxic effects of Spirulina platensis against D-galactosamine induced hepatotoxicity in rats. Saudi Journal of Biological Science 26(4): 647-652.

August, J., Murad, F., Anders, M., Coyle, J. & Packer, L. 1996. Antioxidants in Disease Mechanisms and Therapy. New York: Academic Press.

Bahei-Eldin, I.A., Elgazzar, M.H., Ahmed, A.I. & Mohamed, S.S.A. 2017. The effect of spirulina extract on the healing of skin wounds in adult albino rats: A light and scanning electron microscopic study. Egyptian Journal of Anatomy 40(1): 33-53.

Baluchnejadmojarad, T. & Roghani, M. 2010. The flavonoid hesperetin alleviates behavioral abnormality in 6-hydroxydopamine rat model of hemi-parkinsonism. Basic and Clinical Neuroscience 2: 20-23.

Blinkova, L.P., Gorobets, O.B. & Baturo, A.P. 2001. Biological activity of Spirulina platensis (SP). Zhurnal Mikrobiologii, Epidemiologii, i Immunobiologii 2: 114-118.

Bouayed, J. & Bohn, T. 2010. Exogenous antioxidants- double-edged swords in cellular redox state. Oxidative Medicine and Cellular Longevity 3(4): 228-237.

Campanella, L., Crescentini, G. & Avino, P. 1999. Chemical composition and nutritional evaluation of some natural and commercial food products based on Spirulina. Analusis 27: 533-540.

Chattopadhyaya, I., Gupta, S., Mohammed, A., Mushtaq, N., Chauhan, S. & Ghosh, S. 2015. Neuroprotective effect of Spirulina fusiform and amantadine in the 6-OHDA induced Parkinsonism in rats. BMC Complementary and Alternative Medicine 15(296): 1-11.

Che, R., Yuan, Y., Huang, S. & Zhang, A. 2014. Mitochondrial dysfunction in the pathophysiology of renal diseases. American Journal of Physiology-Renal Physiology 306(4): F367-F378.

Cheong, S.H., Kim, M.Y., Sok, D.E., Hwang, S.Y., Kim, J.H., Kim, H.R., Lee, J.H., Kim, Y.B. & Kim, M.R. 2010. Spirulina prevents atherosclerosis by reducing hypercholesterolemia in rabbits fed a high-cholesterol diet. Journal of Nutritional Science and Vitaminology 56(1): 34-40.

Chin, K.Y. & Ima-Nirwana, S. 2015. The biological effects of tocotrienol on bone: A review on evidence from rodent models. Drug Design, Development and Therapy 8(9): 2049-2061.

Christiana, U.I., Casimir, A.E., Nicholas, A.A., Christian, M.C. & Obiefuna, A.I. 2016. Plasma levels of inflammatory cytokines in adult Nigerians with the metabolic syndrome. Nigerian Medical Journal 57(1): 64-68.

Cicero, A.F.G., Colletti, A., Bajraktari, G., Descamps, O., Djuric, D.M., Ezhov, M. & Banach, M. 2017. Lipid‐lowering nutraceuticals in clinical practice: Position paper from an International Lipid Expert Panel. Nutrition Reviews 75(9): 731-767.

Clark, G. & Wayne, M. 2005. Reperfusion Injury in Stroke. Retrieved from http://www.emedicine.com/neuro/topic602.htm. Accessed on 13th March 2020.

Colla, L.M., Bertolin, T.E. & Costa, J.A.V. 2004. Fatty acids profile of Spirulina platensis grown under different temperatures and nitrogen concentrations. Journal of Biosciences 59(1-2): 55-59.

Collins, K.G., Fitzgerald, G.F., Stanton, C. & Ross, R.P. 2016. Looking beyond the terrestrial: The potential of seaweed derived bioactives to treat non-communicable diseases. Marine Drugs 14(3): 60.

Crewe, C., An, Y.A. & Scherer, P.E. 2017. The ominous triad of adipose tissue dysfunction: Inflammation, fibrosis, and impaired angiogenesis. Journal of Clinical Investigation 127(1): 74-82.

de Figueiredo, D.R., Azeiteiro, U.M., Esteves, S.M., Goncalves, F.J. & Pereira, M.J. 2004. Microcystin-producing blooms - A serious global public health issue. Ecotoxicology and Environmental Safety 59(2): 151-163.

