Turkiye Klinikleri Journal of Medical Sciences

.: REVIEW
COVID-19 and Iron Metabolism: Traditional Review
COVID-19 ve Demir Metabolizması: Geleneksel Derleme
Necat YILMAZa, Esin ERENa, Cemile ÖZb, Zafer KALAYCIc, Ferhat SARİBEKd
aDepartment of Medical Biochemistry and LC/MS-MS Laboratory, University of Health Sciences Antalya Training and Research Hospital, Antalya, TURKEY
bDepartment of Medical Biochemistry, University of Health Sciences Antalya Training and Research Hospital, Antalya, TURKEY
cHealth Services General Directorate, Traditional, Complementary and Functional Medicine Department, Ankara, TURKEY
dOzone Therapy Unit, Kepez State Hospital, Antalya, TURKEY
Turkiye Klinikleri J Med Sci. 2021;41(2):176-88
doi: 10.5336/medsci.2021-81574
Article Language: EN
Full Text
ABSTRACT
 Viruses invade cells to reproduce, and they require an iron-filled cell for efficient reproduction. Together with other viruses, the coronavirus disease-2019 (COVID-19) virus can alter the expression of proteins involved in iron homeostasis. For example, in COVID19 patients, an increase in pro-inflammatory cytokines such as interleukin-6 may stimulate the synthesis of hepcidin, the regulatory hormone of iron metabolism, thereby suppressing ferroportin-mediated cellular iron export. Increased serum levels of ferritin in COVID19 virus infection is associated with a poor prognosis and may be partly due to the virus itself. Some viruses selectively infect iron acceptor cells (e.g. macrophages) by binding to transferrin receptor 1during cell entry. Moreover, human airway secretions in the major route of entry of COVID-19 include transferrin and lactoferrin, and this glycoproteins can bind iron and maintain a chemically inert form. Understanding how iron metabolism and viral infection interact in the COVID-19 outbreak may suggest new ways to control the disease.

Keywords: SARS-CoV-2; COVID-19; iron; ferritin; hepcidin
ÖZET
 Virüsler, çoğalmak için hücreleri istila eder ve verimli üreme için demir dolu bir hücreye ihtiyaç duyarlar. Diğer virüslerle birlikte koronavirüs hastalığı-2019 [coronavirus disease-2019 (COVID-19)] virüsü, demir homeostazına dâhil olan proteinlerin ekspresyonunu değiştirebilir. Örneğin COVID-19 hastalarında, interlökin-6 gibi proinflamatuar sitokinlerdeki bir artış, demir metabolizmasının düzenleyici hormonu olan hepsidin sentezini uyarabilir ve böylece ferroportin aracılı hücresel demir dışa aktarımını baskılayabilir. COVID-19 virüs enfeksiyonunda artan serum ferritin seviyeleri kötü prognozla ilişkilidir ve kısmen virüsün kendisinden kaynaklanıyor olabilir. Bazı virüsler, hücre girişi sırasında transferin reseptörü 1'e bağlanarak seçici olarak demir alıcı hücreleri (örneğin makrofajlar) enfekte eder. Dahası, COVID-19'un ana giriş yolundaki insan hava yolu salgıları arasında transferrin ve laktoferrin bulunur ve bu glikoproteinler demiri bağlayabilir ve kimyasal olarak inert bir formu koruyabilir. COVID-19 salgınında demir metabolizmasının ve viral enfeksiyonun nasıl etkileşime girdiğini anlamak, hastalığı kontrol etmenin yeni yollarını önerebilir.

