Arı Zehri
Özet
Türkiye bulunduğu iklim kuşağı, coğrafi konumu ve yapısı ile zengin bir tabiata ev sahipliği yapmaktadır. Bu durum arıcılık açısından elverişli ve avantajlı bir ortam yaratmaktadır. Bilindiği üzere arının geleneksel ürünü bal olmakla birlikte zengin bir yan ürün potansiyeline de sahiptir. Arı zehri arının kovanını ve kendisini korumak için geliştirdiği savunmanın bir parçasıdır. Bu bölümde arılar tarafından salgılanarak üretilen ve arı iğnesi ile hedefe verilen içeriğinde kuvvetli etkilere sahip fosfolipitler, peptitler, amino asitler, biyoaktif aminler, şekerler, feromonlar, enzimler ve mineraller gibi çok sayıda bileşenler içeren ve özellikle melittin bulunan arı zehiri hakkında genel bilgiler ve sağlık üzerindeki etkileri anlatılacaktır.
Referanslar
Özbek H (2002). Arılar ve doğa. Uludag Arıcılık Dergisi. 3: 22-25.
Weiss, K. (2002). Bees in the Animal Kingdom and in Earth’s History. The Little Book of Bees, 1-13.
Karacoğlu M, Fıratlı Ç (1994). Orta Anadolu, Karadeniz geçit ve Ardahan izole bölgeleri bal arısı ekotiplerinin morfolojik özellikleri. Gaziosmanpaşa Üniversitesi Ziraat Fakültesi Dergisi. 11: 207-214.
Crane, E. (2004). A short history of knowledge about honey bees (Apis) up to 1800. Bee world, 85(1), 6-11.
Papa, G., Maier, R., Durazzo, A., Lucarini, M., Karabagias, I. K., Plutino, M., ... & Negri, I. (2022). The honey bee Apis mellifera: An insect at the interface between human and ecosystem health. Biology, 11(2), 233.
Șahinler, N. (2000). Bee products and their importance in human health. Ziraat Fakultesi Dergisi, Mustafa Kemal Universitesi, 5(1/2), 139-148.
SELÇUK M, DİNÇ H, KARABAĞ K (2010). Bal arısı zehrinin biyokimyasal yapısı ve tıptaki yeri. MYO-ÖS 2010- Ulusal Meslek Yüksekokulları Öğrenci Sempozyumu.
Kokuludağ A (2015). Arı zehiri içeriği ve tıbbi özellikleri. In Arı Ürünleri ve Sağlık (Apiterapi). Ed.: Akçiçek, E., Yücel, B. Sidas, İzmir. s: 147-151.
Bogdanov S (2017). Bee venom: Production, compostion, quality, Biological and therapeutic properties: A review. Erişim adresi: https://www.bee-hexagon.net/english/bee-products/downloads-venom-book/. Erişim tarihi: 20.06.2022.
Pak, S. C. (2017). Chemical composition of bee venom. Bee Products-Chemical and Biological Properties, 279-285.
Zhang, S., Liu, Y., Ye, Y., Wang, X. R., Lin, L. T., Xiao, L. Y., ... & Liu, C. Z. (2018). Bee venom therapy: Potential mechanisms and therapeutic applications. Toxicon, 148, 64-73.
Altintaş, L., & Bektaş, N. (2019). Apiterapi: 1. Ari Zehri. Uludag Bee J, 19, 82-95.
Aufschnaiter, A., Kohler, V., Khalifa, S., Abd El-Wahed, A., Du, M., El-Seedi, H., & Büttner, S. (2020). Apitoxin and its components against cancer, neurodegeneration and rheumatoid arthritis: Limitations and possibilities. Toxins, 12(2), 66.
Pascoal, A., Estevinho, M. M., Choupina, A. B., Sousa-Pimenta, M., & Estevinho, L. M. (2019). An overview of the bioactive compounds, therapeutic properties and toxic effects of apitoxin. Food and chemical toxicology, 134, 110864.
Keskiner AA (2021). Gıda takviyesi olarak kullanılan bazı apiterapik ürünlerin çeşitli kanser hücre hatlarında etkinliğinin belirlenmesi (Master's thesis, Amasya Üniversitesi).
Korkmaz A, Korkmaz V (2015). Arı zehiri üretimi ve apiterapi. 1.baskı. Samsun İli Arı Yetiştiricileri Birliği, Samsun.
