Vitamin C: Evolution, Prehistory, and History

Moacir C. Andrade Jr.^1,

¹Department of Nutrition and Metabolic Disorders, Faculty of Medicine, Instituto Metropolitano de Ensino (IME), Manaus, Brazil

Cite this paper:
Moacir C. Andrade Jr.. Vitamin C: Evolution, Prehistory, and History. Journal of Food and Nutrition Research. 2024; 12(5):255-263. doi: 10.12691/jfnr-12-5-4

Abstract

Normal metabolism ensures the adequate use of nutrients. Enzymes are the most important mediators of metabolism. Vitamin C, also identified as L-ascorbic acid (or L-ascorbate), is an important enzyme cofactor, playing other significant physiological roles in the human organism. During evolution, a few species, including the Homo sapiens, lacked L-gulonolactone oxidase (recommended name), L-gulono-1,4-lactone oxidase (a synonym), i.e., the enzyme that catalyzes the last step of vitamin C biosynthesis. Hereafter, vitamin C is an essential micronutrient for humans and its deficiency (or scurvy) may be fatal. Indeed, scurvy has plagued humankind since prehistoric times. Nevertheless, the industry began producing vitamin C in the early 1930s. Scientific interest in vitamin C became popular thanks to the eminent American chemist Linus Carl Pauling (1901-1994), who helped to spread the vitamin benefits worldwide, especially toward viral infections (e.g., common cold and flu). The COVID-19 pandemic has renewed the interest in vitamin C, opening new perspectives in the vitamin research and potential therapeutic uses. New conceptual elements have emerged, allowing the elucidation of points related to the evolution, prehistory, and history of vitamin C, and motivating the present review article.

Keywords:
ascorbic acid evolution history humans prehistory pseudogenes scurvy

This work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

References:

[1]	Andrade Jr., M.C. de, “Evolutionary aspects of hormones”, Archives of Endocrinology and Metabolism, 46(3). 291-298. 2002.
[2]	Balakirev, E.S., Ayala, F.J., “Pseudogenes: are they “junk” or functional DNA?”, Annual Review of Genetics, 37. 123-151. 2003.
[3]	Zheng, D., Frankish, A., Baertsch, R., Kapranov, P., Reymond, A., Choo, S.W., Lu, Y., Denoeud, F., Antonarakis, S.E., Snyder, M., Ruan, Y., Wei, C.-L., Gingeras, T.R., Guigó, R., Harrow, J., Gerstein, M.B., “Pseudogenes in the ENCODE regions: consensus annotation, analysis of transcription, and evolution”, Genome Research, 17(6). 839-851. 2007.
[4]	Chen, F.-C., Chen, Y.-Z., Chuang, T.-J., “CNVVdb: a database of copy number variations across vertebrate genomes”, Bioinformatics, 25(11). 1419-1421. 2009.
[5]	Zhang, Y., Sun, Y., “PseudoDomain: identification of processed pseudogenes based on protein domain classification”, in Proceedings of the ACM Conference on Bioinformatics, Computational Biology and Biomedicine, 2012, 178-185.
[6]	Chan, W.-L., Yuo, C.-Y., Yang, W.-K., Hung, S.-Y., Chang, Y.-S., Chiu, C.-C., Yeh, K.-T., Huang, H.-D., Chang, J.-G., “Transcribed pseudogene ψPPM1K generates endogenous siRNA to suppress oncogenic cell growth in hepatocellular carcinoma”, Nucleic Acids Research, 41(6). 3734-3747. 2013.
[7]	Zhang, Q., “Using pseudogene database to identify lineage-specific genes and pseudogenes in humans and chimpanzees”, Journal of Heredity, 105(3). 436-443. 2014.
[8]	Bender, D.A., Benders’ dictionary of nutrition and food technology, 8 ed, CRC Press, Boca Raton, 2006.
[9]	Lopez, M.J., Mohiuddin, S.S., Biochemistry, essential amino acids, StatPearls Publishing, Treasure Island (FL), 2023.
[10]	Drouin, G., Godin, J.R., Pagé, B., “The genetics of vitamin C loss in vertebrates”, Current Genomics, 12(5). 371-378. 2011.
[11]	Korus, A., “Changes in the content of minerals, B-group vitamins and tocopherols in processed kale leaves”, Journal of Food Composition and Analysis, 89(103464). 2020.
[12]	Lane, D.J., Richardson, D.R., “The active role of vitamin C in mammalian iron metabolism: much more than just enhanced iron absorption!”, Free Radical Biology and Medicine, 75. 69-83. 2014.
[13]	Andrade Jr., M.C., “Vitamin C deficiency (or scurvy): pathophysiology and clinical manifestations according to age groups”, Journal of Food and Nutrition Research, 11(12). 752-758. 2023.
