Research Article
BibTex RIS Cite

Effect of Homalothecium philippeanum (Spruce) Schimp. (Bryophyta) extract on Acetylcholinesterase enzyme activity

Year 2024, Volume: 14 Issue: 3, 587 - 593, 30.09.2024
https://doi.org/10.31020/mutftd.1479130

Abstract

Objective: Alzheimer's disease is the most common neurological disorder, affecting approximately 50 million people. According to the cholinergic hypothesis, the decrease in the concentration of acetylcholine, which is responsible for nerve conduction, is associated with the disease. It is known that inhibition of the acetylcholineesterase enzyme, which metabolizes acetylcholine, leads to improvement in the course of the disease. Therefore, the present study aims to investigate the acetylcholinesterase enzyme inhibition effect of the extract of Homalothecium philippeanum (Spruce) Schimp., a moss species characterised for the first time.
Methods: Homalothecium philippeanum (Spruce) Schimp. extract was obtained by supercritical fluid (CO2) extraction method at 180 bar pressure, 50 °C temperature and using 5% (v/v) ethanol as cosolvent on the Superex F-500 (Turkey) device. GK/KS analysis was performed using a wax column on the Schimadzu GCMS-QP 2020 system (RESTEK Rtx-Wax column, 30m x 0.25mm x 0.25 µm film thickness). To determine the acetylcholinesterase enzyme inhibition effect of low, medium and high doses of the extract, the spectrophotometric method created by Ellman et al. (1961) was applied with minor modifications.
Results: It has been determined that Homalothecium philippeanum (Spruce) Schimp. extract shows low level anti-Alzheimer activity.
Conclusion: In the light of the data obtained, it was determined that Homalothecium philippeanum (Spruce) Schimp. showed a low level of anti-Alzheimer effect, and in order to fully understand the effect in question and to transform turn it into a commercial product, further research is required to identify and isolate the active ingredient.

