Ghrelin as a Promising Immunostimulant in Aquaculture: Mechanisms and Therapeutic Potential
Authors
-
Danielle Reyes
Center for Genetic Engineering and Biotechnology, Havana, Cuba.
https://orcid.org/0009-0008-3172-0437
-
Mario P. Estrada
Center for Genetic Engineering and Biotechnology, Havana, Cuba
https://orcid.org/0000-0002-9776-719X
-
Rebeca Martínez
Center for Genetic Engineering and Biotechnology, Havana, Cuba
https://orcid.org/0000-0003-4021-6941
DOI:
https://doi.org/10.70099/BJ/2025.02.02.6.Keywords:
Ghrelin, immune system, fish, growth hormone secretagogue, cytokines, antimicrobial activityAbstract
Ghrelin, a peptide hormone originally known for its role in growth hormone secretion and appetite regulation, is a key immunomodulator in vertebrates, including fish. This hormone and its receptor (GHS-R) are widely expressed in immune cells—T cells, B cells, neutrophils, and macrophages—and tissues. In fish, Ghrelin modulates physiological processes (e.g., reproduction or energy balance) and improves immune defense mechanisms. Studies have demonstrated its ability to promote phagocytic activity, regulate cytokine production, and stimulate antimicrobial peptide production, enhancing resistance to pathogenic infections. Likewise, the development of ghrelin mimetics, like GHRP-6, with a wide range of functionalities, further increases the potential of their use in aquaculture, showing promising results in improving growth and immune responses in fish. Ghrelin and its analogs represent a promising alternative for boosting fish's immune response against pathogens. Thus, understanding Ghrelin's regulatory mechanisms in fish immunity may reveal practical applications for aquaculture practices, helping achieve fish welfare and sustainability.
References
1. Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996;273(5277):974-7. doi:10.1126/science.273.5277.974
2. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656-60. doi:10.1038/45230
3. Hattori N. Expression, regulation and biological actions of growth hormone (GH) and Ghrelin in the immune system. Growth Horm IGF Res. 2009;19(3):187-97. doi:10.1016/j.ghir.2008.12.001
4. Akalu Y, Molla MD, Dessie G, Ayelign B. Physiological effect of Ghrelin on body systems. Int J Endocrinol. 2020;2020:1385138. doi:10.1155/2020/1385138
5. Taub DD. Novel connections between the neuroendocrine and immune systems: the ghrelin immunoregulatory network. Vitam Horm. 2007;77:325-46. doi:10.1016/S0083-6729(06)77014-5
6. Miyake S. Mind over cytokines: crosstalk and regulation between the neuroendocrine and immune systems. Clin Exp Neuroimmunol. 2012;3(1):1-15. doi:10.1111/j.1759-1961.2011.00023.x
7. Chowen JA, Argente J. Ghrelin: a link between energy homeostasis and the immune system. Endocrinology. 2017;158(7):2077-81. doi:10.1210/en.2017-00350
8. Han YC, Leaman DW, Shepherd BS. Ghrelin modulates differential expression of genes relevant to immune activities and antimicrobial peptides in primary head kidney cells of rainbow trout (Oncorhynchus mykiss). Animals. 2023;13(10):1683. doi:10.3390/ani13101683
9. Muñoz-Flores C, Roa FJ, Saavedra P, Fuentealba P, Starck MF, Ortega L, et al. Immunomodulatory role of vasoactive intestinal peptide and Ghrelin in Oncorhynchus mykiss. Heliyon. 2023;9(12):e23098. doi:10.1016/j.heliyon.2023.e23098
