Araştırma Makalesi
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Yıl 2024, Cilt: 42 Sayı: 1, 198 - 210, 27.02.2024

Öz

Kaynakça

  • REFERENCES [1] World Health Organization. Accelerating work to overcome the global impact of neglected tropical diseases: A roadmap for implementation: Executive summary. 2012.‎ Available at: https://apps.who.int/iris/handle/10665/70809. Accessed Feb 7, 2024.
  • [2] Giray H, Keskinoğlu P. The prevalence of Enterobius vermicularis in schoolchildren and affecting factors. Turkiye Parazitol Derg 2006;30:99102. [Turkish]
  • [3] Strelkauskas A, Edwards A, Fahnert B, Pryor G, Strelkauskas J. Microbiology: A clinical approach. 2nd ed. New York: Garland Science; 2015. [CrossRef]
  • [4] Jacoby RO, Lindsey JR. Risks of infection among laboratory rats and mice at major biomedical research institutions. ILAR J 1998;39:266271. [CrossRef]
  • [5] Carty AJ. Opportunistic infections of mice and rats: Jacoby and Lindsey revisited. ILAR J 2008;49:272276. [CrossRef]
  • [6] Hedrich HJ. The laboratory mouse. 2nd ed. London, UK: Academic Press, Elsevier; 2012.
  • [7] Mueller JF. Parasites of Laboratory Animals Robert J. Flynn. J Parasitol 1973;59:835. [CrossRef]
  • [8] Willcox M, Bodeker G, Geneviève B, Dhingra V, Falquet J, Ferreira JFS, et al. (2004) Artemisia annua as a traditional herbal antimalarial. In: Willcox M, Bodeker G, Rasaoanaivo P, editors. Traditional Medicine, Medicinal Plants and Malaria. Boca Raton: CRC Press; 2004[CrossRef]
  • [9] Bora KS, Sharma A. The genus Artemisia: A comprehensive review. Pharm Biol 2011;49:101–109. [CrossRef]
  • [10] van der Kooy F, Sullivan SE. The complexity of medicinal plants: The traditional Artemisia annua formulation, current status and future perspectives. J Ethnopharmacol 2013;150:1–13. [CrossRef]
  • [11] Zheng GQ. Cytotoxic terpenoids and flavonoids from Artemisia annua. Planta Med 1994;60:54–57. [CrossRef]
  • [12] Abad MJ, Bedoya LM, Apaza L, Bermejo P. The artemisia L. Genus: A review of bioactive essential oils. Molecules 2012;17:2542–2566. [CrossRef]
  • [13] Wang D, Cui L, Chang X, Guan D. Biosynthesis and characterization of zinc oxide nanoparticles from Artemisia annua and investigate their effect on proliferation, osteogenic differentiation and mineralization in human osteoblast-like MG-63 Cells. J Photochem Photobiol B 2020;202:111652. [CrossRef]
  • [14] Lubbe A, Seibert I, Klimkait T, van der Kooy F. Ethnopharmacology in overdrive: The remarkable anti-HIV activity of Artemisia annua. J Ethnopharmacol 2012;141:854–859. [CrossRef]
  • [15] Juteau F, Masotti V, Bessière JM, Dherbomez M, Viano J. Antibacterial and antioxidant activities of Artemisia annua essential oil. Fitoterapia 2002;73:532–535. [CrossRef]
  • [16] Pirali-Kheirabadi Kh, Teixeira da Silva J. In-vitro assessment of the acaricidal properties of artemisia annua and zataria multiflora essential oils to control cattle ticks. Iran J Parasitol 2011;6:58–65.
  • [17] Nair MS, Huang Y, Fidock DA, Polyak SJ, Wagoner J, Towler MJ, et al. Artemisia annua L. extracts inhibit the in vitro replication of SARS-CoV-2 and two of its variants. J Ethnopharmacol 2021;274:114016. [CrossRef]
  • [18] Faurant C. From bark to weed: The history of artemisinin. Parasite 2011;18:215–218. [CrossRef]
  • [19] Shukla KL, Gund TM, Meshnick SR. Molecular modeling studies of the artemisinin (qinghaosu)-hemin interaction: Docking between the antimalarial agent and its putative receptor. J Mol Graph 1995;13:215–222. [CrossRef]
  • [20] Cheng F, Shen J, Luo X, Zhu W, Gu J, Ji R, et al. Molecular docking and 3-D-QSAR studies on the possible antimalarial mechanism of artemisinin analogues. Bioorg Med Chem 2002;10:2883–2891. [CrossRef]
  • [21] İbn-i Sina. El-kanun fi't-tıbb. (Çev. Kahya E.) Ankara: Atatürk Kültür, Dil ve Tarih Yüksek Kurumu Atatürk Kültür Merkezi; 2010.
  • [22] Cala AC, Ferreira JF, Chagas AC, Gonzalez JM, Rodrigues RA, Foglio MA, et al. Anthelmintic activity of Artemisia annua L. extracts in vitro and the effect of an aqueous extract and artemisinin in sheep naturally infected with gastrointestinal nematodes. Parasitol Res 2014;113:2345–2353. [CrossRef]
  • [23] National Library of Medicine. Friedelin. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/Friedelin. Accessed Feb 11, 2021.