Kolayli, S., & Keskin, M. (2020). Natural bee products and their apitherapeutic applications. Studies in Natural Products Chemistry, 66, 175-196.
Khalil, A., Elesawy, B. H., Ali, T. M., & Ahmed, O. M. (2021). Bee venom: From venom to drug. Molecules, 26(16), 4941.
Gajski, G., Leonova, E., & Sjakste, N. (2024). Bee Venom: Composition and Anticancer Properties. Toxins, 16(3), 117.
Son DJ, Lee JW, Lee YH, Song HS, Lee CK, Hong JT (2007). Therapeutic application of anti-arthritis, pain-releasing, and anti-cancer effects of bee venom and its constituent compounds. Pharmacology & Therapeutics, 115: 246-270.
Bellik Y. ,2015 . Bee venom: its potential use in alternative medicine. Anti-infective agents, 13(1), 3-16.
Wehbe, R., Frangieh, J., Rima, M., El Obeid, D., Sabatier, J. M., & Fajloun, Z. (2019). Bee venom: Overview of main compounds and bioactivities for therapeutic interests. Molecules, 24(16), 2997.
Ullah, A., Aldakheel, F. M., Anjum, S. I., Raza, G., Khan, S. A., & Gajger, I. T. (2023). Pharmacological properties and therapeutic potential of honey bee venom. Saudi Pharmaceutical Journal, 31(1), 96-109.
Chen, J., Guan, S. M., Sun, W., & Fu, H. (2016). Melittin, the major pain-producing substance of bee venom. Neuroscience bulletin, 32, 265-272.
Hossen, M. S., Shapla, U. M., Gan, S. H., & Khalil, M. I. (2016). Impact of bee venom enzymes on diseases and immune responses. Molecules, 22(1), 25.
Eze, O. B., Nwodo, O. F., & Ogugua, V. N. (2016). Therapeutic effect of honey bee venom. Proteins (enzymes), 1(2).
Carpena, M., Nuñez-Estevez, B., Soria-Lopez, A., & Simal-Gandara, J. (2020). Bee venom: an updating review of its bioactive molecules and its health applications. Nutrients, 12(11), 3360.
Chen J, ve Lariviere WR. 2010. The nociceptive and anti-nociceptive effects of bee venom injection and therapy: A double-edged sword. Progress in Neurobiology, C. 92, ss. 151–183. https://doi.org/10.1016/j.pneurobio.2010.06.00 6.
Chen SY, Zhou P, ve Qin Y. 2018. Treatment of Rheumatoid Arthritis by Bee-venom Acupuncture. Zhen ci yan jiu = Acupuncture research, 43(4), 251–254. https://doi.org/10.13702/j.1000-0607.170506.
Senel E, Kuyucu M, ve Süslü I 2014. Honey and bee venom in dermatology: A novel possible alternative or complimentary therapy for psoriasis vulgaris. Ancient Science of Life, 33(3), 190. https://doi.org/10.4103/0257- 7941.144626.
Han SM, Lee KG, Yeo JH, Kım WT, Park KK (2011). Biological effects of treatment of an animal skin wound with honeybee (Apis melifera. L) venom. Journal of Plastic, Reconstructive & Aesthetic Surgery. 64: 67-72.
Park MH, Choi MS, Kwak DH, Oh KW, Yoon DY, Han SB, Hong JT. 2011. Anticancer effect of bee venomin prostate cancer cells through activation of caspase pathway via inactivation of NF-κB. Prostate, 71(8), 801– 812. https://doi.org/10.1002/pros.21296.
Huh JE, Baek YH, Lee MH, Choi DY, Park DS, ve Lee JD. 2010. Bee venom inhibits tumor angiogenesis and metastasis by inhibiting tyrosine phosphorylation of VEGFR2 in LLC-tumor-bearing mice. Cancer Letters, 292(1), 98–110. https://doi.org/10.1016/j.canlet.2009.11.013.
Ip SW, Liao SS, Lin SY, Lin JP, Yang JS, Lin ML, Chung JG. 2008. The role of mitochondria in bee venom-induced apoptosis in human breast cancer MCF7 cells. In Vivo, 22(2), 237–246.
