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Flavonoidlerin Kanser Gelişimi ve Seyri Üzerine Etkileri

Year 2023, , 57 - 65, 27.12.2022

Fatmanur Şirin Şengün , Aliye Özenoğlu

https://doi.org/10.53493/avrasyasbd.1164133

Abstract

Flavonoidler, bitkileri zararlı etkenlere karşı koruyan biyoaktif bileşenlerdir. Sebze, meyve ve tahıllarda bol miktarda bulunan flavonoidlerin; antiinflamatuar, antioksidan, antidiyabetik, antihipertansif, antimikrobiyal olmak üzere birçok önemli özelliklere sahip oldukları saptanmıştır. Bu özellikleri nedeniyle flavonoidler, kanser başta olmak üzere kardiyovasküler hastalıklar, diyabet, obezite gibi bulaşıcı olmayan kronik hastalıkların önlenmesinde ve tedavisinde önem taşımaktadır. Son yıllarda doğal bitkisel tedavilere artan talep ve kansere bağlı ölümlerin artması ile birlikte flavonoidlerin kanser üzerindeki etkileri çalışmalarda sıklıkla araştırılan bir konu haline gelmiştir. Bu derlemede, flavonoidlerin kanser gelişimi ve seyri üzerindeki etkilerini ele alan çalışmalar incelenmiştir.

Keywords

Flavonoidler kanser antioksidan oksidatif stres

Supporting Institution

Yoktur

Project Number

Herhangi bir projeden türetilmemiştir.