  • [24] National Library of Medicine. Stigmasterol. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/Stigmasterol. Accessed Feb 11, 2021. [25] Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, et al. Automated docking using a Lamarckian genetic algorithm and empirical binding free energy function. J Comput Chem 1998;19:1639–1662. [CrossRef]
  • [26] Taylor CM, Wang Q, Rosa BA, Huang SC, Powell K, Schedl T, et al. Discovery of anthelmintic drug targets and drugs using chokepoints in nematode metabolic pathways. PLoS Pathog 2013;9:e1003505. [CrossRef]
  • [27] Huey R, Morris GM, Olson AJ, Goodsell DS. A semiempirical free energy force field with charge-based desolvation. J Comput Chem 2007;28:1145–1152. [CrossRef]
  • [28] Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 2009;30:2785–2791. [CrossRef]
  • [29] Dassault Systèmes. BIOVIA, Discovery Studio Modeling Environment, Release 2020, San Diego: Dssault Systèmes 2020. Available at: https://www.3ds.com/products-services/biovia/. Accessed Feb 8, 2024.
  • [30] Robinson MW, McFerran N, Trudgett A, Hoey L, Fairweather I. A possible model of benzimidazole binding to beta-tubulin disclosed by invoking an inter-domain movement. J Mol Graph Model 2004;23:275–284. [CrossRef]
  • [31] Hsiao YS, Jogl G, Esser V, Tong L. Crystal structure of rat carnitine palmitoyltransferase II (CPT-II). Biochem Biophys Res Commun 2006;346:974–980. [CrossRef]
  • [32] Sterling T, Irwin JJ. ZINC 15--ligand discovery for everyone. J Chem Inf Model 2015;55:2324–2337. [CrossRef]
  • [33] Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, et al. PubChem in 2021: New data content and improved web interfaces. Nucleic Acids Res 2021;49:D1388–D1395. [CrossRef]
  • [34] O'Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: An open chemical toolbox. J Cheminform 2011;3:33. [CrossRef]
  • [35] Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 2017;7:42717. [CrossRef]
  • [36] Satyendra RV, Vishnumurthy KA, Vagdevi HM, Rajesh KP, Manjunatha H, Shruthi A. Synthesis, in vitro antioxidant, anthelmintic and molecular docking studies of novel dichloro substituted benzoxazole-triazolo-thione derivatives. Eur J Med Chem 2011;46:3078–3084. [CrossRef]
  • [37] Salgueiro AC, Folmer V, da Rosa HS, Costa MT, Boligon AA, Paula FR, et al. In vitro and in silico antioxidant and toxicological activities of Achyrocline satureioides. J Ethnopharmacol 2016;194:6–14. [CrossRef]
  • [38] Gogoi S, Yadav AK. In vitro and in vivo anthelmintic effects of Caesalpinia bonducella (L.) Roxb. leaf extract on Hymenolepis diminuta (Cestoda) and Syphacia obvelata (Nematoda). J Intercult Ethnopharmacol 2016;5:427–433. [CrossRef]
  • [39] Kozan E, Çankaya IT, Kahraman C, Akkol EK, Akdemir Z. The in vivo anthelmintic efficacy of some Verbascum species growing in Turkey. Exp Parasitol 2011;129:211–214. [CrossRef]
  • [40] de Amorin A, Borba HR, Carauta JP, Lopes D, Kaplan MA. Anthelmintic activity of the latex of Ficus species. J Ethnopharmacol 1999;64:255–258. [CrossRef]
  • [41] Brisibe EA, Umoren UE, Brisibe F, Magalhäes PM, Ferreira JFS, Luthria D, et al. Nutritional characterisation and antioxidant capacity of different tissues of Artemisia annua L. Food Chem 2009;115:1240–1246. [CrossRef]
  • [42] Noack R. Energy and protein requirements. Report of a Joint FAO/WHO Ad Hoc Expert Committee. WHO Technical Report Series No. 522, 118 S., Genf 1973. Food/Nahrung 1973;18:329–332. [CrossRef]
  • [43] Bahorun T, Luximon-Ramma A, Crozier A, Aruoma OI. Total phenol, flavonoid, proanthocyanidin and vitamin C levels and antioxidant activities of Mauritian vegetables. J Sci Food Agric
  • 2004;84:1553–1561. [CrossRef]
  • [44] Chukwurah PN, Brisibe EA, Osuagwu AN, Okoko T. Protective capacity of Artemisia annua as a potent antioxidant remedy against free radical damage. Asian Pac J Trop Biomed 2014;4(Suppl 1):S92–98. [CrossRef]
  • [45] Keiser J, Veneziano V, Rinaldi L, Mezzino L, Duthaler U, Cringoli G. Anthelmintic activity of artesunate against Fasciola hepatica in naturally infected sheep. Res Vet Sci 2010;88:107–110. [CrossRef]
  • [46] Youn HJ, Noh JW. Screening of the anticoccidial effects of herb extracts against Eimeria tenella. Vet Parasitol 2001;96:257–263. [CrossRef]
  • [47] Vijayakumar BG, Ramesh D, Joji A, Jayachandra Prakasan J, Kannan T. In silico pharmacokinetic and molecular docking studies of natural flavonoids and synthetic indole chalcones against essential proteins of SARS-CoV-2. Eur J Pharmacol 2020;886:173448. [CrossRef]

