Turkiye Klinikleri Journal of Medical Sciences

.: REVIEW
Effects of Sirtuins on Female Reproductivity and Oocyte Quality: Traditional Review
Sirtuinlerin Oosit Kalitesi ve Kadın Üremesi Üzerine Etkisi: Geleneksel Derleme
Esra ŞENa, Hakkı DALÇIKb, Cannur DALÇIKb
aDepartment of Histology and Embryology, İstanbul Aydın University Faculty of Medicine, İstanbul, Türkiye
bDepartment of Anatomy, İstanbul Aydın University Faculty of Medicine, İstanbul, Türkiye
Turkiye Klinikleri J Med Sci. 2022;42(3):230-7
doi: 10.5336/medsci.2021-86890
Article Language: EN
Full Text
ABSTRACT
 Sirtuins (SIRTs) are described as a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases and is able to catalyze post-translational modifications of proteins. It has been documented that, SIRTs respond to metabolic challenges, inflammation molecules, and oxidative stress. Many studies have linked SIRTs with longevity and having anti-aging activity. Our knowledge of SIRTs in reproduction has grown increasingly over the last few years. The majority of these research is carried out primarily on the effects on SIRT1 on female reproduction. It has been demonstarted that down-regulating SIRT1 trigers the reduction of ovarian reserve. Many research has demonstrated that, SIRT1 regulates proliferation and apoptosis in granulosa cells. Activity studies of SIRTs opened the discoveries of the functional aspects of different types of SIRTs in improving the overall quality of in vitro oocytes in humans and animal models. It has been documented that, SIRT1, SIRT2 and SIRT3 protect oocytes against postovulatory aging. The relationship between derangement of SIRT signaling and the imbalance of reactive oxygen species and antioxidant defenses in female reproductive organs has also been documented. The present review aims to put forward information on the mechanism and cellular role of SIRTs and give an update of sirtuin research in female reproduction under physiological and pathological conditions. The final goal of this work is to put forward the therapeutic potential of SIRTs in female infertility.

Keywords: Sirtuins; oocyte; ovary; reproduction; infertility
ÖZET
 Sirtuinler (SIRT), proteinlerin translasyon sonrası modifikasyonlarını katalize eden bir nikotinamid adenin dinükleotid (NAD+) bağımlı deasetilaz ailesidir. Metabolik zorluklara, inflamatuar sinyallere veya hipoksik/oksidatif strese yanıt verirler ve yaşlanma ve uzun yaşam ile ilişkilidirler. SIRT'ler ile ilgili üreme alanındaki bilgimiz son birkaç yılda giderek artmıştır. Şimdiye kadar yapılan çalışmaların çoğu kadın üremesine dönük olup, SIRT1'e odaklanılmıştır. SIRT1 sentezinin azalması sonucunda ovaryan rezervin de azaldığı kanıtlanmıştır. SIRT1'in, granüloza hücre proliferasyonu ve apoptozunu düzenlediği de gösterilmiştir. SIRT'lerin biyokimyasal aktivitesinin ortaya çıkarılmasıyla SIRT1, SIRT2, SIRT3 ve SIRT6'nın insan ve hayvan modellerinde in vitro olarak geliştirilen oositler üzerindeki rollerinin keşfedilmesine yol açmıştır. Son zamanlarda SIRT1, SIRT2 ve SIRT3 oositin postovulatuar yaşlanmaya karşı koruyuculukları ortaya çıkmıştır. Ayrıca SIRT'lerin etkilediği sinyal yolaklarının düzensizleşmesi sonucu, kadın üreme organlarında reaktif oksijen türleri ve antioksidan savunma mekanizmalarındaki dengesizlik gösterilmiştir. Bu derleme, kadın üremesinde fizyolojik ve patolojik koşullar altında SIRT'lerin etki mekanizmaları ve hücresel rolü hakkında güncel bilgi aktarmayı amaçlamaktadır. Bu çalışmanın nihai amacı, kadın infertilitesinde tedavi amaçlı, SIRT'lerin potansiyel bir molekül olabileceği konusunu gündeme taşımaktır.

