Ameliorative Effect of Melittin Encoded DNA Plasmid in an Ovalbumin-induced Murine Model of Allergy
-
Hadi Esmaeili Gouvarchinghaleh
,
Ali Farhadi Biregani
,
Abbas Doosti
,
Ramezan Ali Taheri
,
Morteza Mirzaei
,
Ali Zahiri
,
Gholamreza Farnoosh
Abstract
Melittin is a natural toxin used in traditional medicine as an anti-inflammatory drug. It seems that the anti-inflammatory properties of melittin are caused by suppressing the expression
of inflammatory genes and inhibiting signaling pathways. However, the use of melittin is limited
due to instability, rapid degradation, and impurity. The aim of this study was to investigate the intranasal administration of a melittin-encoded plasmid as a new melittin delivery method for allergic diseases.
After the induction of a mouse model of allergic rhinitis, mice received intranasal melittin plasmid. After the final challenge with allergen and allergic symptom assessment, the required samples were collected and transforming growth factor-beta (TGF-β), interferon-gamma (IFN-γ), and interleukin-4 (IL-4) cytokine levels, serum levels of ovalbumin-specific immunoglobulin (Ig) E, and histopathological changes were assessed. In addition to investigating the immune response, the effect of melittin on the expression level of genes involved in apoptosis was also investigated.
The melittin plasmid significantly improved nasal symptoms and decreased eosinophil infiltration into the nasal mucosa. Moreover, melittin decreased the expression levels of IL-4 and TGF-β in nasal lavage fluid, while IFN-γ expression was increased. Regarding the expression level of genes involved in apoptosis, melittin led to an increase in BAX mRNA expression.
These results suggest intranasal administration of a plasmid encoding melittin can suppress nasal symptoms, eosinophil infiltration, and immunomodulation of the immune response, which can be considered a promising approach in the treatment of inflammatory diseases.
1. Foster S. CPD-How you can help people with allergies. Pharm J. 2011;286(7652):535.
2. Fahy JV. Type 2 inflammation in asthma—present in most, absent in many. Nat Rev Immunol. 2015;15(1):57-65.
3. Liew FY, Pitman NI, McInnes IB. Disease-associated functions of IL-33: the new kid in the IL-1 family. Nat Rev Immunol. 2010;10(2):103-10.
4. Kurowska‐Stolarska M, Hueber A, Stolarski B, McInnes I. Interleukin‐33: a novel mediator with a role in distinct disease pathologies. J Intern Med. 2011;269(1):29-35.
5. Liu Z, Fan Z, Liu J, Wang J, Xu M, Li X, et al. Melittin‐Carrying Nanoparticle Suppress T Cell‐Driven Immunity in a Murine Allergic Dermatitis Model. Adv Sci. 2023:2204184.
6. Pritchard DI, Falcone FH, Mitchell PD. The evolution of IgE‐mediated type I hypersensitivity and its immunological value. Allergy. 2021;76(4):1024-40.
7. Billingham M, Morley J, HANSON JM, Shipolini R, Vernon C. An anti-inflammatory peptide from bee venom. Nature. 1973;245:163-4.
8. Jeong CH, Cheng WN, Bae H, Lee KW, Han SM, Petriello MC, et al. Bee venom decreases LPS-induced inflammatory responses in bovine mammary epithelial cells. J Microbiol Biotechnol. 2017;27(10):1827-36.
9. Lariviere WR, Melzack R. The bee venom test: a new tonic-pain test. PAIN®. 1996;66(2-3):271-7.
10. Tiwari R, Tiwari G, Lahiri A, Ramachandran V, Rai A. Melittin: A Natural Peptide with Expanded Therapeutic Applications. J Nat Prod. 2022;12(2):13-29.
11. Yoon H, Kim MJ, Yoon I, Li DX, Bae H, Kim SK. Nicotinic acetylcholine receptors mediate the suppressive effect of an injection of diluted bee venom into the GV3 acupoint on oxaliplatin-induced neuropathic cold allodynia in rats. Biol Pharm Bull. 2015;38(5):710-4.
