Doğal kaynaklardan elde edilen ham maddeler; fitokimyasal yapıları ve biyolojik aktiviteleri ile her zaman ilgi çekici olmuştur. Bu ham maddeler, hem hayvanlardan hem de bitkilerden elde edilmekte olup, farklı yapı ve özellikte olmaktadır. Triterpenler de doğada bulunan önemli bir grup sekonder bileşiklerdir. Triterpen yapısında olan 'skualen'; insanlar, hayvanlar ve bitkiler tarafından sentezlenebilen biyosentetik bir ara üründür. Skualen, yapısal olarak 6 izoprenmolekülünden oluşan ve 6 çifte bağı bulunan, 30 karbonlu doymamış bir hidrokarbon, izoprenoit yapısına sahip, triterpenler sınıfında yer alan lipfilik bir biyomolekül, kokusuz, renksiz sıvı bir yağ olarak tanımlanmaktadır. Bu bileşik, ilk defa, Squalidae familyasına ait bir köpek balığının karaciğer yağından izole edildiği için, familyasına atfen 'Skualen' ismini almıştır. Daha sonraları pek çok bitkide de bulunduğu tespit edilmiştir. Hem doğal hem de sentetik yöntemlerle üretilen bu metabolit, sahip olduğu önemli etkiler sebebiyle özellikle kozmetik, ilaç ve diğer farmasötik alanlarda oldukça yaygın kullanılmaktadır. Skualen, emilim ve dağılım veriminin yüksek olması, farklı yollarla uygulandığı zaman vücut tarafından iyi tolere edilebilmesi, toksisite profilinin güvenilir olması sebebiyle farklı alanlarda ve birden fazla uygulama yöntemine sahiptir. Özellikle terapötik uygulamalarda farklı şekillerde kullanımı bulunan bu bileşiğin, tarihçesi, elde edildiği kaynakları, etkileri ve kullanım alanları, bu derleme ile birlikte değerlendirilmiş olup; detaylı literatür incelemesinin ardından kapsamlı bir şekilde sunulmuştur. Bu bilgiler ışığında, skualen hakkında genel bilgilerin yanı sıra kozmetik ve farmasötik alanda kullanımına ve üretimine yönelik tüm bilgiler, bu derlemede sunulacak ve böylece bu konuya dair yeni bir pencere açılacaktır.
Anahtar Kelimeler: Skualen; triterpen; antioksidan; antikanser; adjuvan
Raw materials obtained from natural resources have always been fascinating with their phytochemical structures and biological activities. These raw materials are obtained from animals and plants and have different forms and properties. Triterpenes are an important group of secondary compounds found in nature. Squalene, a triterpene structure, is a biosynthetic intermediate that humans, animals, and plants can synthesize. Squalene is defined as a 30-carbon unsaturated hydrocarbon with six double bonds, structurally composed of 6 isoprene molecules and a lipophilic biomolecule with an isoprenoid structure. It is an odorless, colorless liquid oil. Because this compound was first isolated from the shark's liver oil belonging to the Squalidae family, it was named "Squalene" as a reference to its family. The squalene, produced by both natural and synthetic methods, is widely used in cosmetics, medicine, and other pharmaceutical fields due to its important effects. Squalene has more than one application method in different areas due to its high absorption and distribution efficiency, well tolerated by the body when applied in different ways, and its reliable toxicity profile. In this review, this compound's history, sources, effects, and usages, especially in therapeutic applications, have been evaluated and debated comprehensively after a detailed literature screening. In light of this information and general information about squalene, all data about its use and production in cosmetics and pharmaceutical fields will be presented in this review, thus opening a new window on this subject.