10. Zhu J, Zhao H, Aierken A, Zhou T, Menggen M, Gao H, et al. Ghrelin is involved in regulating the progression of Echinococcus granulosus-infected liver lesions through suppression of immunoinflammation and fibrosis. PLoS Negl Trop Dis. 2024;18(10):e0012587. doi:10.1371/journal.pntd.0012587
11. Hattori N, Saito T, Yagyu T, Jiang BH, Kitagawa K, Inagaki C. GH, GH receptor, GH secretagogue receptor, and ghrelin expression in human T cells, B cells, and neutrophils. J Clin Endocrinol Metab. 2001;86(9):4284-91. doi:10.1210/jcem.86.9.7866
12. Baatar D, Patel K, Taub DD. The effects of Ghrelin on inflammation and the immune system. Mol Cell Endocrinol. 2011;340(1):44-58. doi:10.1016/j.mce.2011.04.019
13. Poudel SB, Dixit M, Neginskaya M, Nagaraj K, Pavlov E, Werner H, et al. Effects of GH/IGF on the aging mitochondria. Cells. 2020;9(6):1384. doi:10.3390/cells9061384
14. Noh JY, Herrera M, Patil BS, Tan XD, Wright GA, Sun Y. The expression and function of growth hormone secretagogue receptor in immune cells: a current perspective. Exp Biol Med. 2022;247(24):2184-91. doi:10.1177/15353702221121635
15. Reis MD, Veneziani LP, Porto FL, Lins MP, Mendes-da-Cruz DA, Savino W. Intrathymic somatotropic circuitry: consequences upon thymus involution. Front Immunol. 2023;14:1108630. doi:10.3389/fimmu.2023.1108630
16. Han Z, Zhou Y, Zhang X, Yan J, Xiao J, Luo Y, et al. Ghrelin modulates the immune response and increases resistance to Aeromonas hydrophila infection in hybrid tilapia. Fish Shellfish Immunol. 2020;98:100-8. doi:10.1016/j.fsi.2020.01.006
17. Mathur N, Mehdi SF, Anipindi M, Aziz M, Khan SA, Kondakindi H, et al. Ghrelin as an anti-sepsis peptide: review. Front Immunol. 2021;11:610363. doi:10.3389/fimmu.2020.610363
18. Yanagi S, Sato T, Kangawa K, Nakazato M. The homeostatic force of Ghrelin. Cell Metab. 2018;27(4):786-804. doi:10.1016/j.cmet.2018.02.008
19. De Vriese C, Delporte C. Ghrelin: a new peptide regulating growth hormone release and food intake. Int J Biochem Cell Biol. 2008;40(8):1420-4. doi:10.1016/j.biocel.2007.04.020
20. Wajnrajch MP, Ten IS, Gertner JM, Leibel RL. Genomic organization of the human ghrelin gene. Int J Disabil Hum Dev. 2000;1(4):231-4. doi:10.1515/IJDHD.2000.1.4.231
21. Unniappan S, Peter RE. Structure, distribution and physiological functions of Ghrelin in fish. Comp Biochem Physiol A Mol Integr Physiol. 2005;140(4):396-408. doi:10.1016/j.cbpb.2005.02.011
22. Unniappan S, Lin X, Cervini L, Rivier J, Kaiya H, Kangawa K, et al. Goldfish ghrelin: molecular characterization of the complementary deoxyribonucleic acid, partial gene structure and evidence for its stimulatory role in food intake. Endocrinology. 2002;143(10):4143-6. doi:10.1210/en.2002-220644
23. Zhong H, Hu Y, Yu F. A review on Ghrelin and fish reproduction. Reprod Breed. 2021;1(2):128-35. doi:10.1016/j.repbre.2021.07.004
24. Cornejo MP, Mustafá ER, Barrile F, Cassano D, De Francesco PN, Raingo J, et al. The intriguing ligand-dependent and ligand-independent actions of the growth hormone secretagogue receptor on reward-related behaviors. Neurosci Biobehav Rev. 2021;120:401-16. doi:10.1016/j.neubiorev.2020.10.017
25. Kurowska P, Mlyczynska E, Rak A. Effect of Ghrelin on the apoptosis of various cells. A critical review. J Physiol Pharmacol. 2019;70(1):1-12. doi:10.26402/jpp.2019.1.02