References

  • 1. Emwas AH, et al. Living with the enemy: From protein-misfolding pathologies we know, to those we want to know. Ageing Res Rev 2021;70:101391–101408.
  • 2. Barthelemy NR, et al. A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease. Nat Med 2020;26:398–407.
  • 3. Mattson MP. Pathways towards and away from Alzheimer's disease. Nature 2004;430(7000):631–639.
  • 4. Shah H, et al. The β-Secretase enzyme BACE1: a biochemical enigma for Alzheimer’s disease. CNS Neurol Disord Drug Targets 2020;19:184–194.
  • 5. Wang R, Reddy PH. Role of Glutamate and NMDA receptors in Alzheimer’s disease. J Alzheimer’s Dis 2017;57:1041–1048.
  • 6. Terry AV, Buccafusco JJ. The cholinergic hypothesis of age and Alzheimer’s disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther 2003;306:821–827.
  • 7. Rajasekhar K, Govindaraju T. Current progress, challenges and future prospects of diagnostic and therapeutic interventions in AD. RSC Adv 2018;8:23780–23804.
  • 8. Ding MR, et al. Signal pathways in the treatment of Alzheimer’s disease with traditional Chinese medicine. Biomed Pharmacother 2022;152:113208.
  • 9. Noetzli M, Eap CB. Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer’s disease. Clin Pharmacokinet 2013;52: 225–241.
  • 10. Wang S, et al. Role of natural compounds and target enzymes in the treatment of Alzheimer’s disease. Molecules 2022;27:4175.
  • 11. da Rosa MM, et al. The promising role of natural products in Alzheimer’s disease. Brain Disord 2022;7:100049–100062.
  • 12. Dhahri M, et al. Extraction, characterization, and anticoagulant activity of a sulfated polysaccharide from Bursatellaleachii viscera. Acs Omega 2020;5:14786–14795.
  • 13. Thakral S, et al. Alzheimer's disease: Molecular aspects and treatment opportunities using herbal drugs. Ageing research reviews 2023;88:101960.
  • 14. Glime JM. Medical uses: medical conditions. Chapt. 2-1. In: Glime, J. M. Bryophyte Ecology 5. 2017. Uses. Ebook accessed (give date) at <https://digitalcommons.mtu.edu>.
  • 15. Goffinet B, Shaw AJ. Bryophyte Biology, Second Edition, Cambridge, UK: Cambridge University Press, The Edinburgh Building. 2009.
  • 16. Delwiche CF, Cooper ED. The Evolutionary Origin of a Terrestrial Flora. Current Biology. 2015;25:899–910.
  • 17. Xie CF, Lou HX. Secondary Metabolites in Bryophytes: An Ecological Aspect. Chemistry & Biodiversity. 2009;6:303-312.
  • 18. Chandra S, et al. Bryophytes: Hoard of remedies, an ethnomedicinal review. Journal of Traditional and Complementary Medicine. 2017;7(1):94-98.
  • 19. Asakawa Y. Chemosystematics of the Hepaticae. Phytochemistry. 2004;65(6):623-669.
  • 20. Motti R, Palma AD, de Falco B. Bryophytes Used in Folk Medicine: An Ethnobotanical Overview. Horticulturae 2023;9:137.
  • 21. Asakawa Y. Pharmacologically active substances from oriental bryophytes and inedible mushrooms and fijian kava. In: World Conference on Medicinal and Aromatic Plants Book of Abstracts (Vol. 86). 2001.
  • 22. Zhang J, et al. Marsupellins A–F, ent-longipinane-type sesquiterpenoids from the Chinese liverwort Marsupella alpina with acetylcholinesterase inhibitory activity. J. Nat. Prod. 2014;77(4):1031-1036.
  • 23. Ya-Qi KANG, et al. Scapaundulin C, a novel labdane diterpenoid isolated from Chinese liverwort Scapania undulata, inhibits acetylcholinesterase activity. Chin J. Nat. Med. 2015;13(12):933-936.
  • 24. Wang X, et al. Flavonoids, antioxidant potential, and acetylcholinesterase inhibition activity of the extracts from the gametophyte and archegoniophore of Marchantia polymorpha L. Molecules 2016;21(3):360.
  • 25. Smith AJE. The moss flora of Britain and Ireland, Cambridge (GB): Cambridge University Press. 2004.
  • 26. Cortini Pedrotti C. Flora dei muschi d’Italia, Bryopsida (II parte). Roma: Antonia Delfino Editore. ISBN: 88-7287-370-3, Antonio Delfino Editore Medicina-Scienze. 2006. pp. 817-1235.
  • 27. Ellman GL, et al. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical Pharmacology 1961;7:88-95.
  • 28. Ceylan B, Dayan S, Duğan E. Investigation of anti-Alzheimer and anti-Diabetic activity of callus culture of Bellevalia edirnensis Özhatay & Mathew: An endemic plant from Turkey. Kırklareli Üniversitesi Mühendislik ve Fen Bilimleri Dergisi 2023;9(2):281-288.
  • 29. Digala L, Murala S, Bollu PC. Acetylcholine. In P. C. Bollu (Ed.), Neurochemistry in clinical practice. 2022 (pp.211–237). Springer International Publishing.
  • 30. Baux G, Fossier P. La libération d'acétylcholine et sa régulation. Archives Internationales de Physiologie, de Biochimie et de Biophysique 1992;100(4):A3–A15.
  • 31. Barnard EA. Neuromuscular transmission—Enzymatic destruction of acetylcholine. In J. I. Hubbard (Ed.), The peripheral nervous system. 1974 (pp. 201–224). Springer US.
  • 32. Rajasekhar K, Govindaraju T. Current progress, challenges and future prospects of diagnostic and therapeutic interventions in AD. RSC Adv 2018;8:23780–23804.
  • 33. Ding MR, et al. Signal pathways in the treatment of Alzheimer’s disease with traditional Chinese medicine. Biomed Pharmacother 2022;152:113208.
  • 34. Noetzli M, Eap CB. Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer’s disease. Clin Pharmacokinet 2013;52:225–241.
  • 35. Badshah SL, et al. Isolation, characterization, and medicinal potential of polysaccharides of Morchella esculenta. Molecules 2021;26:1459.
  • 36. da Rosa MM, et al. The promising role of natural products in Alzheimer’s disease. Brain Disord 2022;7:100049–100062.
  • 37. Dhahri M, et al. Extraction, characterization, and anticoagulant activity of a sulfated polysaccharide from Bursatellaleachii viscera. Acs Omega 2020;5:14786–14795.
  • 38. Jeyasri R, et al. Bacopa monnieri and their bioactive compounds inferred multi-target treatment strategy for neurological diseases: a cheminformatics and system pharmacology approach. Biomolecules 2020;10:536.
  • 39. Kuboyama T, Tohda C, Komatsu K. Neuritic regeneration and synaptic reconstruction induced by withanolide A. Br J Pharm 2005;144:961–971.
  • 40. Ghadrdoost B, et al. Protective effects of saffron extract and its active constituent crocin against oxidative stress and spatial learning and memory deficits induced by chronic stress in rats. Eur J Pharm 2011;667:222–229.
  • 41. Vidal B, et al. Curcuma treatment prevents cognitive deficit and alteration of neuronal morphology in the limbic system of aging rats. Synapse 2017;71:e21952.
  • 42. Chaudhari KS, et al. Neurocognitive effect of nootropic drug Brahmi (Bacopa monnieri) in Alzheimer’s disease. Ann Neurosci 2017;24:111–122.
  • 43. Mahaman YAR, et al. Moringa oleifera alleviates homocysteineinduced Alzheimer’s disease-like pathology and cognitive impairments. J Alzheimer’s Dis 2018;63:1141–1159.