Discovery of new herbal anthelmintics from Artemisia Annua L. via in silico molecular docking and in vivo extract application

Yıl 2024, Cilt: 42 Sayı: 1, 198 - 210, 27.02.2024

Öz

One of the most important factors limiting the growth and development of children is gastro-intestinal helminths. A conscious anthelmintic herbal cure is a rational approach to establish-ing a sustainable public health program in the treatment of oxyurid infections that are mostly seen in children, disrupt development, frequently recur and are asymptomatic. This study aims to investigate the molecular mechanisms of the anthelmintic features of Artemisia annua L. and to compare the antinematodal effect of A. annua L. n-hexane extract with Albendazole (ABZ) in naturally infected mice. For this purpose, A. annua L. n-hexane extract was extracted and orally administered to Balb-c mice infected with Syphacia obvelata oxyurid species at 300, 600, and 1200 mg/kg doses for seven days. Mice were examined for changes in S. obvelata egg numbers on days -7, -1, 1, 3, 5, and 7 by the anal tape method. As a reference drug, ABZ was administered at a dose of 5 mg/kg for three days, and as solvent control, corn oil was given in the same way and time as the extract. Some components of A. annua L. were investigated for possible chemical interactions and free energy of binding in Haemonchus contortus β-tubu-lin (Hcβ-tubulin) protein and rat Carnitine Palmitoyltransferase II (RnCPT II) enzyme by in silico docking simulations. Stigmasterol and friedelin inhibit the RnCPT II enzyme in silico
with 9.43 nM and 13.07 nM Ki values, respectively, while not binding to Hcβ-tubulin. Arte-annuin-B and scopoletin inhibited both RnCPT II and Hcβ-tubulin. A. annua L. n-hexane extract at 1200 mg/kg dose reduced oxyurid eggs by 88% on the 7th day. ABZ caused a 65.58% reduction. As the result, arteannuin-B, scopoletin, stigmasterol and friedelin are worthy of isolation and investigation in vitro and in vivo in terms of their anthelmintic effect. They can be evaluated as potential anthelmintic molecules.