26. Sato T, Nakamura Y, Shiimura Y, Ohgusu H, Kangawa K, Kojima M. Structure, regulation and function of Ghrelin. J Biochem. 2012;151(2):119-28. doi:10.1093/jb/mvr134
27. Kissebah AH, Sonnenberg GE, Myklebust J, Goldstein M, Broman K, James RG, et al. Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. Proc Natl Acad Sci USA. 2000;97(26):14478-83. doi:10.1073/pnas.97.26.14478
28. Dixit VD, Taub DD. Ghrelin and immunity: a young player in an old field. Exp Gerontol. 2005;40(11):900-10. doi:10.1016/j.exger.2005.09.003
29. Kojima M, Kangawa K. Ghrelin: structure and function. Physiol Rev. 2005;85(2):495-522. doi:10.1152/physrev.00012.2004
30. Wang P, Fu J, Luo M, Shi X, Zhu W, Wang L, et al. Molecular cloning and expression characteristics of ghrl and ghsr genes in bighead carp (Hypophthalmichthys nobilis). Aquac Fish. 2024;9:100-8. doi:10.1016/j.aaf.2023.12.001
31. Orlova EG, Shirshev SV, Loginova OA. Leptin and Ghrelin regulate dendritic cell maturation and dendritic cell induction of regulatory T-cells. Dokl Biol Sci. 2015;462:171-4. doi:10.1134/S001249661503014X
32. Pereira JA, Silva FC, de Moraes-Vieira PM. The impact of Ghrelin in metabolic diseases: an immune perspective. J Diabetes Res. 2017;2017:4527980. doi:10.1155/2017/4527980
33. Lin L, Lee JH, Buras ED, Yu K, Wang R, Smith CW, et al. Ghrelin receptor regulates adipose tissue inflammation in aging. Aging. 2016;8(1):178-91. doi:10.18632/aging.100888
34. Lee JH, Fang C, Li X, Wu CS, Noh JY, Ye X, et al. GHS-R suppression in adipose tissues protects against obesity and insulin resistance by regulating adipose angiogenesis and fibrosis. Int J Obes. 2021;45(7):1565-75. doi:10.1038/s41366-021-00820-7
35. Dixit VD, Yang H, Sun Y, Weeraratna AT, Youm YH, Smith RG, et al. Ghrelin promotes thymopoiesis during aging. J Clin Invest. 2007;117(10):2778-90. doi:10.1172/JCI30248
36. Orlova EG, Shirshev SV. Ghrelin regulation of in vitro human monocyte functional activity. Dokl Biol Sci. 2010;434(1):368-70. doi:10.1134/S0012496610050200
37. Kaiya H, Kangawa K, Miyazato M. Molecular evolution of GPCRs: ghrelin/ghrelin receptors. J Mol Endocrinol. 2014;52(3):T87-100. doi:10.1530/JME-13-0175
38. Korbonits M, Goldstone AP, Gueorguiev M, Grossman AB. Ghrelin—a hormone with multiple functions. Front Neuroendocrinol. 2004;25(1):27-68. doi:10.1016/j.yfrne.2004.03.002
39. Tine M, Kuhl H, Teske PR, Tschöp MH, Jastroch M. Diversification and coevolution of the ghrelin/growth hormone secretagogue receptor system in vertebrates. Ecol Evol. 2016;6(8):2516-35. doi:10.1002/ece3.2057
40. Kaiya H, Miyazato M, Kangawa K. Recent advances in the phylogenetic study of Ghrelin. Peptides. 2011;32(11):2155-74. doi:10.1016/j.peptides.2011.04.027
41. Heppner KM, Piechowski CL, Müller A, Ottaway N, Sisley S, Smiley DL, et al. Both acyl and des-acyl ghrelin regulate adiposity and glucose metabolism via central nervous system ghrelin receptors. Diabetes. 2013;63(1):122-31. doi:10.2337/db13-0414
42. Li Z, Xu G, Qin Y, Zhang C, Tang H, Yin Y, et al. Ghrelin promotes hepatic lipogenesis by activation of mTOR-PPARγ signaling pathway. Proc Natl Acad Sci USA. 2014;111(36):13163-8. doi:10.1073/pnas.1411571111
43. Geelissen SME, Swennen Q, Geyten SV, Kühn ER, Kaiya H, Kangawa K, et al. Peripheral Ghrelin reduces food intake and respiratory quotient in chicken. Domest Anim Endocrinol. 2006;30(2):108-16. doi:10.1016/j.domaniend.2005.06.005