Homalothecium philippeanum (Spruce) Schimp. (Bryophyta) ekstresinin Asetilkolinesteraz enzim aktivitesine etkisi

Year 2024, Volume: 14 Issue: 3, 587 - 593, 30.09.2024
https://doi.org/10.31020/mutftd.1479130

Abstract

Amaç: Alzheimer hastalığı yaklaşık 50 milyon insanı etkileyen ve en sık görülen nörolojik bozukluktur. Kolinerjik hipoteze göre sinir iletiminden sorumlu asetilkolin konsantrasyonunun azalması hastalıkla ilişkilendirilmektedir. Asetilkolini metabolize eden asetilkolinesteraz enziminin inhibisyonunun hastalık seyrinde düzelmeye yol açtığı bilinmektedir. Bu nedenle bu çalışma, ilk kez karakterizasyonunu yapılan kara yosunu türü Homalothecium philippeanum (Spruce) Schimp. ekstresinin asetilkolinesteraz enzim inhibisyon etkisini araştırmayı amaçlamaktadır.
Yöntem: Homalothecium philippeanum (Spruce) Schimp. ekstresi süperkritik akışkan (CO2) ekstraksiyon yöntemiyle 180 bar basınç, 50 °C sıcaklıkta ve kosolvent olarak %5 (v/v) etanol kullanılarak Superex F-500 (Türkiye) cihazında elde edilmiş olup GK/KS analizi Schimadzu GCMS-QP 2020 sisteminde wax kolon kullanılarak yapılmıştır (RESTEK Rtx-Wax kolon, 30m x 0,25mm x 0,25 µm film kalınlığı). Ekstrenin düşük, orta ve yüksek dozlarının asetilkolinesteraz enzim inhibisyon etkisini belirlemek için Ellman ve ark. (1961) tarafından oluşturulan spektrofotometrik yöntem küçük modifikasyonlarla değiştirilerek uygulanmıştır.
Bulgular: Homalothecium philippeanum (Spruce) Schimp. ekstraktının düşük düzeyde anti-Alzheimer aktivite gösterdiği tespit edilmiştir.
Sonuç: Elde edilen veriler ışığında Homalothecium philippeanum (Spruce) Schimp.’in düşük düzeyde anti-Alzheimer etki gösterdiği saptanmış olup söz konusu etkinin tam olarak anlaşılması ve ticari ürün haline dönüştürülebilmesi için daha ileri araştırmalarla etken madde tespiti ve izolasyonunun yapılması gerekmektedir.
Anahtar kelimeler: Süperkritik akışkan ekstraksiyonu, Alzheimer, Asetilkolinesteraz