Delanghe, S., Delanghe, J.R., Speeckaert, R., Van Biesen, W. & Speeckaert, M.M. 2017. Mechanisms and consequences of carbamoylation. Nature Reviews Nephrology 13: 580-593.

Devesh, C., Kritika, M., Anroop, N., Kumar, S.P. & Sumeet, G. 2012. Spirulina reverses histomorphological changes in diabetic osteoporosis in pioglitazone treated rats. Journal of Diabetes Metabolism 1: 1-7.

Doumouchtsis, K.K., Doumouchtsis, S.K., Doumouchtsis, E.K. & Perrea, D.N. 2009. The effect of lead intoxication on endocrine functions. Journal of Endocrinological Investigation 32(2): 175-183.

Ebrahim, S., Pearce, N., Smeeth, L., Casas, J.P., Jaffar, S. & Piot, P. 2013. Tackling non-communicable diseases in low and middle-income countries: Is the evidence from high-income countries all we need? PLoS Medicine 10(1): e1001377.

Ekantari, N., Harmayani, E., Pranoto, Y. & Marsano, Y. 2017. Calcium of Spirulina paltensis has higher bioavailability than those of calcium carbonate and high-calcium milk in Sprague Dawley rats fed with vitamin D-deficient diet. Pakistan Journal Nutrition 16: 179-186.

El-Baz, F.K., Aly, H.F., El-Sayed, A.B. & Mohamed, A.A. 2013. Role of Spirulina platensis in the control of glycemia in DM2 rats. International Journal of Scientific Engineering and Research 4(12): 1731-1740.

Earthrise. Product typical analysis. 2006. In International Symposium on Cyanobacteria for Health, Science and Development. San Raphael, USA: NIEHS. pp. 104-108.

Esposito, K., Ciotola, M., Schisano, B., Misso, L., Giannetti, G., Ceriello, A. & Giugliano, D. 2006. Oxidative stress in the metabolic syndrome. Journal of Endocrinological Investigation 29(9): 791-795.

Fahn, S. 2003. Description of Parkinson’s disease as a clinical syndrome. Annals of the New York Academy of Science 991: 1-14.

Fortin, M.C., Cory-Slechta, D.A., Ohman-Strickland, P., Nwankwo, C., Moynihan, J., Walton, J., Brooks, A. & Fiedler, N. 2012. Increased lead biomarker levels are associated with changes in hormonal response to stress in occupationally exposed male participants. Environmental Health Perspective 120(2): 278-283.

Fujimoto, M., Tsuneyama, K., Fujimoto, T., Selmi, C., Gershwind, M.E. & Shimadaa, Y. 2012. Spirulina improves non-alcoholic steatohepatitis, visceral fat macrophage aggregation, and serum leptin in a mouse model of metabolic syndrome. Digestive and Liver Disease 44(9): 767-774.

Gargouri, M., Magnéb, C. & El Feki, A. 2016a. Hyperglycemia, oxidative stress, liver damage and dysfunction in alloxan-induced diabetic rat are prevented by Spirulina supplementation. Nutrition Research 36(11): 1255-1268.

Gargouri, M., Saad, H.B., Magné, C. & El Feki, A. 2016b. Toxicity of lead on femoral bone in suckling rats: Alleviation by spirulina. Research and Reviews Bioscience 11(3): 105-118.

Gershwin, M.E. & Belay, A. 2007. Spirulina in Human Nutrition and Health. Boca Raton: CRC Press.

Grattan, R.P. 1989. Spirulina: A source of dietary gamma linolenic acid? Journal of the Science of Food Agriculture 47(1): 85-93.

Grosso, G., Micek, A., Godos, J., Pajak, A., Sciacca, S., Galvano, F. & Giovannucci, E.L. 2017a. Dietary flavonoid and lignan intake and mortality in prospective cohort studies: Systematic review and dose-response meta-analysis. American Journal of Epidemiology 185(12): 1304-1316.

