Antioxidant, cytotoxic and anti-inflammatory properties of Anthemis tricolor Boiss. through a series of cellular assays and inhibition of Turkish Macrovipera lebetina obtusa venom induced inflammation in rat

Year 2023, Volume: 53 Issue: 2, 166 - 176, 30.08.2023

Dilara Aşkın Tuğçe Demiröz Akbulut , Sura Baykan Bayram Göçmen Shabana Khan Petek Ballar Kırmızıbayrak Ayşe Nalbantsoy

https://doi.org/10.26650/IstanbulJPharm.2023.1060622

Abstract

Background and Aims: Venom of Macrovipera lebetina obtusa (Viperidae), Turkey’s biggest viper, is highly toxic to humans and causes inflammation. In Anatolian traditional medicine, many Anthemis L. species are used in wound healing and against inflammatory diseases. In the present study, antioxidant, cytotoxic and anti-inflammatory activities of different endemic A. tricolor Boiss. extracts were evaluated by in vitro assays. Besides, the anti-inflammatory activities of chloroform extract against carrageenan and snake venom induced-edema were investigated in rats.
Methods: Antioxidant and anti-inflammatory activities were evaluated by DCFH-DA, iNOS, NF-κB inhibitions and NAG-1 gene activation, while WST-1 assay was preferred for cytotoxic activity. Besides, the hind paw edema test was used for in vivo studies.
Results: Chloroform extract exhibited the strongest NAG-1-inducing activity. In addition, this extract showed potent iNOS and NF-κB inhibition (IC50:14.0 and 10.75 µg/mL, respectively) and cytotoxic effect against human osteosarcoma (U2OS; IC50: 15.18 µg/mL) and human cervical cancer (HeLa; IC50: 18.3 µg/mL) cell lines. Moreover, chloroform extract had stronger anti-inflammatory effects against both carrageenan and snake venom induced-edema formation than indomethacin. Fifty and 100 mg/kg extracts reduced the paw edema to 1-3% at 4 h after the snake venom injection. On the other hand, 50, 25 and 12.5 mg/kg of the extract completely inhibited inflammation induced by carrageenan.
Conclusion: This is the first report on the antioxidant, cytotoxic and anti-inflammatory effects of endemic A. tricolor by in vitro studies and snake venom-induced paw edema in rats. The plant exhibits strong potential for treating local tissue damage in snake bites.

Keywords

Macrovipera lebetina obtusa, Anthemis tricolor, cytotoxicity, antioxidant, anti-inflammatory, in vivo

Project Number

17-FEN-024

References

• Acquaviva, R., Giacomo, C. Di, Malaguarnera, M., Ragusa, S., San-tangelo, R., Mastrojeni, S. ... Doria, V. A. (2012). Biological activi-ties of extract of Anthemis aetnensis Schouw: In vitro evaluation. Journal of Medicinal Plants Research, 6(10), 1919-1925. https://doi. org/10.5897/JMPR11.1567 google scholar
• Al-Snafi, A. E. (2016). Medical importance of Anthemis nobilis (Chamaemelum nobile)-A review. Asian Journal of Pharmaceutical Science & Technology, 6(2), 89-95. google scholar
• Alexieva, B., Markova, T., Nikolova, E., Aragane, Y., & Higashino, H. (2010). Free radicals, antioxidants and cancer chemotherapy. Acta Medica Kinki University, 35(2), 57-65. google scholar
• Baek, S. J., Wilson, L. C., Lee, C. H., & Eling, T. E. (2002). Dual function of nonsteroidal anti-inflammatory drugs (NSAIDs): Inhibition of cyclooxygenase and induction of NSAID-activated gene. Journal of Pharmacology and Experimental Therapeutics, 301, 1126-1131. google scholar
• Baltaci, S., Kolatan, H. E., Yilmaz, O., & Kivçak, B. (2011). Anti-inflamma-tory activity of Anthemis aciphylla var. aciphylla Boiss. Turkish Journal of Biology, 35, 757-762. https://doi.org/10.3906/biy-1006-15 google scholar