Li B, Gu W, Zhang C, Huang XQ, Han KQ, ve Ling CQ. 2006. Growth arrest and apoptosis of the human hepatocellular carcinoma cell line Bel-7402 induced by melittin. Onkologie, 29(8–9), 367–371. https://doi.org/10.1159/000094711.
Ling CQ, Li B, Zhang C, Zhu DZ, Huang XQ, Gu W, ve Li SX 2005. Inhibitory effect of recombinant adenovirus carrying melittin gene on hepatocellular carcinoma. Annals of Oncology, 16(1), 109–115. https://doi.org/10.1093/annonc/mdi019.
Moon DO, Park SY, Heo MS, Kim KC, Park C, Ko WS, Kim GY. 2006. Key regulators in bee venom-induced apoptosis are Bcl-2 and caspase-3 in human leukemic U937 cells through downregulation of ERK and Akt. International Immunopharmacology, 6(12), 1796–1807.
Moreno M, ve Giralt E. 2015. Three valuable peptides from bee and wasp venoms for therapeutic and biotechnological use: Melittin, apamin and mastoparan. Toxins, 7(4), 1126– 1150. https://doi.org/10.3390/toxins7041126.
Orsolic N, Knezevic A, Sver L, Terzic S, Hackenberger BK, Basic I. 2003. Influence of honey bee products on transplantable murine tumours. Veterinary and Comparative Oncology, 1(4), 216–226. https://doi.org/10.1111/j.1476- 5810.2003.00029.x.
Russell PJ, Hewish D, Carter T, Sterling-Levis K, Ow K, Hattarki M, Kortt AA, 2004. Cytotoxic properties of immunoconjugates containing melittin-like peptide 101 against prostate cancer: In vitro and in vivo studies. Cancer Immunology, Immunotherapy, 53(5), 411–421. https://doi.org/10.1007/s00262-003- 0457-9.
Soman NR, Baldwin SL, Hu G, Marsh JN, Lanza GM, Heuser J E, Schlesinger PH. 2009. Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth. Journal of Clinical Investigation, 119(9), 2830– 2842. https://doi.org/10.1172/JCI38842.
Tu WC, Wu CC, Hsieh HL, Chen CY, Hsu SL 2008. Honeybee venom induces calcium-dependent but caspase-independent apoptotic cell death in human melanoma A2058 cells. Toxicon, 52(2), 318–329. https://doi.org/10.1016/j.toxicon.2008.06.007.
Varanda, EA, Monti, R, ve Tavares, DC 1999. Inhibitory effect of propolis and bee venom on the mutagenicity of some direct-and indirectacting mutagens. Teratogenesis Carcinogenesis and Mutagenesis, 19(6), 403– 413. https://doi.org/10.1002/(SICI)1520- 6866(1999)19:63.0.CO;2-2.
Kelle I (2007). Apiterapi. Dicle Tıp Dergisi, 34 (4): 311-315.
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Özbek H (1990). Bal arısı zehiri. Atatürk Ü. Zir. Fak. Der. 21 (2): 84-100.
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Nowar, E. E. (2016). Venom glands parameters, venom production and composition of honeybee Apis mellifera L. affected by substitute feeding. Middle East J. Agric. Res., 5(4): 596-603
Ali, A. M. (2024). Advancements in bee venom bioactivities for current therapeutic applications: A Review. Advancements in Life Sciences, 11(1), 49-55.
Tanuğur-Samancı AE, & Kekeçoğlu M (2021). An evaluation of the chemical content and microbiological contamination of Anatolian bee venom. PloS one, 16(7), e0255161.
Çaprazlı T, & Kekeçoğlu M (2021). Bal Arisi Zehrinin Kompozisyonunu Ve Üretim Miktarını Etkileyen Faktörler. Uludağ Arıcılık Dergisi, 21(1), 132-145.
Sunay AE, Samancı T (2016). Arı ürünlerinin üretimi. Erişim adresi: http://www.ariplatformu.org/storage/ilgi_cekici_bilgiler.pdf. Erişim tarihi: 10.05.2016.
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Scaccabarozzi, D., Dods, K., Le, T. T., Gummer, J. P., Lussu, M., Milne, L., ... & Priddis, C. (2021). Factors driving the compositional diversity of Apis mellifera bee venom from a Corymbia calophylla (marri) ecosystem, Southwestern Australia. PLoS One, 16(6), e0253838.
