HEALTH OF WOMAN.2017.1(117):89–97; doi 10.15574/HW.2017.117.89

Курченко А. І., Бенюк В. А., Потебня Г. П., Кобись В. Л., Тацький О. Ф., Неймарк О. С.
Національний медичний університет імені О.О. Богомольця, м. Київ
Інститут експериментальної патології, онкології і радіобіології імені Р.Є. Кавецького НАН України, м. Київ
Київський міський клінічний онкологічний центр
ТОВ «Спіріка», м. Київ

Мета дослідження: визначення впливу імунокорекції з використанням екзогенних пептидів MHP (препарат Камелін-Біо) на ефективність лікування дисплазії шийки матки I, II ст., зумовленої змішаною хламідійно-папіломавірусною інфекцією.

Матеріали та методи. Відповідно до завдань дослідження рандомізовано відібрано 72 пацієнтки з дисплазією папіломавірусно-хламідійної етіології. Жінки розподілені на дві групи: основну (n=36) і контрольну (n=36), зіставні за вiком, проявами та тривалістю процесу. Основна група традиційного лікування отримувала препарат Камелін-Біо Капсули у дозі 1 капсула (0,19 г) 3 рази на день 30 днів від початку лікування.

Результати. Зниження вірусного навантаження нижче клінічно значущого порога (3 lg) було досягнуто у 70% пацієнток з групи контролю та у 77,8% – в основній групі. Отже, адекватна комплексна терапія з урахуванням ролі екзогенних пептидів сприяє зменшенню активності ВПЛ, його елімінації, що знижує частоту рецидивів. Ефективність комбінованої терапії дисплазії шийки матки легкого та середнього ступенів з використанням препарату Камелін-Біо становила 88,9%. У групі пацієнток, що отримували стандартну терапію, ефективність становила 83,4%.

Заключення. Для вирішення життєво важливих клінічних завдань у розпорядженні практичного лікаря є інноваційний препарат Камелін-Біо, який, зокрема, дозволяє пришвидшити елімінацію ВПЛ у жінок фертильного віку. Включення у традиційну схему лікування дисплазії шийки матки препарату Камелін-Біо є етіопатогенетично виправданим і дозволяє гармонізувати імунний гомеостаз пацієнток та підвищити ефективність лікування.

Ключові слова: екзогенні пептиди, Т-лімфоцит, макрофаг, інтерлейкіни, імунний гомеостаз, вірус папіломи людини, дисплазія, лікування, ефективність.

Література:
1. Allam R, et al. Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming. EMBO reports. 2014;15:982–990. https://doi.org/10.15252/embr.201438463; PMid:24990442 PMCid:PMC4198042

2. Arend WP, Palmer G, Gabay C. IL-1, IL-18, and IL-33 families of cytokines. Immunol Rev. 2008;223:20–38. https://doi.org/10.1111/j.1600-065X.2008.00624.x; PMid:18613828

3. A.Elssner, M.Duncan, M.Gavrilin, M.D. Wewers. A Novel P2X7 Receptor Activator, the Human Cathelicidin-Derived Peptide LL37, Induces IL-1 Beta Processing and Release. J Immunol 172 (8), 4987-4994. 2004. https://doi.org/10.4049/jimmunol.172.8.4987; PMid:15067080

4. Bals R, Wilson JM. Cathelicidins-a family of multifunctional antimicrobial peptides. Cell Mol Life Sci. 2003;60:711-720. https://doi.org/10.1007/s00018-003-2186-9; PMid:12785718

5. Bandurska K, Berdowska A, Barczyсska-Felusiak, Krupa P. Unique features of human cathelicidin LL-37.

6. Barlow PG, Svoboda P, Mackellar A, Nash AA, York IA, Pohl J, Davidson DJ, Donis RO. Antiviral activity and increased host defense against influenza infection elicited by the human cathelicidin LL-37. PLoS One. 2011.