12. Lim B-S, Moon HJ, Li DX, Gil M, Min JK, Lee G, et al. Effect of bee venom acupuncture on oxaliplatin-induced cold allodynia in rats. J Evid Based Complementary Altern Med. 2013;2013.
13. Baek YH, Huh JE, Lee JD, Park DS. Antinociceptive effect and the mechanism of bee venom acupuncture (Apipuncture) on inflammatory pain in the rat model of collagen-induced arthritis: Mediation by α2-Adrenoceptors. Brain Res. 2006;1073:305-10.
14. Varanda EA, Monti R, Tavares DC. Inhibitory effect of propolis and bee venom on the mutagenicity of some direct‐and indirect‐acting mutagens. Teratog Carcinog Mutagen. 1999;19(6):403-13.
15. Gajski G, Garaj-Vrhovac V. Radioprotective effects of honeybee venom (Apis mellifera) against 915-mhz microwave radiation–induced DNA damage in wistar rat lymphocytes: In vitro study. Int J Toxicol. 2009;28(2):88-98.
16. Askari P, Namaei MH, Ghazvini K, Hosseini M. In vitro and in vivo toxicity and antibacterial efficacy of melittin against clinical extensively drug-resistant bacteria. BMC Pharmacol Toxicol. 2021;22:1-12.
17. Memariani H, Memariani M, Moravvej H, Shahidi-Dadras M. Melittin: a venom-derived peptide with promising anti-viral properties. Eur J Clin Microbiol Infect Dis. 2020;39:5-17.
18. Kim W-H, An H-J, Kim J-Y, Gwon M-G, Gu H, Jeon M, et al. Beneficial effects of melittin on ovalbumin-induced atopic dermatitis in mouse. Sci Rep. 2017;7(1):17679.
19. Lee G, Bae H. Anti-inflammatory applications of melittin, a major component of bee venom: Detailed mechanism of action and adverse effects. Molecules. 2016;21(5):616.
20. Tosteson M, Tosteson D. The sting. Melittin forms channels in lipid bilayers. Biophys J. 1981;36(1):109-16.
21. Moon D-O, Park S-Y, Lee K-J, Heo M-S, Kim K-C, Kim M-O, et al. Bee venom and melittin reduce proinflammatory mediators in lipopolysaccharide-stimulated BV2 microglia. Int Immunopharmacol. 2007;7(8):1092-101.
22. Han SM, Kim JM, Park KK, Chang YC, Pak SC. Neuroprotective effects of melittin on hydrogen peroxide-induced apoptotic cell death in neuroblastoma SH-SY5Y cells. BMC Complement Altern Med. 2014;14(1):1-8.
23. Son DJ, Kang J, Kim TJ, Song H-S, Sung K-J, Yun DY, Hong JT. Melittin, a major bioactive component of bee venom toxin, inhibits PDGF receptor beta-tyrosine phosphorylation and downstream intracellular signal transduction in rat aortic vascular smooth muscle cells. J Toxicol Environ Health - A. 2007;70(15-16):1350-5.
24. Kim S-J, Park J-H, Kim K-H, Lee W-R, Kim K-S, Park K-K. Melittin inhibits atherosclerosis in LPS/high-fat treated mice through atheroprotective actions. J Atheroscler Thromb. 2011;18(12):1117-26.
25. Cho H-J, Kang J-H, Park K-K, Choe J-Y, Park Y-Y, Moon Y-S, et al. Comparative proteome analysis of Tumor necrosis factor α-stimulated human Vascular Smooth Muscle Cells in response to melittin. Proteome sci. 2013;11(1):1-9.
26. Park J-H, Kum Y-S, Lee T-I, Kim S-J, Lee W-R, Kim B-I, et al. Melittin attenuates liver injury in thioacetamide-treated mice through modulating inflammation and fibrogenesis. Exp Biol Med. 2011;236(11):1306-13.
27. Kim K-H, Sung H-J, Lee W-R, An H-J, Kim J-Y, Pak SC, et al. Effects of melittin treatment in cholangitis and biliary fibrosis in a model of xenobiotic-induced cholestasis in mice. Toxins. 2015;7(9):3372-87.
