Journal of Literature Pharmacy Sciences

RNA Hasarı ve Patolojik Durumlarla İlişkisi
RNA Damage and its Relationship with Pathological Conditions
Selinay Başak ERDEMLİ KÖSEa,b, Anıl YİRÜNa,c, Aylin BALCIa, Pınar ERKEKOĞLUa
aHacettepe Üniversitesi Eczacılık Fakültesi, Farmasötik Toksikoloji ABD, Ankara, TÜRKİYE
bBurdur Mehmet Akif Ersoy Üniversitesi Fen-Edebiyat Fakültesi, Kimya Bölümü, Burdur, TÜRKİYE
cÇukurova Üniversitesi Eczacılık Fakültesi, Farmasötik Toksikoloji ABD, Adana, TÜRKİYE
J Lit Pharm Sci. 2020;9(2):184-96
doi: 10.5336/pharmsci.2019-72329
Article Language: TR
Full Text
ÖZET
Hücrede makromoleküllerin özellikle de nükleik asitler, lipid, protein ve karbohidratların, başta oksidatif stres olmak üzere birçok farklı mekanizmayla hasara uğrayabildiği bilinmektedir. Son yıllarda DNA'nın yanı sıra RNA'nın da oksidatif hasara maruz kaldığı tespit edilmiş ve bu durum RNA oksidasyonunun moleküler ve hücresel düzeylerde etki mekanizmasının aydınlatılması ihtiyacını doğurmuştur. RNA hasarları, başta ultraviyole (UV) maruziyeti olmak üzere birçok farklı etmen nedeni ile gelişebilir. RNA'da günümüzde ençok tespit edilen oksidatif hasar 8-hidroksideoksiguanozin (8-OHdG)'dir. Ancak sadece guaninin değil, farklı bazların da hasar görmesi ve buna bağlı RNA hasarının gelişmesi de mümkündür. En sık saptanan diğer hasarlı baz ürünleri ise 8-hidroksiadenin, 2,6-diamino-4-hidroksi-5-formamidoguanin, 4,6-diamino-5-formamidoadenin ve sitozin glikoldür. Okside olan RNA bazlarının, dejeneratif hastalıkların patogenezi ile ilişkisi üzerine kanıtlar her geçen gün artmaktadır. RNA oksidasyonunun, özellikle nörodejeneratif hastalıkların patolojik ilerleyişinde erken dönemde etkili bir durum olduğunu gösteren çok sayıda çalışma vardır. Alzheimer hastalığı, Parkinson hastalığı, amyotrofik lateral skleroz, spinal kord yaralanmaları, epilepsi, Lewy cisimcikli demans, miyopatiler, birçok farklı kanser, prion hastalıkları, subakut sklerozan panensefalit, kseroderma pigmentozum ve ateroskleroz RNA oksidasyonuyla ilişkilendirilmiş hastalıklardan bazılarıdır. DNA'nın maruz kaldığı oksidatif hasar üzerine çok sayıda çalışma bulunmasına rağmen RNA hasarı üzerine çalışmalar sınırlıdır. Bu derlemede RNA hasarı, RNA hasarına yol açan etkenler, RNA hasarıyla ilişkili hastalıklar, RNA onarım mekanizmaları ve RNA hasarının toksikolojik önemi hakkında bilgi verilmesi amaçlanmıştır.