7. Baroja-Mazo A, et al. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nature immunology. 2014;15:738–748. https://doi.org/10.1038/ni.2919; PMid:24952504

8. Baroni MV, Chiabrando GA, Costa C, Wunderlin DA. Assessment of the floral origin of honey by SDS-page immunoblot techniques. J Agric Food Chem. 2002 Mar 13;50(6):1362-7. https://doi.org/10.1021/jf011214i; PMid:11879003

9. Bauernfeind F, Bartok E, Rieger A, Franchi L, Nunez G, Hornung V. Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome. Journal of immunology. 2011;187:613–617. https://doi.org/10.4049/jimmunol.1100613; PMid:21677136 PMCid:PMC3131480

10. Bucki R, Leszczynska K, Namiot A, Sokolowski W. Cathelicidin LL-37: a multitask antimicrobial peptide. Arch Immunol Ther Exp (Warsz) 2010;58:15–25. https://doi.org/10.1007/s00005-009-0057-2; PMid:20049649

11. Buettner R, Mora LB, Jove R. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res. 2002;8(4):945–954. PMid:11948098

12. Burns K, Martinon F, Tschopp J (2003) New insights into the mechanism of IL-1beta maturation. Curr Opin Immunol 15: 26–30. https://doi.org/10.1016/S0952-7915(02)00017-1

13. B.N.Martin, C.Wang, C.Zhang, Z.Kang, M.F.Gulen, J.A Zepp, J.Zhao, G.Bian, J.Do, B.Min, P.G. Pavicic Jr, C.El-Sanadi, P.L.Fox, A.Akitsu, Y.Iwakura, A.Sarkar, M.D.Wewers, W.J.Kaiser, E.S.Mocarski, M.E.Rothenberg, A.G.Hise, G.R.Dubyak, R.M.Ransohoff, X.Li. T cell–intrinsic ASC critically promotes TH17-mediated experimental autoimmune encephalomyelitis. Nature Immunology 17, 583–592 (2016). https://doi.org/10.1038/ni.3389; PMid:26998763 PMCid:PMC5385929

14. Chua LS, Lee JY, Chan GF. Honey protein extraction and determination by mass spectrometry. Anal Bioanal Chem. 2013 Apr;405(10):3063-74. https://doi.org/10.1007/s00216-012-6630-2; PMid:23292042

15. Compan V, et al. Cell volume regulation modulates NLRP3 inflammasome activation. Immunity. 2012;37:487-500. https://doi.org/10.1016/j.immuni.2012.06.013; PMid:22981536

16. Cain K, Langlais C, Sun XM, Brown DG, Cohen GM. Physiological concentrations of K+ inhibit cytochrome c-dependent formation of the apoptosome. The Journal of biological chemistry. 2001;276:41985-41990. https://doi.org/10.1074/jbc.M107419200; PMid:11553634

17. Davis BK, Wen H, Ting JPY (2011) The Inflammasome NLRs in Immunity, Inflammation, and Associated Diseases. Annual Review of Immunology 29: 707–735. https://doi.org/10.1146/annurev-immunol-031210-101405; PMid:21219188 PMCid:PMC4067317

18. Dinarello CA (2009) Immunological and Inflammatory Functions of the Interleukin-1 Family. Annual Review of Immunology 27: 519–550. https://doi.org/10.1146/annurev.immunol.021908.132612; PMid:19302047

19. Dongiovanni P., Fracanzani A. L., Fargion S., Valenti L. Iron in fatty liver and in the metabolic syndrome: a promising therapeutic target. Journal of Hepatology. 2011;55(4):920–932. https://doi.org/10.1016/j.jhep.2011.05.008; PMid:21718726

20. Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science. 2008;320:674-677. https://doi.org/10.1126/science.1156995; PMid:18403674 PMCid:PMC2396588

21. D.M. Mosser, J.P. Edwards. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008 Dec; 8(12): 958–969. https://doi.org/10.1038/nri2448; PMid:19029990 PMCid:PMC2724991