Anahtar Kelimeler: SARS-CoV-2; COVID-19; demir; ferritin; hepsidin
REFERENCES:
  1. Jia HP, Look DC, Shi L, Hickey M, Pewe L, Netland J, et al. ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia. J Virol. 2005;79(23):14614-21. [Crossref] [PubMed] [PMC] 
  2. Sun P, Lu X, Xu C, Sun W, Pan B. Understanding of COVID-19 based on current evidence. J Med Virol. 2020;92(6):548-51. [Crossref] [PubMed] [PMC] 
  3. Cavezzi A, Troiani E, Corrao S. COVID-19: hemoglobin, iron, and hypoxia beyond inflammation. A narrative review. Clin Pract. 2020;10(2):1271. [Crossref] [PubMed] [PMC] 
  4. Yılmaz N, Eren E, Öz C. COVID-19 and ozone. Cyprus J Med Sci. 2020;5(4):365-72. [Crossref] 
  5. Garrick MD, Ghio AJ. Iron chelation may harm patients with COVID-19. Eur J Clin Pharmacol. 2021;77(2):265-6. Erratum in: Eur J Clin Pharmacol. 2021 Feb;77(2):265-266. [Crossref] [PubMed] [PMC] 
  6. Lin Z, Long F, Yang Y, Chen X, Xu L, Yang M. Serum ferritin as an independent risk factor for severity in COVID-19 patients. J Infect. 2020;81(4):647-79. [Crossref] [PubMed] [PMC] 
  7. Kappert K, Jahić A, Tauber R. Assessment of serum ferritin as a biomarker in COVID-19: bystander or participant? Insights by comparison with other infectious and non-infectious diseases. Biomarkers. 2020;25(8):616-25. [Crossref] [PubMed] 
  8. Altschul DJ, Esenwa C, Haranhalli N, Unda SR, de La Garza Ramos R, Dardick J, et al. Predictors of mortality for patients with COVID-19 and large vessel occlusion. Interv Neuroradiol. 2020;26(5):623-8. [Crossref] [PubMed] [PMC] 
  9. Taneri PE, Gómez-Ochoa SA, Llanaj E, Raguindin PF, Rojas LZ, Roa-Díaz ZM, et al. Anemia and iron metabolism in COVID-19: a systematic review and meta-analysis. Eur J Epidemiol. 2020;35(8):763-73. [Crossref] [PubMed] [PMC] 
  10. Edeas M, Saleh J, Peyssonnaux C. Iron: Innocent bystander or vicious culprit in COVID-19 pathogenesis? Int J Infect Dis. 2020;97:303-5. [Crossref] [PubMed] [PMC] 
  11. Shenoy S. Coronavirus (Covid-19) sepsis: revisiting mitochondrial dysfunction in pathogenesis, aging, inflammation, and mortality. Inflamm Res. 2020;69(11):1077-85. [Crossref] [PubMed] [PMC] 
  12. Giannis D, Ziogas IA, Gianni P. Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past. J Clin Virol. 2020;127:104362. [Crossref] [PubMed] [PMC] 
  13. Wertheim JO, Chu DK, Peiris JS, Kosakovsky Pond SL, Poon LL. A case for the ancient origin of coronaviruses. J Virol. 2013;87(12):7039-45. [Crossref] [PubMed] [PMC] 
  14. Dhama K, Khan S, Tiwari R, Sircar S, Bhat S, Malik YS, et al. Coronavirus Disease 2019-COVID-19. Clin Microbiol Rev. 2020;33(4):e00028-20. [Crossref] [PubMed] [PMC] 
  15. Yoshimoto FK. The Proteins of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2 or n-COV19), the Cause of COVID-19. Protein J. 2020;39(3):198-216. [Crossref] [PubMed] [PMC] 
  16. Wächtershäuser G. Groundworks for an evolutionary biochemistry: the iron-sulphur world. Prog Biophys Mol Biol. 1992;58(2):85-201. [Crossref] [PubMed] 
  17. Drakesmith H, Prentice A. Viral infection and iron metabolism. Nat Rev Microbiol. 2008;6(7):541-52. [Crossref] [PubMed] 
  18. Chifman J, Laubenbacher R, Torti SV. A systems biology approach to iron metabolism. Adv Exp Med Biol. 2014;844:201-25. [Crossref] [PubMed] [PMC] 
  19. Cohen LA, Gutierrez L, Weiss A, Leichtmann-Bardoogo Y, Zhang DL, Crooks DR, et al. Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. Blood. 2010;116(9):1574-84. [Crossref] [PubMed] 
  20. Arosio P, Levi S. Cytosolic and mitochondrial ferritins in the regulation of cellular iron homeostasis and oxidative damage. Biochim Biophys Acta. 2010;1800(8):783-92. [Crossref] [PubMed] 