Anahtar Kelimeler: RNA hasarı; oksidatif stres; nörodejeneratif hastalıklar; alzheimer hastalığı; parkinson hastalığı; RNA onarım mekanizmaları
ABSTRACT
It is known that celllular macromolecules, particularly nucleic acids, lipids, proteins and carbohydrates can be damaged by several different mechanisms, including oxidative stress. In recent years, it has been found that RNA has been exposed to oxidative damage as well as DNA and this has led to the need to elucidate the mechanism of action of RNA oxidation at molecular and cellular levels. RNA damage can arise from different factors, especially by ultraviolet (UV) exposure. However, not only guanine but other bases can be damaged and RNA damage due to these damages can also develop. The mostly encountered oxidative damage of RNA is 8-hydroxydeoxyguanosine (8-OHdG) today. Other damaged base products include 8-hydroxyadenine, 2,6-diamino-4-hydroxy-5-formamidoguanine, 4,6-diamino-5-formamidoadenine ve cytosine glycol. Evidence on the association of oxidized RNA with the pathogenesis of degenerative diseases is increasing day by day. There are numerous studies showing that RNA oxidation is an early stage situation in the pathological progression of neurodegenerative diseases. Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injuries, epilepsy, Lewy body dementia, myopathies, different types of cancer, prion diseases, subacute sclerosing panencephalitis, xeroderma pigmentosum and atherosclerosis are some of the diseases associated with RNA oxidation. Although there are numerous studies on oxidative damage to DNA, studies on RNA damage are limited. In this review, it is aimed to give information about RNA damage, factors causing RNA damage, RNA damage related diseases, RNA repair mechanisms and toxicological importance of RNA damage.