22. Eder C (2009) Mechanisms of interleukin-1[beta] release. Immunobiology 214: 543-553. https://doi.org/10.1016/j.imbio.2008.11.007; PMid:19250700

23. El Hallani S, Boisselier B, Peglion F et al. A new alternative mechanism in glioblastoma vascularization: tubular vasculogenic mimicry. Brain 2010;133:973-982. https://doi.org/10.1093/brain/awq044; PMid:20375132 PMCid:PMC4861203

24. Everett KD.. Chlamydia and Chlamydiales: more than meets the eye. Vet Microbiol 2000; 75:109–26. https://doi.org/10.1016/S0378-1135(00)00213-3

25. Foss FM. Immunologic mechanisms of antitumor activity. Semin Oncol. 2002 Jun;29(3 Suppl 7):5-11. https://doi.org/10.1053/sonc.2002.33076; PMid:12068382

26. Franchi L, et al. Cytosolic Double-Stranded RNA Activates the NLRP3 Inflammasome via MAVS-Induced Membrane Permeabilization and K+ Efflux. Journal of immunology. 2014;193:4214-4222. https://doi.org/10.4049/jimmunol.1400582; PMid:25225670 PMCid:PMC4185247

27. Franchi L, Eigenbrod T, Munoz-Planillo R, Nunez G (2009) The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol 10: 241–247. https://doi.org/10.1038/ni.1703; PMid:19221555 PMCid:PMC2820724

28. Franklin BS, et al. The adaptor ASC has extracellular and ‘prionoid’ activities that propagate inflammation. Nature immunology. 2014;15:727–737. https://doi.org/10.1038/ni.2913; PMid:24952505 PMCid:PMC4116676

29. Gringhuis SI, Kaptein TM, Wevers BA, Theelen B, van der Vlist M, Boekhout T, Geijtenbeek TB. Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1beta via a noncanonical caspase-8 inflammasome. Nat Immunol. 2012. https://doi.org/10.1038/ni.2222; PMid:22267217

30. Guillemin GJ, Brew BJ. Microglia, macrophages, perivascular macrophages, and pericytes: a review of function and identification. J Leukoc Biol. 2004;75:388–397. https://doi.org/10.1189/jlb.0303114; PMid:14612429

31. Gurung P, et al. FADD and caspase-8 mediate priming and activation of the canonical and noncanonical Nlrp3 inflammasomes. Journal of immunology. 2014;192:1835-1846. https://doi.org/10.4049/jimmunol.1302839; PMid:24453255 PMCid:PMC3933570

32. Nasarian H., Taghavizad R., Majd A. Origin of honey proteins and method for its quality control. Pak. J. Bot., 2010; 42(5): 3221-3228.

33. den Hertog AL, van Marle J, van Veen HA, Van’t Hof W, Bolscher JG, Veerman EC, Nieuw Amerongen AV. Candidacidal effects of two antimicrobial peptides: histatin 5 causes small membrane defects, but LL-37 causes massive disruption of the cell membrane. Biochem J. 2005;388:689–695. https://doi.org/10.1042/BJ20042099; PMid:15707390 PMCid:PMC1138977

34. H.Yilmaz., O.Kufrevioglu. Proteins in honey. GIDA. 2003, 28 (2): 155–157.

35. Hendrix MJ, Seftor EA, Seftor RE, Chao JT, Chien DS, Chu YW. Tumor cell vascular mimicry: Novel targeting opportunity in melanoma. Pharmacol Ther. 2016 Mar;159:83–92. https://doi.org/10.1016/j.pharmthera.2016.01.006; PMid:26808163 PMCid:PMC4779708

36. Hentze H, Lin XY, Choi MS, Porter AG. Critical role for cathepsin B in mediating caspase-1-dependent interleukin-18 maturation and caspase-1-independent necrosis triggered by the microbial toxin nigericin. Cell Death Differ. 2003;10(9):956–968. https://doi.org/10.1038/sj.cdd.4401264; PMid:12934070