Thanks

Yoktur

References

  • Arul, D., & Subramanian, P. (2013). Naringenin (Citrus Flavonone) İnduces Growth İnhibition, Cell Cycle Arrest And Apoptosis İn Human Hepatocellular Carcinoma Cells. Pathology Oncology Research : Por, 19(4), 763–770. Https://Doi.Org/10.1007/S12253-013-9641-1
  • Baião, D., de Freitas, C. S., Gomes, L. P., da Silva, D., Correa, A., Pereira, P. R., Aguila, E., & Paschoalin, V. (2017). Polyphenols from Root, Tubercles and Grains Cropped in Brazil: Chemical and Nutritional Characterization and Their Effects on Human Health and Diseases. Nutrients, 9(9), 1044. https://doi.org/10.3390/nu9091044
  • Barreca, D., Gattuso, G., Bellocco, E., Calderaro, A., Trombetta, D., Smeriglio, A., Laganà, G., Daglia, M., Meneghini, S., & Nabavi, S. M. (2017). Flavanones: Citrus Phytochemical With Health-Promoting Properties. Biofactors (Oxford, England), 43(4), 495–506. Https://Doi.Org/10.1002/Biof.1363
  • Çimen F., Polat H., Ekici L. (2020). Polifenollerin Bağırsak Mikrobiyota Kompozisyonunu Düzenleyici ve Nöroprotektif Etkileri. Akademik Gıda, 18 (2), 190-208. DOI: 10.24323/akademik-gida.758838
  • Demir T, Akpınar Ö. (2022). Bitkilerde Bulunan Fitokimyasalların Biyolojik Aktiviteleri. Türk-Tarım, Gıda, Bilim ve Teknoloji Dergisi, 8(8), 1734-1746. Doi: 1024925/turjaf.v8i8. 1734-1746.3484
  • Di Lorenzo, C., Colombo, F., Biella, S., Stockley, C., & Restani, P. (2021). Polyphenols and Human Health: The Role of Bioavailability. Nutrients, 13(1), 273. https://doi.org/10.3390/nu13010273
  • Forni, C., Rossi, M., Borromeo, I., Feriotto, G., Platamone, G., Tabolacci, C., Mischiati, C., & Beninati, S. (2021). Flavonoids: A Myth or a Reality for Cancer Therapy?.Molecules (Basel, Switzerland), 26(12), 3583. https://doi.org/10.3390/molecules26123583
  • Ganesan, K., & Xu, B. (2017). A Critical Review on Polyphenols and Health Benefits of Black Soybeans. Nutrients, 9(5), 455. https://doi.org/10.3390/nu9050455
  • Greten, F.R., Grivennikov, S.I. (2019). Inflammation and Cancer: Triggers, Mechanisms, and Consequences. Immunity, 51(1), 27-41. https://doi.org/10.1016/j.immuni.2019.06.025.
  • Gold-Smith, F., Fernandez, A., & Bishop, K. (2016). Mangiferin and Cancer: Mechanisms of Action. Nutrients, 8(7), 396. https://doi.org/10.3390/nu8070396
  • Hostetler, G. L., Ralston, R. A., & Schwartz, S. J. (2017). Flavones: Food Sources, Bioavailability, Metabolism, and Bioactivity. Advances in nutrition (Bethesda, Md.), 8(3), 423–435. https://doi.org/10.3945/an.116.012948
  • Islam, J., Shree, A., Vafa, A., Afzal, S. M., & Sultana, S. (2021). Taxifolin ameliorates Benzo[a]pyrene-induced lung injury possibly via stimulating the Nrf2 signalling pathway. International immunopharmacology, 96, 107566. https://doi.org/10.1016/j.intimp.2021.107566
  • Kuhnle G. (2018). Nutrition epidemiology of flavan-3-ols: The known unknowns. Molecular aspects of medicine, 61, 2–11. https://doi.org/10.1016/j.mam.2017.10.003
  • Kumar, S., & Pandey, A. K. (2013). Chemistry and biological activities of flavonoids: an overview. TheScientificWorldJournal, 2013, 162750. https://doi.org/10.1155/2013/162750
  • Lei, L., Yang, Y., He, H., Chen, E., Du, L., Dong, J., & Yang, J. (2016). Flavan-3-ols consumption and cancer risk: A meta-analysis of epidemiologic studies. Oncotarget, 7(45), 73573–73592. https://doi.org/10.18632/oncotarget.12017
  • Liu R. H. (2013). Health-promoting components of fruits and vegetables in the diet. Advances in nutrition (Bethesda, Md.), 4(3), 384S–92S. https://doi.org/10.3945/an.112.003517
  • Liu, H., Dong, Y., Gao, Y., Du, Z., Wang, Y., Cheng, P., Chen, A., & Huang, H. (2016). The Fascinating Effects Of Baicalein On Cancer: A Review. International Journal Of Molecular Sciences, 17(10), 1681. Https://Doi.Org/10.3390/İjms17101681
  • Mohammed, F. S., Günal, S., Pehlivan, M., Doğan, M., Sevindik, M. & Akgül, H. (2020). Phenolic Content, Antioxidant and Antimicrobial Potential of Endemic Ferulago platycarpa. Gazi University Journal of Science, 33 (4), 670-677. DOI: 10.35378/gujs.707555