Keywords: RNA damage; oxidative stress; neurodegenerative diseases; alzheimer's disease; parkinson's disease; RNA repair mechanisms
REFERENCES:
  1. Fimognari C. Role of oxidative RNA damage in chronic-degenerative diseases. Oxid Med Cell Longev. 2015:1-8. [Crossref]  [PubMed]  [PMC] 
  2. Wurtmann EJ, Wolin SL. RNA under attack: cellular handling of RNA damage. Crit Rev Biochem Mol Biol. 2009;44(1):34-49. [Crossref]  [PubMed]  [PMC] 
  3. Cao X, Yeo G, Muotri AR, Kuwabara T, Gage FH. Noncoding RNAs in the mammalian central nervous system. Annu Rev Neurosci. 2006;29:77-103. [Crossref]  [PubMed] 
  4. Costa FF. Non-coding RNAs: new players in eukaryotic biology. Gene. 2005;357(2):83-94. [Crossref]  [PubMed] 
  5. Mehler MF, Mattick JS. Non-coding RNAs in the nervous system. J Physiol. 2006;575(Pt 2):333-41. [Crossref]  [PubMed]  [PMC] 
  6. Thorp HH. The importance of being r: greater oxidative stability of RNA compared with DNA. Chem Biol. 2000;7(2):R33-6. [Crossref]  [PubMed] 
  7. Cadet J, Sage E, Douki T. Ultraviolet radiation-mediated damage to cellular DNA. Mutat Res. 2005;571(1-2):3-17. [Crossref]  [PubMed] 
  8. Ravanat JL, Douki T, Cadet J. Direct and indirect effects of UV radiation on DNA and its components. J Photochem Photobiol B. 2001;63(1-3):88-102. [Crossref]  [PubMed] 
  9. Sedgwick B. Repairing DNA-methylation damage. Nat Rev Mol Cell Biol. 2004;5(2):148-57. [Crossref]  [PubMed] 
  10. Liu B, Fournier MJ. Interference probing of rRNA with snoRNPs: a novel approach for functional mapping of RNA in vivo. RNA. 2004;10(7):1130-41. [Crossref]  [PubMed]  [PMC] 
  11. Ougland R, Zhang CM, Liiv A, Johansen RF, Seeberg E, Hou YM, et al. AlkB restores the biological function of mRNA and tRNA inactivated by chemical methylation. Mol Cell. 2004;16(1):107-16. [Crossref]  [PubMed] 
  12. Hawkins CL, Pattison DI, Whiteman M, Davies MJ. Chlorination and nitration of DNA and nucleic acid components. In: Evans MD, Cooke MS, ed. Oxidative Damage to Nucleic Acids. 1st ed. Austin: Landes Bioscience; 2007. p.14-39. [Crossref] 
  13. Menon R. Oxidative stress damage as a detrimental factor in preterm birth pathology. Front Immunol. 2014;5:567. [Crossref]  [PubMed] 
  14. Cooke MS, Evans MD, Dizdaroglu M, Lunec J. Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J. 2003;17(10):1195-214. [Crossref]  [PubMed] 
  15. Cadet J, Wagner JR, Shafirovich V, Geacintov NE. One-electron oxidation reactions of purine and pyrimidine bases in cellular DNA. Int J Radiat Biol. 2014;90(6):423-32. [Crossref]  [PubMed]  [PMC] 
  16. Fleming AM, Alshykhly OR, Zhu J, Muller JG, Burrows CJ. Rates of chemical cleavage of DNA and RNA oligomers containing guanine oxidation products. Chem Res Toxicol. 2015;28(6):1292-300. [Crossref]  [PubMed]  [PMC] 
  17. Ding Q, Markesbery WR, Chen Q, Li F, Keller JN. Ribosome dysfunction is an early event in Alzheimer's disease. J Neurosci. 2005;25(40):9171-5. [Crossref]  [PubMed]  [PMC] 
  18. Hofer T, Badouard C, Bajak E, Ravanat JL, Mattsson A, Cotgreave IA. Hydrogen peroxide causes greater oxidation in cellular RNA than in DNA. Biol Chem. 2005;386(4):333-7. [Crossref]  [PubMed] 
  19. Wu J, Li Z. Human polynucleotide phosphorylase reduces oxidative RNA damage and protects HeLa cell against oxidative stress. Biochem Biophys Res Commun. 2008;372(2):288-92. [Crossref]  [PubMed]  [PMC] 
  20. Nunomura A, Perry G, Pappolla MA, Wade R, Hirai K, Chiba S, et al. RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer's disease. J Neurosci. 1999;19(6):1959-64. [Crossref]  [PubMed]  [PMC] 