37. Hornung V, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nature immunology. 2008;9:847-856. https://doi.org/10.1038/ni.1631; PMid:18604214 PMCid:PMC2834784

38. Iacob SA, Iacob DG. Antibacterial function of the human cathelicidin-18 peptide (LL-37) between theory and practice. Protein Pept Lett. 2014;21(12):1247–56. PMid:25101632

39. Hawkins J. Investigating Antibacterial Plant-Derived Compounds from Natural Honey.2015.Cardiff Univ: 11.

40. Majtan J., Kovбcovб E., Bilikova K., Simъth J.. The immunostimulatory effect of the recombinant apalbumin 1-major honeybee royal jelly protein-on TNFa release. International Immunopharmacology, 2006; 6(2):269–78. https://doi.org/10.1016/j.intimp.2005.08.014; PMid:16399632

41. Jamasbi RJ, Wan X, Stoner GD. Epitope masking of rat esophageal carcinoma tumor-associated antigen by certain coexisting glycolipid and phospholipid molecules: a potential mechanism for tumor cell escape from the host immune responses. Cancer Immunol Immunother. 1994 Feb;38(2):99–106. https://doi.org/10.1007/BF01526204; https://doi.org/10.1007/s002620050041; PMid:7508339

42. Kailasan Vanaja S, et al. Bacterial RNA:DNA hybrids are activators of the NLRP3 inflammasome. Proceedings of the National Academy of Sciences of the United States of America. 2014;111:7765–7770. https://doi.org/10.1073/pnas.1400075111; PMid:24828532 PMCid:PMC4040571

43. Kai-Larsen Y, Agerberth B. The role of the multifunctional peptide LL-37 in host defense. Front Biosci. 2008;13:3760–3767. https://doi.org/10.2741/2964; PMid:18508470

44. Karlsson J, Carlsson G, Larne O, Andersson M, Putsep K. Vitamin D3 induces pro-LL-37 expression in myeloid precursors from patients with severe congenital neutropenia. J Leukoc Biol. 2008;84:1279–1286. https://doi.org/10.1189/jlb.0607437; PMid:18703682

45. Kanneganti TD, et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature. 2006;440:233–236. https://doi.org/10.1038/nature04517; PMid:16407888

46. Kanneganti TD. Central roles of NLRs and inflammasomes in viral infection. Nature reviews Immunology. 2010;10:688–698. https://doi.org/10.1038/nri2851; PMid:20847744 PMCid:PMC3909537

47. Lai Y, Gallo RL. AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense. Trends Immunol. 2009;30:131–141. https://doi.org/10.1016/j.it.2008.12.003; PMid:19217824 PMCid:PMC2765035

48. Latz E (2010) The inflammasomes: mechanisms of activation and function. Current Opinion in Immunology 22: 28–33. https://doi.org/10.1016/j.coi.2009.12.004; PMid:20060699 PMCid:PMC2844336

49. Li HM, Chen J, Xiong CM, Wei H, Yin CC, Ruan JL. Apoptosis Induction by the Total Flavonoids from Arachniodes exilis in HepG2 Cells through Reactive Oxygen Species-Mediated Mitochondrial Dysfunction Involving MAPK Activation. Evid-Based Compl Alt. 2014;2014(5):906941.

50. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zugel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311:1770–1773. https://doi.org/10.1126/science.1123933; PMid:16497887

51. Locati M, Mantovani A, Sica A. Macrophage activation and polarization as an adaptive component of innate immunity. Adv Immunol. 2013;120:163–84. https://doi.org/10.1016/B978-0-12-417028-5.00006-5; PMid:24070384

52. L.S.Chua, J.Y.Lee, G.F.Chan. Characterization of the Proteins in Honey. Analytical Letters. Volume 48, 2015 – Issue 4; 697–709. https://doi.org/10.1080/00032719.2014.952374

53. L.Wang, H.Fu, G.Nanayakkara, Y. Li, Y.Shao, C.Johnson, J.Cheng, W.Y. Yang, F.Yang, M.Lavallee, Y.Xu, X.Cheng, H.Xi, J.Yi, J.Yu, E.T. Choi, H.Wang, X.Yang. Novel extracellular and nuclear caspase-1 and inflammasomes propagate inflammation and regulate gene expression: a comprehensive database mining study. J Hematol Oncol. 2016; 9: 122. https://doi.org/10.1186/s13045-016-0351-5; PMid:27842563 PMCid:PMC5109738

54. Lupfer C, Kanneganti TD. The expanding role of NLRs in antiviral immunity. Immunological reviews. 2013;255:13–24. https://doi.org/10.1111/imr.12089; PMid:23947344 PMCid:PMC3759815

55. Mariathasan S, et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature. 2006;440:228–232. https://doi.org/10.1038/nature04515; PMid:16407890

56. Marina-Garcia N, et al. Pannexin-1-mediated intracellular delivery of muramyl dipeptide induces caspase-1 activation via cryopyrin/NLRP3 independently of Nod2. Journal of immunology. 2008;180:4050–4057. https://doi.org/10.4049/jimmunol.180.6.4050

57. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440:237–241. https://doi.org/10.1038/nature04516; PMid:16407889

58. Martinon F, Agostini L, Meylan E, Tschopp J. Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome. Current biology : CB. 2004;14:1929–1934. https://doi.org/10.1016/j.cub.2004.10.027; PMid:15530394

59. Martinon F, Mayor A, Tschopp (2009) The Inflammasomes: Guardians of the Body. Annual Review of Immunology 27: 229–265. https://doi.org/10.1146/annurev.immunol.021908.132715; PMid:19302040

60. McDonald DM, Munn L, Jain RK. Vasculogenic mimicry: how convincing, how novel, and how significant? Am J Pathol 2000;156:383–388. https://doi.org/10.1016/S0002-9440(10)64740-2

61. Mesaik MA, Dastagir N, Uddin N, Rehman K, Azim MK. Characterization of Immunomodulatory Activities of Honey Glycoproteins and Glycopeptides. J Agric Food Chem. 2015 Jan 14;63(1):177–84. https://doi.org/10.1021/jf505131p; PMid:25496517

62. M.Pazgier, B.Ericksen, M.Ling, E.Toth, J.Shi, X.Li, A.Galliher-Beckley, L.Lan,G.Zou, C. Zhan, W.Yuan, E.Pozharski, W.Lu. Structural and functional analysis of the pro-domain of human cathelicidin, LL-37. Biochemistry. 2013 Mar 5; 52(9): 1547–1558. https://doi.org/10.1021/bi301008r; PMid:23406372 PMCid:PMC3634326

63. Mello T, Zanieri F, Ceni E, Galli A. Oxidative Stress in the Healthy and Wounded Hepatocyte: A Cellular Organelles Perspective. Oxid Med Cell Longev. 2016;2016:8327410. https://doi.org/10.1155/2016/8327410; PMid:26788252 PMCid:PMC4691634

64. Mocarski ES, Upton JW, Kaiser WJ. Viral infection and the evolution of caspase 8-regulated apoptotic and necrotic death pathways. Nat Rev Immunol. 2012;12:79–88.