References

  • 1. Emwas AH, et al. Living with the enemy: From protein-misfolding pathologies we know, to those we want to know. Ageing Res Rev 2021;70:101391–101408.
  • 2. Barthelemy NR, et al. A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease. Nat Med 2020;26:398–407.
  • 3. Mattson MP. Pathways towards and away from Alzheimer's disease. Nature 2004;430(7000):631–639.
  • 4. Shah H, et al. The β-Secretase enzyme BACE1: a biochemical enigma for Alzheimer’s disease. CNS Neurol Disord Drug Targets 2020;19:184–194.
  • 5. Wang R, Reddy PH. Role of Glutamate and NMDA receptors in Alzheimer’s disease. J Alzheimer’s Dis 2017;57:1041–1048.
  • 6. Terry AV, Buccafusco JJ. The cholinergic hypothesis of age and Alzheimer’s disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther 2003;306:821–827.
  • 7. Rajasekhar K, Govindaraju T. Current progress, challenges and future prospects of diagnostic and therapeutic interventions in AD. RSC Adv 2018;8:23780–23804.
  • 8. Ding MR, et al. Signal pathways in the treatment of Alzheimer’s disease with traditional Chinese medicine. Biomed Pharmacother 2022;152:113208.
  • 9. Noetzli M, Eap CB. Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer’s disease. Clin Pharmacokinet 2013;52: 225–241.
  • 10. Wang S, et al. Role of natural compounds and target enzymes in the treatment of Alzheimer’s disease. Molecules 2022;27:4175.
  • 11. da Rosa MM, et al. The promising role of natural products in Alzheimer’s disease. Brain Disord 2022;7:100049–100062.
  • 12. Dhahri M, et al. Extraction, characterization, and anticoagulant activity of a sulfated polysaccharide from Bursatellaleachii viscera. Acs Omega 2020;5:14786–14795.
  • 13. Thakral S, et al. Alzheimer's disease: Molecular aspects and treatment opportunities using herbal drugs. Ageing research reviews 2023;88:101960.
  • 14. Glime JM. Medical uses: medical conditions. Chapt. 2-1. In: Glime, J. M. Bryophyte Ecology 5. 2017. Uses. Ebook accessed (give date) at <https://digitalcommons.mtu.edu>.
  • 15. Goffinet B, Shaw AJ. Bryophyte Biology, Second Edition, Cambridge, UK: Cambridge University Press, The Edinburgh Building. 2009.
  • 16. Delwiche CF, Cooper ED. The Evolutionary Origin of a Terrestrial Flora. Current Biology. 2015;25:899–910.
  • 17. Xie CF, Lou HX. Secondary Metabolites in Bryophytes: An Ecological Aspect. Chemistry & Biodiversity. 2009;6:303-312.
  • 18. Chandra S, et al. Bryophytes: Hoard of remedies, an ethnomedicinal review. Journal of Traditional and Complementary Medicine. 2017;7(1):94-98.
  • 19. Asakawa Y. Chemosystematics of the Hepaticae. Phytochemistry. 2004;65(6):623-669.
  • 20. Motti R, Palma AD, de Falco B. Bryophytes Used in Folk Medicine: An Ethnobotanical Overview. Horticulturae 2023;9:137.
  • 21. Asakawa Y. Pharmacologically active substances from oriental bryophytes and inedible mushrooms and fijian kava. In: World Conference on Medicinal and Aromatic Plants Book of Abstracts (Vol. 86). 2001.
  • 22. Zhang J, et al. Marsupellins A–F, ent-longipinane-type sesquiterpenoids from the Chinese liverwort Marsupella alpina with acetylcholinesterase inhibitory activity. J. Nat. Prod. 2014;77(4):1031-1036.
  • 23. Ya-Qi KANG, et al. Scapaundulin C, a novel labdane diterpenoid isolated from Chinese liverwort Scapania undulata, inhibits acetylcholinesterase activity. Chin J. Nat. Med. 2015;13(12):933-936.
