Journal of Traditional Medical Complementary Therapies

.: REVIEW
Skualen: Biyolojik Etkileri ve Uygulama Alanları: Geleneksel Derleme
Squalene: Biological Effects and Applications: Traditional Review
Ahsen Sevde ÇINARa,b, Özge YILMAZb, Alev ÖNDERb
aLokman Hekim Üniversitesi Eczacılık Fakültesi, Farmakognozi/Farmasötik Botanik ABD, Ankara, TÜRKİYE
bAnkara Üniversitesi Eczacılık Fakültesi, Farmakognozi ABD, Ankara, TÜRKİYE
J Tradit Complem Med. 2021;4(3):415-25
doi: 10.5336/jtracom.2021-84639
Article Language: TR
Full Text
ÖZET
 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
ABSTRACT
 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
REFERENCES:
  1. Bergman ME, Davis B, Phillips MA. Medically useful plant terpenoids: biosynthesis, occurrence, and mechanism of action. Molecules. 2019;24(21):3961. [Crossref]  [PubMed]  [PMC] 
  2. 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] 
  3. 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] 
  4. 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] 
  5. 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] 
  6. 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] 
  7. 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] 
  8. 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] 
  9. 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] 
  10. Xu R, Fazio GC, Matsuda SP. On the origins of triterpenoid skeletal diversity. Phytochemistry. 2004;65(3):261-91. [Crossref]  [PubMed] 
  11. 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] 
  12. 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] 
  13. 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] 
  14. 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] 
  15. Lyon CK, Becker R. Extraction and refining of oil from amaranth seed. J Am Oil Chem Soc. 1987;64:233-6. [Crossref] 
  16. 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] 
  17. 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] 
  18. 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] 
  19. 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] 
  20. 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] 
  21. 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] 
  22. 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] 
  23. 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] 
  24. 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] 
  25. 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] 
  26. 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] 
  27. 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] 
  28. Smith TJ. Squalene: potential chemopreventive agent. Expert Opin Investig Drugs. 2000; 9(8):1841-8. [Crossref]  [PubMed] 
  29. 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] 
  30. 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] 
  31. 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] 
  32. 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] 
  33. Chua NK, Coates HW, Brown AJ. Squalene monooxygenase: a journey to the heart of cholesterol synthesis. Prog Lipid Res. 2020;79:101033. [Crossref]  [PubMed] 
  34. 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] 
  35. 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] 
  36. 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] 
  37. Mackowiak B, Wang H. Mechanisms of xenobiotic receptor activation: Direct vs. indirect. Biochim Biophys Acta. 2016;1859(9):1130-40. [Crossref]  [PubMed]  [PMC] 
  38. Kelly GS. Squalene and its potential clinical uses. Altern Med Rev. 1999;4(1):29-36. [PubMed] 
  39. 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] 
  40. Queirolo IAE, Morales MG, Sussanick AI. plombemia y squalene. Tendencias, Actualidad en pedia­tria. 2007;10:131-7. [Link] 
  41. 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] 
  42. 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] 
  43. 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] 
  44. 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] 
  45. 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] 
  46. Güneş FE. Medical use of squalene as a natural antioxidant. MÜSBED. 2013;3(4):220-8. [Link] 
  47. Saudek CD, Frier BM, Liu GC. Plasma squalene: lipoprotein distribution and kinetic analysis. J Lipid Res. 1978;19(7):827-35. [Crossref]  [PubMed] 
  48. Mesa C, Fernández LE. Challenges facing adjuvants for cancer immunotherapy. Immunol Cell Biol. 2004;82(6):644-50. [Crossref]  [PubMed] 
  49. 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] 
  50. 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] 
  51. 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] 
  52. 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] 
  53. 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] 
  54. 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] 
  55. 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] 
  56. 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] 
  57. 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] 
  58. 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] 
  59. 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] 
  60. Fox CB. Squalene emulsions for parenteral vaccine and drug delivery. Molecules. 2009;14(9):3286-312. [Crossref]  [PubMed]  [PMC] 
  61. 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] 
  62. 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] 
  63. Desmaële D, Gref R, Couvreur P. Squalenoylation: a generic platform for nanoparticular drug delivery. J Control Release. 2012; 161(2):609-18. [Crossref]  [PubMed] 
  64. 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] 
  65. 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] 
  66. 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] 
  67. 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] 
  68. 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] 
  69. 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] 
  70. Yaman G, Berktaş M, Güdücüoğlu H. Tartışılan adjuvan: skualen [Squalene: the controversial adjuvant]. ANKEM Derg. 2012;26(1):46-54. [Crossref] 
  71. 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] 
  72. Popa I, Băbeanu NE, Niță, S, Popa O. Squalene-natural resources and applications. Farmacia. 2014;62(5):840-62. [Link] 
  73. Global Opportunity Analysis and Industry Forecast, (2014-2022). Squalene Market by Source. [Link] 

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4.2. People benefiting from the services provided by "Turkiye Klinikleri" and using the website can use the "SITE" only according to the law and only for personal reasons. Users have the criminal and civil liability for every process and action they take in the "SITE". Every USER agrees, declares and undertakes that they will not proceed by any function or action infringement of rights of "Turkiye Klinikleri"s and/or other third parties', they are the exclusive right holder on usage, processing, storage, made public and revealing any written, visual or auditory information reported to Turkiye Klinikleri" and/or "SITE" to the third parties. "USER" agrees and undertakes that s/he will not duplicate, copy, distribute, process, the pictures, text, visual and auditory images, video clips, files, databases, catalogs and lists within the "SITE", s/he will not be using these actions or with other ways to compete with "Turkiye Klinikleri", directly or indirectly.

4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com