65. Mohamed Lamkanfi VMD (2009) Inflammasomes: guardians of cytosolic sanctity. Immunological Reviews 227: 95–105. https://doi.org/10.1111/j.1600-065X.2008.00730.x; PMid:19120479

66. M.Lamkanfi, A.Sarkar, L.Vande Walle, A.C. Vitari, A.O.Amer, M.D. Wewers, K.J. Tracey, T. Kanneganti, V.M. Dixit. Inflammasome-Dependent Release of the Alarmin HMGB1 in Endotoxemia. J Immunol. 2010 Oct 1; 185(7): 4385–4392. https://doi.org/10.4049/jimmunol.1000803; PMid:20802146 PMCid:PMC3428148

67. Nakatsura T, Komori H, Kubo T, Yoshitake Y, Senju S, Katagiri T, Furukawa Y, Ogawa M, Nakamura Y, Nishimura Y. Mouse homologue of a novel human oncofetal antigen, glypican-3, evokes T-cell-mediated tumor rejection without autoimmune reactions in mice. Clin Cancer Res. 2004;10:8630–8640. https://doi.org/10.1158/1078-0432.CCR-04-1177; PMid:15623647

68. Nijnik A, Pistolic J, Filewod NC, Hancock RE. Signaling pathways mediating chemokine induction in keratinocytes by cathelicidin LL-37 and flagellin. J Innate Immun. 2012;4:377–386. https://doi.org/10.1159/000335901; PMid:22516952

69. Nьrnberger T, Brunner F, Kemmerling B, Piater L. Innate immunity in plants and animals: striking similarities and obvious differences. Immunol. Rev. 2004; 198: 249–266. https://doi.org/10.1111/j.0105-2896.2004.0119.x; PMid:15199967

70. Okamura H, Tsutsi H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, Torigoe K, Okura T, Nukada Y, Hattori K. Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature. 1995;378(6552):88–91. https://doi.org/10.1038/378088a0; PMid:7477296

71. Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T, Gallo RL, Leung DY. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med. 2002;347:1151–1160. https://doi.org/10.1056/NEJMoa021481; PMid:12374875

72. Ostojic S, Dubanchet S, Chaouat G, Abdelkarim M, Truyens C, Capron F. Demonstration of the presence of IL-16, IL-17 and IL-18 at the murine fetomaternal interface during murine pregnancy. Am J Reprod Immunol. 2003;49(2):101-112. https://doi.org/10.1034/j.1600-0897.2003.01150.x; PMid:12765349

73. Pedra JHF, Cassel SL, Sutterwala FS (2009) Sensing pathogens and danger signals by the inflammasome. Current Opinion in Immunology 21: 10–16. https://doi.org/10.1016/j.coi.2009.01.006; PMid:19223160 PMCid:PMC2701640

74. Putsep K, Carlsson G, Boman HG, Andersson M. Deficiency of antibacterial peptides in patients with morbus Kostmann: an observation study. Lancet. 2002;360:1144–1149. https://doi.org/10.1016/S0140-6736(02)11201-3

75. Rico-Mata R, De Leon-Rodriguez LM, Avila EE. Effect of antimicrobial peptides derived from human cathelicidin LL-37 on Entamoeba histolytica trophozoites. Exp Parasitol. 2013;133:300–306. https://doi.org/10.1016/j.exppara.2012.12.009; PMid:23274811

76. S.Ahmed, N.H.Othman. Honey as a Potential Natural Anticancer Agent: A Review of Its Mechanisms. Evid Based Complement Alternat Med. 2013; 2013:829070. https://doi.org/10.1155/2013/829070; PMid:24363771 PMCid:PMC3865795

77. Sander LE, et al. Detection of prokaryotic mRNA signifies microbial viability and promotes immunity. Nature. 2011;474:385–389. https://doi.org/10.1038/nature10072; PMid:21602824 PMCid:PMC3289942

78. Sachse K, Laroucau K, Riege K, Wehner S, Dilcher M, Creasy HH, Weidmann M, Myers G, Vorimore F, Vicari N, et al. Evidence for the existence of two new members of the family Chlamydiaceae and proposal of Chlamydia avium sp. nov. and Chlamydia gallinacea sp. nov. Syst Appl Microbiol 2014; 37:79–88. https://doi.org/10.1016/j.syapm.2013.12.004; PMid:24461712