Keywords: Squalene; triterpene; antioxidant; anticancer; adjuvant
- Bergman ME, Davis B, Phillips MA. Medically useful plant terpenoids: biosynthesis, occurrence, and mechanism of action. Molecules. 2019;24(21):3961. [Crossref] [PubMed] [PMC]
- Reddy LH, Couvreur P. Squalene: A natural triterpene for use in disease management and therapy. Adv Drug Deliv Rev. 2009;61(15): 412-26. [Crossref] [PubMed]
- Ghimire GP, Thuan NH, Koirala N, Sohng JK. Advances in biochemistry and microbial production of squalene and its derivatives. J Microbiol Biotechnol. 2016;26(3):441-51. [Crossref] [PubMed]
- Micera M, Botto A, Geddo F, Antoniotti S, Bertea CM, Levi R, et al. Squalene: more than a step toward sterols. Antioxidants (Basel). 2020;9(8):688. [Crossref] [PubMed] [PMC]
- Wołosik K, Knaś M, Zalewska A, Niczyporuk M, Przystupa AW. The importance and perspective of plant-based squalene in cosmetology. J Cosmet Sci. 2013;64(1):59-66. [PubMed]
- Lozano-Grande A, Gorinstein S, Espitia-Rangel E, Dávila-Ortiz G, Martínez-Ayala A. Plant sources, extraction methods, and uses of squalene. Int J Agron. 2018:13. [Crossref]
- Popa O, Băbeanu NE, Popa I, Niță S, Dinu-Pârvu CE. Methods for obtaining and determination of squalene from natural sources. Biomed Res Int. 2015;2015:367202. [Crossref] [PubMed] [PMC]
- Bozbulut R, Akbulut G. Kansere karşı koruyucu yeni bir öge: skualen [A new item for protection against cancer: squalene]. Bes Diy Der. 2016;44(2):160-8. [Link]
- Gohil N, Bhattacharjee G, Khambhati K, Braddick D, Singh V. Engineering strategies in microorganisms for the enhanced production of squalene: advances, challenges and opportunities. Front Bioeng Biotechnol. 2019;7:50. Erratum in: Front Bioeng Biotechnol. 2019;7:114. [Crossref] [PubMed] [PMC]
- Xu R, Fazio GC, Matsuda SP. On the origins of triterpenoid skeletal diversity. Phytochemistry. 2004;65(3):261-91. [Crossref] [PubMed]
- Mantzouridou F, Tsimidou MZ. Observations on squalene accumulation in Saccharomyces cerevisiae due to the manipulation of HMG2 and ERG6. FEMS Yeast Res. 2010;10(6):699-707. [Crossref] [PubMed]
- Katabami A, Li L, Iwasaki M, Furubayashi M, Saito K, Umeno D. Production of squalene by squalene synthases and their truncated mutants in Escherichia coli. J Biosci Bioeng. 2015;119(2):165-71. [Crossref] [PubMed]
- Kostyuk V, Potapovich A, Stancato A, De Luca C, Lulli D, Pastore S, et al. Photo-oxidation products of skin surface squalene mediate metabolic and inflammatory responses to solar UV in human keratinocytes. PLoS One. 2012;7(8):e44472. [Crossref] [PubMed] [PMC]
- Kraujalis P, Venskutonis PR. Supercritical carbon dioxide extraction of squalene and tocopherols from amaranth and assessment of extracts antioxidant activity. J Supercrit Fluids. 2013;80:78-85. [Crossref]
- Lyon CK, Becker R. Extraction and refining of oil from amaranth seed. J Am Oil Chem Soc. 1987;64:233-6. [Crossref]
- Czaplicki S, Ogrodowska D, Zadernowski R, Derewiaka D. Characteristics of biologically-active substances of amaranth oil obtained by various techniques. Pol J Food Nutr Sci. 2012;62(4):235-9. [Crossref]
- He HP, Corke H, Cai JG. Supercritical carbon dioxide extraction of oil and squalene from amaranthus grain. J Agric Food Chem. 2003;51(27):7921-5. [Crossref] [PubMed]
- Krulj J, Brlek T, Pezo L, Brkljača J, Popović S, Zeković Z, et al. Extraction methods of Amaranthus sp. grain oil isolation. J Sci Food Agric. 2016;96(10):3552-8. [Crossref] [PubMed]
- Wejnerowska G, Heinrich P, Gaca J. Separation of squalene and oil from Amaranthus seeds by supercritical carbon dioxide. Sep Purif Technol. 2013;110:39-43. [Crossref]