Kaynakça

  • REFERENCES [1] World Health Organization. Accelerating work to overcome the global impact of neglected tropical diseases: A roadmap for implementation: Executive summary. 2012.‎ Available at: https://apps.who.int/iris/handle/10665/70809. Accessed Feb 7, 2024.
  • [2] Giray H, Keskinoğlu P. The prevalence of Enterobius vermicularis in schoolchildren and affecting factors. Turkiye Parazitol Derg 2006;30:99102. [Turkish]
  • [3] Strelkauskas A, Edwards A, Fahnert B, Pryor G, Strelkauskas J. Microbiology: A clinical approach. 2nd ed. New York: Garland Science; 2015. [CrossRef]
  • [4] Jacoby RO, Lindsey JR. Risks of infection among laboratory rats and mice at major biomedical research institutions. ILAR J 1998;39:266271. [CrossRef]
  • [5] Carty AJ. Opportunistic infections of mice and rats: Jacoby and Lindsey revisited. ILAR J 2008;49:272276. [CrossRef]
  • [6] Hedrich HJ. The laboratory mouse. 2nd ed. London, UK: Academic Press, Elsevier; 2012.
  • [7] Mueller JF. Parasites of Laboratory Animals Robert J. Flynn. J Parasitol 1973;59:835. [CrossRef]
  • [8] Willcox M, Bodeker G, Geneviève B, Dhingra V, Falquet J, Ferreira JFS, et al. (2004) Artemisia annua as a traditional herbal antimalarial. In: Willcox M, Bodeker G, Rasaoanaivo P, editors. Traditional Medicine, Medicinal Plants and Malaria. Boca Raton: CRC Press; 2004[CrossRef]
  • [9] Bora KS, Sharma A. The genus Artemisia: A comprehensive review. Pharm Biol 2011;49:101–109. [CrossRef]
  • [10] van der Kooy F, Sullivan SE. The complexity of medicinal plants: The traditional Artemisia annua formulation, current status and future perspectives. J Ethnopharmacol 2013;150:1–13. [CrossRef]
  • [11] Zheng GQ. Cytotoxic terpenoids and flavonoids from Artemisia annua. Planta Med 1994;60:54–57. [CrossRef]
  • [12] Abad MJ, Bedoya LM, Apaza L, Bermejo P. The artemisia L. Genus: A review of bioactive essential oils. Molecules 2012;17:2542–2566. [CrossRef]
  • [13] Wang D, Cui L, Chang X, Guan D. Biosynthesis and characterization of zinc oxide nanoparticles from Artemisia annua and investigate their effect on proliferation, osteogenic differentiation and mineralization in human osteoblast-like MG-63 Cells. J Photochem Photobiol B 2020;202:111652. [CrossRef]
  • [14] Lubbe A, Seibert I, Klimkait T, van der Kooy F. Ethnopharmacology in overdrive: The remarkable anti-HIV activity of Artemisia annua. J Ethnopharmacol 2012;141:854–859. [CrossRef]
  • [15] Juteau F, Masotti V, Bessière JM, Dherbomez M, Viano J. Antibacterial and antioxidant activities of Artemisia annua essential oil. Fitoterapia 2002;73:532–535. [CrossRef]
  • [16] Pirali-Kheirabadi Kh, Teixeira da Silva J. In-vitro assessment of the acaricidal properties of artemisia annua and zataria multiflora essential oils to control cattle ticks. Iran J Parasitol 2011;6:58–65.
  • [17] Nair MS, Huang Y, Fidock DA, Polyak SJ, Wagoner J, Towler MJ, et al. Artemisia annua L. extracts inhibit the in vitro replication of SARS-CoV-2 and two of its variants. J Ethnopharmacol 2021;274:114016. [CrossRef]
  • [18] Faurant C. From bark to weed: The history of artemisinin. Parasite 2011;18:215–218. [CrossRef]