  • 24. Wang X, et al. Flavonoids, antioxidant potential, and acetylcholinesterase inhibition activity of the extracts from the gametophyte and archegoniophore of Marchantia polymorpha L. Molecules 2016;21(3):360.
  • 25. Smith AJE. The moss flora of Britain and Ireland, Cambridge (GB): Cambridge University Press. 2004.
  • 26. Cortini Pedrotti C. Flora dei muschi d’Italia, Bryopsida (II parte). Roma: Antonia Delfino Editore. ISBN: 88-7287-370-3, Antonio Delfino Editore Medicina-Scienze. 2006. pp. 817-1235.
  • 27. Ellman GL, et al. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical Pharmacology 1961;7:88-95.
  • 28. Ceylan B, Dayan S, Duğan E. Investigation of anti-Alzheimer and anti-Diabetic activity of callus culture of Bellevalia edirnensis Özhatay & Mathew: An endemic plant from Turkey. Kırklareli Üniversitesi Mühendislik ve Fen Bilimleri Dergisi 2023;9(2):281-288.
  • 29. Digala L, Murala S, Bollu PC. Acetylcholine. In P. C. Bollu (Ed.), Neurochemistry in clinical practice. 2022 (pp.211–237). Springer International Publishing.
  • 30. Baux G, Fossier P. La libération d'acétylcholine et sa régulation. Archives Internationales de Physiologie, de Biochimie et de Biophysique 1992;100(4):A3–A15.
  • 31. Barnard EA. Neuromuscular transmission—Enzymatic destruction of acetylcholine. In J. I. Hubbard (Ed.), The peripheral nervous system. 1974 (pp. 201–224). Springer US.
  • 32. Rajasekhar K, Govindaraju T. Current progress, challenges and future prospects of diagnostic and therapeutic interventions in AD. RSC Adv 2018;8:23780–23804.
  • 33. Ding MR, et al. Signal pathways in the treatment of Alzheimer’s disease with traditional Chinese medicine. Biomed Pharmacother 2022;152:113208.
  • 34. Noetzli M, Eap CB. Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer’s disease. Clin Pharmacokinet 2013;52:225–241.
  • 35. Badshah SL, et al. Isolation, characterization, and medicinal potential of polysaccharides of Morchella esculenta. Molecules 2021;26:1459.
  • 36. da Rosa MM, et al. The promising role of natural products in Alzheimer’s disease. Brain Disord 2022;7:100049–100062.
  • 37. Dhahri M, et al. Extraction, characterization, and anticoagulant activity of a sulfated polysaccharide from Bursatellaleachii viscera. Acs Omega 2020;5:14786–14795.
  • 38. Jeyasri R, et al. Bacopa monnieri and their bioactive compounds inferred multi-target treatment strategy for neurological diseases: a cheminformatics and system pharmacology approach. Biomolecules 2020;10:536.
  • 39. Kuboyama T, Tohda C, Komatsu K. Neuritic regeneration and synaptic reconstruction induced by withanolide A. Br J Pharm 2005;144:961–971.
  • 40. Ghadrdoost B, et al. Protective effects of saffron extract and its active constituent crocin against oxidative stress and spatial learning and memory deficits induced by chronic stress in rats. Eur J Pharm 2011;667:222–229.
  • 41. Vidal B, et al. Curcuma treatment prevents cognitive deficit and alteration of neuronal morphology in the limbic system of aging rats. Synapse 2017;71:e21952.
  • 42. Chaudhari KS, et al. Neurocognitive effect of nootropic drug Brahmi (Bacopa monnieri) in Alzheimer’s disease. Ann Neurosci 2017;24:111–122.
  • 43. Mahaman YAR, et al. Moringa oleifera alleviates homocysteineinduced Alzheimer’s disease-like pathology and cognitive impairments. J Alzheimer’s Dis 2018;63:1141–1159.
There are 43 citations in total.