  21. Shen Z, Wu W, Hazen SL. Activated leukocytes oxidatively damage DNA, RNA, and the nucleotide pool through halide-dependent formation of hydroxyl radical. Biochemistry. 2000;39(18):5474-82. [Crossref]  [PubMed] 
  22. Fiala ES, Conaway CC, Mathis JE. Oxidative DNA and RNA damage in the livers of Sprague-Dawley rats treated with the hepatocarcinogen 2-nitropropane. Cancer Res. 1989;49(20):5518-22. [PubMed] 
  23. Hofer T, Seo AY, Prudencio M, Leeuwenburgh C. A method to determine RNA and DNA oxidation simultaneously by HPLC-ECD: greater RNA than DNA oxidation in rat liver after doxorubicin administration. Biol Chem. 2006;387(1):103-11. [Crossref]  [PubMed] 
  24. Honda K, Smith MA, Zhu X, Baus D, Merrick WC, Tartakoff AM, et al. Ribosomal RNA in Alzheimer disease is oxidized by bound redox-active iron. J Biol Chem. 2005;280(22):20978-86. [Crossref]  [PubMed] 
  25. Hofer T, Marzetti E, Xu J, Seo AY, Gulec S, Knutson MD, et al. Increased iron content and RNA oxidative damage in skeletal muscle with aging and disuse atrophy. Exp Gerontol. 2008;43(6):563-70. [Crossref]  [PubMed]  [PMC] 
  26. Nunomura A, Moreira PI, Takeda A, Smith MA, Perry G. Oxidative RNA damage and neurodegeneration. Curr Med Chem. 2007;14(28):2968-75. [Crossref]  [PubMed] 
  27. Shan X, Tashiro H, Lin CLG. The identification and characterization of oxidized RNAs in Alzheimer's disease. J Neurosci. 2003;23(12):4913-21. [Crossref]  [PubMed]  [PMC] 
  28. Shan X, Chang Y, Lin CLG. Messenger RNA oxidation is an early event preceding cell death and causes reduced protein expression. FASEB J. 2007;21(11):2753-64. [Crossref]  [PubMed] 
  29. Sayre LM, Perry G, Harris PL, Liu Y, Schubert KA, Smith MA. In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer's disease: a central role for bound transition metals. J Neurochem. 2000;74(1):270-9. [Crossref]  [PubMed] 
  30. Connor JR, Milward EA, Moalem S, Sampietro M, Boyer P, Percy ME, et al. Is hemochromatosis a risk factor for Alzheimer's disease? J Alzheimers Dis. 2001;3(5):471-7. [Crossref]  [PubMed] 
  31. Casadesus G, Smith MA, Zhu X, Aliev G, Cash AD, Honda K, et al. Alzheimer disease: evidence for a central pathogenic role of iron-mediated reactive oxygen species. J Alzheimers Dis. 2004;6(2):165-9. [Crossref]  [PubMed] 
  32. Honda K, Casadesus G, Petersen RB, Perry G, Smith MA. Oxidative stress and redox-active iron in Alzheimer's disease. Ann N Y Acad Sci. 2004;1012:179-82. [Crossref]  [PubMed] 
  33. Rogers JT, Randall JD, Cahill CM, Eder PS, Huang X, Gunshin H, et al. An iron-responsive element type II in the 5′-untranslated region of the Alzheimer's amyloid precursor protein transcript. J Biol Chem. 2002;277(47):45518-28. [Crossref]  [PubMed] 
  34. Atwood CS, Perry G, Zeng H, Kato Y, Jones WD, Ling KQ, et al. Copper mediates dityrosine cross-linking of Alzheimer's amyloid-beta. Biochemistry. 2004;43(2):560-8. [Crossref]  [PubMed] 
  35. Nunomura A, Perry G, Hirai K, Aliev G, Takeda A, Chiba S, et al. Neuronal RNA oxidation in Alzheimer's disease and Down's syndrome. Ann NY Acad Sci. 1999;893:362-4. [Crossref]  [PubMed] 
  36. Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, et al. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol. 2001;60(8):759-67. [Crossref]  [PubMed] 
  37. Zhang J, Perry G, Smith MA, Robertson D, Olson SJ, Graham DG, et al. Parkinson's disease is associated with oxidative damage to cytoplasmic DNA and RNA in substantia nigra neurons. Am J Pathol. 1999;154(5):1423-9. [Crossref]  [PubMed] 
  38. Kong Q, Lin CLG. Oxidative damage to RNA: mechanisms, consequences, and diseases. Cell Mol Life Sci. 2010;67(11):1817-29. [Crossref]  [PubMed]  [PMC] 