  21. Zhang Q, Huang X. Induction of interleukin-6 by coal containing bioavailable iron is through both hydroxyl radical and ferryl species. J Biosci. 2003;28(1):95-100. [Crossref] [PubMed] 
  22. Innes AJ, Cook LB, Marks S, Bataillard E, Crossette-Thambiah C, Sivasubramaniam G, et al. Ruxolitinib for tocilizumab-refractory severe COVID-19 infection. Br J Haematol. 2020;190(4):e198-e200. [Crossref] [PubMed] [PMC] 
  23. Luo P, Liu Y, Qiu L, Liu X, Liu D, Li J. Tocilizumab treatment in COVID-19: A single center experience. J Med Virol. 2020;92(7):814-8. [Crossref] [PubMed] [PMC] 
  24. Li Y, Zhou Y, Zhang D, Wu WY, Kang X, Wu Q, et al. Hypobaric hypoxia regulates iron metabolism in rats. J Cell Biochem. 2019;120(8):14076-87. [Crossref] [PubMed] 
  25. Perricone C, Bartoloni E, Bursi R, Cafaro G, Guidelli GM, Shoenfeld Y, et al. COVID-19 as part of the hyperferritinemic syndromes: the role of iron depletion therapy. Immunol Res. 2020;68(4):213-24. [Crossref] [PubMed] [PMC] 
  26. Quiros Roldan E, Biasiotto G, Magro P, Zanella I. The possible mechanisms of action of 4-aminoquinolines (chloroquine/hydroxychloroquine) against Sars-Cov-2 infection (COVID-19): A role for iron homeostasis? Pharmacol Res. 2020;158:104904. [Crossref] [PubMed] [PMC] 
  27. Abo-Zeid Y, Ismail NSM, McLean GR, Hamdy NM. A molecular docking study repurposes FDA approved iron oxide nanoparticles to treat and control COVID-19 infection. Eur J Pharm Sci. 2020;153:105465. [Crossref] [PubMed] [PMC] 
  28. Hadadi A, Mortezazadeh M, Kolahdouzan K, Alavian G. Does recombinant human erythropoietin administration in critically ill COVID-19 patients have miraculous therapeutic effects? J Med Virol. 2020;92(7):915-8. [Crossref] [PubMed] [PMC] 
  29. Sukhomlin T. Could an acute respiratory distress syndrome in COVID-19 infected patients be calmed down simply by iron withdrawal from lung tissues? J Med Virol. 2021;93(2):577-8. [Crossref] [PubMed] 
  30. Cecchini R, Cecchini AL. SARS-CoV-2 infection pathogenesis is related to oxidative stress as a response to aggression. Med Hypotheses. 2020;143:110102. [Crossref] [PubMed] [PMC] 
  31. Lim PJ, Duarte TL, Arezes J, Garcia-Santos D, Hamdi A, Pasricha SR, et al. Nrf2 controls iron homeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin. Nat Metab. 2019;1(5):519-31. [Crossref] [PubMed] [PMC] 
  32. Zhao K, Huang J, Dai D, Feng Y, Liu L, Nie S. Serum iron level as a potential predictor of coronavirus disease 2019 severity and mortality: A retrospective study. Open Forum Infect Dis. 2020;7(7):ofaa250. [Crossref] [PubMed] [PMC] 
  33. Sun Y, Chen P, Zhai B, Zhang M, Xiang Y, Fang J, et al. The emerging role of ferroptosis in inflammation. Biomed Pharmacother. 2020;127:110108. [Crossref] [PubMed] 
  34. Wagener FADTG, Pickkers P, Peterson SJ, Immenschuh S, Abraham NG. Targeting the heme-heme oxygenase system to prevent severe complications following COVID-19 infections. Antioxidants (Basel). 2020;9(6):540. [Crossref] [PubMed] [PMC] 
  35. Cooper CE. Nitric oxide and iron proteins. Biochim Biophys Acta. 1999;1411(2-3):290-309. [Crossref] [PubMed] 
  36. Gan ZS, Wang QQ, Li JH, Wang XL, Wang YZ, Du HH. Iron reduces M1 macrophage polarization in RAW264.7 Macrophages Associated with Inhibition of STAT1. Mediators Inflamm. 2017;2017:8570818. [Crossref] [PubMed] [PMC] 
  37. Arber N, Moshkowitz M, Konikoff F, Halpern Z, Hallak A, Santo M, et al. Elevated serum iron predicts poor response to interferon treatment in patients with chronic HCV infection. Dig Dis Sci. 1995;40(11):2431-3. [Crossref] [PubMed] 
  38. Kanamori Y, Murakami M, Sugiyama M, Hashimoto O, Matsui T, Funaba M. Hepcidin and IL-1β. Vitam Horm. 2019;110:143-56. [Crossref] [PubMed] 