• Baytop, T. (1999). Türkiye’de bitkilerle tedavi (geçmişte ve bugün) (2nd edn.). Istanbul, Turkey: Nobel Tıp Kitabevleri. google scholar
• Boukhary, R., Aboul-ElA, M., & El-Lakany, A. (2019). Review on chemical constituents and biological activities of genus An-themis. Pharmacognosy Journal, 11(5), 1155-1166. https://doi. org/10.5530/pj.2019.11.180 google scholar
• Bruno, M., Maggio, A., Arnold, A. N., Diaz, J. G., & Herz, W. (1998). Sesquiterpene lactones from Anthemis plutonia. Phytochemistry, 49, 1739-1740. google scholar
• Cakilcioglu, U., Khatun, S., Turkoglu, I., & Hayta, S. (2011). Ethno-pharmacological survey of medicinal plants in Maden (Elazig-Turkey). Journal of Ethnopharmacology, 137, 469-486. google scholar
• Chemsa, A. E., Zellagui, A., Öztürk, M., Erol, E., Ceylan, O., Duru, M. E., & Lahouel, M. (2018). Chemical composition, antioxidant, anticholinesterase, antimicrobial and antibiofilm activities of es-sential oil and methanolic extract of Anthemis stiparum subsp. sabulicola (Pomel) Oberpr. Microbial Pathogenesis, 119(February), 233-240. https://doi.org/10.1016/j.micpath.2018.04.033 google scholar
• Chippaux, J. P. (1998). Snake-bites: appraisal of the global situa-tion. Bulletin of the World Health Organization, 76(5), 515-524. google scholar
• Chippaux, J. P., Williams, V., & White, J. (1991). Snake venom vari-ability: methods of study, results and interpretation. Toxicon, 29(11), 1279-1303. google scholar
• Conforti, F., Menichini, F., Formisano, C., Rigano, D., Senatore, F., Bruno, M. . Çelik, S. (2012). Anthemis wiedemanniana essential oil prevents LPS-induced production of NO in RAW 264.7 mac-rophages and exerts antiproliferative and antibacterial activities invitro. Natural Product Research, 26(17), 1594-1601. https://doi.or g/10.1080/14786419.2011.585988 google scholar
• Cragg, G. M., & Newman, D. J. (2005). Plants as a source of anti-cancer agents. Journal of Ethnopharmacology, 100, 72-79. google scholar
• Creer, S., Chou, W.-H., Malhotra, A., & Thorpe, R. S. (2002). Offshore insular variation in the diet of the Taiwanese bamboo viper Tri-meresurus stejnegeri (Schmidt). Zoological Science, 19, 907-931. google scholar
• Daltry, J. C., Wüster, W., & Thorpe, R. S. (1996). Diet and snake ven-om evolution. Nature, 379, 537-540. google scholar
• De Toni, L. G. B., Menaldo, D. L., Cintra, A. C. O., Figueiredo, M. J., de Souza, A. R., Maximiano, W. M., . Sampaio, S. V. (2015). Inflammato-ry mediators involved in the paw edema and hyperalgesia induced by Batroxase, a metalloproteinase isolated from Bothrops atrox snake venom. International Immunopharmacology, 28, 199-207. google scholar
• Demirkan, S., Özçınar, Ö., & Kıvçak, B. (2019). Anti-inflammatory ac-tivity of Anthemis tricolor Boiss. Advances in Dermatology and Aller-gology, 36(6), 677-680. https://doi.org/10.5114/ada.2019.91417 google scholar
• Demiroz, T., Albayrak, G., Nalbantsoy, A., Gocmen, B., & Baykan, S. (2018). Anti-inflammatory properties of Centaurea calolepis Boiss. and cnicin against Macrovipera lebetina obtusa (Dwigubsky, 1832) and Montivipera xanthina (Gray, 1849) venoms in rat. Toxicon, 152(May), 37-42. https://doi.org/10.1016/j.toxicon.2018.07.016 Demiroz, T., Nalbantsoy, A., Kose, F. A., & Baykan, S. (2020). Phy-tochemical composition and antioxidant, cytotoxic and anti-inflammatory properties of Psephellus goeksunensis (Aytaç & H. Duman) Greuter & Raab-Straube. South African Journal of Botany, 130, 1-7. https://doi.org/10.1016/j.sajb.2019.11.021 google scholar