28. Park HJ, Son DJ, Lee CW, Choi MS, Lee US, Song HS, et al. Melittin inhibits inflammatory target gene expression and mediator generation via interaction with IκB kinase. Biochem Pharmacol. 2007;73(2):237-47.
29. Du G, He P, Zhao J, He C, Jiang M, Zhang Z, et al. Polymeric microneedle-mediated transdermal delivery of melittin for rheumatoid arthritis treatment. J Control Release. 2021;336:537-48.
30. Biregani AF, Khodadadi A, Doosti A, Asadirad A, Dehcheshmeh MG, Ghadiri AA. Allergen specific immunotherapy with plasmid DNA encoding OVA-immunodominant T cell epitope fused to Tregitope in a murine model of allergy. Cell Immunol. 2022;376:104534.
31. Wang Y, Zhou Y, Zhu Y, Yu W, Wang J, Fu J, et al. The comparation of intraperitoneal injection and nasal-only delivery allergic rhinitis model challenged with different allergen concentration. Am J Rhinol. 2019;33(2):145-52.
32. Liang M-J, Fu Q-L, Jiang H-Y, Chen F-H, Chen D, Chen D-H, et al. Immune responses to different patterns of exposure to ovalbumin in a mouse model of allergic rhinitis. Eur Arch Otorhinolaryngol. 2016;273:3783-8.
33. Jung H, Kim YS, Jung D-M, Lee K-S, Lee J-M, Kim KK. Melittin-derived peptides exhibit variations in cytotoxicity and antioxidant, anti-inflammatory and allergenic activities. Anim Cells Syst. 2022;26(4):158-65.
34. Hartman D, Tomchek L, Lugay J, Lewin A, Chau T, Carlson R. Comparison of antiinflammatory and antiallergic drugs in the melittin-and D49 PLA2-induced mouse paw edema models. Agents and Actions. 1991;34(1-2):84-8.
35. An HJ, Kim JY, Kim WH, Gwon MG, Gu HM, Jeon MJ, et al. Therapeutic effects of bee venom and its major component, melittin, on atopic dermatitis in vivo and in vitro. Br J Pharmacol. 2018;175(23):4310-24.
36. Liu Z, Fan Z, Liu J, Wang J, Xu M, Li X, et al. Melittin‐Carrying Nanoparticle Suppress T Cell‐Driven Immunity in a Murine Allergic Dermatitis Model. Adv Sci. 2023;10(7):2204184.
37. Qi J, Chen Y, Xue T, Lin Y, Huang S, Cao S, et al. Graphene oxide-based magnetic nanocomposites for the delivery of melittin to cervical cancer HeLa cells. Nanotechnology. 2020 Jan 31;31(6):065102.
38. Ou J, Shi W, Xu Y, Tao Z. Intranasal immunization with DNA vaccine coexpressing Der p 1 and ubiquitin in an allergic rhinitis mouse model. Ann Allergy Asthma Immunol. 2014;113(6):658-65. e1.
39. Kumar M, Behera AK, Lockey RF, Vesely DL, Mohapatra SS. Atrial natriuretic peptide gene transfer by means of intranasal administration attenuates airway reactivity in a mouse model of allergic sensitization. J Allergy Clin Immunol. 2002;110(6):879-82.
40. Shim B-S, Park S-M, Quan J-S, Jere D, Chu H, Song MK, et al. Intranasal immunization with plasmid DNA encoding spike protein of SARS-coronavirus/polyethylenimine nanoparticles elicits antigen-specific humoral and cellular immune responses. BMC Immunol. 2010;11:1-9.
41. Steinke JW, Borish L. Th2 cytokines and asthma—Interleukin-4: its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists. Respir Res. 2001;2(2):1-5.
42. Jin Y, Wi HJ, Choi M-H, Hong S-T, Bae YM. Regulation of anti-inflammatory cytokines IL-10 and TGF-β in mouse dendritic cells through treatment with Clonorchis sinensis crude antigen. Exp Mol Med. 2014;46(1):e74-e.
43. Zhou J, Wan C, Cheng J, Huang H, Lovell JF, Jin H. Delivery strategies for melittin-based cancer therapy. ACS Appl Mater Interfaces. 2021;13(15):17158-73.