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Urtubey N (2005). Apitoxin: From Bee Venom to Apitoxin for Medical Use. Termas de Rio Grande Santiago del Estero, Argentina.
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Han SM, Lee KG, Yeo HJ, Hwang SJ, Chenoweth PJ, Pak SC. 2009. Somatic cell count in milk of bee venom treated dairy cows with mastitis. Journal of Applied Animal Scence. 2009; 1 (4):104-109.
Han SM, Lee KG, Park KK, et al. 2013. Antimicrobial activity of honey bee venom against select infectious fish pathogens. North American Journal of Aquaculture, 75(3): 445-8.
Anonim, (2014), Geleneksel Ve Tamamlayıcı Tıp Uygulamaları Yönetmeliği. Erişim Adresi: https://www.resmigazete.gov.tr/eskiler/2014/10/20141027-3.htm. Erişim Tarihi: 01.07.2022
Castro HJ, Mendez-Inocencio JI, Omidvar B, Omidvar J, Santilli J, Nielsen Jr HS, ... & Bellanti JA. (2005, November). A phase I study of the safety of honeybee venom extract as a possible treatment for patients with progressive forms of multiple sclerosis. In Allergy & Asthma Proceedings (Vol. 26, No. 6).
Yunusoğlu O, Bozkurt A, & Özdemir, H. (2022). Parkinson Hastalığında Fitoterapi, Apiterapi ve Aromaterapi Uygulamaları.
Aydın ON (2015). Algolojide arı zehiri. In Arı Ürünleri ve Sağlık (Apiterapi). Ed.: Akçiçek, E., Yücel, B. Sidas, İzmir. s: 164-172.
Jo M, Park MH, Kollıpara PS, An BJ, Song HS, Han SB, Kım JH, Song MJ, Hong JT (2012). Anti-cancer effect of bee venom toxin and melittin in ovarian cancer cells through induction of death receptors and inhibition of JAK2/STAT3 pathway. Toxicology and Applied Pharmacology. 258: 72–81.
Jang DM, Song HS (2013). Inhibitory Effects of Bee Venom on Growth of A549 Lung Cancer Cells via Induction of Death Receptors. Journal of Korean Acupuncture & Moxibustion Medicine Society. 30 (1): 57-70.
Lee SM, Yang EJ, Choı SM, Kım SH, Baek MG, Jıang JH (2012). Effects of Bee Venom on Glutamate-Induced Toxicity in Neuronal and Glial Cells. Evidence-Based Complementary and Alternative Medicine. Article ID 368196, DOI: 10.1155/2012/368196.
Çetin E, Özdemir AY, Erfen Ş, & Onur MA. (2022). Photoprotective and therapeutic effects of Apamin, Melittin and Phospholipase A2 on human keratinocyte cell line. Hacettepe Journal of Biology and Chemistry, 50(1), 13-24.
Park KK (2015). The therapeutic effects of bee venom on liver fibrosis. 44th Apimondia international apicultural congress abstract book. South Korea. s: 279.
Saber M, Daoud E, Gendyl AA, Wahhab K, Hegazı A (2015). Effect of Bee venom acupuncture as a complementary modality for treatment of chronic low back pain. 44th Apimondia international apicultural congress abstract book. South Korea. s: 301.
Han S, Chun S, Park K, Nıchollos YM, Pak S (2015). Anti-wrinkle effects of honeybee venom serum on facial wrinkles. 44th Apimondia international apicultural congress abstract book. South Korea. s: 302.
Jung BG, Lee JA, Park SB, Hyun PM, Park JK, Suh GH, Lee BJ (2013). Immunoprophylactic Effects of Administering Honeybee (Apis melifera) Venom Spray against Salmonella Gallinarum in Broiler Chicks. J. Vet. Med. Sci. 75 (10): 1287–1295.
Referanslar
Özbek H (2002). Arılar ve doğa. Uludag Arıcılık Dergisi. 3: 22-25.
Weiss, K. (2002). Bees in the Animal Kingdom and in Earth’s History. The Little Book of Bees, 1-13.
Karacoğlu M, Fıratlı Ç (1994). Orta Anadolu, Karadeniz geçit ve Ardahan izole bölgeleri bal arısı ekotiplerinin morfolojik özellikleri. Gaziosmanpaşa Üniversitesi Ziraat Fakültesi Dergisi. 11: 207-214.