• Durban, J., Juarez, P., Angulo, Y., Lomonte, B., Flores-Diaz, M., Ala-pe-Giron, A., . Calvete, J. J. (2011). Profiling the venom gland transcriptomes of Costa Rican snakes by 454 pyrosequencing. BMC Genomics, 12, 259. google scholar
• Emir, A., & Emir, C. (2020). Anthemis tinctoria L. var. tinctoria L. Bitkisine Ait Fenolik Bileşiklerin LC-ESI-MS/MS ile Miktar Tayini ve Bitkinin Biyolojik Aktivitelerinin Belirlenmesi. Gümüşhane Üniversitesi Fen Bilimleri Enstitüsü Dergisi, 10(4), 996-1006. https://doi. org/10.17714/gumusfenbil.687185 google scholar
• Farsky, S. H., Gonçalves, L. R., Gutierrez, J. M., Correa, A. P., Rucavado, A., Gasque, P., & Tambourgi, D. V. (2000). Bothrops asper snake venom and its metalloproteinase BaP-1 activate the complement system. Role in leucocyte recruitment. Mediators ofInflammation, 9, 213-221. Forgey, W. W. (2008). Basic Illustrated Wilderness First Aid (Basic Essentials Series) (First). Guilford/USA: Falcon Guides. google scholar
• Ghafoor, A. (2010). The importance of natural product charac-terization in studies of their anti-inflammatory activity. Pakistan Journal of Botany, 42, 79-98. google scholar
• Ghazaryan, N. A., Ghulikyan, L. A., Kishmiryan, A. V., Kirakosyan, G. R., Nazaryan, O. H., Ghevondyan, T. H., . Ayvazyan, N. M. (2015). Anti-tumor effect investigation of obtustatin and crude Macro-vipera lebetina obtusa venom in S-180 sarcoma bearing mice. European Journal of Pharmacology, 764, 340-345. https://doi. org/10.1016/j.ejphar.2015.07.011 google scholar
• Gönenç, T., Akkol, E., Süntar, I., Erdoğan, T., & Kvçak, B. (2014). Fatty acid composition and preclinical researches on Anthemis wied-emanniana Fisch. & Mey.: Discovery of a new anti-inflammatory agent. Pharmacognosy Magazine, 10(37), 53-60. https://doi. org/10.4103/0973-1296.126660 google scholar
• Gonenc, T., Argyropoulou, C., Erdogan, T., Gousiadou, C., Juergen-liemk, G., Kivcak, B., & Skaltsa, H. (2011). Chemical constituents from Anthemis wiedemanniana Fisch & Mey. Biochemical System-atics and Ecology, 39, 51-55. google scholar
• Gosslau, A., Li, S., Chi-Tang, H., Chen, K. Y., & Rawson, N. E. (2001). The importance of natural product characterization in studies of their anti-inflammatory activity. Molecular Nutrition & Food Re-search, 55(1), 74-82. google scholar
• Gubensek, F., Sket, D., Turk, V., & Lebez, D. (1974). Fractionation of Vipera ammodytes Venom and Seasonal Variation of Its Composi-tion. Toxicon, 12(2), 167-171. google scholar
• Gulsoy Toplan, G., Tuysuz, M., Mat, A., & Sariyar, G. (2017). Anti-bacterial Activity of Anthemis tricolor Boiss. from Cyprus. 65th International Congress and Annual Meeting of the Society for Medicinal Plant and Natural Product Research (GA 2017), 4(S 01), 1608478. New York: Planta Medica International Open. https:// doi.org/10.1055/s-0037-1608478 google scholar
• Gutierrez, J. M., Rucavado, A., Escalante, T., & Diaz, C. (2005). Hem-orrhage induced by snake venom metalloproteinases: biochemi-cal and biophysical mechanisms involved in microvessel dam-age. Toxicon, 45(997-1011). google scholar
• Hajdu, Z., Zupko, I., Rethy, B., Forgo, P., & Hohmann, J. (2010). Bioactivity-guided isolation of cytotoxic sesquiterpenes and flavonoids from Anthemis ruthenica. Planta Medica, 76(1), 94-96. https://doi.org/10.1055/s-0029-1185942 google scholar