[14]	Nelson, D.L., Cox, M.M., Hoskins, A.A., Lehninger principles of biochemistry, 8 ed, Macmillan Learning, New York, 2021.
[15]	Poole, A., Jeffares, D., Penny, D., “Early evolution: prokaryotes, the new kids on the block”, BioEssays, 21(10). 880-889. 1999.
[16]	De la Cruz, A.A., Chernoff, N., Sinclair, J.L., Hill, D., Diggs, D.L., Lynch, A.T., “Introduction to cyanobacteria and cyanotoxins”, in Hiskia, A.E., Triantis, T.M., Antoniou, M.G., Kaloudis, T., Dionysiou, D.D., Eds., Water treatment for purification from cyanobacteria and cyanotoxins, John Wiley & Sons Ltd., New Jersey, 2020, 1-35.
[17]	Kristensen, T., Guillaume, F., “Different regimes for classification of DNA sequences”, in IEEE 7th International Conference on Cybernetics and Intelligent Systems (CIS) and IEEE Conference on Robotics, Automation and Mechatronics, Siem Reap, Cambodia, 15-17 July, 2015.
[18]	Olagunju, O.F., “Incidence of mycotoxigenic fungi during processing and storage of bambara groundnut (Vigna subterranea) composite flour”, Doctor Degree, Durban, South Africa, Department of Biotechnology and Food Technology, Durban University of Technology, 2019.
[19]	Sunter J.D., Moreira-Leite F., Gull K., “Dependency relationships between IFT-dependent flagellum elongation and cell morphogenesis in Leishmania”, Royal Society Open Biology, 8(11). 180124. 2018.
[20]	Olivier, M., Hassani, K, “Protease inhibitors as prophylaxis against leishmaniasis: new hope from the major surface protease gp63”, Future Medicinal Chemistry, 2(4). 539-542. 2010.
[21]	Dolan, M.F., “The missing piece: the microtubule cytoskeleton and the origin of the eukaryotes”, in Sapp, J., Ed., Microbial phylogeny and evolution: concepts and controversies, Oxford University Press, Inc., New York, 2005, 281-289.
[22]	King, R.C., Stansfield, W.D., and Mulligan, P.K., A dictionary of genetics, 7 ed, Oxford University Press, New York, 2006.
[23]	Liffner, B., and Absalon, S., “Expansion microscopy of apicomplexan parasites” Molecular Microbiology. 2023.
[24]	Smirnoff, N., “Ascorbic acid metabolism and functions: a comparison of plants and mammals”, Free Radical Biology and Medicine, 122. 116-129. 2018.
[25]	Branduardi, P., Fossati, T., Sauer, M., Pagani, R., Mattanovich, D., Porro, D., “Biosynthesis of vitamin C by yeast leads to increased stress resistance”, PLoS ONE, 2(10). 2007.
[26]	Evers, M.S., Roullier-Gall, C., Morge, C., Sparrow, C., Gobert, A., Alexandre, H., “Vitamins in wine: which, what for, and how much?”, Comprehensive Reviews in Food Science and Food Safety, 20. 2991-3035. 2021.
[27]	Köhler, J.R., Acosta-Zaldívar, M., Qi, W., “Phosphate in virulence of Candida albicans and Candida glabrata”, Journal of Fungi, 6(2). 2020.
[28]	Zhitkovich, A., “Nuclear and cytoplasmic functions of vitamin C”, Chemical Research in Toxicology, 33(10). 2515-2526. 2020.
[29]	Hancock, R.D., Galpin, J.R., Viola, R., “Biosynthesis of L-ascorbic acid (vitamin C) by Saccharomyces cerevisiae”, FEMS Microbiology Letters, 186(2). 245-250. 2000.
[30]	Andrade Jr., M.C, Andrade J.S., Fermented foods in general and ethnic fermented foods in particular, LAP LAMBERT Academic Publishing, Saarbrücken, 2015.
[31]	Han, B., Nimni, M.E., “Transdermal delivery of amino acids and antioxidants enhance collagen synthesis: in vivo and in vitro studies”, Connective Tissue Research, 46. 251-257. 2005.
[32]	Kramer, K.J., Seib, P.A., “Ascorbic acid and the growth and development of insects”, in Ascorbic acid: chemistry, metabolism, and uses, ACS Publications, Washington, DC, 1982, 275-291.
[33]	Huang, J., Sun, W., Seong, K.M., Mittapalli, O., Ojo, J., Coates, B., Paige, K.N., Clark, J.M., Pittendrigh, B.R., “Dietary antioxidant vitamin C influences the evolutionary path of insecticide resistance in Drosophila melanogaster”, Pesticide Biochemistry and Physiology, 168(104631). 2020.