- Cho S, Choi CW, Lee DH, Won CH, Kim SM, Lee S, et al. High-dose squalene ingestion increases type I procollagen and decreases ultraviolet-induced DNA damage in human skin in vivo but is associated with transient adverse effects. Clin Exp Dermatol. 2009;34(4):500-8. [Crossref] [PubMed]
- Huang ZR, Lin YK, Fang JY. Biological and pharmacological activities of squalene and related compounds: potential uses in cosmetic dermatology. Molecules. 2009;14(1):540-54. [Crossref] [PubMed] [PMC]
- Lacatusu I, Badea N, Ovidiu O, Bojin D, Meghea A. Highly antioxidant carotene-lipid nanocarriers: synthesis and antibacterial activity. J Nanopart Res. 2012;14(6). [Crossref]
- Warleta F, Campos M, Allouche Y, Sánchez-Quesada C, Ruiz-Mora J, Beltrán G, et al. Squalene protects against oxidative DNA damage in MCF10A human mammary epithelial cells but not in MCF7 and MDA-MB-231 human breast cancer cells. Food Chem Toxicol. 2010;48(4):1092-100. [Crossref] [PubMed]
- Kabuto H, Yamanushi TT, Janjua N, Takayama F, Mankura M. Effects of squalene/squalane on dopamine levels, antioxidant enzyme activity, and fatty acid composition in the striatum of Parkinson's disease mouse model. J Oleo Sci. 2013;62(1):21-8. [Crossref] [PubMed]
- Fernando IPS, Sanjeewa KKA, Samarakoon KW, Lee WW, Kim HS, Jeon YJ. Squalene isolated from marine macroalgae Caulerpa racemosa and its potent antioxidant and anti- inflammatory activities. J Food Biochem. 2018;42(5):e12628. [Crossref]
- Ohkuma T, Otagiri K, Tanaka S, Ikekawa T. Intensification of host's immunity by squalene in sarcoma 180 bearing ICR mice. J Pharmacobiodyn. 1983;6(2):148-51. [Crossref] [PubMed]
- Nakagawa M, Yamaguchi T, Fukawa H, Ogata J, Komiyama S, Akiyama S, et al. Potentiation by squalene of the cytotoxicity of anticancer agents against cultured mammalian cells and murine tumor. Jpn J Cancer Res. 1985;76(4): 315-20. [PubMed]
- Smith TJ. Squalene: potential chemopreventive agent. Expert Opin Investig Drugs. 2000; 9(8):1841-8. [Crossref] [PubMed]
- Senthilkumar S, Yogeeta SK, Subashini R, Devaki T. Attenuation of cyclophosphamide induced toxicity by squalene in experimental rats. Chem Biol Interact. 2006;160(3):252-60. [Crossref] [PubMed]
- Das B, Antoon R, Tsuchida R, Lotfi S, Morozova O, Farhat W, et al. Squalene selectively protects mouse bone marrow progenitors against cisplatin and carboplatin-induced cytotoxicity in vivo without protecting tumor growth. Neoplasia. 2008;10(10):1105-19. [Crossref] [PubMed] [PMC]
- Yang YF, Chang YC, Jan YH, Yang CJ, Huang MS, Hsiao M. Squalene synthase promotes the invasion of lung cancer cells via the osteopontin/ERK pathway. Oncogenesis. 2020; 9(8):78. [Crossref] [PubMed] [PMC]
- Cirmena G, Franceschelli P, Isnaldi E, Ferrando L, De Mariano M, Ballestrero A, et al. Squalene epoxidase as a promising metabolic target in cancer treatment. Cancer Lett. 2018;425:13-20. [Crossref] [PubMed]
- Chua NK, Coates HW, Brown AJ. Squalene monooxygenase: a journey to the heart of cholesterol synthesis. Prog Lipid Res. 2020;79:101033. [Crossref] [PubMed]
- Nowicki R, Barańska-Rybak W. Olej z watroby rekina jako terapia wspomagajaca w atopowym zapaleniu skóry [Shark liver oil as a supporting therapy in atopic dermatitis]. Pol Merkur Lekarski. 2007;22(130):312-3. Polish. [PubMed]
- Shanmugarajan TS, Selvan NK, Uppuluri VNVA. Development and characterization of squalene-loaded topical agar-based emulgel scaffold: wound healing potential in full-thickness burn model. Int J Low Extrem Wounds. 2020:1534734620921629. [Crossref] [PubMed]
- Omiecinski CJ, Vanden Heuvel JP, Perdew GH, Peters JM. Xenobiotic metabolism, disposition, and regulation by receptors: from biochemical phenomenon to predictors of major toxicities. Toxicol Sci. 2011;120 Suppl 1(Suppl 1):S49-75. [Crossref] [PubMed] [PMC]