44. Seim I, Jeffery PL, Herington AC, Chopin LK. Comparative analysis reveals loss of the appetite-regulating peptide hormone ghrelin in falcons. Gen Comp Endocrinol. 2015;216:98-102. doi:10.1016/j.ygcen.2014.11.016
45. Jönsson E, Kaiya H, Björnsson BT. Ghrelin decreases food intake in juvenile rainbow trout (Oncorhynchus mykiss) through the central anorexigenic corticotropin-releasing factor system. Gen Comp Endocrinol. 2010;166(1):39-46. doi:10.1016/j.ygcen.2009.11.001
46. Jönsson E. The role of Ghrelin in energy balance regulation in fish. Gen Comp Endocrinol. 2013;187:79-85. doi:10.1016/j.ygcen.2013.03.013
47. Izzo G, Ferrara D, Napolitano F, Crispo AA, d’Istria M, Aniello F, et al. Identification of a cDNA encoding for Ghrelin in the testis of the frog Pelophylax esculentus and its involvement in spermatogenesis. Comp Biochem Physiol A Mol Integr Physiol. 2011;158(4):367-73. doi:10.1016/j.cbpa.2010.09.005
48. Dar SA, Mattoo S, Srivastava PP. Ghrelin and its role in reproductive physiology of fish. In: Recent updates in molecular endocrinology and reproductive physiology of fish. Springer; 2021. p. 171-9. doi:10.1007/978-981-15-8369-8_12
49. Dupont J, Maillard V, Coyral-Castel S, Ramé C, Froment P. Ghrelin in female and male reproduction. Int J Pept. 2010;2010:158102. doi:10.1155/2010/158102
50. Hashimoto H, Ueta Y. Central effects of Ghrelin on appetite and fluid/water drinking behavior. Curr Protein Pept Sci. 2011;12(4):280-7. doi:10.2174/138920311795906727
51. van der Lely AJ, Tschöp M, Heiman ML, Ghigo E. Biological, physiological, pathophysiological, and pharmacological aspects of Ghrelin. Endocr Rev. 2004;25(3):426-57. doi:10.1210/er.2002-0029
52. Harvey RE, Howard VG, Lemus MB, Jois T, Andrews ZB, Sleeman MW. The ghrelin/GOAT system regulates obesity-induced inflammation in male mice. Endocrinology. 2017;158(7):2179-89. doi:10.1210/en.2016-1832
53. Mabudi H, Jamili S, Majd NE, Vosoughi G, Fatemi MR, Rashed S. The effects of Ghrelin on ovary histology in Barbus sharpeyi. J Anim Physiol Anim Nutr. 2011;95(5):599-602. doi:10.1111/j.1439-0396.2010.01089.x
54. Rajeswari JJ, Hatef A, Golshan M, Alavi SMH, Unniappan S. Metabolic stress leads to divergent changes in the ghrelinergic system in goldfish (Carassius auratus) gonads. Comp Biochem Physiol A Mol Integr Physiol. 2019;235:112-20. doi:10.1016/j.cbpa.2019.05.027
55. Sokołowska-Mikołajczyk M, Socha M, Szczerbik P, Epler P. The effects of Ghrelin on the in vitro spontaneous and sGnRH-A stimulated luteinizing hormone (LH) release from the pituitary cells of common carp (Cyprinus carpio L.). Comp Biochem Physiol A Mol Integr Physiol. 2009;153(4):386-90. doi:10.1016/j.cbpa.2009.03.012
56. Grey CL, Grayfer L, Belosevic M, Chang JP. Ghrelin stimulation of gonadotropin (LH) release from goldfish pituitary cells: presence of the growth hormone secretagogue receptor (GHS-R1a) and involvement of voltage-sensitive Ca2+ channels. Mol Cell Endocrinol. 2010;317(1):64-77. doi:10.1016/j.mce.2009.12.024
57. Navarro-Guillén C, Dias J, Rocha F, Castanheira MF, Martins CIM, Laizé V, et al. Does a ghrelin stimulus during zebrafish embryonic stage modulate its performance on the long-term? Comp Biochem Physiol A Mol Integr Physiol. 2019;228:1-8. doi:10.1016/j.cbpa.2018.10.019