Anahtar Kelimeler: Sirtuinler; oosit; ovaryum; üreme; infertilite
REFERENCES:
  1. Sirotkin AV. The role and application of sirtuins and mtor signaling in the control of ovarian functions. Cells. 2016;5(4):42. [Crossref]  [PubMed]  [PMC] 
  2. Artimani T, Karimi J, Mehdizadeh M, Yavangi M, Khanlarzadeh E, Ghorbani M, et al. Evaluation of pro-oxidant-antioxidant balance (PAB) and its association with inflammatory cytokines in polycystic ovary syndrome (PCOS). Gynecol Endocrinol. 2018;34(2):148-52. [Crossref]  [PubMed] 
  3. Yuan B, Schafferer S, Tang Q, Scheffler M, Nees J, Heil J, et al. A plasma metabolite panel as biomarkers for early primary breast cancer detection. Int J Cancer. 2019;144(11):2833-42. [Crossref]  [PubMed] 
  4. Lim JH, Lee YM, Chun YS, Chen J, Kim JE, Park JW. Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Mol Cell. 2010;38(6):864-78. [Crossref]  [PubMed] 
  5. Liu Y, Dentin R, Chen D, Hedrick S, Ravnskjaer K, Schenk S, et al. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature. 2008;456(7219):269-73. [Crossref]  [PubMed]  [PMC] 
  6. Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, Mostoslavsky R, et al. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J. 2007;26(7):1913-23. [Crossref]  [PubMed]  [PMC] 
  7. Kauppinen A, Suuronen T, Ojala J, Kaarniranta K, Salminen A. Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell Signal. 2013;25(10):1939-48. [Crossref]  [PubMed] 
  8. Schultze SM, Hemmings BA, Niessen M, Tschopp O. PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis. Expert Rev Mol Med. 2012;14:e1. [Crossref]  [PubMed] 
  9. Wang T, Geng SL, Guan YM, Xu WH. Deacetylation of metabolic enzymes by Sirt2 modulates pyruvate homeostasis to extend insect lifespan. Aging (Albany NY). 2018;10(5):1053-72. [Crossref]  [PubMed]  [PMC] 
  10. Wang B, Zhang Y, Cao W, Wei X, Chen J, Ying W. SIRT2 Plays Significant Roles in Lipopolysaccharides-Induced Neuroinflammation and Brain Injury in Mice. Neurochem Res. 2016;41(9):2490-500. [Crossref]  [PubMed] 
  11. Chen X, Wales P, Quinti L, Zuo F, Moniot S, Herisson F, et al. The sirtuin-2 inhibitor AK7 is neuroprotective in models of Parkinson's disease but not amyotrophic lateral sclerosis and cerebral ischemia. PLoS One. 2015;10(1):e0116919. [Crossref]  [PubMed]  [PMC] 
  12. Liu R, Dang W, Du Y, Zhou Q, Jiao K, Liu Z. SIRT2 is involved in the modulation of depressive behaviors. Sci Rep. 2015;5:8415. [Crossref]  [PubMed]  [PMC] 
  13. Toussaint O, Medrano EE, von Zglinicki T. Cellular and molecular mechanisms of stress-induced premature senescence (SIPS) of human diploid fibroblasts and melanocytes. Exp Gerontol. 2000;35(8):927-45. [Crossref]  [PubMed] 
  14. Stenesen D, Suh JM, Seo J, Yu K, Lee KS, Kim JS, et al. Adenosine nucleotide biosynthesis and AMPK regulate adult life span and mediate the longevity benefit of caloric restriction in flies. Cell Metab. 2013;17(1):101-12. [Crossref]  [PubMed]  [PMC] 
  15. Ido Y, Duranton A, Lan F, Weikel KA, Breton L, Ruderman NB. Resveratrol prevents oxidative stress-induced senescence and proliferative dysfunction by activating the AMPK-FOXO3 cascade in cultured primary human keratinocytes. PLoS One. 2015;10(2):e0115341. [Crossref]  [PubMed]  [PMC] 
  16. Salminen A, Kaarniranta K. AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev. 2012;11(2):230-41. [Crossref]  [PubMed] 