  39. Abe T, Isobe C, Murata T, Sato C, Tohgi H. Alteration of 8-hydroxyguanosine concentrations in the cerebrospinal fluid and serum from patients with Parkinson's disease. Neurosci Lett. 2003;336(2):105-8. [Crossref]  [PubMed] 
  40. Oikawa S, Hirosawa I, Tada-Oikawa S, Furukawa A, Nishiura K, Kawanishi S. Mechanism for manganese enhancement of dopamine-induced oxidative DNA damage and neuronal cell death. Free Radic Biol Med. 2006;41(5):748-56. [Crossref]  [PubMed] 
  41. Boillée S, Velde CV, Cleveland DW. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron. 2006;52(1):39-59. [Crossref]  [PubMed] 
  42. Chang Y, Kong Q, Shan X, Tian G, Ilieva H, Cleveland DW, et al. Messenger RNA oxidation occurs early in disease pathogenesis and promotes motor neuron degeneration in ALS. PLoS One. 2008;3(8):e2849. [Crossref]  [PubMed]  [PMC] 
  43. Julien JP, Kriz J. Transgenic mouse models of amyotrophic lateral sclerosis. Biochim Biophys Acta. 2006;1762(11-12):1013-24. [Crossref]  [PubMed] 
  44. Turner BJ, Talbot K. Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS. Prog Neurobiol. 2008;85(1):94-134. [Crossref]  [PubMed] 
  45. Kakulas BA. A review of the neuropathology of human spinal cord injury with emphasis on special features. J Spinal Cord Med. 1999;22(2):119-24. [Crossref]  [PubMed] 
  46. Springer JE, Azbill RD, Mark RJ, Begley JG, Waeg G, Mattson MP. 4-hydroxynonenal, a lipid peroxidation product, rapidly accumulates following traumatic spinal cord injury and inhibits glutamate uptake. J Neurochem. 1997;68(6):2469-76. [Crossref]  [PubMed] 
  47. Henshall DC, Bonislawski DP, Skradski SL, Lan JQ, Meller R, Simon RP. Cleavage of bid may amplify caspase-8-induced neuronal death following focally evoked limbic seizures. Neurobiol Dis. 2001;8(4):568-80. [Crossref]  [PubMed] 
  48. Shin EJ, Jeong JH, Chung YH, Kim WK, Ko KH, Bach JH, et al. Role of oxidative stress in epileptic seizures. Neurochem Int. 2011;59(2):122-37. [Crossref]  [PubMed]  [PMC] 
  49. Bellacosa A, Moss EG. RNA Repair: Damage Control. Curr Biol. 2003;13(12):R482-4. [Crossref]  [PubMed] 
  50. Smith DJ, Anderson RC. Toxicity and metabolism of nitroalkanes and substituted nitroalkanes. J Agric Food Chem. 2013;61(4):763-79. [Crossref]  [PubMed] 
  51. Van Steeg H, Kraemer KH. Xeroderma pigmentosum and the role of UV-induced DNA damage in skin cancer. Mol Med Today. 1999;5(2):86-94. [Crossref]  [PubMed] 
  52. Bernard JJ, Cowing-Zitron C, Nakatsuji T, Muehleisen B, Muto J, Borkowski AW, et al. Ultraviolet radiation damages self noncoding RNA and is detected by TLR3. Nat Med. 2012;18(8):1286-90. [Crossref]  [PubMed]  [PMC] 
  53. Martinet W, De Meyer GRY, Herman AG, Kockx MM. Reactive oxygen species induce RNA damage in human atherosclerosis. Eur J Clin Invest. 2004;34(5):323-7. [Crossref]  [PubMed] 
  54. Xu XM, Zhou XY, Li XY, Guo J, Wang HZ, Li Y, et al. Increased oxidative damage of RNA in liver injury caused by hepatitis B virus (HBV) infection. Free Radic Res. 2018;52(4):426-33. [Crossref]  [PubMed] 
  55. Nunomura A, Chiba S, Kosaka K, Takeda A, Castellani RJ, Smith MA, et al. Neuronal RNA oxidation is a prominent feature of dementia with Lewy bodies. Neuroreport. 2002;13(16):2035-9. [Crossref]  [PubMed] 
  56. Guentchev M, Siedlak SL, Jarius C, Tagliavini F, Castellani RJ, Perry G, et al. Oxidative damage to nucleic acids in human prion disease. Neurobiol Dis. 2002;9(3):275-81. [Crossref]  [PubMed] 
  57. Hayashi M, Arai N, Satoh J, Suzuki H, Katayama K, Tamagawa K, et al. Neurodegenerative mechanisms in subacute sclerosing panencephalitis. J Child Neurol. 2002;17(10):725-30. [Crossref]  [PubMed] 