• Hanada, T., & Yoshimura, A. (2002). Regulation of cytokine sig-naling and inflammation. Cytokine & Growth Factor Reviews, 13, 413-421. google scholar
• Harris, S. G., Padilla, J., Koumas, L., Ray, D., & Phipps, R. P. (2002). Prostaglandins as modulators of immunity. Trends in Immunology, 23, 144-150. google scholar
• Hirata, T., & Narumiya, S. (2012). 5 Prostanoids as Regulators of Innate and Adaptive Immunity. Advances in Immunology, 116, 143-174. google scholar
• Hung, Y. C., Hsu, C. C., Chung, C. H., & Huang, T. F. (2016). The dis-integrin, trimucrin, suppresses LPS-induced activation of phago-cytes primarily through blockade of NF-kB and MAPK activation. Naunyn-Schmiedeberg’s. Archives of Pharmacology, 369(7), 723737. google scholar
• Igci, N., & Demiralp, D. O. (2012). A preliminary investigation into the venom proteome of Macrovipera lebetina obtusa (Dwigub-sky, 1832) from Southeastern Anatolia by MALDI-TOF mass spec-trometry and comparison of venom protein profiles with Macro-vipera lebetina lebetina (Linnaeus, 1758) fro. Archives of Toxicology, 86(3), 441-451. google scholar
• India Ministry of Health & Family Welfare, I. G. (2006). Manage-ment of Snake Bite. In Standard Treatment Guidelines. India. google scholar
• Isbister, G. K., Brown, S. G. A., Page, C. B., McCoubrie, D. L., Greene, S. L., & Buckley, N. A. (2013). Snakebite in Australia: a practical ap-proach to diagnosis and treatment. The Medical Journal of Austra-lia, 199(11), 763-768. google scholar
• Jassbi, A. R., Firuzi, O., Miri, R., Salhei, S., Zare, S., Zare, M., ... Bald-win, I. T. (2016). Cytotoxic activity and chemical constituents of Anthemis mirheydari. Pharmaceutical Biology, 54(10), 2044-2049. https://doi.org/10.3109/13880209.2016.1141220 google scholar
• Kang, T. S., Georgieva, D., Genov, N., Murakami, M. T., Sinha, M., Kumar, R. P., . Kini, R. M. (2011). Enzymatic toxins from snake venom: structural characterization and mechanism of catalysis. The FEBS Journal, 287, 4544-4576. google scholar
• Karaalp, C., Baykan Erel, S., Nalbantsoy, A., Gucel, S., Demirci, B., & Baser, K. H. C. (2014). The essential oil composition of aerial parts of Anthemis tricolor Boiss. from Cyprus. Natural Product Research, 28(7), 488-491. google scholar
• Khosravi, M., Mirzaie, A., Kashtali, A. B., & Noorbazargan, H. (2020). Antibacterial, anti-efflux, anti-biofilm, anti-slime (exopolysaccha-ride) production and urease inhibitory efficacies of novel syn-thesized gold nanoparticles coated Anthemis atropatana extract against multidrug-resistant Klebsiella pneumoniae strains. Archives of Microbiology, 202(8), 2105-2115. https://doi.org/10.1007/ s00203-020-01930-y google scholar
• Lomonte, B., & Rangel, J. (2012). Snake venom Lys49 myotoxins: from phospholipases A2 to non-enzymatic membrane disrup-tors. Toxicon, 60, 520-530. google scholar
• Ma, G., Khan, S. I., Benavides, G., Schühly, W., Fischer, N. H., Khan, I. A., & Pasco, D. S. (2007). Inhibition of NF-kB-mediated transcrip-tion and induction of apoptosis by melampolides and repan-dolides. Cancer Chemotherapy and Pharmacology, 60(1), 35-43. https://doi.org/10.1007/s00280-006-0344-0 google scholar
• Mantle, D., Eddeb, F., & Pickering, A. T. (2000). Comparison of relative antioxidant activities of British medicinal plant species in vitro. Journal of Ethnopharmacology, 72(1-2), 47-51. https://doi. org/10.1016/S0378-8741(00)00199-9 google scholar