58. Kang KS, Yahashi S, Matsuda K. The effects of Ghrelin on energy balance and psychomotor activity in a goldfish model: an overview. Int J Pept. 2011;2011:171034. doi:10.1155/2011/171034
59. Kang KS, Yahashi S, Matsuda K. Central and peripheral effects of Ghrelin on energy balance, food intake and lipid metabolism in teleost fish. Peptides. 2011;32(11):2242-7. doi:10.1016/j.peptides.2011.05.006
60. Miandare HK, Farahmand H, Ramezanpour S, Nematollahi MA, Rafiee G, Amiri BM. Effects of Ghrelin on some plasma hormonal changes in juvenile Persian sturgeon (Acipenser persicus). Comp Clin Pathol. 2012;21(5):1099-102. doi:10.1007/s00580-011-1239-y
61. Cruz SA, Tseng YC, Kaiya H, Hwang PP. Ghrelin affects carbohydrate-glycogen metabolism via insulin inhibition and glucagon stimulation in the zebrafish (Danio rerio) brain. Comp Biochem Physiol A Mol Integr Physiol. 2010;156(2):190-200. doi:10.1016/j.cbpa.2010.01.019
62. Blanco AM, Bertucci JI, Ramesh N, Delgado MJ, Valenciano AI, Unniappan S. Ghrelin facilitates GLUT2-, SGLT1- and SGLT2-mediated intestinal glucose transport in goldfish (Carassius auratus). Sci Rep. 2017;7:45024. doi:10.1038/srep45024
63. Velasco C, Librán-Pérez M, Otero-Rodiño C, López-Patiño MA, Míguez JM, Cerdá-Reverter JM, et al. Ghrelin modulates hypothalamic fatty acid-sensing and control of food intake in rainbow trout. J Endocrinol. 2016;228(1):25-37. doi:10.1530/JOE-15-0391
64. Salmerón C, Johansson M, Asaad M, Angotzi AR, Rønnestad I, Stefansson SO, et al. Roles of leptin and Ghrelin in adipogenesis and lipid metabolism of rainbow trout adipocytes in vitro. Comp Biochem Physiol A Mol Integr Physiol. 2015;188:40-8. doi:10.1016/j.cbpa.2015.06.017
65. Ma Y, Zhang H, Guo W, Yu L. Potential role of Ghrelin in the regulation of inflammation. FASEB J. 2022;36(9):e22508. doi:10.1096/fj.202200634R
66. Naseri F, Sirati-Sabet M, Sarlaki F, Keimasi M, Mokarram P, Siri M, et al. Ghrelin regulates crosstalk between apoptosis, necroptosis and autophagy programmed cell death pathways in the hippocampal neurons of amyloid-β 1–42-induced rat model of Alzheimer's disease. Res Square. 2022. doi:10.1007/s10989-022-10457-3
67. Shirshev SV, Nekrasova IV, Orlova EG, Gorbunova OL. Effects of leptin and Ghrelin on the expression of membrane molecules and cytokine production by NK cells from the peripheral blood. Biochem Mosc Suppl Ser Membr Cell Biol. 2017;11(1):54-61. doi:10.1134/S199074781604019X
68. Zhang X, Zeng Z, Liu Y, Liu D. Emerging relevance of Ghrelin in programmed cell death and its application in diseases. Int J Mol Sci. 2023;24(24):17254. doi:10.3390/ijms242417254
69. Smith RG, Jiang H, Sun Y. Developments in ghrelin biology and potential clinical relevance. Trends Endocrinol Metab. 2005;16(9):436-42. doi:10.1016/j.tem.2005.09.004
70. Esteban MÁ, Cuesta A, Chaves-Pozo E, Meseguer J. Phagocytosis in teleosts: implications of the new cells involved. Biology. 2015;4(4):907-22. doi:10.3390/biology4040907
71. Li B, Zeng M, Zheng H, Huang C, He W, Lu G, et al. Effects of Ghrelin on the apoptosis of human neutrophils in vitro. Int J Mol Med. 2016;38(3):794-802. doi:10.3892/ijmm.2016.2668
72. Tümer C, Bilgin HM, Obay BD, Diken H, Taşdemir E, Şermet A. Effect of ghrelin administration on phagocytic activity in acute cold-restraint stress exposed rats. Regul Pept. 2007;138(2):113-7. doi:10.1016/j.regpep.2006.08.010