  • [19] Shukla KL, Gund TM, Meshnick SR. Molecular modeling studies of the artemisinin (qinghaosu)-hemin interaction: Docking between the antimalarial agent and its putative receptor. J Mol Graph 1995;13:215–222. [CrossRef]
  • [20] Cheng F, Shen J, Luo X, Zhu W, Gu J, Ji R, et al. Molecular docking and 3-D-QSAR studies on the possible antimalarial mechanism of artemisinin analogues. Bioorg Med Chem 2002;10:2883–2891. [CrossRef]
  • [21] İbn-i Sina. El-kanun fi't-tıbb. (Çev. Kahya E.) Ankara: Atatürk Kültür, Dil ve Tarih Yüksek Kurumu Atatürk Kültür Merkezi; 2010.
  • [22] Cala AC, Ferreira JF, Chagas AC, Gonzalez JM, Rodrigues RA, Foglio MA, et al. Anthelmintic activity of Artemisia annua L. extracts in vitro and the effect of an aqueous extract and artemisinin in sheep naturally infected with gastrointestinal nematodes. Parasitol Res 2014;113:2345–2353. [CrossRef]
  • [23] National Library of Medicine. Friedelin. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/Friedelin. Accessed Feb 11, 2021.
  • [24] National Library of Medicine. Stigmasterol. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/Stigmasterol. Accessed Feb 11, 2021. [25] Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, et al. Automated docking using a Lamarckian genetic algorithm and empirical binding free energy function. J Comput Chem 1998;19:1639–1662. [CrossRef]
  • [26] Taylor CM, Wang Q, Rosa BA, Huang SC, Powell K, Schedl T, et al. Discovery of anthelmintic drug targets and drugs using chokepoints in nematode metabolic pathways. PLoS Pathog 2013;9:e1003505. [CrossRef]
  • [27] Huey R, Morris GM, Olson AJ, Goodsell DS. A semiempirical free energy force field with charge-based desolvation. J Comput Chem 2007;28:1145–1152. [CrossRef]
  • [28] Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 2009;30:2785–2791. [CrossRef]
  • [29] Dassault Systèmes. BIOVIA, Discovery Studio Modeling Environment, Release 2020, San Diego: Dssault Systèmes 2020. Available at: https://www.3ds.com/products-services/biovia/. Accessed Feb 8, 2024.
  • [30] Robinson MW, McFerran N, Trudgett A, Hoey L, Fairweather I. A possible model of benzimidazole binding to beta-tubulin disclosed by invoking an inter-domain movement. J Mol Graph Model 2004;23:275–284. [CrossRef]
  • [31] Hsiao YS, Jogl G, Esser V, Tong L. Crystal structure of rat carnitine palmitoyltransferase II (CPT-II). Biochem Biophys Res Commun 2006;346:974–980. [CrossRef]
  • [32] Sterling T, Irwin JJ. ZINC 15--ligand discovery for everyone. J Chem Inf Model 2015;55:2324–2337. [CrossRef]
  • [33] Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, et al. PubChem in 2021: New data content and improved web interfaces. Nucleic Acids Res 2021;49:D1388–D1395. [CrossRef]
  • [34] O'Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: An open chemical toolbox. J Cheminform 2011;3:33. [CrossRef]
  • [35] Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 2017;7:42717. [CrossRef]
  • [36] Satyendra RV, Vishnumurthy KA, Vagdevi HM, Rajesh KP, Manjunatha H, Shruthi A. Synthesis, in vitro antioxidant, anthelmintic and molecular docking studies of novel dichloro substituted benzoxazole-triazolo-thione derivatives. Eur J Med Chem 2011;46:3078–3084. [CrossRef]