  17. Mo C, Wang L, Zhang J, Numazawa S, Tang H, Tang X, et al. The crosstalk between Nrf2 and AMPK signal pathways is important for the anti-inflammatory effect of berberine in LPS-stimulated macrophages and endotoxin-shocked mice. Antioxid Redox Signal. 2014;20(4):574-88. [Crossref]  [PubMed]  [PMC] 
  18. Lipinski MM, Zheng B, Lu T, Yan Z, Py BF, Ng A, et al. Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease. Proc Natl Acad Sci U S A. 2010;107(32):14164-9. [Crossref]  [PubMed]  [PMC] 
  19. Klionsky DJ, Abdalla FC, Abeliovich H, Abraham RT, Acevedo-Arozena A, Adeli K, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2012;8(4):445-44. [PubMed]  [PMC] 
  20. Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L, et al. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013;155(7):1624-38. [Crossref]  [PubMed]  [PMC] 
  21. Han X, Tai H, Wang X, Wang Z, Zhou J, Wei X, et al. AMPK activation protects cells from oxidative stress-induced senescence via autophagic flux restoration and intracellular NAD(+) elevation. Aging Cell. 2016;15(3):416-27. [Crossref]  [PubMed]  [PMC] 
  22. Lee D, Goldberg AL. SIRT1 protein, by blocking the activities of transcription factors FoxO1 and FoxO3, inhibits muscle atrophy and promotes muscle growth. J Biol Chem. 2013;288(42):30515-26. [Crossref]  [PubMed]  [PMC] 
  23. Yuan HF, Zhai C, Yan XL, Zhao DD, Wang JX, Zeng Q, et al. SIRT1 is required for long-term growth of human mesenchymal stem cells. J Mol Med (Berl). 2012;90(4):389-400. [Crossref]  [PubMed] 
  24. Yamashita S, Ogawa K, Ikei T, Udono M, Fujiki T, Katakura Y. SIRT1 prevents replicative senescence of normal human umbilical cord fibroblast through potentiating the transcription of human telomerase reverse transcriptase gene. Biochem Biophys Res Commun. 2012;417(1):630-4. [Crossref]  [PubMed] 
  25. Xu D, Takeshita F, Hino Y, Fukunaga S, Kudo Y, Tamaki A, et al. miR-22 represses cancer progression by inducing cellular senescence. J Cell Biol. 2011;193(2):409-24. [Crossref]  [PubMed]  [PMC] 
  26. Revollo JR, Li X. The ways and means that fine tune Sirt1 activity. Trends Biochem Sci. 2013;38(3):160-7. [Crossref]  [PubMed]  [PMC] 
  27. Braidy N, Guillemin GJ, Mansour H, Chan-Ling T, Poljak A, Grant R. Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in wistar rats. PLoS One. 2011;6(4):e19194. [Crossref]  [PubMed]  [PMC] 
  28. Falone S, D'Alessandro A, Mirabilio A, Cacchio M, Di Ilio C, Di Loreto S, et al. Late-onset running biphasically improves redox balance, energy- and methylglyoxal-related status, as well as SIRT1 expression in mouse hippocampus. PLoS One. 2012;7(10):e48334. [Crossref]  [PubMed]  [PMC] 
  29. Pallàs M, Pizarro JG, Gutierrez-Cuesta J, Crespo-Biel N, Alvira D, Tajes M, et al. Modulation of SIRT1 expression in different neurodegenerative models and human pathologies. Neuroscience. 2008;154(4):1388-97. [Crossref]  [PubMed] 
  30. Roupa Z, Polikandrioti M, Sotiropoulou P, Faros E, Koulouri A, Wozniak G, et al. Causes of infertility in women at reproductive age. Heal Sci J. 2009;3(2):80-7. [Link] 
  31. Nu-ez-Calonge R, Cortés S, Gutierrez Gonzalez LM, Kireev R, Vara E, Ortega L, et al. Oxidative stress in follicular fluid of young women with low response compared with fertile oocyte donors. Reprod Biomed Online. 2016;32(4):446-56. [Crossref]  [PubMed] 
  32. Marcu R, Wiczer BM, Neeley CK, Hawkins BJ. Mitochondrial matrix Ca²⁺ accumulation regulates cytosolic NAD⁺/NADH metabolism, protein acetylation, and sirtuin expression. Mol Cell Biol. 2014;34(15):2890-902. [Crossref]  [PubMed]  [PMC] 