73. Corrêa da Silva F, Aguiar C, Pereira JAS, de Brito Monteiro L, Davanzo GG, Codo AC, et al. Ghrelin effects on mitochondrial fitness modulates macrophage function. Free Radic Biol Med. 2019;145:61-6. doi:10.1016/j.freeradbiomed.2019.09.012
74. Peterson BC, Small BC, Bilodeau L. Effects of GH on immune and endocrine responses of channel catfish challenged with Edwardsiella ictaluri. Comp Biochem Physiol A Mol Integr Physiol. 2007;146(1):47-53. doi:10.1016/j.cbpa.2006.08.042
75. Sakai M, Kobayashi M, Kawauchi H. In vitro activation of fish phagocytic cells by GH, prolactin and somatolactin. J Endocrinol. 1996;151(1):113-8. doi:10.1677/joe.0.1510113
76. Yada T, Kaiya H, Mutoh K, Azuma T, Hyodo S, Kangawa K. Ghrelin stimulates phagocytosis and superoxide production in fish leukocytes. J Endocrinol. 2006;189(1):57-65. doi:10.1677/joe.1.06187
77. Liu C, Chu D, Kalantar-Zadeh K, George J, Young HA, Liu G. Cytokines: from clinical significance to quantification. Adv Sci. 2021;8(15):2004433. doi:10.1002/advs.202004433
78. Chang RJ, Wang HL, Qin MB, Liang ZH, He JP, Wei YL, et al. Ghrelin inhibits IKKβ/NF-κB activation and reduces proinflammatory cytokine production in pancreatic acinar AR42J cells treated with cerulein. Hepatobiliary Pancreat Dis Int. 2021;20(4):366-75. doi:10.1016/j.hbpd.2020.05.004
79. Beynon AL, Brown MR, Wright R, Rees MI, Sheldon IM, Davies JS. Ghrelin inhibits LPS-induced release of IL-6 from mouse dopaminergic neurones. J Neuroinflammation. 2013;10:40. doi:10.1186/1742-2094-10-40
80. Jafari A, Sadeghpour S, Ghasemnejad-Berenji H, Pashapour S, Ghasemnejad-Berenji M. Potential antioxidative, anti-inflammatory and immunomodulatory effects of Ghrelin, an endogenous peptide from the stomach in SARS-CoV2 infection. Int J Pept Res Ther. 2021;27(3):1875-83. doi:10.1007/s10989-021-10217-9
81. Xia Q, Pang W, Pan H, Zheng Y, Kang JS, Zhu SG. Effects of Ghrelin on the proliferation and secretion of splenic T lymphocytes in mice. Regul Pept. 2004;122(3):173-8. doi:10.1016/j.regpep.2004.06.016
82. Sakai M, Hikima J, Kono T. Fish cytokines: current research and applications. Fish Sci. 2021;87(1):1-9. doi:10.1007/s12562-020-01476-4
83. Shved N, Berishvili G, Mazel P, Baroiller JF, Eppler E. Growth hormone (GH) treatment acts on the endocrine and autocrine/paracrine GH/IGF-axis and on TNF-α expression in bony fish pituitary and immune organs. Fish Shellfish Immunol. 2011;31(6):944-52. doi:10.1016/j.fsi.2011.08.012
84. Kono T, Kitao Y, Sonoda K, Nomoto R, Mekata T, Sakai M. Identification and expression analysis of ghrelin gene in common carp Cyprinus carpio. Fish Sci. 2008;74(3):603-12. doi:10.1111/j.1444-2906.2008.01564.x
85. Dixit VD, Schaffer EM, Pyle RS, Collins GD, Sakthivel SK, Palaniappan R, et al. Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells. J Clin Invest. 2004;114(1):57-66. doi:10.1172/JCI21134
86. Koo GC, Huang C, Camacho R, Trainor C, Blake JT, Sirotina-Meisher A, et al. Immune enhancing effect of a growth hormone secretagogue. J Immunol. 2001;166(6):4195-201. doi:10.4049/jimmunol.166.6.4195
87. Zhou M, Aziz M, Ochani M, Yang WL, Sharma A, Wang P. The protective role of human Ghrelin in sepsis: restoration of CD4 T cell proliferation. PLoS One. 2018;13(7):e0201139. doi:10.1371/journal.pone.0201139