  • Pan, H., Hu, Q., Wang, J., Liu, Z., Wu, D., Lu, W., & Huang, J. (2016). Myricetin is a novel inhibitor of human inosine 5'-monophosphate dehydrogenase with anti-leukemia activity. Biochemical and biophysical research communications, 477(4), 915–922. https://doi.org/10.1016/j.bbrc.2016.06.158
  • Pichler, C., Ferk, F., Al-Serori, H., Huber, W., Jäger, W., Waldherr, M., Mišík, M., Kundi, M., Nersesyan, A., Herbacek, I., & Knasmueller, S. (2017). Xanthohumol Prevents DNA Damage by Dietary Carcinogens: Results of a Human Intervention Trial. Cancer prevention research (Philadelphia, Pa.), 10(2), 153–160. https://doi.org/10.1158/1940-6207.CAPR-15-0378
  • Rock, C. L., Thomson, C., Gansler, T., Gapstur, S. M., McCullough, M. L., Patel, A. V., Andrews, K. S., Bandera, E. V., Spees, C. K., Robien, K., Hartman, S., Sullivan, K., Grant, B. L., Hamilton, K. K., Kushi, L. H., Caan, B. J., Kibbe, D., Black, J. D., Wiedt, T. L., McMahon, C., … Doyle, C. (2020). American Cancer Society guideline for diet and physical activity for cancer prevention. CA: a cancer journal for clinicians, 70(4), 245–271. https://doi.org/10.3322/caac.21591
  • Samavat, H., Ursin, G., Emory, T. H., Lee, E., Wang, R., Torkelson, C. J., Dostal, A. M., Swenson, K., Le, C. T., Yang, C. S., Yu, M. C., Yee, D., Wu, A. H., Yuan, J. M., & Kurzer, M. S. (2017). A Randomized Controlled Trial of Green Tea Extract Supplementation and Mammographic Density in Postmenopausal Women at Increased Risk of Breast Cancer. Cancer prevention research (Philadelphia, Pa.), 10(12), 710–718. https://doi.org/10.1158/1940-6207.CAPR-17-0187
  • Suna, G., & Ayaz, A. (2019). Turunçgil Flavonoidlerinin Kardiyovasküler Sağlık Üzerine Etkileri. Beslenme ve Diyet Dergisi, 47(2), 99-107. Https://Doi.Org/10.33076/2019.Bdd.511
  • Tahir, M. S., Almezgagi, M., Zhang, Y., Bashir, A., Abdullah, H. M., Gamah, M., Wang, X., Zhu, Q., Shen, X., Ma, Q., Ali, M., Solangi, Z. A., Malik, W. S., & Zhang, W. (2021). Mechanistic new insights of flavonols on neurodegenerative diseases. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 137, 111253. https://doi.org/10.1016/j.biopha.2021.111253
  • Torricelli, P., Elia, A. C., Magara, G., Feriotto, G., Forni, C., Borromeo, I., De Martino, A., Tabolacci, C., Mischiati, C., & Beninati, S. (2021). Reduction Of Oxidative Stress And Ornithine Decarboxylase Expression İn A Human Prostate Cancer Cell Line Pc-3 By A Combined Treatment With Α-Tocopherol And Naringenin. Amino Acids, 53(1), 63–72. Https://Doi.Org/10.1007/S00726-020-02925-1
  • Wallace, T. C., & Giusti, M. M. (2015). Anthocyanins. Advances in nutrition (Bethesda, Md.), 6(5), 620–622. https://doi.org/10.3945/an.115.009233
  • World Health Organization (WHO). Factsheed: Cancer. (2022). Erişim: 01.06.2022 https://www.who.int/health-topics/cancer#tab=tab_1
  • Yu, J., Bi, X., Yu, B., & Chen, D. (2016). Isoflavones: Anti-Inflammatory Benefit And Possible Caveats. Nutrients, 8(6), 361. Https://Doi.Org/10.3390/Nu8060361
  • Yuvaraj, S., Ramprasath, T., Saravanan, B., Vasudevan, V., Sasikumar, S., & Selvam, G. S. (2021). Chrysin attenuates high-fat-diet-induced myocardial oxidative stress via upregulating eNOS and Nrf2 target genes in rats. Molecular and cellular biochemistry, 476(7), 2719–2727. https://doi.org/10.1007/s11010-021-04105-5
  • Zakaryan, H., Arabyan, E., Oo, A., & Zandi, K. (2017). Flavonoids: promising natural compounds against viral infections. Archives of virology, 162(9), 2539–2551. https://doi.org/10.1007/s00705-017-3417-y
  • Zhang, F. F., Haslam, D. E., Terry, M. B., Knight, J. A., Andrulis, I. L., Daly, M. B., Buys, S. . S., & John, E. M. (2017). Dietary isoflavone intake and all-cause mortality in breast cancer survivors: The Breast Cancer Family Registry. Cancer, 123(11), 2070–2079.
  • Zhao, H., Wu, L., Yan, G. et al. (2021). Inflammation and tumor progression: signaling pathways and targeted intervention. Sig Transduct Target Ther 6, 263 https://doi.org/10.1038/s41392-021-00658-5