Grosso, G., Godos, J., Lamuela-Raventos, R., Ray, S., Micek, A., Pajak, A., Sciacca, S., D’Orazio, N., Del-Rio, D. & Galvano, F. 2017b. A comprehensive meta-analysis on dietary flavonoid and lignan intake and cancer risk: Level of evidence and limitations. Molecular Nutrition and Food Research 61(4): 1-20.

Gunes, S., Tamburaci, S., Dalay, M.C.  & Gurhan, I.D. 2017.  In vitro evaluation of Spirulina platensis extract incorporated skin cream with its wound healing and antioxidant activities. Pharmaceutical Biology 55(1): 1824-1832.

Guo, J., Zhao, X., Li, Y., Li, G. & Liu, X. 2018. Damage to dopaminergic neurons by oxidative stress in Parkinson's disease (review). International Journal Molecular Medicine 41(4): 1817-1825.

Gupta, S., Hrishikeshvan, H.J. & Sehajpal, P.P. 2010. Spirulina protects against Rosiglitazone induced osteoporosis in insulin resistance rats. Diabetes Research and Clinical Practice 87(1): 38-43.

Gutiérrez-Salmeán, G., Fabila-Castillo, L. & Chamorro-Cevallos, G. 2015. Nutritional and toxicological aspects of Spirulina (Arthrospira). Nutricion Hospitalaria 32(1): 34-40.

Hartman, J. & Frishman, W.H. 2014. Inflammation and atherosclerosis: A review of the role of interleukin-6 in the development of atherosclerosis and the potential for targeted drug therapy. Cardiology in Review 22(3): 147-151.

Hector, A. & Gonzalez-Usigli, H.A. 2019. Parkinsonism (Secondary Parkinsonism; a typical Parkinsonism). https://www.msdmanuals.com/home/brain,-spinal-cord,-and-nerve-disorders/movement-disorders/parkinsonism#. Accessed on 13th March 2020.

Heo, M.G. & Choung, S.Y. 2018. Anti-obesity effects of Spirulina maxima in high fat diet induced obese rats via the activation of AMPK pathway and SIRT1. Food and Function 9(9): 4906-4915.

Hooper, L., Kroon, P.A., Rimm, E.B., Cohn, J.S., Harvey, I., Le Cornu, K.A., Ryder, J.J., Hall, W.L. & Cassidy, A. 2008. Flavonoids, flavonoid-rich foods, and cardiovascular risk: A meta-analysis of randomised controlled trials. American Journal of Clinical Nutrition 88(1): 38-50.

Howlett, J., Edwards, D.G., Cockburn, A., Hepburn, P., Kleiner, J., Knorr, D., Kozianowski, G., Müller, D., Peijenburg, A., Perrin, I., Poulsen, M. & Walker, R. 2003. The safety assessment of novel foods and concepts to determine their safety in use. International Journal of Food Science and Nutrition 54: S1-S32.

Hurrle, S. & Hsu, W.H. 2017. The etiology of oxidative stress in insulin resistance. Biomedical Journal 40(5): 257-262.

Jadeja, R.N., Devkar, R.V. & Nammi, S. 2017. Oxidative stress in liver diseases: Pathogenesis, prevention, and therapeutics. Oxidative Medicine and Cell Longevity 2017: 8341286.

Jankowska, M., Rutkowski, B. & Dębska-Ślizień, A. 2017. Vitamins and microelement bioavailability in different stages of chronic kidney disease. Nutrients 9(3): 282.

Jung, F., Kruger-Genge, A., Waldeck, P. & Kupper, J.H. 2019. Spirulina platensis, a super food? Journal of Cell Biotechnology 5(1): 43-54.

Kaur, J. 2014. A comprehensive review on metabolic syndrome. Cardiology Research and Practice 2014(21): 943162.

Khan, Z., Bhadouria, P. & Bisen, P.S. 2005. Nutritional and therapeutic potential of Spirulina. Current Pharmaceutical Biotechnology 6(5): 373-379.

Kassi, E., Pervanidou, P., Kaltsas, G. & Chrusos, G. 2011. Metabolic syndrome: Definitions and controversies. BMC Medicine 9: 48.