• McCleary, R. J. R., Sridharan, S., Dunstan, N. L., Mirtschin, P. J., & Kini, R. M. (2016). Proteomic comparisons of venoms of long-term cap-tive and recently wild-caught Eastern brown snakes (Pseudonaja textilis) indicate venom does not change due to captivity. Journal of Proteomics, 20(144), 51-62. google scholar
• Melo, M. M., Habermehl, G. G., Oliveira, N. J. F., & Nascimento, E. F. (2005). Treatment of Bothrops alternatus envenomation by Cur-cuma longa and Calendula officinalis extracts and ar-turmerone. Arquivo Brasileiro de Medicina Veterinaria e Zootecnia, 57, 7-17. google scholar
• Menezes, M. C., Furtado, M. F., Travaglia-Cardoso, S. R., Camargo, A. C. M., & Serrano, S. M. T. (2006). Sex-based individual variation of snake venom proteome among eighteen Bothrops jararaca sib-lings. Toxicon, 47, 304-312. google scholar
• Mermer, A., Gocmen, B., & Cicek, K. (2012). Extreme cases of colour pattern and size in Levantine Viper, Macrovipera lebetina (L., 1758) from the West of Euphrates Basin (Southern Anatolia, Turkey). Bi-harean Biologist, 6(1), 70-71. google scholar
• Morais, J. F., De Freitas, M. C. W., Yamaguchi, I. K., Dos-Santos, M. C., & DaSilva, W. D. (1994). Snake antivenom from hyperimmunized horses: biological properties of their whole IgG and F(ab)2 frag-ments. Toxicon, 32, 725-734. google scholar
• Moreiraa, V., Teixeiraa, C., Silva, H. B., D’Imperio Limab, M. R., & Dos-Santos, M. C. (2016). The role of TLR2 in the acute inflammatory response induced by Bothrops atrox snake venom. Toxicon, 118, 121-128. google scholar
• Moura-da-Silva, A. M., Butera, D., & Tanjoni, I. (2007). Importance of Snake Venom Metalloproteinases in Cell Biology: Effects on Plate-lets, Inflammatory and Endothelial Cells. Current Pharmaceutical Design, 13(28), 2893-2905. google scholar
• Nalbantsoy, A., Nesil, T., Yılmaz-Dilsiz, O., Aksu, G., Khan, S., & Bedir, E. (2012). Evaluation of immunomodulatory properties in mice and in vitro anti-inflammatory activity of cycloartane type saponins from Astragalus species. Journal of Ethnopharmacology, 139(2), 574-581. google scholar
• Nilson, G., & Andren, C. (1988). Vipera lebetina transmediterranea, a new subspecies of viper from North Africa, with remarks on the taxonomy of Vipera lebetina and Vipera mauritanica. Bonner Zoolo-gische Beitrage, 39, 371-379. google scholar
• Oberprieler, C., & Vogt, R. (1999). Notes on some species of Anthe-mis (Compositae, Anthemideae) in Cyprus. Bocconea, 11, 89-104. Ohsaka, A. (1979). Hemorrhagic, necrotizing and edema-form-ing effects of snake venoms. In C. Y. Lee (Ed.), Handbook of Ex-perimental Pharmacology (vol. 52, pp. 481-546). Berlin: Springer-Verlag. google scholar
• Otero, R., Gutierrez, J., Mesa, M. B., Duque, E., Rodrfguez, O., Aran-go, J. L., ... D^az, A. (2002). Complications of Bothrops, Porthidium, and Bothriechis snakebites in Colombia. A clinical and epidemio-logical study of 39 cases attended in a university hospital. Toxicon, 40(8), 1107-1114. google scholar
• Ozen, M. O., Igci, N., Yalcin, H. T., Gocmen, B., & Nalbantsoy, A. (2015). Screening of cytotoxic and antimicrobial activity poten-tial of Anatolian Macrovipera lebetina obtusa (Ophidia: Viperidae) crude venom. Frontiers in Life Science, 8(4), 363-370. google scholar
• Pang, K.L., Chow, Y.Y., Leong, L.M., Law, J.X., Ghafar, N.A., Soelaim-an, I.N. & Chin, K.Y. (2021). Establishing SW1353 Chondrocytes as a Cellular Model of Chondrolysis. Life, 11(272), 1-17. google scholar