  33. Okamoto N, Kawamura K, Kawamura N, Nishijima C, Ishizuka B, Suzuki N, et al. Effects of maternal aging on expression of sirtuin genes in ovulated oocyte and cumulus cells. J Mamm Ova Res. 2013;30(1):24-9. [Crossref] 
  34. Luo H, Han Y, Liu J, Zhang Y. Identification of microRNAs in granulosa cells from patients with different levels of ovarian reserve function and the potential regulatory function of miR-23a in granulosa cell apoptosis. Gene. 2019;686:250-60. [Crossref]  [PubMed] 
  35. Pacella-Ince L, Zander-Fox DL, Lan M. Mitochondrial SIRT3 and its target glutamate dehydrogenase are altered in follicular cells of women with reduced ovarian reserve or advanced maternal age. Hum Reprod. 2014;29(7):1490-9. [Crossref]  [PubMed] 
  36. Pacella-Ince L, Zander-Fox DL, Lane M. Mitochondrial SIRT5 is present in follicular cells and is altered by reduced ovarian reserve and advanced maternal age. Reprod Fertil Dev. 2014;26(8):1072-83. [Crossref]  [PubMed] 
  37. Zhao HC, Ding T, Ren Y, Li TJ, Li R, Fan Y, et al. Role of Sirt3 in mitochondrial biogenesis and developmental competence of human in vitro matured oocytes. Hum Reprod. 2016;31(3):607-22. [Crossref]  [PubMed] 
  38. Izhar R, Husain S, Tahir S, Husain S. Occult form of premature ovarian insufficiency in women with infertility and oligomenorrhea as assessed by poor ovarian response criteria. J Reprod Infertil. 2017;18(4):361-7. [PubMed]  [PMC] 
  39. Durlinger AL, Kramer P, Karels B, de Jong FH, Uilenbroek JT, Grootegoed JA, et al. Control of primordial follicle recruitment by anti-Müllerian hormone in the mouse ovary. Endocrinology. 1999;140(12):5789-96. [Crossref]  [PubMed] 
  40. Pellatt L, Rice S, Dilaver N, Heshri A, Galea R, Brincat M, et al. Anti-Müllerian hormone reduces follicle sensitivity to follicle-stimulating hormone in human granulosa cells. Fertil Steril. 2011;96(5):1246-51.e1. [Crossref]  [PubMed] 
  41. Grisendi V, La Marca A. Individualization of controlled ovarian stimulation in vitro fertilization using ovarian reserve markers. Minerva Ginecol. 2017;69(3):250-8. [Crossref]  [PubMed] 
  42. Tatone C, Di Emidio G, Vitti M, Di Carlo M, Santini S Jr, D'Alessandro AM, et al. Sirtuin functions in female fertility: possible role in oxidative stress and aging. Oxid Med Cell Longev. 2015;2015:659687. [Crossref]  [PubMed]  [PMC] 
  43. Morita Y, Wada-Hiraike O, Yano T, Shirane A, Hirano M, Hiraike H, et al. Resveratrol promotes expression of SIRT1 and StAR in rat ovarian granulosa cells: an implicative role of SIRT1 in the ovary. Reprod Biol Endocrinol. 2012;10:14. [Crossref]  [PubMed]  [PMC] 
  44. Pavlová S, Klucska K, Va?íček D, Ryban L, Harrath AH, Alwasel SH, et al. The involvement of SIRT1 and transcription factor NF-κB (p50/p65) in regulation of porcine ovarian cell function. Anim Reprod Sci. 2013;140(3-4):180-8. [Crossref]  [PubMed] 
  45. Sirotkin AV, Dekanová P, Harrath AH, Alwasel SH, Va?íček D. Interrelationships between sirtuin 1 and transcription factors p53 and NF-κB (p50/p65) in the control of ovarian cell apoptosis and proliferation. Cell Tissue Res. 2014;358(2):627-32. [Crossref]  [PubMed] 
  46. Sirotkin AV, Alexa R, Dekanová P, Kádasi A, ?tochmaľová A, Grossmann R, et al. The mTOR system can affect basic porcine ovarian cell functions and mediate the effect of ovarian hormonal regulators. Int J Pharmacol. 2015;11(6):570-8. [Crossref] 
  47. Alam F, Syed H, Amjad S, Baig M, Khan TA, Rehman R. Interplay between oxidative stress, SIRT1, reproductive and metabolic functions. Curr Res Physiol. 2021;4:119-124. [Crossref]  [PubMed]  [PMC] 