79. Se-Ra Won, Deug-Chan Lee, Seuk Hyun Ko, Jang-Won Kim, Hae-Ik Rhee. Honey major protein characterization and its application to adulteration detection. Food Research International 41 (2008) 952–956. https://doi.org/10.1016/j.foodres.2008.07.014

80. Sims JE, Smith DE (2010) The IL-1 family: regulators of immunity. Nat Rev Immunol 10: 89–102. https://doi.org/10.1038/nri2691; PMid:20081871

81. Sha W, et al. Human NLRP3 inflammasome senses multiple types of bacterial RNAs. Proceedings of the National Academy of Sciences of the United States of America. 2014. https://doi.org/10.1073/pnas.1412487111

82. Steinstraesser L, Tippler B, Mertens J, Lamme E, Homann HH, Lehnhardt M, Wildner O, Steinau HU, Uberla K. Inhibition of early steps in the lentiviral replication cycle by cathelicidin host defense peptides. Retrovirology. 2005;2:2. https://doi.org/10.1186/1742-4690-2-S1-P2; https://doi.org/10.1186/1742-4690-2-S1-S2; https://doi.org/10.1186/1742-4690-2-2; PMid:15656908 PMCid:PMC548510

83. Stout RD, Suttles J. Functional plasticity of macrophages: reversible adaptation to changing microenvironments. J Leukoc Biol. 2004;76:509–513. https://doi.org/10.1189/jlb.0504272; PMid:15218057 PMCid:PMC1201486

84. Strowig T, Henao-Mejia J, Elinav E, Flavell R (2012) Inflammasomes in health and disease. Nature 481: 278–286. https://doi.org/10.1038/nature10759; PMid:22258606

85. T.Hayashi, N.Takamatsu, T.Nakashima, T.Arita. Immunological Characterization of Honey Proteins and Identification of MRJP 1 as an IgE-binding protein. Biosci Biotechnol Biochem. 2011;75(3):556–60. https://doi.org/10.1271/bbb.100778; PMid:21389615

86. T.Szczкsna. Protein content and amino acid composition of bee-collected pollen from selected botanical origins. Journal of Apicultural Science. Vol. 50 No. 2, 2006; 81–90.

87. Tнmбr J., Tуvбri J., Rбsу E., Mйszбros L., Bereczky B., Lapis K. Platelet-Mimicry of Cancer Cells: Epiphenomenon with Clinical Significance. Oncology 2005;69:185–201. https://doi.org/10.1159/000088069; PMid:16138000

88. Thomas PG, et al. The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1. Immunity. 2009;30:566–575. https://doi.org/10.1016/j.immuni.2009.02.006; PMid:19362023 PMCid:PMC2765464

89. Tsai WH, Chuang HY, Chen HH, Wu YW, Cheng SH, Huang TC. Application of sugaring-out extraction for the determination of sulfonamides in honey by high-performance liquid chromatography with fluorescence detection. J Chromatogr A. 2010 Dec 3;1217(49):7812–5. https://doi.org/10.1016/j.chroma.2010.10.008; PMid:21044783

90. Turkson J, Jove R. STAT proteins: novel molecular targets for cancer drug discovery. Oncogene. 2000;19(56):6613–6626. https://doi.org/10.1038/sj.onc.1204086; PMid:11426647

91. Unemo M, Seth-Smith HMB, Cutcliffe LT, Skilton RJ, Barlow D, Goulding D, Persson K, Harris SR, Kelly A, Bjartling C, et al. 2010. The Swedish new variant of Chlamydia trachomatis: Genome sequence, morphology, cell tropism and phenotypic characterization. Microbiology 156: 1394–1404. https://doi.org/10.1099/mic.0.036830-0; PMid:20093289 PMCid:PMC3541825

92. Voog E, Ricksten A, Stenglein M, Jonassen F, Ternesten A, Ryd W, Lцwhagen GB. Are acetowhite lesions of the cervix correlated to the presence of Epstein-Barr virus DNA? Int J STD AIDS. 1997;8:432–436. https://doi.org/10.1258/0956462971920488; PMid:9228590

93. Wang G. Tool developments for structure-function studies of host defense peptides. Protein Pept Lett. 2007;14:57–69. https://doi.org/10.2174/092986607779117182; PMid:17266652

94. Wang G. Natural antimicrobial peptides as promising anti-HIV candidates. Curr. Topics Peptide Proteins. 2012;13:93–110.