Koppula, S., Kumar, H., More, S.V., Kim, B.W. & Choi, D.K. 2012. Recent advances on the neuroprotective potential of antioxidants in experimental models of Parkinson’s disease. International Journal Molecular Science 13(8): 10608-10629.

Kurdikeri, S.M. 2006. Effect of spirulina on lipid profile of hyperlipidemics. MSc Thesis. Bangalore, University of Agricultural Sciences (Unpublished).

Layam, A. & Reddy, C.L.K. 2006. Antidiabetic property of spirulina. Diabetologia Croatica 35(2): 29-33.

Lee, J., Park, A., Kim, M.J., Lim, H.J., Rha, Y.A. & Kang, H.G. 2017. Spirulina extract enhanced a protective effect in type 1 diabetes by anti-apoptosis and anti-ROS production. Nutrients 9(1363): 1-20.

Lin, W.W. & Karin, M. 2007. A cytokine-mediated link between innate immunity, inflammation, and cancer. Journal of Clinical Investigation 117(5): 1175-1183.

Lips, P. & van Schoor, N.M. 2011. The effect of vitamin D on bone and osteoporosis. Best Practice & Research Clinical Endocrinology & Metabolism 25(4): 585-591.

Ma, Z.F. & Zhang, H. 2017. Phytochemical constituents, health benefits, and industrial applications of grape seeds: A mini-review. Antioxidants 6(3): 71.

Maeda, K. & Ruel, M. 2015. Prevention of ischemia-reperfusion injury in cardiac surgery: Therapeutic strategies targeting signaling pathways. The Journal of Thoracic and Cardiovascular Surgery 149(3): 910-911.

Mani, U.V., Desai, S. & Iyer, U. 2000. Studies on the long-term effect of spirulina supplementation on serum lipid profile and glycated proteins in NIDDM patients. Journal of Nutraceuticals, Functional and Medicinal Foods 2(3): 25-32.

Martin, S.J. & Sabina, E.P. 2016. Amelioration of antituberculosis drug induced oxidative stress in kidneys by Spirulina fusiformis in a rat model. Renal Failure 38(7): 1115-1121.

Martínez-Sámano, J., Torres-Montes de Oca, A., Luqueño-Bocardo, O.I., Torres-Durán, P.V. & Juárez-Oropeza, M.A. 2018. Spirulina maxima decreases endothelial damage and oxidative stress indicators in patients with systemic arterial hypertension: Results from exploratory controlled clinical trial. Marine Drugs 16(12): 496.

Mayer-Foulkes, D. 2011. A survey of macro damages from non-communicable chronic diseases: Another challenge for global governance. Global Economy Journal 11(1): 1-27.

McLaughlin, T., Ackerman, S.E., Shen, L. & Engleman, E. 2017. Role of innate and adaptive immunity in obesity-associated metabolic disease. Journal of Clinical Investigations 127(1): 5-13.

Miczke, A., Szulińska, M., Hansdorfer-Korzon, R., Kręgielska-Narożna, M., Suliburska, J, Walkowiak, J. & Bogdański, P. 2016. Effects of spirulina consumption on body weight, blood pressure, and endothelial function in overweight hypertensive Caucasians: A double-blind, placebo-controlled, randomised trial. European Review for Medical and Pharmacological Sciences 20(1): 150-156.

Muthuraman, P., Senthilkumar, R. & Srikumar, K. 2009. Alterations in beta-islets of Langerhans in alloxan induced diabetic rats by marine Spirulina platensis. Journal of Enzyme Inhibition and Medicinal Chemistry 24(6): 1253-1256.

Nasirian, F., Mesbahzadeh, B., Maleki, S.A., Mogharnasi, M. & Kor, N.M. 2017. The effects of oral supplementation of Spirulina platensis microalgae on haematological parameters in streptozotocin-induced diabetic rats. American Journal of Translational Research 9(12): 5238-5244.

Nasirian, F., Dadkhah, M., Moradi-kor, N. & Obeidavi, N. 2018. Effects of Spirulina platensis microalgae on antioxidant and anti-inflammatory factors in diabetic rats. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2018(11): 375-380.

National Centre for Biotechnology Information. 2020. MeSH: Non-Communicable Diseases: U.S. Library of Medicine. https://www.ncbi.nlm.nih.gov/mesh/?term= non-communicable+disease. Accessed on 11th March 2020.