Year 2023, , 57 - 65, 27.12.2022

Fatmanur Şirin Şengün , Aliye Özenoğlu

https://doi.org/10.53493/avrasyasbd.1164133

Abstract

Project Number

Herhangi bir projeden türetilmemiştir.

References

  • Arul, D., & Subramanian, P. (2013). Naringenin (Citrus Flavonone) İnduces Growth İnhibition, Cell Cycle Arrest And Apoptosis İn Human Hepatocellular Carcinoma Cells. Pathology Oncology Research : Por, 19(4), 763–770. Https://Doi.Org/10.1007/S12253-013-9641-1
  • Baião, D., de Freitas, C. S., Gomes, L. P., da Silva, D., Correa, A., Pereira, P. R., Aguila, E., & Paschoalin, V. (2017). Polyphenols from Root, Tubercles and Grains Cropped in Brazil: Chemical and Nutritional Characterization and Their Effects on Human Health and Diseases. Nutrients, 9(9), 1044. https://doi.org/10.3390/nu9091044
  • Barreca, D., Gattuso, G., Bellocco, E., Calderaro, A., Trombetta, D., Smeriglio, A., Laganà, G., Daglia, M., Meneghini, S., & Nabavi, S. M. (2017). Flavanones: Citrus Phytochemical With Health-Promoting Properties. Biofactors (Oxford, England), 43(4), 495–506. Https://Doi.Org/10.1002/Biof.1363
  • Çimen F., Polat H., Ekici L. (2020). Polifenollerin Bağırsak Mikrobiyota Kompozisyonunu Düzenleyici ve Nöroprotektif Etkileri. Akademik Gıda, 18 (2), 190-208. DOI: 10.24323/akademik-gida.758838
  • Demir T, Akpınar Ö. (2022). Bitkilerde Bulunan Fitokimyasalların Biyolojik Aktiviteleri. Türk-Tarım, Gıda, Bilim ve Teknoloji Dergisi, 8(8), 1734-1746. Doi: 1024925/turjaf.v8i8. 1734-1746.3484
  • Di Lorenzo, C., Colombo, F., Biella, S., Stockley, C., & Restani, P. (2021). Polyphenols and Human Health: The Role of Bioavailability. Nutrients, 13(1), 273. https://doi.org/10.3390/nu13010273
  • Forni, C., Rossi, M., Borromeo, I., Feriotto, G., Platamone, G., Tabolacci, C., Mischiati, C., & Beninati, S. (2021). Flavonoids: A Myth or a Reality for Cancer Therapy?.Molecules (Basel, Switzerland), 26(12), 3583. https://doi.org/10.3390/molecules26123583
  • Ganesan, K., & Xu, B. (2017). A Critical Review on Polyphenols and Health Benefits of Black Soybeans. Nutrients, 9(5), 455. https://doi.org/10.3390/nu9050455
  • Greten, F.R., Grivennikov, S.I. (2019). Inflammation and Cancer: Triggers, Mechanisms, and Consequences. Immunity, 51(1), 27-41. https://doi.org/10.1016/j.immuni.2019.06.025.
  • Gold-Smith, F., Fernandez, A., & Bishop, K. (2016). Mangiferin and Cancer: Mechanisms of Action. Nutrients, 8(7), 396. https://doi.org/10.3390/nu8070396
  • Hostetler, G. L., Ralston, R. A., & Schwartz, S. J. (2017). Flavones: Food Sources, Bioavailability, Metabolism, and Bioactivity. Advances in nutrition (Bethesda, Md.), 8(3), 423–435. https://doi.org/10.3945/an.116.012948
  • Islam, J., Shree, A., Vafa, A., Afzal, S. M., & Sultana, S. (2021). Taxifolin ameliorates Benzo[a]pyrene-induced lung injury possibly via stimulating the Nrf2 signalling pathway. International immunopharmacology, 96, 107566. https://doi.org/10.1016/j.intimp.2021.107566
  • Kuhnle G. (2018). Nutrition epidemiology of flavan-3-ols: The known unknowns. Molecular aspects of medicine, 61, 2–11. https://doi.org/10.1016/j.mam.2017.10.003
  • Kumar, S., & Pandey, A. K. (2013). Chemistry and biological activities of flavonoids: an overview. TheScientificWorldJournal, 2013, 162750. https://doi.org/10.1155/2013/162750
  • Lei, L., Yang, Y., He, H., Chen, E., Du, L., Dong, J., & Yang, J. (2016). Flavan-3-ols consumption and cancer risk: A meta-analysis of epidemiologic studies. Oncotarget, 7(45), 73573–73592. https://doi.org/10.18632/oncotarget.12017
  • Liu R. H. (2013). Health-promoting components of fruits and vegetables in the diet. Advances in nutrition (Bethesda, Md.), 4(3), 384S–92S. https://doi.org/10.3945/an.112.003517
  • Liu, H., Dong, Y., Gao, Y., Du, Z., Wang, Y., Cheng, P., Chen, A., & Huang, H. (2016). The Fascinating Effects Of Baicalein On Cancer: A Review. International Journal Of Molecular Sciences, 17(10), 1681. Https://Doi.Org/10.3390/İjms17101681
  • Mohammed, F. S., Günal, S., Pehlivan, M., Doğan, M., Sevindik, M. & Akgül, H. (2020). Phenolic Content, Antioxidant and Antimicrobial Potential of Endemic Ferulago platycarpa. Gazi University Journal of Science, 33 (4), 670-677. DOI: 10.35378/gujs.707555