  58. Hayashi M, Araki S, Kohyama J, Shioda K, Fukatsu R. Oxidative nucleotide damage and superoxide dismutase expression in the brains of xeroderma pigmentosum group A and Cockayne syndrome. Brain Dev. 2005;27(1):34-8. [Crossref]  [PubMed] 
  59. Deslee G, Woods JC, Moore C, Conradi SH, Gierada DS, Atkinson JJ, et al. Oxidative damage to nucleic acids in severe emphysema. Chest. 2009;135(4):965-74. [Crossref]  [PubMed]  [PMC] 
  60. Aas PA, Otterlei M, Falnes PO, Vågbø CB, Skorpen F, Akbari M, et al. Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA. Nature. 2003;421(6925):859-63. [Crossref]  [PubMed] 
  61. Aravind L, Koonin EV. The DNA-repair protein AlkB, EGL-9, and leprecan define new families of 2-oxoglutarate- and iron-dependent dioxygenases. Genome Biol. 2001;2(3):RESEARCH0007. [Crossref]  [PubMed]  [PMC] 
  62. Duncan T, Trewick SC, Koivisto P, Bates PA, Lindahl T, Sedgwick B. Reversal of DNA alkylation damage by two human dioxygenases. Proc Natl Acad Sci USA. 2002;99(26):16660-5. [Crossref]  [PubMed]  [PMC] 
  63. Kajitani K, Yamaguchi H, Dan Y, Furuichi M, Kang D, Nakabeppu Y. MTH1, an oxidized purine nucleoside triphosphatase, suppresses the accumulation of oxidative damage of nucleic acids in the hippocampal microglia during kainate-induced excitotoxicity. J Neurosci. 2006;26(6):1688-98. [Crossref]  [PubMed]  [PMC] 
  64. Hayakawa H, Kuwano M, Sekiguchi M. Specific binding of 8-oxoguanine-containing RNA to polynucleotide phosphorylase protein. Biochemistry. 2001;40(33):9977-82. [Crossref]  [PubMed] 
  65. Hayakawa H, Hofer A, Thelander L, Kitajima S, Cai Y, Oshiro S, et al. Metabolic fate of oxidized guanine ribonucleotides in mammalian cells. Biochemistry. 1999;38(12):3610-4. [Crossref]  [PubMed] 
  66. Brégeon D, Sarasin A. Hypothetical role of RNA damage avoidance in preventing human disease. Mutat Res. 2005;577(1-2):293-302. [Crossref]  [PubMed] 
  67. Janz M, Harbeck N, Dettmar P, Berger U, Schmidt A, Jürchott K, et al. Y-box factor YB-1 predicts drug resistance and patient outcome in breast cancer independent of clinically relevant tumor biologic factors HER2, uPA and PAI-1. Int J Cancer. 2002;97(3):278-82. [Crossref]  [PubMed] 
  68. Doma MK, Parker R. RNA quality control in eukaryotes. Cell. 2007;131(4):660-8. [Crossref]  [PubMed] 
  69. Tanaka M, Chock PB, Stadtman ER. Oxidized messenger RNA induces translation errors. Proc Natl Acad Sci USA. 2007;104(1):66-71. [Crossref]  [PubMed]  [PMC] 
  70. Deutscher MP. Degradation of RNA in bacteria: comparison of mRNA and stable RNA. Nucleic Acids Res. 2006;34(2):659-66. [Crossref]  [PubMed]  [PMC] 
  71. Ding Q, Markesbery WR, Cecarini V, Keller JN. Decreased RNA, and increased RNA oxidation, in ribosomes from early Alzheimer's disease. Neurochem Res. 2006;31(5):705-10. [Crossref]  [PubMed] 
  72. Thompson DM, Lu C, Green PJ, Parker R. tRNA cleavage is a conserved response to oxidative stress in eukaryotes. RNA. 2008;14(10):2095-103. [Crossref]  [PubMed]  [PMC] 
  73. Takahashi S, Suzuki S, Inaguma S, Cho YM, Ikeda Y, Hayashi N, et al. Down-regulation of Lsm1 is involved in human prostate cancer progression. Br J Cancer. 2002;86(6):940-6. [Crossref]  [PubMed]  [PMC] 
  74. Fimognari C, Sestili P, Lenzi M, Bucchini A, Cantelli-Forti G, Hrelia P. RNA as a new target for toxic and protective agents. Mutat Res. 2008;648(1-2):15-22. [Crossref]  [PubMed] 
  75. Dunn W, Trang P, Khan U, Zhu J, Liu F. RNase P-mediated inhibition of cytomegalovirus protease expression and viral DNA encapsidation by oligonucleotide external guide sequences. Proc Natl Acad Sci USA. 2001;98(26):14831-6. [Crossref]  [PubMed]  [PMC] 