• Parlar, S., Erzurumlu, Y., Ilhan, R., Ballar Kırmızıbayrak, P., Alptüzün, V., & Erciyas, E. (2018). Synthesis and Evaluation of Pyridinium-Hydrazone Derivatives as Potential Antitumoral Agents. Chemical Biology & Drug Design, 92(1), 1198-1205. google scholar
• Pavlovic, M., Kovacevic, N., Couladis, M., & Tzakou, O. (2006). Phe-nolic constituents of Anthemis triumfetti (L.) DC. Biochemical Sys-tematics and Ecology, 34, 449-452. google scholar
• Picolo, G., Chacur, M., Gutierrez, J. M., Teixeira, C. F. P., & Cury, Y. (2002). Evaluation of antivenoms in the neutralization of hyper-algesia and edema induced by Bothrops jararaca and Bothrops asper snake venoms. Brazilian Journal of Medical and Biological Research, 35, 1221-1228. google scholar
• Quaerenghi, M. V., Tereschuk, M. L., Baigori, M. D., & Abdala, L. R. (2000). Antimicrobial activity of flowers from Anthemis cotula. Fi-toterapia, 71(6), 710-712. google scholar
• RaduloviC, N. S., Mladenovic, M. Z., Blagojevic, P D., Stojanovic-Radic, Z. Z., Ilic-Tomic, T., Senerovic, L., & Nikodinovic-Runic, J. (2013). Toxic essential oils. Part III: Identification and biological activity of new allylmethoxyphenyl esters from a Chamomile spe-cies (Anthemis segetalis Ten.). Food and Chemical Toxicology, 62, 554-565. https://doi.org/10.1016Zj.fct.2013.09.017 google scholar
• Reddy, M. K., Gupta, S. K., Jacob, M. R., Khan, S. I., & Ferreira, D. (2007). Antioxidant, antimalarial and antimicrobial activities of tannin-rich fractions, ellagitannins and phenolic acids from Pu-nica granatum. Planta Medica, 73, 461-467. google scholar
• Rethy, B., Csupor-Löffler, B., Zupko, I., Hajdu, Z., Mathe, I., Hohm-ann, J.,... Falkay, G. (2007). Antiproliferative Activity of Hungar-ian Asteraceae Species against Human Cancer Cell Lines. Part I. Phytotherapy Research, 2, 1200-1208. https://doi.org/10.1002/ ptr google scholar
• Rosenfeld, G. (1971). Symptomatology, pathology and treatment of snake bites in South America. In W. Bucherl & E. E. Buckley (Eds.), Venomous Animals and Their Venoms. (pp. 345-403). New York: Academic Press. google scholar
• Rossi, T., Melegari, M., Bianchi, A., Albasini, A., & Vampa, G. (1988). Sedative, anti-inflammatory and anti-diuretic effects induced in rats by essential oils of varieties of Anthemis nobilis: A compara-tive study. Pharmacological Research Communications, 20(Supple-ment V), 71-74. https://doi.org/10.1016/S0031-6989(88)80844-0 google scholar
• Rucavado, A., Nunez, J., & Gutierrez, J. M. (1998). Blister formation and skin damage induced by BaP1, a haemorrhagic metallopro-teinase from the venom of the snake Bothrops asper. Internation-al Journal of Experimental Pathology, 79, 245-254. google scholar
• Rüngeler, P., Castro, V., Mora, G., Goren, N., Vichnewski, W., Pahl, H. L,...T.J., S. (1999). Inhibition of transcription factor NF-kB by ses-quiterpene lactones: a proposed molecular mechanism of action. Bioorganic & Medicinal Chemistry, 7(11), 2343-2352. google scholar
• Sanz, L., Ayvazyan, N., & Calvete, J. J. (2008). Snake venomics of the Armenian mountain vipers Macrovipera lebetina obtusa and Vipera raddei. Journal of Proteomics, 71, 198-209. google scholar
• Sarhan, M., Mostafa, A., Elbehiry, S. E., & Saber, S. (2017). Intersexual Variation in Tail Length, Venom Composition, Toxicity, and Anti-cancer Activity of Cerastes cerastes (Viperidae). The Egyptian Jour-nal of Hospital Medicine, 66, 81-90. google scholar
• Sarikurkcu, C. (2020). Anthemis chia: Biological capacity and phy-tochemistry. Industrial Crops and Products, 153, 1-9. https://doi. org/10.1016/j.indcrop.2020.112578 google scholar