  • [37] Salgueiro AC, Folmer V, da Rosa HS, Costa MT, Boligon AA, Paula FR, et al. In vitro and in silico antioxidant and toxicological activities of Achyrocline satureioides. J Ethnopharmacol 2016;194:6–14. [CrossRef]
  • [38] Gogoi S, Yadav AK. In vitro and in vivo anthelmintic effects of Caesalpinia bonducella (L.) Roxb. leaf extract on Hymenolepis diminuta (Cestoda) and Syphacia obvelata (Nematoda). J Intercult Ethnopharmacol 2016;5:427–433. [CrossRef]
  • [39] Kozan E, Çankaya IT, Kahraman C, Akkol EK, Akdemir Z. The in vivo anthelmintic efficacy of some Verbascum species growing in Turkey. Exp Parasitol 2011;129:211–214. [CrossRef]
  • [40] de Amorin A, Borba HR, Carauta JP, Lopes D, Kaplan MA. Anthelmintic activity of the latex of Ficus species. J Ethnopharmacol 1999;64:255–258. [CrossRef]
  • [41] Brisibe EA, Umoren UE, Brisibe F, Magalhäes PM, Ferreira JFS, Luthria D, et al. Nutritional characterisation and antioxidant capacity of different tissues of Artemisia annua L. Food Chem 2009;115:1240–1246. [CrossRef]
  • [42] Noack R. Energy and protein requirements. Report of a Joint FAO/WHO Ad Hoc Expert Committee. WHO Technical Report Series No. 522, 118 S., Genf 1973. Food/Nahrung 1973;18:329–332. [CrossRef]
  • [43] Bahorun T, Luximon-Ramma A, Crozier A, Aruoma OI. Total phenol, flavonoid, proanthocyanidin and vitamin C levels and antioxidant activities of Mauritian vegetables. J Sci Food Agric
  • 2004;84:1553–1561. [CrossRef]
  • [44] Chukwurah PN, Brisibe EA, Osuagwu AN, Okoko T. Protective capacity of Artemisia annua as a potent antioxidant remedy against free radical damage. Asian Pac J Trop Biomed 2014;4(Suppl 1):S92–98. [CrossRef]
  • [45] Keiser J, Veneziano V, Rinaldi L, Mezzino L, Duthaler U, Cringoli G. Anthelmintic activity of artesunate against Fasciola hepatica in naturally infected sheep. Res Vet Sci 2010;88:107–110. [CrossRef]
  • [46] Youn HJ, Noh JW. Screening of the anticoccidial effects of herb extracts against Eimeria tenella. Vet Parasitol 2001;96:257–263. [CrossRef]
  • [47] Vijayakumar BG, Ramesh D, Joji A, Jayachandra Prakasan J, Kannan T. In silico pharmacokinetic and molecular docking studies of natural flavonoids and synthetic indole chalcones against essential proteins of SARS-CoV-2. Eur J Pharmacol 2020;886:173448. [CrossRef]
Toplam 47 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Ampirik Yazılım Mühendisliği
Bölüm Research Articles
Yazarlar

Dilara Karaman 0000-0003-4386-8531

Oya Girişgin Bu kişi benim 0000-0001-9896-1093

Ahmet Onur Girişgin 0000-0002-0020-2708

Prof.dr.hulusi Malyer 0000-0002-6283-4540

Yayımlanma Tarihi 27 Şubat 2024
Gönderilme Tarihi 14 Aralık 2021
Yayımlandığı Sayı Yıl 2024 Cilt: 42 Sayı: 1

Kaynak Göster

Vancouver Karaman D, Girişgin O, Girişgin AO, Malyer P. Discovery of new herbal anthelmintics from Artemisia Annua L. via in silico molecular docking and in vivo extract application. SIGMA. 2024;42(1):198-210.

IMPORTANT NOTE: JOURNAL SUBMISSION LINK https://eds.yildiz.edu.tr/sigma/