.: Up To Date

Login



Contact


Ortadoğu Reklam Tanıtım Yayıncılık Turizm Eğitim İnşaat Sanayi ve Ticaret A.Ş.

.: Address

Turkocagi Caddesi No:30 06520 Balgat / ANKARA
Phone: +90 312 286 56 56
Fax: +90 312 220 04 70
E-mail: info@turkiyeklinikleri.com

.: Manuscript Editing Department

Phone: +90 312 286 56 56/ 2
E-mail: yaziisleri@turkiyeklinikleri.com

.: English Language Redaction

Phone: +90 312 286 56 56/ 145
E-mail: tkyayindestek@turkiyeklinikleri.com

.: Marketing Sales-Project Department

Phone: +90 312 286 56 56/ 142
E-mail: reklam@turkiyeklinikleri.com

.: Subscription and Public Relations Department

Phone: +90 312 286 56 56/ 118
E-mail: abone@turkiyeklinikleri.com

.: Customer Services

Phone: +90 312 286 56 56/ 118
E-mail: satisdestek@turkiyeklinikleri.com

1. TERMS OF USE

1.1. To use the web pages with http://www.turkiyeklinikleri.com domain name or the websites reached through the sub domain names attached to the domain name (They will be collectively referred as "SITE"), please read the conditions below. If you do not accept these terms, please cease to use the "SITE." "SITE" owner reserves the right to change the information on the website, forms, contents, the "SITE," "SITE" terms of use anytime they want.

1.2. The owner of the "SITE" is Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. (From now on it is going to be referred as "Turkiye Klinikleri", shortly) and it resides at Turkocagi cad. No:30, 06520 Balgat Ankara. The services in the "SITE" are provided by "Turkiye Klinikleri."

1.3. Anyone accessing the "SITE" with or without a fee whether they are a natural person or a legal identity is considered to agree these terms of use. In this contract hereby, "Turkiye Klinikleri" may change the stated terms anytime. These changes will be published in the "SITE" periodically and they will be valid when they are published. Any natural person or legal identity benefiting from and reaching to the "SITE" are considered to be agreed to any change on hereby contract terms done by "Turkiye Klinikleri."

1.4. The "Terms of Use" hereby is published in the website with the last change on March 30th 2014 and the "SITE" is activated by enabling the access to everyone. The "Terms of Use" hereby is also a part of the any "USER Contract" was and/or will be done with the users using "Turkiye Klinikleri" services with or without a fee an inseparable.

2. DEFINITIONS

2.1. "SITE": A website offering different kind of services and context with a certain frame determined by "Turkiye Klinikleri" and it is accessible on-line on http://www.turkiyeklinikleri.com domain name and/or subdomains connected to the domain name.

2.2. USER: A natural person or a legal identity accessing to the "SITE" through online settings.

2.3. LINK: A link enabling to access to another website through the "SITE", the files, the context or through another website to the "SITE", the files and the context.

2.4. CONTEXT: Any visual, literary and auditory images published in the "Turkiye Klinikleri", "SITE" and/or any website or any accessible information, file, picture, number/figures, price, etc.

2.5. "USER CONTRACT": An electronically signed contract between a natural or a legal identity benefiting from special services "Turkiye Klinikleri" will provide and "Turkiye Klinikleri".

3. SCOPE OF THE SERVICES

3.1. "Turkiye Klinikleri" is completely free to determine the scope and quality of the services via the "SITE".

3.2. To benefit the services of "Turkiye Klinikleri" "SITE", the "USER" must deliver the features that will be specified by "Turkiye Klinikleri". "Turkiye Klinikleri" may change this necessity any time single-sided.

3.3. Not for a limited number, the services "Turkiye Klinikleri" will provide through the "SITE" for a certain price or for free are;

- Providing scientific articles, books and informative publications for health industry.

- Providing structural, statistical and editorial support to article preparation stage for scientific journals.

4. GENERAL PROVISIONS

4.1. "Turkiye Klinikleri" is completely free to determine which of the services and contents provided in the "SITE" will be charged.

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