44. Shin SH, Ye MK, Choi SY, Park KK. Anti-inflammatory effect of bee venom in an allergic chronic rhinosinusitis mouse model. Mol Med Rep. 2018;17(5):6632-8.
45. Gautier EL, Ivanov S, Lesnik P, Randolph GJ. Local apoptosis mediates clearance of macrophages from resolving inflammation in mice. Am J Hematol. 2013;122(15):2714-22.
46. Gordon S, Plüddemann A. Macrophage clearance of apoptotic cells: a critical assessment. Front immunol. 2018;9:127.
47. Szondy Z, Sarang Z, Kiss B, Garabuczi É, Köröskényi K. Anti-inflammatory mechanisms triggered by apoptotic cells during their clearance. Front immunol. 2017;8:909.
2. Fahy JV. Type 2 inflammation in asthma—present in most, absent in many. Nat Rev Immunol. 2015;15(1):57-65.
3. Liew FY, Pitman NI, McInnes IB. Disease-associated functions of IL-33: the new kid in the IL-1 family. Nat Rev Immunol. 2010;10(2):103-10.
4. Kurowska‐Stolarska M, Hueber A, Stolarski B, McInnes I. Interleukin‐33: a novel mediator with a role in distinct disease pathologies. J Intern Med. 2011;269(1):29-35.
5. Liu Z, Fan Z, Liu J, Wang J, Xu M, Li X, et al. Melittin‐Carrying Nanoparticle Suppress T Cell‐Driven Immunity in a Murine Allergic Dermatitis Model. Adv Sci. 2023:2204184.
6. Pritchard DI, Falcone FH, Mitchell PD. The evolution of IgE‐mediated type I hypersensitivity and its immunological value. Allergy. 2021;76(4):1024-40.
7. Billingham M, Morley J, HANSON JM, Shipolini R, Vernon C. An anti-inflammatory peptide from bee venom. Nature. 1973;245:163-4.
8. Jeong CH, Cheng WN, Bae H, Lee KW, Han SM, Petriello MC, et al. Bee venom decreases LPS-induced inflammatory responses in bovine mammary epithelial cells. J Microbiol Biotechnol. 2017;27(10):1827-36.
9. Lariviere WR, Melzack R. The bee venom test: a new tonic-pain test. PAIN®. 1996;66(2-3):271-7.
10. Tiwari R, Tiwari G, Lahiri A, Ramachandran V, Rai A. Melittin: A Natural Peptide with Expanded Therapeutic Applications. J Nat Prod. 2022;12(2):13-29.
11. Yoon H, Kim MJ, Yoon I, Li DX, Bae H, Kim SK. Nicotinic acetylcholine receptors mediate the suppressive effect of an injection of diluted bee venom into the GV3 acupoint on oxaliplatin-induced neuropathic cold allodynia in rats. Biol Pharm Bull. 2015;38(5):710-4.
12. Lim B-S, Moon HJ, Li DX, Gil M, Min JK, Lee G, et al. Effect of bee venom acupuncture on oxaliplatin-induced cold allodynia in rats. J Evid Based Complementary Altern Med. 2013;2013.
13. Baek YH, Huh JE, Lee JD, Park DS. Antinociceptive effect and the mechanism of bee venom acupuncture (Apipuncture) on inflammatory pain in the rat model of collagen-induced arthritis: Mediation by α2-Adrenoceptors. Brain Res. 2006;1073:305-10.
14. Varanda EA, Monti R, Tavares DC. Inhibitory effect of propolis and bee venom on the mutagenicity of some direct‐and indirect‐acting mutagens. Teratog Carcinog Mutagen. 1999;19(6):403-13.
15. Gajski G, Garaj-Vrhovac V. Radioprotective effects of honeybee venom (Apis mellifera) against 915-mhz microwave radiation–induced DNA damage in wistar rat lymphocytes: In vitro study. Int J Toxicol. 2009;28(2):88-98.
16. Askari P, Namaei MH, Ghazvini K, Hosseini M. In vitro and in vivo toxicity and antibacterial efficacy of melittin against clinical extensively drug-resistant bacteria. BMC Pharmacol Toxicol. 2021;22:1-12.