95. Wang G, Epand RF, Mishra B, Lushnikova T, Thomas VC, Bayles KW, Epand RM. Decoding the functional roles of cationic side chains of the major antimicrobial region of human cathelicidin LL-37. Antimicrob Agents Chemother. 2012;56:845–856. https://doi.org/10.1128/AAC.05637-11; PMid:22083479 PMCid:PMC3264245

96. Wang G, Watson KM, Buckheit RW., Jr. Anti-human immunodeficiency virus type 1 activities of antimicrobial peptides derived from human and bovine cathelicidins. Antimicrob Agents Chemother. 2008;52:3438–3440. https://doi.org/10.1128/AAC.00452-08; PMid:18591279 PMCid:PMC2533476

97. Williamson A.L. Chattopadhyay K., Hazra A., Dandara C. The combined risks of reduced or increased function variants in cell death pathway genes differentially influence cervical cancer risk and herpes simplex virus type 2 infection among black Africans and the Mixed Ancestry population of South Africa. BMC Cancer. 2015; 15: 680. https://doi.org/10.1186/s12885-015-1678-y; PMid:26458812 PMCid:PMC4603903

98. Wright TC, Stoler MH, Behrens CM, Sharma A, Zhang G, Wright TL. Primary cervical cancer screening with human papillomavirus: end of study results from the ATHENA study using HPV as the first-line screening test. Gynecol Oncol. 2015;136:189–197. https://doi.org/10.1016/j.ygyno.2014.11.076; PMid:25579108

99. D.Wohlmeister, D. Barreto Vianna, Vi. Etges Helfer, F.Gimenes, M.Lopes Consolaro, R. Bones Barcellos, M.L.Rossetti, L.Calil, A.Buffon, D.A. Pilger. Association of human papillomavirus and Chlamydia trachomatis with intraepithelial alterations in cervix samples. Mem Inst Oswaldo Cruz. 2016 Feb; 111(2): 106–113. https://doi.org/10.1590/0074-02760150330; PMid:26841046 PMCid:PMC4750450

100. Wu WK, Wang G, Coffelt SB, Betancourt AM, Lee CW, Fan D, Wu K, Yu J, Sung JJ, Cho CH. Emerging roles of the host defense peptide LL-37 in human cancer and its potential therapeutic applications. Int J Cancer. 2010;127: 1741–1747. https://doi.org/10.1002/ijc.25489; PMid:20521250 PMCid:PMC2930073

101. Y.Haruyama, H.Kataoka. Glypican-3 is a prognostic factor and an immunotherapeutic target in hepatocellular carcinoma. World J Gastroenterol. 2016 Jan 7; 22(1): 275–283. https://doi.org/10.3748/wjg.v22.i1.275; PMid:26755876 PMCid:PMC4698492

102. Zanetti M. The role of cathelicidins in the innate host defenses of mammals. Curr Issues Mol Biol. 2005;7:179–196. PMid:16053249

103. Zhang C, Jia X, Bao J, Chen S, Wang K, Zhang Y, Li P, Wan JB, Su H, Wang Y, Mei Z, He C. Polyphyllin VII induces apoptosis in HepG2 cells through ROS-mediated mitochondrial dysfunction and MAPK pathways. BMC Complement Altern Med. 2016 Feb 9;16:58. https://doi.org/10.1186/s12906-016-1036-x; PMid:26861252 PMCid:PMC4746894