[34]	Lohakare, J.D., Kim, J.K., Ryu, M.H., Hahn, T.-W., Chae, B.J., “Effects of vitamin C and vitamin D interaction on the performance, immunity, and bone characteristics of commercial broilers”, Journal of Applied Poultry Research, 14(4). 670-678. 2005.
[35]	Leskovec, J., Levart, A., Nemec Svete, A., Perić, L., Đukić Stojčić, M., Žikić, D., Salobir, J., Rezar, V., “Effects of supplementation with α-tocopherol, ascorbic acid, selenium, or their combination in linseed oil-enriched diets on the oxidative status in broilers”, Poultry Science, 97(5). 1641-1650. 2018.
[36]	Meduri, G.U., Chrousos, G.P., “General adaptation in critical illness: glucocorticoid receptor-alpha master regulator of homeostatic corrections”, Frontiers in Endocrinology, 11(161). 2020.
[37]	Deacon, T.W., “A degenerative process underlying hierarchic transitions in evolution”, Biosystems, 222(104770). 2022.
[38]	Nishikimi, M., Yagi, K., “Molecular basis for the deficiency in humans of gulonolactone oxidase, a key enzyme for ascorbic acid biosynthesis”, The American Journal of Clinical Nutrition, 54(6). 1203S-1208S. 1991.
[39]	Duque, P., Vieira, C.P., Bastos, B., Vieira, J., “The evolution of vitamin C biosynthesis and transport in animals”, BMC Ecology and Evolution, 22(1). 1-21. 2022.
[40]	Larkum, A.W.D., “The golden apples of the sun: the history of photosynthesis—so far, in Photosynthesis research for food, fuel and the future: 15th International Conference on Photosynthesis, Springer, Berlin, Heidelberg. 2013.
[41]	Kuivanen, J., Penttilä, M., Richard, P, “Metabolic engineering of the fungal D-galacturonate pathway for L-ascorbic acid production”, Microbial Cell Factories, 14(1). 1-9. 2015.
[42]	Fernie, A.R., Tohge, T., “A cross-kingdom history”, eLife, 4(e07527). 2015.
[43]	Smirnoff, N., Wheeler, G.L., “The ascorbate biosynthesis pathway in plants is known but there is a way to go with understanding control and functions”, Journal of Experimental Botany, erad505. 2024.
[44]	Inai, Y., Ohta, Y., Nishikimi, M., “The whole structure of the human nonfunctional L-gulono-γ-lactone oxidase gene-the gene responsible for scurvy-and the evolution of repetitive sequences thereon”, Journal of Nutritional Science and Vitaminology, 49(5). 315-319. 2003.
[45]	Lincoln, R.J., Boxshall, G.A., Clark, P.F., A dictionary of ecology, evolution and systematics, Cambridge University Press, Cambridge. 1982.
[46]	Amberger, J.S., Hamosh, A., Mckusick, V.A., “Morbid anatomy of human genome”, Scriver, C.R., Beaudet, A.L., Sly, W.S., Valle, D., Eds., in The metabolic and molecular bases of inherited disease, New York, 2001, 47-125.
[47]	Gerstein, M., Zheng, D., “The real life of pseudogenes”, Scientific American, 295(2). 48-55. 2006.
[48]	Li, Z., Hoshino, Y., Tran, L., Gaucher, E.A., “Phylogenetic articulation of uric acid evolution in mammals and how it informs a therapeutic uricase”, Molecular Biology and Evolution, 39(1). 2022.
[49]	Ligrone, R., “The emergence of humanity”, in Biological innovations that built the world, Springer Nature Switzerland AG, Cham, 2019, 399-470.
[50]	Kvist, U., “Spermatology in Sweden”, in XIIIth International Symposium on Spermatology, Björndahl, L., Flanagan, J., Holmberg, R., Kvist, U., Eds., Springer International Publishing, Cham, 2021, 19-32.
[51]	Sauer, G., “Astrobiology, a new chapter in the book of nature”, Theology and Science. 1-12. 2024.
[52]	Moran, L.A., Horton, H.R., Scrimgeour, K.G., Perry, M.D., Principles of biochemistry, 5 ed, Pearson Education, Inc., Boston, 2012.
[53]	Coleman, M.A., “Algae in the Anthropocene: managing, conserving, and utilizing algae in an era of rapid environmental change” Journal of Phycology. 2023.
[54]	Richerson, P.J., Boyd, R.T., Efferson, C., “Agentic processes in cultural evolution: relevance to Anthropocene sustainability”, Philosophical Transactions of the Royal Society B, 379(1893). 2024.
[55]	Vicentino, C., [General history], História geral, 8 ed, Scipione, São Paulo, 2000.