NIH. 2001. Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. JAMA 285: 785-795.

Odén, A., McCloskey, E.V., Kanis, J.A., Harvey, N.C. & Johansson, H. 2015. Burden of high fracture probability worldwide: Secular increases 2010-2040. Osteoporosis International 26(9): 2243-2248.

Olsson, M., Järbrink, K., Divakar, U., Bajpai, R., Upton, Z., Schmidtchen, A. & Car, J. 2019. The humanistic and economic burden of chronic wounds: A systematic review. Wound Repair Regen 27(1): 114-125.

Pangestuti, R. & Kim, S.K. 2011. Biological activities and health benefit effects of natural pigments derived from marine algae. Journal of Functional Foods 3(4): 255-266.

Patel, H. & Patel, V.H. 2015. Inflammation and metabolic syndrome - An overview. Current Research in Nutrition and Food Science 3(3): 263-268.

Pihl, E., Zilmer, K., Kullisaar, T., Kairane, C., Magi, A. & Zilmer, M. 2006. Atherogenic inflammatory and oxidative stress markers in relation to overweight values in male former athletes. International Journal of Obesity 30(1): 141-146.

Ramos, S., Martin, M.A. & Goya, L. 2017. Effects of cocoa antioxidants in type 2 diabetes mellitus. Antioxidants 6(4): 84.

Ranasinghe, P., Mathangasinghe, Y., Jayawardena, R., Hills, A.P. & Misra, A. 2017. Prevalence and trends of metabolic syndrome among adults in the Asia-Pacific region: A systematic review. BMC Public Health 17(1): 101.

Ravichanthiran, K., Ma, Z.F., Zhang, H., Cao, Y., Wang, C.W., Muhammad, S., Aglago, E.K., Zhang, Y., Jin, Y. & Pan, B. 2018. Phytochemical profile of brown rice and its nutrigenomic implications. Antioxidants 7(6): 71.

Rieger, S., Zhao, H., Martin, P., Abe, K. & Lisse, T.S. 2014. The role of nuclear hormone receptors in cutaneous wound repair. Cell Biochemistry and Function 33(1): 1-13.

Rodríguez, J. & Mandalunis, P.M. 2018. A review of metal exposure and its effects on bone health. Journal of Toxicology 2018: 4854152.

Rodríguez-Hernández, A., Blé-Castilloa, J.L., Juárez-Oropezac, M.A. & Díaz-Zagoyab, J.C. 2001. Spirulina maxima prevents fatty liver formation in CD-1 male and female mice with experimental diabetes. Life Sciences 69(9): 1029-1037.

Roy-Lachapelle, A., Solliec, M., Bouchard, M.F. & Sauve, S. 2017. Detection of cyanotoxins in algae dietary supplements. Toxins 9(3): 76.

Sadek, K.M., Lebdab, M.A., Nasr, S.M. & Shoukry, M. 2017. Spirulina platensis prevents hyperglycaemia in rats by modulating gluconeogenesis and apoptosis via modification of oxidative stress and MAPK-pathways. Biomedicine and Pharmacotherapy 92: 1085-1094.

Seo, Y.J., Kim, K.J., Choi, J., Koh, E.J. & Lee, B.Y. 2018. Spirulina maxima extract reduces obesity through suppression of adipogenesis and activation of browning in 3T3-L1 Cells and high-fat diet-induced obese mice. Nutrients 10(712): 1-15.

Sharifi, A.M., Ghazanfari, R., Tekiyehmaroof, N. & Sharifi, M.A. 2011. Investigating the effect of lead acetate on rat bone marrow-derived mesenchymal stem cells toxicity: Role of apoptosis. Toxicology Mechanisms and Methods 21(3): 225-230.

Sibal, L., Agarwal, S.C., Home, P.D. & Boger, R.H. 2010. The role of asymmetric dimethylarginine (ADMA) in endothelial dysfunction and cardiovascular disease. Current Cardiology Reviews 6(2): 82-90.

Sies, H. 2015. Oxidative stress: A concept in redox biology and medicine. Redox Biology 4: 180-183.