Crane, E. (2004). A short history of knowledge about honey bees (Apis) up to 1800. Bee world, 85(1), 6-11.
Papa, G., Maier, R., Durazzo, A., Lucarini, M., Karabagias, I. K., Plutino, M., ... & Negri, I. (2022). The honey bee Apis mellifera: An insect at the interface between human and ecosystem health. Biology, 11(2), 233.
Șahinler, N. (2000). Bee products and their importance in human health. Ziraat Fakultesi Dergisi, Mustafa Kemal Universitesi, 5(1/2), 139-148.
SELÇUK M, DİNÇ H, KARABAĞ K (2010). Bal arısı zehrinin biyokimyasal yapısı ve tıptaki yeri. MYO-ÖS 2010- Ulusal Meslek Yüksekokulları Öğrenci Sempozyumu.
Kokuludağ A (2015). Arı zehiri içeriği ve tıbbi özellikleri. In Arı Ürünleri ve Sağlık (Apiterapi). Ed.: Akçiçek, E., Yücel, B. Sidas, İzmir. s: 147-151.
Bogdanov S (2017). Bee venom: Production, compostion, quality, Biological and therapeutic properties: A review. Erişim adresi: https://www.bee-hexagon.net/english/bee-products/downloads-venom-book/. Erişim tarihi: 20.06.2022.
Pak, S. C. (2017). Chemical composition of bee venom. Bee Products-Chemical and Biological Properties, 279-285.
Zhang, S., Liu, Y., Ye, Y., Wang, X. R., Lin, L. T., Xiao, L. Y., ... & Liu, C. Z. (2018). Bee venom therapy: Potential mechanisms and therapeutic applications. Toxicon, 148, 64-73.
Altintaş, L., & Bektaş, N. (2019). Apiterapi: 1. Ari Zehri. Uludag Bee J, 19, 82-95.
Aufschnaiter, A., Kohler, V., Khalifa, S., Abd El-Wahed, A., Du, M., El-Seedi, H., & Büttner, S. (2020). Apitoxin and its components against cancer, neurodegeneration and rheumatoid arthritis: Limitations and possibilities. Toxins, 12(2), 66.
Pascoal, A., Estevinho, M. M., Choupina, A. B., Sousa-Pimenta, M., & Estevinho, L. M. (2019). An overview of the bioactive compounds, therapeutic properties and toxic effects of apitoxin. Food and chemical toxicology, 134, 110864.
Keskiner AA (2021). Gıda takviyesi olarak kullanılan bazı apiterapik ürünlerin çeşitli kanser hücre hatlarında etkinliğinin belirlenmesi (Master's thesis, Amasya Üniversitesi).
Korkmaz A, Korkmaz V (2015). Arı zehiri üretimi ve apiterapi. 1.baskı. Samsun İli Arı Yetiştiricileri Birliği, Samsun.
Kolayli, S., & Keskin, M. (2020). Natural bee products and their apitherapeutic applications. Studies in Natural Products Chemistry, 66, 175-196.
Khalil, A., Elesawy, B. H., Ali, T. M., & Ahmed, O. M. (2021). Bee venom: From venom to drug. Molecules, 26(16), 4941.
Gajski, G., Leonova, E., & Sjakste, N. (2024). Bee Venom: Composition and Anticancer Properties. Toxins, 16(3), 117.
Son DJ, Lee JW, Lee YH, Song HS, Lee CK, Hong JT (2007). Therapeutic application of anti-arthritis, pain-releasing, and anti-cancer effects of bee venom and its constituent compounds. Pharmacology & Therapeutics, 115: 246-270.
Bellik Y. ,2015 . Bee venom: its potential use in alternative medicine. Anti-infective agents, 13(1), 3-16.
Wehbe, R., Frangieh, J., Rima, M., El Obeid, D., Sabatier, J. M., & Fajloun, Z. (2019). Bee venom: Overview of main compounds and bioactivities for therapeutic interests. Molecules, 24(16), 2997.
Ullah, A., Aldakheel, F. M., Anjum, S. I., Raza, G., Khan, S. A., & Gajger, I. T. (2023). Pharmacological properties and therapeutic potential of honey bee venom. Saudi Pharmaceutical Journal, 31(1), 96-109.