[56]	Flodin, N.W., “Nutritional influences in the geographic dispersal of Pleistocene man”, Ecology of Food and Nutrition, 38(1). 71-99. 1999.
[57]	Kerr, M.E., Bender, C.M., Monti, E.J., “An introduction to oxygen free radicals”, Heart & Lung: the Journal of Critical Care, 25(3). 200-209. 1996.
[58]	Aust, S.D., Chignell, C.F., Bray, T.M., Kalyanaraman, B., Mason, R.P., “Free radicals in toxicology”, Toxicology and Applied Pharmacology, 120(2). 168-178. 1993.
[59]	Gudasi, S., Gharge, S., Koli, R., Patil, K., “Antioxidant properties and cytotoxic effects of Oxalis corniculata on human Hepatocarcinoma (Hep-G2) cell line: an in vitro and in silico evaluation”, Future Journal of Pharmaceutical Sciences, 9(25). 2023.
[60]	Li, M., Niu, C., Chen, Y., “Diverse response pattern to anoxia in three freshwater turtle species”, Biology, 12(1). 2022.
[61]	Erisman, J.W., Galloway, J.N., Seitzinger, S., Bleeker, A., Dise, N.B., Petrescu, A.M.R., Leach, A.M., de Vries, W., “Consequences of human modification of the global nitrogen cycle”, Philosophical Transactions of the Royal Society B: Biological Sciences, 368(1621). 20130116. 2013.
[62]	Chen, B., Niu, C., Yuan, L., Zhang, W., “Physiological responses in vitamin C system during hibernation in juvenile Chinese soft-shelled turtle Pelodiscus sinensis”, Journal of Oceanology and Limnology, 37(2). 767-776. 2019.
[63]	Nandi, A., Mukhopadhyay, C.K., Ghosh, M.K., Chattopadhyay, D.J., Chatterjee, I.B., “Evolutionary significance of vitamin C biosynthesis in terrestrial vertebrates”, Free Radical Biology and Medicine, 22(6). 1047-1054. 1997.
[64]	Kietzmann, T., “Vitamin C: from nutrition to oxygen sensing and epigenetics”, Redox Biology, 63(102753). 2023.
[65]	Thompson, R.F., Einstein, F.H., “Epigenetic basis for fetal origins of age-related disease”, Journal of Women's Health, 19(3). 581-587. 2010.
[66]	Kuo, C.F., Grainge, M.J., Zhang, W., Doherty, M., “Global epidemiology of gout: prevalence, incidence and risk factors”, Nature Reviews Rheumatology, 11(11). 649-662. 2015.
[67]	Santos, C.S., Salgueiro, R.R., Morales, C.M., Castro, C.Á., Álvarez, E.D., “Risk factors for cardiovascular disease in primary Sjögren’s syndrome (pSS): a 20-year follow-up study”, Clinical Rheumatology, 42(11). 3021-3031. 2023.
[68]	Chang, A., Jeske, L., Ulbrich, S., Hofmann, J., Koblitz, J., Schomburg, I., Neumann-Schaa, l.M., Jahn, D., Schomburg, D., “BRENDA, the ELIXIR core data resource in 2021: new developments and updates”, Nucleic Acids Research, 49(D1). D498-D508. 2021.
[69]	Crews, K.R., Zhou, Y., Pauley, J.L., Howard, S.C., Jeha, S., Relling, M.V., Pui, C.H., “Effect of allopurinol versus urate oxidase on methotrexate pharmacokinetics in children with newly diagnosed acute lymphoblastic leukemia”, Cancer: Interdisciplinary International Journal of the American Cancer Society, 116(1). 227-232. 2010.
[70]	Jiang, N., Xu, C., Zhang, L., Chen, J., ““Resurrected” human-source urate oxidase with high uricolytic activity and stability”, Enzyme and Microbial Technology, 149(109852). 2021.
[71]	Birat, J.P., “Society and materials: how it all started, a few million years ago”, Matériaux & Techniques, 104(6-7). 605. 2016.
[72]	Wastegård, S., “The Holocene of Sweden–a review”, GFF, 144(2). 126-149. 2022.
[73]	Castaneda, D., Archaeology, ED-Tech Press, Waltham Abbey, 2018.
[74]	Singh, V., “Study of history purpose and methods of archaeology”, Asian Journal Of Multidimensional Research, 10(7). 70-74. 2021.
[75]	Brooks, C., Western civilization: a concise history, Portland Community College, Portland, 2022.
[76]	Rausing, G., “Stone Age man, anemia and iron oxide”, Fornvännen: Journal of Swedish Antiquarian Research, 87. 127-128. 1992.
[77]	Mann, N., “Dietary lean red meat and human evolution”, European Journal of Nutrition, 39. 71-79. 2000.