Simon, J.P., Baskaran, U.L., Shallauddin, K.B., Ramalingam, G. & Prince, S.E. 2018. Evidence of antidiabetic activity of Spirulina fusiformis against streptozotocin‑induced diabetic Wistar albino rats. 3 Biotech 8(2): 129.

Sinha, S., Patro, N. & Patro, I.K. 2018. Maternal protein malnutrition: Current and future perspectives of spirulina supplementation in neuroprotection. Frontier of Neuroscience 12(966): 1-18.

Siva, K.R.R., Madhu, G.M. & Satyanarayana, S.V. 2015. Spirulina in combating Protein Energy Malnutrition (PEM) and protein energy wasting (PEW) - A review. Journal of Nutrition Research 3(1): 62-79.

Sözen, T., Özışık, L. & Başaran, N.Ç. 2017. An overview and management of osteoporosis. European Journal of Rheumatology 4(1): 46-56.

Stahl, W. & Sies, H. 1997. Antioxidant defense: Vitamins E and C and carotenoids. Diabetes 46(2): 14-18.

Sureshbabu, A., Ryter, S.W. & Choi, M.E. 2015. Oxidative stress and autophagy: Crucial modulators of kidney injury. Redox Biology 4: 208-214.

Syarina, P.N., Karthivashan, G., Abas, F., Arulselvan, P. & Fakurazi, S. 2015. Wound healing potential of Spirulina platensis extracts on human dermal fibroblast cells. EXCLI Journal 14: 385-393.

Tbahriti, H.F., Kaddous, A., Bouchenak, M. & Mekki, K. 2013. Effect of different stages of chronic kidney disease and renal replacement therapies on oxidant-antioxidant balance in uremic patients. Biochemistry Research International 2013: 358985.

Thaler, J.P., Yi, C.X., Schur, E.A., Guyenet, S.J., Hwang, B.H., Dietrich, M.O., Zhao, X., Sarruf, D.A., Izgur, V., Maravilla, K.R., Nguyen, H.T., Fischer, J.D., Matsen, M.E., Wisse, B.E., Morton, G.J., Horvath, T.L., Baskin, D.G., Tschöp, M.H. & Schwartz, M.W. 2012 Obesity is associated with hypothalamic injury in rodents and humans. Journal of Clinical Investigations 122(1): 153-162.

US National Institutes of Health. 2017. Blue-green algae. Retrieved from https://medlineplus.gov/druginfo/natural/923.html. Accessed on 18th February 2020.

Vergara-Jimenez, M., Almatrafi, M.M.  & Fernandez, M.L. 2017. Bioactive components in Moringa oleifera leaves protect against chronic disease. Antioxidants 6(4): 91.

Walker-Bone, K. 2012. Recognizing and treating secondary osteoporosis. Nature Reviews, Rheumatology 8(8): 480-492.

Walsh, M.C., Kim, N., Kadono, Y., Rho, J., Lee, S.Y., Lorenzo, J. & Choi, Y. 2006.  Osteoimmunology: Interplay between the immune system and bone metabolism. Annual Review of Immunology 24: 33-63.

Wan, X.Z., Li, T.T., Zhong, R.T., Chen, H.B., Xia, X., Gao, L.Y., Gao, X.X., Liu, B., Zhang, H.Y. & Zhao, C. 2019. Anti-diabetic activity of PUFAs-rich extracts of Chlorella pyrenoidosa and Spirulina platensis in rats. Food Chemistry and Toxicology 128: 233-239.

Wang, Y., Chang, C.F., Chou, J., Chen, H.L., Deng, X., Harvey, B.K., Cadet, J.L. & Bickford, P.C. 2005. Dietary supplementation with blueberries, spinach, or spirulina reduces ischemic brain damage. Experimental Neurology 193(1): 75-84.

Wang, Z. & Nakayama, T. 2010. Inflammation, a link between obesity and cardiovascular disease. Mediators of Inflammation 2010: 535918.

Ward, R.A. & McLeish, K.R. 1995. Polymorphonuclear leukocyte oxidative burst is enhanced in patients with chronic renal insufficiency. Journal of American Society of Nephrology 5(9): 1697-1702.