Details

Primary Language Turkish
Subjects Traditional Chinese Medicine and Treatments
Journal Section Research Article
Authors

Ulaş Değirmenci 0000-0001-5208-6430

Tülay Ezer 0000-0002-6485-5505

Publication Date September 30, 2024
Submission Date May 6, 2024
Acceptance Date August 2, 2024
Published in Issue Year 2024 Volume: 14 Issue: 3

Cite

APA Değirmenci, U., & Ezer, T. (2024). Homalothecium philippeanum (Spruce) Schimp. (Bryophyta) ekstresinin Asetilkolinesteraz enzim aktivitesine etkisi. Mersin Üniversitesi Tıp Fakültesi Lokman Hekim Tıp Tarihi Ve Folklorik Tıp Dergisi, 14(3), 587-593. https://doi.org/10.31020/mutftd.1479130
AMA Değirmenci U, Ezer T. Homalothecium philippeanum (Spruce) Schimp. (Bryophyta) ekstresinin Asetilkolinesteraz enzim aktivitesine etkisi. Mersin Üniversitesi Tıp Fakültesi Lokman Hekim Tıp Tarihi ve Folklorik Tıp Dergisi. September 2024;14(3):587-593. doi:10.31020/mutftd.1479130
Chicago Değirmenci, Ulaş, and Tülay Ezer. “Homalothecium Philippeanum (Spruce) Schimp. (Bryophyta) Ekstresinin Asetilkolinesteraz Enzim Aktivitesine Etkisi”. Mersin Üniversitesi Tıp Fakültesi Lokman Hekim Tıp Tarihi Ve Folklorik Tıp Dergisi 14, no. 3 (September 2024): 587-93. https://doi.org/10.31020/mutftd.1479130.
EndNote Değirmenci U, Ezer T (September 1, 2024) Homalothecium philippeanum (Spruce) Schimp. (Bryophyta) ekstresinin Asetilkolinesteraz enzim aktivitesine etkisi. Mersin Üniversitesi Tıp Fakültesi Lokman Hekim Tıp Tarihi ve Folklorik Tıp Dergisi 14 3 587–593.
IEEE U. Değirmenci and T. Ezer, “Homalothecium philippeanum (Spruce) Schimp. (Bryophyta) ekstresinin Asetilkolinesteraz enzim aktivitesine etkisi”, Mersin Üniversitesi Tıp Fakültesi Lokman Hekim Tıp Tarihi ve Folklorik Tıp Dergisi, vol. 14, no. 3, pp. 587–593, 2024, doi: 10.31020/mutftd.1479130.
ISNAD Değirmenci, Ulaş - Ezer, Tülay. “Homalothecium Philippeanum (Spruce) Schimp. (Bryophyta) Ekstresinin Asetilkolinesteraz Enzim Aktivitesine Etkisi”. Mersin Üniversitesi Tıp Fakültesi Lokman Hekim Tıp Tarihi ve Folklorik Tıp Dergisi 14/3 (September 2024), 587-593. https://doi.org/10.31020/mutftd.1479130.
JAMA Değirmenci U, Ezer T. Homalothecium philippeanum (Spruce) Schimp. (Bryophyta) ekstresinin Asetilkolinesteraz enzim aktivitesine etkisi. Mersin Üniversitesi Tıp Fakültesi Lokman Hekim Tıp Tarihi ve Folklorik Tıp Dergisi. 2024;14:587–593.
MLA Değirmenci, Ulaş and Tülay Ezer. “Homalothecium Philippeanum (Spruce) Schimp. (Bryophyta) Ekstresinin Asetilkolinesteraz Enzim Aktivitesine Etkisi”. Mersin Üniversitesi Tıp Fakültesi Lokman Hekim Tıp Tarihi Ve Folklorik Tıp Dergisi, vol. 14, no. 3, 2024, pp. 587-93, doi:10.31020/mutftd.1479130.
Vancouver Değirmenci U, Ezer T. Homalothecium philippeanum (Spruce) Schimp. (Bryophyta) ekstresinin Asetilkolinesteraz enzim aktivitesine etkisi. Mersin Üniversitesi Tıp Fakültesi Lokman Hekim Tıp Tarihi ve Folklorik Tıp Dergisi. 2024;14(3):587-93.

                                                                                                                                  Creative Commons Lisansı                        
                                                                  This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

  

                                    Periodical scientific publication of Mersin University School of Medicine. Can not be cited without referenceResponsibility of the articles belong to the authors

  Cover

Ayşegül Tuğuz

from composition of İlter Uzel named Dioscorides and his Student

Address

Mersin Üniversitesi Tıp Fakültesi Tıp Tarihi ve Etik Anabilim Dalı Çiftlikköy Kampüsü

Yenişehir / Mersin