  48. Barbagallo F, Condorelli RA, Mongioì LM, Cannarella R, Cimino L, Magagnini MC, et al. Molecular Mechanisms Underlying the Relationship between Obesity and Male Infertility. Metabolites. 2021;11(12):840. [Crossref]  [PubMed]  [PMC] 
  49. Benayoun BA, Georges AB, L'Hôte D, Andersson N, Dipietromaria A, Todeschini AL, et al. Transcription factor FOXL2 protects granulosa cells from stress and delays cell cycle: role of its regulation by the SIRT1 deacetylase. Hum Mol Genet. 2011;20(9):1673-86. [Crossref]  [PubMed] 
  50. Zhang J, Yin XJ, Xu CJ, Ning YX, Chen M, Zhang H, et al. The histone deacetylase SIRT6 inhibits ovarian cancer cell proliferation via down-regulation of Notch 3 expression. Eur Rev Med Pharmacol Sci. 2015;19(5):818-24. [PubMed] 
  51. Zhang XM, Li L, Xu JJ, Wang N, Liu WJ, Lin XH, et al. Rapamycin preserves the follicle pool reserve and prolongs the ovarian lifespan of female rats via modulating mTOR activation and sirtuin expression. Gene. 2013;523(1):82-7. [Crossref]  [PubMed] 
  52. Kashiyama T, Oda K, Ikeda Y, Shiose Y, Hirota Y, Inaba K, et al. Antitumor activity and induction of TP53-dependent apoptosis toward ovarian clear cell adenocarcinoma by the dual PI3K/mTOR inhibitor DS-7423. PLoS One. 2014;9(2):e87220. [Crossref]  [PubMed]  [PMC] 
  53. Liu M, Yin Y, Ye X, Zeng M, Zhao Q, Keefe DL, et al. Resveratrol protects against age-associated infertility in mice. Hum Reprod. 2013;28(3):707-17. [Crossref]  [PubMed] 
  54. Zhou XL, Xu JJ, Ni YH, Chen XC, Zhang HX, Zhang XM, et al. SIRT1 activator (SRT1720) improves the follicle reserve and prolongs the ovarian lifespan of diet-induced obesity in female mice via activating SIRT1 and suppressing mTOR signaling. J Ovarian Res. 2014;7:97. [Crossref]  [PubMed]  [PMC] 
  55. Yu J, Yaba A, Kasiman C, Thomson T, Johnson J. mTOR controls ovarian follicle growth by regulating granulosa cell proliferation. PLoS One. 2011;6(7):e21415. [Crossref]  [PubMed]  [PMC] 
  56. Ortega I, Villanueva JA, Wong DH, Cress AB, Sokalska A, Stanley SD, et al. Resveratrol reduces steroidogenesis in rat ovarian theca-interstitial cells: the role of inhibition of Akt/PKB signaling pathway. Endocrinology. 2012;153(8):4019-29. [Crossref]  [PubMed]  [PMC] 
  57. Liu WJ, Zhang XM, Wang N, Zhou XL, Fu YC, Luo LL. Calorie restriction inhibits ovarian follicle development and follicle loss through activating SIRT1 signaling in mice. Eur J Med Res. 2015;20(1):22. [Crossref]  [PubMed]  [PMC] 
  58. Zhang J, Fang L, Lu Z, Xiong J, Wu M, Shi L, et al. Are sirtuins markers of ovarian aging? Gene. 2016;575(2 Pt 3):680-6. [Crossref]  [PubMed] 
  59. Furat Rencber S, Kurnaz Ozbek S, Eraldemır C, Sezer Z, Kum T, Ceylan S, et al. Effect of resveratrol and metformin on ovarian reserve and ultrastructure in PCOS: an experimental study. J Ovarian Res. 2018;11(1):55. [Crossref]  [PubMed]  [PMC] 
  60. Yoo JY, Kim TH, Fazleabas AT, Palomino WA, Ahn SH, Tayade C, et al. KRAS Activation and over-expression of SIRT1/BCL6 contributes to the pathogenesis of endometriosis and progesterone resistance. Sci Rep. 2017;7(1):6765. [Crossref]  [PubMed]  [PMC] 
  61. Yao LN, Zhang TF, Lin WQ, Jiang N, Cao HF, Li H, et al. Value of serum and follicular fluid sirtuin (SIRT)1 and SIRT2 protein levels in predicting the outcome of assisted reproduction. Ann Transl Med. 2021;9(4):343. [Crossref]  [PubMed]  [PMC] 

.: Up To Date

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