Williams, L.M., Campbell, F.M., Drew, J.E., Koch, C., Hoggard, N., Rees, W.D., Kamolrat, T., Thi Ngo, H., Steffensen, I.L., Gray, S.R. & Tups, A. 2014. The development of diet-induced obesity and glucose intolerance in C57BL/6 mice on a highfat diet consists of distinct phases. PLoS ONE 9(8): e106159.

Wolf, E., Braun-Reichhart, C., Streckel, E. & Renner, S. 2014. Genetically engineered pig models for diabetes research. Transgenic Research 23(1): 27-38.

Wong, S.K., Chin, K.Y., Suhaimi, F.H., Ahmad, F. & Ima-Nirwana, S. 2018a. The effects of a modified high-carbohydrate high-fat diet on metabolic syndrome parameters in male rats. Experimental and Clinical Endocrinology and Diabetes 126(04): 205-212.

Wong, S.K., Chin, K.Y., Suhaimi, F.H., Ahmad, F., Jamil N.A. & Ima-Nirwana, S. 2018b. Osteoporosis is associated with metabolic syndrome induced by high-carbohydrate high-fat diet in a rat model. Biomedicine and Pharmacotherapy 98: 191-200.

Wong, S.K., Chin, K.Y., Suhaimi, F.H., Ahmad, F. & Ima-Nirwana, S. 2018c. The effects of palm tocotrienol on metabolic syndrome and bone loss in male rats induced by high-carbohydrate high-fat diet. Journal of Functional Foods 44: 246-254.

Wong, S.K., Chin, K.Y., Suhaimi, F.H., Ahmad, F. & Soelaiman, I.N. 2016. The relationship between metabolic syndrome and osteoporosis: A review. Nutrients 8(6): 347.

WHO. 2018. Noncommunicable Diseases Country Profiles. Geneva: World Health Organization.

WHO. 2017. Noncommunicable Diseases Progress Monitor. Geneva: World Health Organization.

WHO. 2015. Noncommunicable Diseases Progress Monitor. Geneva: World Health Organization.

WHO. 2014. Attaining the Nine Global Noncommunicable Disease Targets; A Shared Responsibility. World Health Organization. Global Status of Noncommunicable Disease Report No. 1211.

WHO. 2014. Global Status Report on Noncommunicable Diseases. Geneva: World Health Organization.

Yamagata, K. 2018. Do coffee polyphenols have a preventive action on metabolic syndrome associated endothelial dysfunctions? An assessment of the current evidence. Antioxidants 7(2): 26.

Yang, Z.H., Miyahara, H., Takeo, J. & Katayama, M. 2012. Diet high in fat and sucrose induces rapid onset of obesity-related metabolic syndrome partly through rapid response of genes involved in lipogenesis, insulin signalling and inflammation in mice. Diabetology and Metabolic Syndrome 4(32): 1-10.

Yousefi, R., Mottaghi, A. & Saidpour, A. 2018a. Spirulina platensis effectively ameliorates anthropometric measurements and obesity-related metabolic disorders in obese or overweight healthy individuals: A randomised controlled trial. Complementary Therapies in Medicine 40: 106-112.

Yousefi, R., Saidpour, A. & Mottaghi, A. 2018b. Effects of combined administration of weight reducing diet and spirulina platensis on anthropometric measures and glycemic markers in obese and overweight subjects: A randomised, double-blinded, placebo-controlled clinical trial. Indian Journal of Endocrinology and Metabolism 20(1): 10-21.

Yu, M., Kim, Y.J. & Kang, D.H. 2010. Indoxyl sulfate-induced endothelial dysfunction in patients with chronic kidney disease via an induction of oxidative stress. The Clinical Journal of the American Society of Nephrology 6(1): 30-39.

Zhang, H., Ma, Z.F., Luo, X. & Li, X. 2018. Effects of mulberry fruit (Morus alba L.) consumption on health outcomes: A mini-review. Antioxidants 7(5): 69.

Zhang, X., Zhang, G., Zhang, H., Karin, M., Bai, H. & Cai, D. 2008. Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 135(1): 61-73.

*Pengarang untuk surat-menyurat; email: chinkokyong@ppukm.ukm.edu.my