88. Di Giovangiulio M, Stakenborg N, Bosmans G, Meroni E, Farro G, Gomez-Pinilla PJ, et al. Ghrelin receptor modulates T helper cells during intestinal inflammation. Neurogastroenterol Motil. 2015;27(11):1542-52. doi:10.1111/nmo.12640
89. Batista CR, Figueiredo MA, Almeida DV, Romano LA, Marins LF. Effects of somatotrophic axis (GH/GHR) double transgenesis on structural and molecular aspects of the zebrafish immune system. Fish Shellfish Immunol. 2015;45(2):725-32. doi:10.1016/j.fsi.2015.05.034
90. Chorny A, Anderson P, Gonzalez-Rey E, Delgado M. Ghrelin protects against experimental sepsis by inhibiting high-mobility group box 1 release and by killing bacteria. J Immunol. 2008;180(12):8369-77. doi:10.4049/jimmunol.180.12.8369
91. Xiao Y, Jin L, Zhang C. From a hunger-regulating hormone to an antimicrobial peptide: gastrointestinal derived circulating endocrine hormone-peptide YY exerts exocrine antimicrobial effects against selective gut microbiota. Gut Microbes. 2024;16(1):2316927. doi:10.1080/19490976.2024.2316927
92. Min C, Ohta K, Kajiya M, Zhu T, Sharma K, Shin J, et al. The antimicrobial activity of the appetite peptide hormone ghrelin. Peptides. 2012;36(2):151-6. doi:10.1016/j.peptides.2012.05.006
93. van Muilekom DR, Collet B, Rebl H, Zlatina K, Sarais F, Goldammer T, Rebl A. Lost and found: the family of NF-κB inhibitors is larger than assumed in salmonid fish. Int J Mol Sci. 2023;24(12):10229. doi:10.3390/ijms241210229
94. Zhu J, Zhou T, Menggen M, Aimulajiang K, Wen H. Ghrelin regulating liver activity and its potential effects on liver fibrosis and Echinococcosis. Front Cell Infect Microbiol. 2024;13:1324134. doi:10.3389/fcimb.2023.1324134
95. Gao F, Zhao Y, Shi X, Qiao D, Pei C, Kong X. Signalling regulation of reactive oxygen species in fish inflammation. Rev Aquac. 2024;16(3):1266-85. doi:10.1111/raq.12895
96. Bian DD, Zhang X, Zhu XR, Tang WH, Peng Q, Chen YH, et al. The Nrf2-Keap1/ARE signaling pathway in aquatic animals. Int J Biol Macromol. 2025;254:142595. doi:10.1016/j.ijbiomac.2025.142595
97. Olavarría VH, Sepulcre MP, Figueroa JE, Mulero V. Prolactin-induced production of reactive oxygen species and IL-1β in leukocytes from the bony fish gilthead seabream involves Jak/Stat and NF-κB signaling pathways. J Immunol. 2010;185(7):3873-83. doi:10.4049/jimmunol.0902306
98. Philip AM, Vijayan MM. Stress-immune-growth interactions: cortisol modulates suppressors of cytokine signaling and JAK/STAT pathway in rainbow trout liver. PLoS One. 2015;10(6):e0129299. doi:10.1371/journal.pone.0129299
99. Liongue C, O'Sullivan LA, Trengove MC, Ward AC. Evolution of JAK-STAT pathway components: mechanisms and role in immune system development. PLoS One. 2012;7(3):e32777. doi:10.1371/journal.pone.0032777
100. Ishida J, Saitoh M, Ebner N, Springer J, Anker SD, von Haehling S. Growth hormone secretagogues: history, mechanism of action, and clinical development. JCSM Rapid Commun. 2020;3(1):25-37. doi:10.1002/rco2.9
101. Bowers CY, Momany FA, Reynolds GA, Hong A. On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology. 1984;114(5):1537-45. doi:10.1210/endo-114-5-1537
102. Cibrián D, Ajamieh H, Berlanga J, León OS, Alba JS, Kim MJT, et al. Use of growth-hormone-releasing peptide-6 (GHRP-6) for the prevention of multiple organ failure. Clin Sci. 2006;110(5):563-73. doi:10.1042/CS20050374