[78]	Siminialayi, I.M., “The rising burden of non-communicable disease and food as medicine”, Niger Delta Medical Journal, 2(1). 19-36. 2017.
[79]	Guil-Guerrero, J.L., “The role of large mammals as vitamin C sources for MIS 3 hominins”, Quaternary, 6(1). 2023.
[80]	Szczęsny, T.J., “Was the 4.2 ka event an anthropogenic disaster?”, Open Journal of Ecology, 6(10). 2016.
[81]	Abdel-Haleem, H., Bowman, J.G., Kanazin, V., Surber, L., Talbert, H., Hayes, P.M., and Blake, T., “Quantitative trait loci for dry matter digestibility and particle size traits in two-rowed × six-rowed barley population”, Euphytica, 172. 419-433. 2010.
[82]	Haak, W., Lazaridis, I., Patterson, N., Rohland, N., Mallick, S., Llamas, B., Brandt, G., Nordenfelt, S., Harney, E., Stewardson, K., Fu, Q., Mittnik, A., Bánffy, E., Economou, C., Francken, M., Friederich, S., Pena, R.G., Hallgren, F., Khartanovich, V., Khokhlov, A., Kunst, M., Kuznetsov, P., Meller, H., Mochalov, O., Moiseyev, V., Nicklisch, N., Pichler, S.L., Risch, R., Guerra, M.A.R., Roth, C., Szécsényi-Nagy, A., Wahl, J., Meyer, M., Krause, J., Brown, D., Anthony, D., Cooper, A., Alt, K.W., Reich, D., “Massive migration from the steppe was a source for Indo-European languages in Europe”, Nature, 522(7555). 7555. 2015.
[83]	Naugler, C., “Hemochromatosis: a Neolithic adaptation to cereal grain diets”, Medical Hypotheses, 70(3). 691-692. 2008.
[84]	Pinyopornpanish, K., Tantiworawit, A., Leerapun, A., Soontornpun, A., Thongsawat, S., “Secondary iron overload and the liver: a comprehensive review”, Journal of Clinical and Translational Hepatology, 11(4). 932-941. 2023.
[85]	Dorak, M.T., Relton, C.L., Hammal, D., Hall, A.G., Parker, L,. “HFE-C282Y association in childhood ALL: pointing towards iron?”, in Children with Leukaemia Conference, London, 2004.
[86]	Machado, C.C., Dinis-Oliveira, R.J., “Clinical and forensic signs resulting from exposure to heavy metals and other chemical elements of the periodic table”, Journal of Clinical Medicine, 12(7). 2023.
[87]	Thompson, J.E., Power, R.K., Mercieca-Spiteri, B., Magnussen, J.S., Pardey, M., Buck, L.T., Stock, J.T., McLaughlin, T.R., Stoddart, S., Malone, C., “Analysis of periosteal lesions from commingled human remains at the Xagħra Circle hypogeum reveals the first case of probable scurvy from Neolithic Malta”, International Journal of Osteoarchaeology, 32(1). 18-37. 2022.
[88]	Greydanus, D.E., Apple, R.W., Chahin, S.S., “Integrated behavioral health care: reflections of the past”, Pediatric Clinics, 68(3). 519-531. 2021.
[89]	Khalil, R.B., Richa, S., “When affective disorders were considered to emanate from the heart: the Ebers papyrus”, American Journal of Psychiatry, 171(3). 275. 2014.
[90]	Santos-Gallego, C.G., Badimon, J. “Overview of aspirin and platelet biology”, American Journal of Cardiology, 144(supplement 1). S2-S9. 2021.
[91]	Kinlin, L.M., Weinstein, M., “Scurvy: old disease, new lessons”, Paediatrics and International Child Health, 43(4). 83-94. 2023.
[92]	De Villiers, J.C., “The Dutch East India Company, scurvy and the victualling station at the Cape: history of medicine: SAMJ forum”, South African Medical Journal, 96(2). 105-110. 2006.
[93]	Wilson, J.V.K., “Diseases of Babylon: an examination of selected texts”, Journal of the Royal Society of Medicine, 89(3). 135-140. 1996.
[94]	Ben-Noun, L., Scurvy: forgotten but still exists, B.N. Publication House, Beersheba, 2022.
[95]	Artés, F., Marin, J.G., Martínez, J.A., “Controlled atmosphere storage of pomegranate”, Zeitschrift für Lebensmittel-Untersuchung und Forschung, 203. 33-37. 1996.
[96]	Horowitz, S., “The power of the pomegranate: biblical fruit with medicinal properties”, Alternative & Complementary Therapies, 12(3). 121-126. 2006.