  39. Agarwal AK, Yee J. Hepcidin. Adv Chronic Kidney Dis. 2019;26(4):298-305. [Crossref] [PubMed] 
  40. Girelli D, Nemeth E, Swinkels DW. Hepcidin in the diagnosis of iron disorders. Blood. 2016;127(23):2809-13. [Crossref] [PubMed] [PMC] 
  41. Rishi G, Wallace DF, Subramaniam VN. Hepcidin: regulation of the master iron regulator. Biosci Rep. 2015;35(3):e00192. [Crossref] [PubMed] [PMC] 
  42. Vargas-Vargas M, Cortés-Rojo C. Ferritin levels and COVID-19. Rev Panam Salud Publica. 2020;44:e72. [Crossref] [PubMed] [PMC] 
  43. Velavan TP, Meyer CG. Mild versus severe COVID-19: Laboratory markers. Int J Infect Dis. 2020;95:304-7. [Crossref] [PubMed] [PMC] 
  44. Di Paola L, Hadi-Alijanvand H, Song X, Hu G, Giuliani A. The discovery of a putative allosteric Site in the SARS-CoV-2 spike protein using an ıntegrated structural/dynamic approach. J Proteome Res. 2020;19(11):4576-86. [Crossref] [PubMed] [PMC] 
  45. Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, et al; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;75(23):2950-73. [Crossref] [PubMed] [PMC] 
  46. Zhang V, Ganz T, Nemeth E, Kim A. Iron overload causes a mild and transient increase in acute lung injury. Physiol Rep. 2020;8(12):e14470. [Crossref] [PubMed] [PMC] 
  47. Patel KP, Patel PA, Vunnam RR, Hewlett AT, Jain R, Jing R, et al. Gastrointestinal, hepatobiliary, and pancreatic manifestations of COVID-19. J Clin Virol. 2020;128:104386. [Crossref] [PubMed] [PMC] 
  48. Zang R, Gomez Castro MF, McCune BT, Zeng Q, Rothlauf PW, Sonnek NM, et al. TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes. Sci Immunol. 2020;5(47):eabc3582. [Crossref] [PubMed] [PMC] 
  49. Auguet T, Aragonès G, Berlanga A, Martínez S, Sabench F, Binetti J, et al. Hepcidin in morbidly obese women with non-alcoholic fatty liver disease. PLoS One. 2017;12(10):e0187065. [Crossref] [PubMed] [PMC] 
  50. Gammella E, Buratti P, Cairo G, Recalcati S. The transferrin receptor: the cellular iron gate. Metallomics. 2017;9(10):1367-75. [Crossref] [PubMed] 
  51. Bellmann-Weiler R, Lanser L, Barket R, Rangger L, Schapfl A, Schaber M, et al. Prevalence and predictive value of anemia and dysregulated iron homeostasis in patients with COVID-19 infection. J Clin Med. 2020;9(8):2429. [Crossref] [PubMed] [PMC] 
  52. Muckenthaler MU, Galy B, Hentze MW. Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. Annu Rev Nutr. 2008;28:197-213. [Crossref] [PubMed] 
  53. Gao G, Li J, Zhang Y, Chang YZ. Cellular Iron Metabolism and Regulation. Adv Exp Med Biol. 2019;1173:21-32. [Crossref] [PubMed] 
  54. Toniati P, Piva S, Cattalini M, Garrafa E, Regola F, Castelli F, et al. Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: A single center study of 100 patients in Brescia, Italy. Autoimmun Rev. 2020;19(7):102568. [Crossref] [PubMed] [PMC] 
  55. Neves J, Haider T, Gassmann M, Muckenthaler MU. Iron Homeostasis in the Lungs-A Balance between Health and Disease. Pharmaceuticals (Basel). 2019;12(1):5. [Crossref] [PubMed] [PMC] 
  56. Dorward DA, Russell CD, Um IH, Elshani M, Armstrong SD, Penrice-Randal R, et al. Tissue-Specific Immunopathology in Fatal COVID-19. Am J Respir Crit Care Med. 2021;203(2):192-201. [Crossref] [PubMed] [PMC] 
  57. Ghio AJ, Wang X, Silbajoris R, Garrick MD, Piantadosi CA, Yang F. DMT1 expression is increased in the lungs of hypotransferrinemic mice. Am J Physiol Lung Cell Mol Physiol. 2003;284(6):L938-44. [Crossref] [PubMed] 
  58. Soares MP, Hamza I. Macrophages and iron metabolism. Immunity. 2016;44(3):492-504. [Crossref] [PubMed] [PMC] 