- Mackowiak B, Wang H. Mechanisms of xenobiotic receptor activation: Direct vs. indirect. Biochim Biophys Acta. 2016;1859(9):1130-40. [Crossref] [PubMed] [PMC]
- Kelly GS. Squalene and its potential clinical uses. Altern Med Rev. 1999;4(1):29-36. [PubMed]
- Richter E, Fichtl B, Schäfer SG. Effects of dietary paraffin, squalane and sucrose polyester on residue disposition and elimination of hexachlorobenzene in rats. Chem Biol Interact. 1982;40(3):335-44. [Crossref] [PubMed]
- Queirolo IAE, Morales MG, Sussanick AI. plombemia y squalene. Tendencias, Actualidad en pediatria. 2007;10:131-7. [Link]
- Ronco AL, De Stèfani E. Squalene: a multitask link in the crossroads of cancer and aging. Func Foods Health Dis. 2013;3(12): 462-76. [Crossref]
- Sabeena Farvin KH, Anandan R, Kumar SH, Shiny KS, Sankar TV, Thankappan TK. Effect of squalene on tissue defense system in isoproterenol-induced myocardial infarction in rats. Pharmacol Res. 2004;50(3):231-6. [Crossref] [PubMed]
- Chan P, Tomlinson B, Lee CB, Lee YS. Effectiveness and safety of low-dose pravastatin and squalene, alone and in combination, in elderly patients with hypercholesterolemia. J Clin Pharmacol. 1996;36(5):422-7. [Crossref] [PubMed]
- Farvin KH, Anandan R, Kumar SH, Shiny KS, Mathew S, Sankar TV, et al. Cardioprotective effect of squalene on lipid profile in isoprenaline-induced myocardial infarction in rats. J Med Food. 2006;9(4):531-6. [Crossref] [PubMed]
- Liu Y, Xu X, Bi D, Wang X, Zhang X, Dai H, et al. Influence of squalene feeding on plasma leptin, testosterone & blood pressure in rats. Indian J Med Res. 2009;129(2):150-3. [PubMed]
- Güneş FE. Medical use of squalene as a natural antioxidant. MÜSBED. 2013;3(4):220-8. [Link]
- Saudek CD, Frier BM, Liu GC. Plasma squalene: lipoprotein distribution and kinetic analysis. J Lipid Res. 1978;19(7):827-35. [Crossref] [PubMed]
- Mesa C, Fernández LE. Challenges facing adjuvants for cancer immunotherapy. Immunol Cell Biol. 2004;82(6):644-50. [Crossref] [PubMed]
- Del Giudice G, Fragapane E, Bugarini R, Hora M, Henriksson T, Palla E, et al. Vaccines with the MF59 adjuvant do not stimulate antibody responses against squalene. Clin Vaccine Immunol. 2006;13(9):1010-3. [Crossref] [PubMed] [PMC]
- Nguyen-Contant P, Sangster MY, Topham DJ. Squalene-based influenza vaccine adjuvants and their impact on the hemagglutinin-specific B cell response. Pathogens. 2021;10(3):355. [Crossref] [PubMed] [PMC]
- Wang S, Yang G, Nie J, Yang R, Du M, Su J, et al. Recombinant Erns-E2 protein vaccine formulated with MF59 and CPG-ODN promotes T cell immunity against bovine viral diarrhea virus infection. Vaccine. 2020;38(22): 3881-91. [Crossref] [PubMed]
- Seubert A, Monaci E, Pizza M, O'Hagan DT, Wack A. The adjuvants aluminum hydroxide and MF59 induce monocyte and granulocyte chemoattractants and enhance monocyte differentiation toward dendritic cells. J Immunol. 2008;180(8):5402-12. Erratum in: J Immunol. 2009;182(1):726. [Crossref] [PubMed]
- Schetters STT, Kruijssen LJW, Crommentuijn MHW, Kalay H, den Haan JMM, van Kooyk Y. Immunological dynamics after subcutaneous immunization with a squalene-based oil-in-water adjuvant. FASEB J. 2020;34(9):12406-18. [Crossref] [PubMed] [PMC]
- Yang J, Zhang J, Han T, Liu C, Li X, Yan L, et al. Effectiveness, immunogenicity, and safety of influenza vaccines with MF59 adjuvant in healthy people of different age groups: A systematic review and meta-analysis. Medicine (Baltimore). 2020;99(7):e19095. [Crossref] [PubMed] [PMC]
- Watterson D, Wijesundara DK, Modhiran N, Mordant FL, Li Z, Avumegah MS, et al. Preclinical development of a molecular clamp-stabilised subunit vaccine for severe acute respiratory syndrome coronavirus 2. Clin Transl Immunology. 2021;10(4):e1269. [Crossref] [PubMed] [PMC]