  • Pan, H., Hu, Q., Wang, J., Liu, Z., Wu, D., Lu, W., & Huang, J. (2016). Myricetin is a novel inhibitor of human inosine 5'-monophosphate dehydrogenase with anti-leukemia activity. Biochemical and biophysical research communications, 477(4), 915–922. https://doi.org/10.1016/j.bbrc.2016.06.158
  • Pichler, C., Ferk, F., Al-Serori, H., Huber, W., Jäger, W., Waldherr, M., Mišík, M., Kundi, M., Nersesyan, A., Herbacek, I., & Knasmueller, S. (2017). Xanthohumol Prevents DNA Damage by Dietary Carcinogens: Results of a Human Intervention Trial. Cancer prevention research (Philadelphia, Pa.), 10(2), 153–160. https://doi.org/10.1158/1940-6207.CAPR-15-0378
  • Rock, C. L., Thomson, C., Gansler, T., Gapstur, S. M., McCullough, M. L., Patel, A. V., Andrews, K. S., Bandera, E. V., Spees, C. K., Robien, K., Hartman, S., Sullivan, K., Grant, B. L., Hamilton, K. K., Kushi, L. H., Caan, B. J., Kibbe, D., Black, J. D., Wiedt, T. L., McMahon, C., … Doyle, C. (2020). American Cancer Society guideline for diet and physical activity for cancer prevention. CA: a cancer journal for clinicians, 70(4), 245–271. https://doi.org/10.3322/caac.21591
  • Samavat, H., Ursin, G., Emory, T. H., Lee, E., Wang, R., Torkelson, C. J., Dostal, A. M., Swenson, K., Le, C. T., Yang, C. S., Yu, M. C., Yee, D., Wu, A. H., Yuan, J. M., & Kurzer, M. S. (2017). A Randomized Controlled Trial of Green Tea Extract Supplementation and Mammographic Density in Postmenopausal Women at Increased Risk of Breast Cancer. Cancer prevention research (Philadelphia, Pa.), 10(12), 710–718. https://doi.org/10.1158/1940-6207.CAPR-17-0187
  • Suna, G., & Ayaz, A. (2019). Turunçgil Flavonoidlerinin Kardiyovasküler Sağlık Üzerine Etkileri. Beslenme ve Diyet Dergisi, 47(2), 99-107. Https://Doi.Org/10.33076/2019.Bdd.511
  • Tahir, M. S., Almezgagi, M., Zhang, Y., Bashir, A., Abdullah, H. M., Gamah, M., Wang, X., Zhu, Q., Shen, X., Ma, Q., Ali, M., Solangi, Z. A., Malik, W. S., & Zhang, W. (2021). Mechanistic new insights of flavonols on neurodegenerative diseases. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 137, 111253. https://doi.org/10.1016/j.biopha.2021.111253
  • Torricelli, P., Elia, A. C., Magara, G., Feriotto, G., Forni, C., Borromeo, I., De Martino, A., Tabolacci, C., Mischiati, C., & Beninati, S. (2021). Reduction Of Oxidative Stress And Ornithine Decarboxylase Expression İn A Human Prostate Cancer Cell Line Pc-3 By A Combined Treatment With Α-Tocopherol And Naringenin. Amino Acids, 53(1), 63–72. Https://Doi.Org/10.1007/S00726-020-02925-1
  • Wallace, T. C., & Giusti, M. M. (2015). Anthocyanins. Advances in nutrition (Bethesda, Md.), 6(5), 620–622. https://doi.org/10.3945/an.115.009233
  • World Health Organization (WHO). Factsheed: Cancer. (2022). Erişim: 01.06.2022 https://www.who.int/health-topics/cancer#tab=tab_1
  • Yu, J., Bi, X., Yu, B., & Chen, D. (2016). Isoflavones: Anti-Inflammatory Benefit And Possible Caveats. Nutrients, 8(6), 361. Https://Doi.Org/10.3390/Nu8060361
  • Yuvaraj, S., Ramprasath, T., Saravanan, B., Vasudevan, V., Sasikumar, S., & Selvam, G. S. (2021). Chrysin attenuates high-fat-diet-induced myocardial oxidative stress via upregulating eNOS and Nrf2 target genes in rats. Molecular and cellular biochemistry, 476(7), 2719–2727. https://doi.org/10.1007/s11010-021-04105-5
  • Zakaryan, H., Arabyan, E., Oo, A., & Zandi, K. (2017). Flavonoids: promising natural compounds against viral infections. Archives of virology, 162(9), 2539–2551. https://doi.org/10.1007/s00705-017-3417-y
  • Zhang, F. F., Haslam, D. E., Terry, M. B., Knight, J. A., Andrulis, I. L., Daly, M. B., Buys, S. . S., & John, E. M. (2017). Dietary isoflavone intake and all-cause mortality in breast cancer survivors: The Breast Cancer Family Registry. Cancer, 123(11), 2070–2079.
  • Zhao, H., Wu, L., Yan, G. et al. (2021). Inflammation and tumor progression: signaling pathways and targeted intervention. Sig Transduct Target Ther 6, 263 https://doi.org/10.1038/s41392-021-00658-5
There are 32 citations in total.