  59. Ganz T. Iron and infection. Int J Hematol. 2018;107(1):7-15. Erratum in: Int J Hematol. 2017 Dec 2. [Crossref] [PubMed] 
  60. Bolondi G, Russo E, Gamberini E, Circelli A, Meca MCC, Brogi E, et al. Iron metabolism and lymphocyte characterisation during Covid-19 infection in ICU patients: an observational cohort study. World J Emerg Surg. 2020;15(1):41. [Crossref] [PubMed] [PMC] 
  61. Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol. 2020;20(6):355-62. Erratum in: Nat Rev Immunol. 2020. [Crossref] [PubMed] [PMC] 
  62. Woodward JE, Bayer AL, Chavin KD, Boleza KA, Baliga P. Anti-transferrin receptor monoclonal antibody: a novel immunosuppressant. Transplantation. 1998;65(1):6-9. [Crossref] [PubMed] 
  63. McLaughlin KM, Bechtel M, Bojkova D, Münch C, Ciesek S, Wass MN, Michaelis M, Cinatl J Jr. COVID-19-Related Coagulopathy-Is Transferrin a Missing Link? Diagnostics (Basel). 2020;10(8):539. [Crossref] [PubMed] [PMC] 
  64. Chen ST, Ni YH, Li CC, Liu SH. Hepcidin correlates with interleukin-1β and interleukin-6 but not iron deficiency in children with Helicobacter pylori infection. Pediatr Neonatol. 2018;59(6):611-7. [Crossref] [PubMed] 
  65. Sabelli M, Montosi G, Garuti C, Caleffi A, Oliveto S, Biffo S, et al. Human macrophage ferroportin biology and the basis for the ferroportin disease. Hepatology. 2017;65(5):1512-25. [Crossref] [PubMed] [PMC] 
  66. Hirayama M, Kohgo Y, Kondo H, Shintani N, Fujikawa K, Sasaki K, et al. Regulation of iron metabolism in HepG2 cells: a possible role for cytokines in the hepatic deposition of iron. Hepatology. 1993;18(4):874-80. [Crossref] [PubMed] 
  67. Soy M, Keser G, Atagündüz P, Tabak F, Atagündüz I, Kayhan S. Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clin Rheumatol. 2020;39(7):2085-94. [Crossref] [PubMed] [PMC] 
  68. Oxley TJ, Mocco J, Majidi S, Kellner CP, Shoirah H, Singh IP, et al. Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young. N Engl J Med. 2020;382(20):e60. [Crossref] [PubMed] [PMC] 
  69. Jafarzadeh A, Chauhan P, Saha B, Jafarzadeh S, Nemati M. Contribution of monocytes and macrophages to the local tissue inflammation and cytokine storm in COVID-19: Lessons from SARS and MERS, and potential therapeutic interventions. Life Sci. 2020;257:118102. [Crossref] [PubMed] [PMC] 
  70. Root-Bernstein R. Age and Location in Severity of COVID-19 Pathology: Do Lactoferrin and Pneumococcal Vaccination Explain Low Infant Mortality and Regional Differences? Bioessays. 2020;42(11):e2000076. [Crossref] [PubMed] 
  71. Ehsani S. COVID-19 and iron dysregulation: distant sequence similarity between hepcidin and the novel coronavirus spike glycoprotein. Biol Direct. 2020;15(1):19. [Crossref] [PubMed] [PMC] 
  72. Berlutti F, Pantanella F, Natalizi T, Frioni A, Paesano R, Polimeni A, et al. Antiviral properties of lactoferrin--a natural immunity molecule. Molecules. 2011;16(8):6992-7018. [Crossref] [PubMed] [PMC] 
  73. Lang J, Yang N, Deng J, Liu K, Yang P, Zhang G, et al. Inhibition of SARS pseudovirus cell entry by lactoferrin binding to heparan sulfate proteoglycans. PLoS One. 2011;6(8):e23710. [Crossref] [PubMed] [PMC] 
  74. Peroni DG, Fanos V. Lactoferrin is an important factor when breastfeeding and COVID-19 are considered. Acta Paediatr. 2020;109(10):2139-40. [Crossref] [PubMed] [PMC] 
  75. Powell AE, Zhang K, Sanyal M, Tang S, Weidenbacher PA, Li S, et al. A Single Immunization with Spike-Functionalized Ferritin Vaccines Elicits Neutralizing Antibody Responses against SARS-CoV-2 in Mice. ACS Cent Sci. 2021;7(1):183-99. [Crossref] [PubMed] [PMC] 

.: Up To Date

.: Process List

Login

 Forgot your password?

 New Registration  

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