103. Berlanga-Acosta J, Cibrian D, Valiente-Mustelier J, Suárez-Alba J, García-Ojalvo A, Falcón-Cama V, et al. Growth hormone releasing peptide-6 (GHRP-6) prevents doxorubicin-induced myocardial and extra-myocardial damages by activating prosurvival mechanisms. Front Pharmacol. 2024;15:1402138. doi:10.3389/fphar.2024.1402138
104. Martínez R, Carpio Y, Arenal A, Lugo JM, Morales R, Martín L, et al. Significant improvement of shrimp growth performance by growth hormone-releasing peptide-6 immersion treatments. Aquac Res. 2017;48(9):4632-45. doi:10.1111/are.13286
105. Berlanga-Acosta J, Abreu-Cruz A, Barco Herrera DG, Mendoza-Marí Y, Rodríguez-Ulloa A, García-Ojalvo A, et al. Synthetic growth hormone-releasing peptides (GHRPs): a historical appraisal of the evidences supporting their cytoprotective effects. Clin Med Insights Cardiol. 2017;11:1179546817694558. doi:10.1177/1179546817694558
106. Martinez R, Carpio Y, Morales A, Lugo JM, Herrera F, Zaldívar C, et al. Oral administration of the growth hormone secretagogue-6 (GHRP-6) enhances growth and non-specific immune responses in tilapia (Oreochromis sp.). Aquaculture. 2016;452:304-10. doi:10.1016/j.aquaculture.2015.11.014
107. Hernández L, Camacho H, Nuñez-Robainas A, Palenzuela DO, Morales A, Basabe L, et al. Growth hormone secretagogue peptide-6 enhances oreochromicins transcription and antimicrobial activity in tilapia (Oreochromis sp.). Fish Shellfish Immunol. 2021;119:508-15. doi:10.1016/j.fsi.2021.08.011
108. Rodríguez-Viera L, Martí I, Martínez R, Perera E, Estrada MP, Mancera JM, Martos-Sitcha JA. Feed supplementation with the GHRP-6 peptide, a ghrelin analog, improves feed intake, growth performance and aerobic metabolism in the gilthead sea bream Sparus aurata. Fishes. 2022;7(1):31. doi:10.3390/fishes7010031
109. Martinez R, Gonzalez K, Gonzalez A, Ubieta K, Herrera F, Reyes O, et al. Biological activity of a new growth hormone secretagogue: study in fish and murine cell line. J Biotechnol Biomater. 2016;1(3):5. doi:10.4172/2155-952X.1000e113
110. Martinez R, Ubieta K, Herrera F, Forellat A, Morales R, de la Nuez A, et al. A novel GH secretagogue, A233, exhibits enhanced growth activity and innate immune system stimulation in teleosts fish. J Endocrinol. 2012;214(3):409-19. doi:10.1530/JOE-11-0373
111. Martinez R, Fernández-Trujillo MA, Hernández L, Page A, Béjar J, Estrada MP. Growth hormone secretagogue peptide A233 upregulates Mx expression in teleost fish in vitro and in vivo. Arch Virol. 2022;167(10):2041-7. doi:10.1007/s00705-022-05504-9
112. Mishra SS, Das R, Choudhary P, Debbarma J, Sahoo SN. Present status of fisheries and impact of emerging diseases of fish and shellfish in Indian aquaculture. J Aquat Res Mar Sci. 2017;5:5-26. doi:10.29199/ARMS.2017.03
113. Vignesh R, Karthikeyan BS, Periyasamy N, Devanathan K. Antibiotics in aquaculture: an overview. South Asian J Exp Biol. 2011;1(3):114-20.
Published
How to Cite
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors who publish with BioNatura Journal agree to the following terms: Authors retain copyright and grant the BioNatura Institutional Publishing Consortium (BIPC) right of first publication with the work simultaneously licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). This allows others to share the work with an acknowledgment of the work's authorship and initial publication in this journal.This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