[97]	Byard, R.W., Maxwell-Stewart, H., “Scurvy—characteristic features and forensic issues”, American Journal of Forensic Medicine and Pathology, 40(1). 43-46. 2018.
[98]	Magiorkinis, E., Beloukas, A., Diamantis, A., “Scurvy: past, present and future”, European Journal of Internal Medicine, 22(2). 147-152. 2011.
[99]	Mikula, K., Ambroz, M., Mokošová, R., “What was the river Ister in the time of Strabo? A mathematical approach”, Tatra Mountains Mathematical Publications, 80(3). 71-118. 2021.
[100]	Galtung, J., “Dialogue of faiths”, World Affairs: The Journal of International Issues, 7(2). 15-30. 2003.
[101]	Belfiglio, V., “Discordibus culturis in antiquitate”, World Wide Journal of Multidisciplinary Research and Development, 3(8). 227-223. 2017.
[102]	Bender, D.A., Introduction to nutrition and metabolism, 4 ed., CRC Press, Boca Raton, 2008.
[103]	World Health Organization (WHO), Scurvy and its prevention and control in major emergencies, WHO/NHD/99.11, 1999.
[104]	Claridge, J.A., Fabian, T.C., “History and development of evidence-based medicine”, World Journal of Surgery, 29(547-553). 547. 2005.
[105]	Diniz, A.J.A., “[Reflections on the New World Order], Reflexões sobre a Nova Ordem Mundial”, Revista da Faculdade de Direito da Universidade Federal Minas Gerais, 34. 145-157. 1994.
[106]	Yoder, C., “Let them eat cake? Status-based differences in diet in medieval Denmark”, Journal of Archaeological Science, 39. 1183- 1193. 2012.
[107]	Bhattacharyya, B., Baruah, M.P., Kalra, B,. “The vitamin which defeated Napoleon”, Journal of Medical Nutrition and Nutraceuticals, 1(2). 59-60. 2012.
[108]	Liu, S., Li, S., Ho, C.T., “Dietary bioactives and essential oils of lemon and lime fruits”, Food Science and Human Wellness, 11(4). 753-764. 2022.
[109]	Pucci, L., Addor, O., Duplain, H., “Haemodynamic instability of uncommon aetiology in Switzerland”, BMJ Case Reports. bcr2015214050. 2016.
[110]	Cameron, E., Pauling, L., Leibovitz, B., “Ascorbic acid and cancer: a review”, Cancer Research, 39. 663-681. 1979.
[111]	Meiklejohn, A.P., “The curious obscurity of Dr. James Lind”, Journal of the History of Medicine and Allied Sciences, 9(3). 304-310. 1954.
[112]	Yang, W., Xu, H., “Industrial fermentation of vitamin C”, in Vandamme, E.J., Revuelta, J.L., Eds., Industrial biotechnology of vitamins, biopigments, and antioxidants, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2016, 161-192.
[113]	Norum, K.R., Grav, H.J., “Axel Holst and Theodor Frolich – pioneers in the combat of scurvy”, Tidsskrift for den Norske Laegeforening: Tidsskrift for Praktisk Medicin, ny Raekke, 122(17). 1686-1687. 2002.
[114]	Vieth, R., “Vitamin D supplementation: cholecalciferol, calcifediol, and calcitriol”, European Journal of Clinical Nutrition, 74(11). 1493-1497. 2020.
[115]	Toniato, E., Spinas, E., Saggini, A., Kritas, S.K., Caraffa, A., Antinolfi, P., Saggini, R., Pandolfi, F., Conti, P., “Immunomodulatory effects of vitamin D on skin inflammation”, Journal of Biological Regulators and Homeostatic Agents, 29(3). 563-567. 2015.
[116]	Rosenfeld, L., “Vitamine—vitamin. The early years of discovery”, Clinical Chemistry, 43(4). 680-685. 1997.
[117]	Vieth, R., “Why “vitamin D” is not a hormone, and not a synonym for 1, 25-dihydroxy-vitamin D, its analogs or deltanoids”, Journal of Steroid Biochemistry and Molecular Biology, 89-90. 571-573. 2004.
[118]	Albert Szent-Györgyi–Facts–Nobel Lecture. https:// www.nobelprize.org/ prizes/ medicine/1937/szent-gyorgyi/facts/. Accessed Sun. 27 Mar 2022, 2022.
[119]	Lipnizki, F., “Basic aspects and applications of membrane processes in agro-food and bulk biotech industries”, in Drioli, E., Giorno, L., Eds., Compreehensive membrane science and engineering II, Elsevier Science Publishers B.V., Kidlington, 2017, 189-213.
[120]	Paterson, D., “The fruits of labor: the first industrial synthesis of vitamin C”, Karger Gazette, 71. 2010.