• Sawai, Y. (1980). Studies on snakebites in the Asian areas. In D. Eaker & T. Wadstrom (Eds.), Natural Toxins (pp. 25-32). Oxford: Per-gamon Press. google scholar
• Staneva, J., Todorova, M., & Evstatieva, L. (2008). Sesquiterpene lactones as chemotaxonomic markers in genus Anthemis. Phyto-chemistry, 69, 607-618. google scholar
• Sut, S., Dall’Acqua, S., Zengin, G., Senkardes, I., Bulut, G., Cvetanovic, A., . Mahomoodally, F. (2019). Influence of different extraction techniques on the chemical profile and biological properties of Anthemis cotula L.: Multifunctional aspects for potential pharma-ceutical applications. Journal of Pharmaceutical and Biomedical Analysis, 173, 75-85. https://doi.org/10.1016/j.jpba.2019.05.028 google scholar
• Suzergoz, F., Igci, N., Cavus, C., Yıldız, M. Z., Coskun, M. B., & Gocmen, B. (2016). In Vitro Cytotoxic and Proapoptotic Activities of Anatolian Macrovipera Lebetina Obtusa (Dwigubski, 1832) Crude Venom on Cultured K562 Human Chronic Myelogenous Leukemia Cells. Inter-national Journal of Hematology and Oncology., 1(26), 37-46. google scholar
• Teixeira, C. F., Cury, Y., Moreira, V., Picolob, G., & Chaves, F. (2009). Inflammation induced by Bothrops asper venom. Toxicon, 54, 988-997. google scholar
• Tetik, F., Civelek, S., & Cakilcioglu, U. (2013). Traditional uses of some medicinal plants in Malatya (Turkey). Journal of Ethnophar-macology, 146(1), 331-346. google scholar
• Teufelhofer, O., Weiss, R.M., Parzefall, W., Schulte-Hermann, R., Micksche, M., Berger, W. & Elbling, L. (2003). Promyelocytic HL60 Cells Express NADPH Oxidase and Are Excellent Targets in a Rapid Spectrophotometric Microplate Assay for Extracellular Superox-ide. Toxicological Sciences, 76, 376-383. google scholar
• Todorova, M., Trendafilova, A., Danova, K., & Dimitrov, D. (2011). Phytochemical study of Anthemis rumelica (Velen) Stoj. & Acth. Biochemical Systematics and Ecology, 39(4-6), 868-871. https:// doi.org/https://doi.org/10.1016/j.bse.2011.06.003 google scholar
• Trummal, K., Tonismagi, K., Siigur, E., Aaspollu, A., Lopp, A., & Sillat, T. (2005). A novel metalloprotease from Vipera lebetina venom induces human endothelial cell apoptosis. Toxicon, 46, 46-61. google scholar
• Vuckovic, I., Vujisic, L., Klaas, C. A., Merfort, I., & MilosavljeviC, S. (2011). NF-B DNA binding activity of sesquiterpene lactones from Anthemis arvensis and Anthemis cotula. Natural Product Research, 25(8), 800-805. https://doi.org/10.1080/14786410902941402 google scholar
• Wong, H. R., & Menendez, I. Y. (1999). Sesquiterpene lactones in-hibit inducible nitric oxide synthase gene expression in cultured rat aortic smooth muscle cells. Biochemical and Biophysical Re-search Communications, 262(2), 375-378. google scholar
• Yusufoglu, H. S., Alam, A., Salkini, M. A. A., & Zaghloul, A. M. (2014). Anti-inflammatory and hepatoprotective activities of methanolic extract of Anthemis scrobicularis herbs. Pharmacognosy Journal, 6(3), 55-61. https://doi.org/10.5530/pj.2014.3.9 google scholar
• Zhang, J. M., & An, J. (2007). Cytokines, Inflammation and Pain. International Anesthesiology Clinics, 45(2), 27-37. google scholar
• Zhao, J., Khan, S. I., Wang, M., Vasquez, Y., Yang, M. H., Avula, B., . Khan, I. A. (2014). Octulosonic acid derivatives from Roman chamomile (Chamaemelum nobile) with activities against in-flammation and metabolic disorder. Journal of Natural Products, 77, 509-515. https://doi.org/10.1021/np400780n google scholar