Chen, J., Guan, S. M., Sun, W., & Fu, H. (2016). Melittin, the major pain-producing substance of bee venom. Neuroscience bulletin, 32, 265-272.
Hossen, M. S., Shapla, U. M., Gan, S. H., & Khalil, M. I. (2016). Impact of bee venom enzymes on diseases and immune responses. Molecules, 22(1), 25.
Eze, O. B., Nwodo, O. F., & Ogugua, V. N. (2016). Therapeutic effect of honey bee venom. Proteins (enzymes), 1(2).
Carpena, M., Nuñez-Estevez, B., Soria-Lopez, A., & Simal-Gandara, J. (2020). Bee venom: an updating review of its bioactive molecules and its health applications. Nutrients, 12(11), 3360.
Chen J, ve Lariviere WR. 2010. The nociceptive and anti-nociceptive effects of bee venom injection and therapy: A double-edged sword. Progress in Neurobiology, C. 92, ss. 151–183. https://doi.org/10.1016/j.pneurobio.2010.06.00 6.
Chen SY, Zhou P, ve Qin Y. 2018. Treatment of Rheumatoid Arthritis by Bee-venom Acupuncture. Zhen ci yan jiu = Acupuncture research, 43(4), 251–254. https://doi.org/10.13702/j.1000-0607.170506.
Senel E, Kuyucu M, ve Süslü I 2014. Honey and bee venom in dermatology: A novel possible alternative or complimentary therapy for psoriasis vulgaris. Ancient Science of Life, 33(3), 190. https://doi.org/10.4103/0257- 7941.144626.
Han SM, Lee KG, Yeo JH, Kım WT, Park KK (2011). Biological effects of treatment of an animal skin wound with honeybee (Apis melifera. L) venom. Journal of Plastic, Reconstructive & Aesthetic Surgery. 64: 67-72.
Park MH, Choi MS, Kwak DH, Oh KW, Yoon DY, Han SB, Hong JT. 2011. Anticancer effect of bee venomin prostate cancer cells through activation of caspase pathway via inactivation of NF-κB. Prostate, 71(8), 801– 812. https://doi.org/10.1002/pros.21296.
Huh JE, Baek YH, Lee MH, Choi DY, Park DS, ve Lee JD. 2010. Bee venom inhibits tumor angiogenesis and metastasis by inhibiting tyrosine phosphorylation of VEGFR2 in LLC-tumor-bearing mice. Cancer Letters, 292(1), 98–110. https://doi.org/10.1016/j.canlet.2009.11.013.
Ip SW, Liao SS, Lin SY, Lin JP, Yang JS, Lin ML, Chung JG. 2008. The role of mitochondria in bee venom-induced apoptosis in human breast cancer MCF7 cells. In Vivo, 22(2), 237–246.
Li B, Gu W, Zhang C, Huang XQ, Han KQ, ve Ling CQ. 2006. Growth arrest and apoptosis of the human hepatocellular carcinoma cell line Bel-7402 induced by melittin. Onkologie, 29(8–9), 367–371. https://doi.org/10.1159/000094711.
Ling CQ, Li B, Zhang C, Zhu DZ, Huang XQ, Gu W, ve Li SX 2005. Inhibitory effect of recombinant adenovirus carrying melittin gene on hepatocellular carcinoma. Annals of Oncology, 16(1), 109–115. https://doi.org/10.1093/annonc/mdi019.
Moon DO, Park SY, Heo MS, Kim KC, Park C, Ko WS, Kim GY. 2006. Key regulators in bee venom-induced apoptosis are Bcl-2 and caspase-3 in human leukemic U937 cells through downregulation of ERK and Akt. International Immunopharmacology, 6(12), 1796–1807.
Moreno M, ve Giralt E. 2015. Three valuable peptides from bee and wasp venoms for therapeutic and biotechnological use: Melittin, apamin and mastoparan. Toxins, 7(4), 1126– 1150. https://doi.org/10.3390/toxins7041126.
Orsolic N, Knezevic A, Sver L, Terzic S, Hackenberger BK, Basic I. 2003. Influence of honey bee products on transplantable murine tumours. Veterinary and Comparative Oncology, 1(4), 216–226. https://doi.org/10.1111/j.1476- 5810.2003.00029.x.
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