[121]	Pappenberger, G., Hohmann, H.P., “Direct microbial routes to vitamin C production”, in Vandamme, E.J.,. Revuelta, J.L., Eds., Industrial biotechnology of vitamins, biopigments, and antioxidants, Wiley-VCH Verlag GmbH & Co. KGaA., Weinheim, 2016, 193-225.
[122]	Yang, W., Xu, H., “Industrial fermentation of vitamin C”, in Vandamme, E.J., Revuelta, J.L., Eds., Industrial biotechnology of vitamins, biopigments, and antioxidants, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2016, 161-192.
[123]	Hancock, R., Viola, R., “The use of micro-organisms for L-ascorbic acid production: current status and future perspectives”, Applied Microbiology and Biotechnology, 56. 567-576. 2001.
[124]	Pauling, L., Vitamin C, the common cold and the flu, A Berkley Book/published by arrangement with W.H. Freeman and Company, San Francisco, 1970.
[125]	Pauling, L., “Evolution and the need for ascorbic acid”, Proceedings of the National Academy of Sciences, 67(4). 1643-1648. 1970.
[126]	Pauling, L., “Vitamin C and the common cold”, Canadian Medical Association Journal, 105. 448,450. 1971.
[127]	Pauling, L., “The significance of the evidence about ascorbic acid and the common cold”, Proceedings of the National Academy of Sciences, 68(11). 2678-2681. 1971.
[128]	Pauling, L., “Are recommended daily allowances for vitamin C adequate?” Proceedings of the National Academy of Sciences, 71(11). 4442-4446. 1974.
[129]	Pauling, L., “Early evidence about vitamin C and the common cold”, Journal of Orthomolecular Psychiatry, 3(3). 139-151. 1974.
[130]	Pauling, L., Nixon, J.C., Stitt, F., Marcuson, R., Dunham, W.B., Barth, R., Bensch, K., Herman, Z.S., Blaisdell, B.E., Tsao, C., “Effect of dietary ascorbic acid on the incidence of spontaneous mammary tumors in RIII mice”, Proceedings of the National Academy of Sciences, 82(15). 5185-5189. 1985.
[131]	Pauling, L., Moertel, C., “A proposition: megadoses of vitamin C are valuable in the treatment of cancer”, Nutrition Reviews, 44(1). 28-29. 1986.
[132]	Pauling, L., How to live longer and feel better, Avon Books/published by arrangement with W.H. Freeman and Company, New York, 1986.
[133]	Pauling, L., “Vitamin C papers”, Science, 243(4898). 1535. 1989.
[134]	Pauling, L., “Respect for vitamin C”, Science, 254(5039). 1712. 1991.
[135]	McBeath, M., Pauling, L,. “A case history: lysine/ascorbate-related amelioration of angina pectoris”, Journal of Orthomolecular Medicine, 8. 77-78. 1993.
[136]	Kartha, C.C., “Linus Pauling and vitamin C”, Current Science, 67(5). 411-414. 1994.
[137]	Bland, J.S., “Linus Pauling (1901-1994)”, Integrative Medicine: A Clinician's Journal, 18(3). 50-51. 2019.
[138]	Weiss, K.J., “Linus Pauling, Ph. D.(1901–1994): from chemical bond to civilization”, American Journal of Psychiatry, 174(6). 518-519. 2017.
[139]	Rodemeister, S., Biesalski, H.K., “There’s life in the old dog yet: vitamin C as a therapeutic option in endothelial dysfunction”, Critical Care, 18(461). 1-2. 2014.
[140]	Cabanillas, F., “Vitamin C and cancer: what can we conclude-1,609 Patients and 33 Years later?”, Puerto Rico Health Sciences Journal, 29(3). 215-217. 2010.
[141]	Frei, B., Lawson, S., “Vitamin C and cancer revisited”, Proceedings of the National Academy of Sciences, 105(32). 11037-11038. 2008.
[142]	Wang, Q.-H., Wang, J., Wang, Y.-Y., He, W., Feng, C., Gao, J., Lu, Q., Wang, Y., Dun, S., Zhang, Q., Zou, L.-P., “Accelerated course of cerebral adrenoleukodystrophy after coronavirus disease 2019 infection”, Pediatric Neurology, 152. 87-92. 2024.
[143]	Firouzi, S., Pahlavani, N., Navashenaq, J.G., Clayton, Z.S., Beigmohammadi, M.T., Malekahmadi, M., “The effect of vitamin C and Zn supplementation on the immune system and clinical outcomes in COVID-19 patients”, Clinical Nutrition Open Science, 44. 144-154. 2022.
[144]	Şenay, Ş., “Coronavirus pandemic and cardiovascular issues”, Turkish Journal of Thoracic and Cardiovascular Surgery, 28(2). 227-228. 2020.