Details

Primary Language Turkish
Subjects Health Care Administration
Journal Section Derlemeler
Authors

Fatmanur Şirin Şengün 0000-0001-8608-0061

Aliye Özenoğlu 0000-0003-3101-7342

Project Number Herhangi bir projeden türetilmemiştir.
Publication Date December 27, 2022
Submission Date August 18, 2022
Published in Issue Year 2023

Cite

APA Şengün, F. Ş., & Özenoğlu, A. (2022). Flavonoidlerin Kanser Gelişimi ve Seyri Üzerine Etkileri. Avrasya Sağlık Bilimleri Dergisi, 6(1), 57-65. https://doi.org/10.53493/avrasyasbd.1164133
AMA Şengün FŞ, Özenoğlu A. Flavonoidlerin Kanser Gelişimi ve Seyri Üzerine Etkileri. AvrasyaSBD. December 2022;6(1):57-65. doi:10.53493/avrasyasbd.1164133
Chicago Şengün, Fatmanur Şirin, and Aliye Özenoğlu. “Flavonoidlerin Kanser Gelişimi Ve Seyri Üzerine Etkileri”. Avrasya Sağlık Bilimleri Dergisi 6, no. 1 (December 2022): 57-65. https://doi.org/10.53493/avrasyasbd.1164133.
EndNote Şengün FŞ, Özenoğlu A (December 1, 2022) Flavonoidlerin Kanser Gelişimi ve Seyri Üzerine Etkileri. Avrasya Sağlık Bilimleri Dergisi 6 1 57–65.
IEEE F. Ş. Şengün and A. Özenoğlu, “Flavonoidlerin Kanser Gelişimi ve Seyri Üzerine Etkileri”, AvrasyaSBD, vol. 6, no. 1, pp. 57–65, 2022, doi: 10.53493/avrasyasbd.1164133.
ISNAD Şengün, Fatmanur Şirin - Özenoğlu, Aliye. “Flavonoidlerin Kanser Gelişimi Ve Seyri Üzerine Etkileri”. Avrasya Sağlık Bilimleri Dergisi 6/1 (December 2022), 57-65. https://doi.org/10.53493/avrasyasbd.1164133.
JAMA Şengün FŞ, Özenoğlu A. Flavonoidlerin Kanser Gelişimi ve Seyri Üzerine Etkileri. AvrasyaSBD. 2022;6:57–65.
MLA Şengün, Fatmanur Şirin and Aliye Özenoğlu. “Flavonoidlerin Kanser Gelişimi Ve Seyri Üzerine Etkileri”. Avrasya Sağlık Bilimleri Dergisi, vol. 6, no. 1, 2022, pp. 57-65, doi:10.53493/avrasyasbd.1164133.
Vancouver Şengün FŞ, Özenoğlu A. Flavonoidlerin Kanser Gelişimi ve Seyri Üzerine Etkileri. AvrasyaSBD. 2022;6(1):57-65.