17. Memariani H, Memariani M, Moravvej H, Shahidi-Dadras M. Melittin: a venom-derived peptide with promising anti-viral properties. Eur J Clin Microbiol Infect Dis. 2020;39:5-17.
18. Kim W-H, An H-J, Kim J-Y, Gwon M-G, Gu H, Jeon M, et al. Beneficial effects of melittin on ovalbumin-induced atopic dermatitis in mouse. Sci Rep. 2017;7(1):17679.
19. Lee G, Bae H. Anti-inflammatory applications of melittin, a major component of bee venom: Detailed mechanism of action and adverse effects. Molecules. 2016;21(5):616.
20. Tosteson M, Tosteson D. The sting. Melittin forms channels in lipid bilayers. Biophys J. 1981;36(1):109-16.
21. Moon D-O, Park S-Y, Lee K-J, Heo M-S, Kim K-C, Kim M-O, et al. Bee venom and melittin reduce proinflammatory mediators in lipopolysaccharide-stimulated BV2 microglia. Int Immunopharmacol. 2007;7(8):1092-101.
22. Han SM, Kim JM, Park KK, Chang YC, Pak SC. Neuroprotective effects of melittin on hydrogen peroxide-induced apoptotic cell death in neuroblastoma SH-SY5Y cells. BMC Complement Altern Med. 2014;14(1):1-8.
23. Son DJ, Kang J, Kim TJ, Song H-S, Sung K-J, Yun DY, Hong JT. Melittin, a major bioactive component of bee venom toxin, inhibits PDGF receptor beta-tyrosine phosphorylation and downstream intracellular signal transduction in rat aortic vascular smooth muscle cells. J Toxicol Environ Health - A. 2007;70(15-16):1350-5.
24. Kim S-J, Park J-H, Kim K-H, Lee W-R, Kim K-S, Park K-K. Melittin inhibits atherosclerosis in LPS/high-fat treated mice through atheroprotective actions. J Atheroscler Thromb. 2011;18(12):1117-26.
25. Cho H-J, Kang J-H, Park K-K, Choe J-Y, Park Y-Y, Moon Y-S, et al. Comparative proteome analysis of Tumor necrosis factor α-stimulated human Vascular Smooth Muscle Cells in response to melittin. Proteome sci. 2013;11(1):1-9.
26. Park J-H, Kum Y-S, Lee T-I, Kim S-J, Lee W-R, Kim B-I, et al. Melittin attenuates liver injury in thioacetamide-treated mice through modulating inflammation and fibrogenesis. Exp Biol Med. 2011;236(11):1306-13.
27. Kim K-H, Sung H-J, Lee W-R, An H-J, Kim J-Y, Pak SC, et al. Effects of melittin treatment in cholangitis and biliary fibrosis in a model of xenobiotic-induced cholestasis in mice. Toxins. 2015;7(9):3372-87.
28. Park HJ, Son DJ, Lee CW, Choi MS, Lee US, Song HS, et al. Melittin inhibits inflammatory target gene expression and mediator generation via interaction with IκB kinase. Biochem Pharmacol. 2007;73(2):237-47.
29. Du G, He P, Zhao J, He C, Jiang M, Zhang Z, et al. Polymeric microneedle-mediated transdermal delivery of melittin for rheumatoid arthritis treatment. J Control Release. 2021;336:537-48.
30. Biregani AF, Khodadadi A, Doosti A, Asadirad A, Dehcheshmeh MG, Ghadiri AA. Allergen specific immunotherapy with plasmid DNA encoding OVA-immunodominant T cell epitope fused to Tregitope in a murine model of allergy. Cell Immunol. 2022;376:104534.
31. Wang Y, Zhou Y, Zhu Y, Yu W, Wang J, Fu J, et al. The comparation of intraperitoneal injection and nasal-only delivery allergic rhinitis model challenged with different allergen concentration. Am J Rhinol. 2019;33(2):145-52.
32. Liang M-J, Fu Q-L, Jiang H-Y, Chen F-H, Chen D, Chen D-H, et al. Immune responses to different patterns of exposure to ovalbumin in a mouse model of allergic rhinitis. Eur Arch Otorhinolaryngol. 2016;273:3783-8.