[145]	Arunachalam, K., Sasidharan, S.P., Yang, X., “A concise review of mushrooms antiviral and immunomodulatory properties that may combat against COVID-19”, Food Chemistry Advances, 1. 100023. 2022.
[146]	Tang, S., Ji, L., Bishwajit, G., Guo, S., “Uptake of COVID-19 and influenza vaccines in relation to preexisting chronic conditions in the European countries”, BMC Geriatrics, 24(56). 2024.
[147]	Malakar, S., “Bioactive food chemicals and gastrointestinal symptoms: a focus of salicylates”, Journal of Gastroenterology and Hepatology, 32(S1). 73-77. 2017.
[148]	Hemilä, H., “Vitamin C, respiratory infections and the immune system”, Trends in Immunology, 24(11). 579-580. 2003.
[149]	Carr, A.C., Maggini, S., “Vitamin C and immune function”, Nutrients, 9(11). 2017.
[150]	Mortaz, E., Bezemer, G., Alipoor, S.D., Varahram, M., Mumby, S., Folkerts, G., Garssen, J., Adcock, I.M., “Nutritional impact and its potential consequences on COVID-19 severity”, Frontiers in Nutrition, 8. 698617. 2021.
[151]	Naidu, A.S., Pressman, P., Clemens, R.A., “Coronavirus and nutrition: what is the evidence for dietary supplements usage for COVID-19 control and management?”, Nutrition Today, 56(1) 19-25. 2021.
[152]	Cerullo, G., Negro, M., Parimbelli, M., Pecoraro, M., Perna, S., Liguori, G., Rondanelli, M., Cena, H., D’Antona, G., “The long history of vitamin C: from prevention of the common cold to potential aid in the treatment of COVID-19”, Frontiers in Immunology, 11. 574029. 2020.
[153]	Neethu, R.S., Reddy, M.J., Batra, S., Srivastava, S.K., Syal, K., “Vitamin C and its therapeutic potential in the management of COVID19”, Clinical Nutrition ESPEN, 50. 8-14. 2022.
[154]	Infusino, F., Marazzato, M., Mancone, M., Fedele, F., Mastroianni, C.M., Severino, P., Ceccarelli, G., Santinelli, L., Cavarretta, E., Marullo, A.G.M., Miraldi, F., Carnevale, R., Nocella, C., Biondi-Zoccai, G., Pagnini, C., Schiavon, S., Pugliese, F., Frati, G., d’Ettorre, G., “Diet supplementation, probiotics, and nutraceuticals in SARS-CoV-2 infection: a scoping review”, Nutrients, 12. 1718. 2020.
[155]	Dos Santos, W.G., “Natural history of COVID-19 and current knowledge on treatment therapeutic options”, Biomedicine & Pharmacotherapy, 129. 110493. 2020.
[156]	Peter, T., Aruna, A., “Prevention and treatment of COVID–19: a review”, World Journal of Advanced Research and Reviews, 9(3). 272-280. 2021.
[157]	Yıldız, Y., Şahin, B.Ö., Taşdemir, M.C., Demir, Ş., Çifci, B., Köktürk, N., Çiftçi, T.U., Yurdakul, A.S., Demirci, N.Y., Aydoğdu, M., Dizbay, M., Oğuzülgen, İ.K., “Risk factors for post-acute sequelae of COVID-19 in hospitalized patients: an observational study based on a survey in a tertiary care center in Türkiye”, Tüberküloz ve Toraks, 71(3). 261-272. 2023.
[158]	Low, R.N., Low, R.J., Akrami, A., “A review of cytokine-based pathophysiology of long COVID symptoms”, Frontiers in Medicine, 10. 1011936. 2023.
[159]	Chung, M.Y., Hong, S.J., Lee, J.Y., “The influence of obesity on postoperative inflammatory cytokine levels”, Journal of International Medical Research, 39(6). 2370-2378. 2011.
[160]	Grewal, T., Buechler, C., “Adipokines as diagnostic and prognostic markers for the severity of COVID-19”, Biomedicines, 11(5). 2023.
[161]	Kim, J.W., Kim, J.H., Lee, Y.J., “The role of adipokines in tumor progression and its association with obesity”, Biomedicines, 12(1). 2024.
[162]	Kiernan, K., MacIver, N.J., “The role of the adipokine leptin in immune cell function in health and disease”, Frontiers in Immunology, 11. 622468. 2021.
[163]	Sawadogo, W., Tsegaye, M., Gizaw, A., Adera, T., “Overweight and obesity as risk factors for COVID-19-associated hospitalisations and death: systematic review and meta-analysis”, BMJ Nutrition, Prevention & Health, 5(1). 2022.