- Desai KN, Wei H, Lamartiniere CA. The preventive and therapeutic potential of the squalene-containing compound, Roidex, on tumor promotion and regression. Cancer Lett. 1996;101(1):93-6. [Crossref] [PubMed]
- Yamaguchi T, Nakagawa M, Hidaka K, Yoshida T, Sasaki T, Akiyama S, et al. Potentiation by squalene of antitumor effect of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-nitros ourea in a murine tumor system. Jpn J Cancer Res. 1985;76(10):1021-6. [PubMed]
- Soppimath KS, Aminabhavi TM, Kulkarni AR, Rudzinski WE. Biodegradable polymeric nanoparticles as drug delivery devices. J Control Release. 2001;70(1-2):1-20. [Crossref] [PubMed]
- Wang JJ, Sung KC, Yeh CH, Fang JY. The delivery and antinociceptive effects of morphine and its ester prodrugs from lipid emulsions. Int J Pharm. 2008;353(1-2):95-104. [Crossref] [PubMed]
- Fox CB. Squalene emulsions for parenteral vaccine and drug delivery. Molecules. 2009;14(9):3286-312. [Crossref] [PubMed] [PMC]
- Kwon SM, Nam HY, Nam T, Park K, Lee S, Kim K, et al. In vivo time-dependent gene expression of cationic lipid-based emulsion as a stable and biocompatible non-viral gene carrier. J Control Release. 2008;128(1):89-97. Erratum in: J Control Release. 2009;140(1):74. Kim, Jun [corrected to Kim, Joon]. [Crossref] [PubMed]
- Chung H, Kim TW, Kwon M, Kwon IC, Jeong SY. Oil components modulate physical characteristics and function of the natural oil emulsions as drug or gene delivery system. J Control Release. 2001;71(3):339-50. [Crossref] [PubMed]
- Desmaële D, Gref R, Couvreur P. Squalenoylation: a generic platform for nanoparticular drug delivery. J Control Release. 2012; 161(2):609-18. [Crossref] [PubMed]
- Reid JM, Qu W, Safgren SL, Ames MM, Krailo MD, Seibel NL, et al. Phase I trial and pharmacokinetics of gemcitabine in children with advanced solid tumors. J Clin Oncol. 2004;22(12):2445-51. [Crossref] [PubMed]
- Aghaei M, Erfani-Moghadam V, Daneshmandi L, Soltani A, Abdolahi N, Cordani M, et al. Non-ionic surfactant vesicles as novel delivery systems for sulfasalazine: evaluation of the physicochemical and cytotoxic properties. J Mol Struct. 2021;1230. [Crossref]
- Feng J, Lepetre-Mouelhi S, Gautier A, Mura S, Cailleau C, Coudore F, et al. A new painkiller nanomedicine to bypass the blood-brain barrier and the use of morphine. Sci Adv. 2019;5(2):eaau5148. [Crossref] [PubMed] [PMC]
- Schultze V, D'Agosto V, Wack A, Novicki D, Zorn J, Hennig R. Safety of MF59 adjuvant. Vaccine. 2008;26(26):3209-22. [Crossref] [PubMed]
- Ketomäki A, Gylling H, Miettinen TA. Removal of intravenous Intralipid in patients with familial hypercholesterolemia during inhibition of cholesterol absorption and synthesis. Clin Chim Acta. 2004;344(1-2):83-93. [Crossref] [PubMed]
- Pellegrini M, Nicolay U, Lindert K, Groth N, Della Cioppa G. MF59-adjuvanted versus non-adjuvanted influenza vaccines: integrated analysis from a large safety database. Vaccine. 2009;27(49):6959-65. [Crossref] [PubMed]
- Yaman G, Berktaş M, Güdücüoğlu H. Tartışılan adjuvan: skualen [Squalene: the controversial adjuvant]. ANKEM Derg. 2012;26(1):46-54. [Crossref]
- Tateno M, Stone BJ, Srodulski SJ, Reedy S, Gawriluk TR, Chambers TM, et al. Synthetic biology-derived triterpenes as efficacious immunomodulating adjuvants. Sci Rep. 2020;10(1):17090. [Crossref] [PubMed] [PMC]
- Popa I, Băbeanu NE, Niță, S, Popa O. Squalene-natural resources and applications. Farmacia. 2014;62(5):840-62. [Link]
- Global Opportunity Analysis and Industry Forecast, (2014-2022). Squalene Market by Source. [Link]
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