33. Jung H, Kim YS, Jung D-M, Lee K-S, Lee J-M, Kim KK. Melittin-derived peptides exhibit variations in cytotoxicity and antioxidant, anti-inflammatory and allergenic activities. Anim Cells Syst. 2022;26(4):158-65.
34. Hartman D, Tomchek L, Lugay J, Lewin A, Chau T, Carlson R. Comparison of antiinflammatory and antiallergic drugs in the melittin-and D49 PLA2-induced mouse paw edema models. Agents and Actions. 1991;34(1-2):84-8.
35. An HJ, Kim JY, Kim WH, Gwon MG, Gu HM, Jeon MJ, et al. Therapeutic effects of bee venom and its major component, melittin, on atopic dermatitis in vivo and in vitro. Br J Pharmacol. 2018;175(23):4310-24.
36. Liu Z, Fan Z, Liu J, Wang J, Xu M, Li X, et al. Melittin‐Carrying Nanoparticle Suppress T Cell‐Driven Immunity in a Murine Allergic Dermatitis Model. Adv Sci. 2023;10(7):2204184.
37. Qi J, Chen Y, Xue T, Lin Y, Huang S, Cao S, et al. Graphene oxide-based magnetic nanocomposites for the delivery of melittin to cervical cancer HeLa cells. Nanotechnology. 2020 Jan 31;31(6):065102.
38. Ou J, Shi W, Xu Y, Tao Z. Intranasal immunization with DNA vaccine coexpressing Der p 1 and ubiquitin in an allergic rhinitis mouse model. Ann Allergy Asthma Immunol. 2014;113(6):658-65. e1.
39. Kumar M, Behera AK, Lockey RF, Vesely DL, Mohapatra SS. Atrial natriuretic peptide gene transfer by means of intranasal administration attenuates airway reactivity in a mouse model of allergic sensitization. J Allergy Clin Immunol. 2002;110(6):879-82.
40. Shim B-S, Park S-M, Quan J-S, Jere D, Chu H, Song MK, et al. Intranasal immunization with plasmid DNA encoding spike protein of SARS-coronavirus/polyethylenimine nanoparticles elicits antigen-specific humoral and cellular immune responses. BMC Immunol. 2010;11:1-9.
41. Steinke JW, Borish L. Th2 cytokines and asthma—Interleukin-4: its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists. Respir Res. 2001;2(2):1-5.
42. Jin Y, Wi HJ, Choi M-H, Hong S-T, Bae YM. Regulation of anti-inflammatory cytokines IL-10 and TGF-β in mouse dendritic cells through treatment with Clonorchis sinensis crude antigen. Exp Mol Med. 2014;46(1):e74-e.
43. Zhou J, Wan C, Cheng J, Huang H, Lovell JF, Jin H. Delivery strategies for melittin-based cancer therapy. ACS Appl Mater Interfaces. 2021;13(15):17158-73.
44. Shin SH, Ye MK, Choi SY, Park KK. Anti-inflammatory effect of bee venom in an allergic chronic rhinosinusitis mouse model. Mol Med Rep. 2018;17(5):6632-8.
45. Gautier EL, Ivanov S, Lesnik P, Randolph GJ. Local apoptosis mediates clearance of macrophages from resolving inflammation in mice. Am J Hematol. 2013;122(15):2714-22.
46. Gordon S, Plüddemann A. Macrophage clearance of apoptotic cells: a critical assessment. Front immunol. 2018;9:127.
47. Szondy Z, Sarang Z, Kiss B, Garabuczi É, Köröskényi K. Anti-inflammatory mechanisms triggered by apoptotic cells during their clearance. Front immunol. 2017;8:909.
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How to Cite
1.
Esmaeili Gouvarchinghaleh H, Farhadi Biregani A, Doosti A, Taheri RA, Mirzaei M, Zahiri A, Farnoosh G. Ameliorative Effect of Melittin Encoded DNA Plasmid in an Ovalbumin-induced Murine Model of Allergy. Iran J Allergy Asthma Immunol. 2024;:1-11.
