ВЛИЯНИЕ СОЕВОГО ИНГИБИТОРА ТРИПСИНА НА ГЕМАТОЛОГИЧЕСКИЕ ПОКАЗАТЕЛИ В УСЛОВИЯХ ВОДНОЙ И ПИЩЕВОЙ ДЕПРИВАЦИИ У КРЫС
УДК: 612.11 DOI: 10.31588/2413_4201_1883_2_266_55
Ключевые слова:
трипсин, соевый ингибитор трипсина, сериновые протеазы, гематологические показатели, депривация, крысыАннотация
Показано, что такие протеазы как тромбин, трипсин и катепсин G, играют ключевую роль не только в процессе расщепления белков во внеклеточном пространстве, но и в регуляции различных физиологических процессов. Их функции опосредуются взаимодействием с рецепторами, активируемыми протеазами (PARs), которые широко экспрессируются в различных органах и тканях. Сериновые протеазы, циркулирующие в крови, обычно не проявляют своей ферментативной активности из-за наличия белков-ингибиторов, что предотвращает их взаимодействие с PARs. В настоящее время также известны экзогенные ингибиторы протеаз, такие как соевый ингибитор трипсина (СИТ), который может замедлять процессы гемостаза, фибринолиза и агрегации тромбоцитов. Ранее проведённые исследования показали взаимосвязь между биохимическими показателями крови и активностью трипсина --- основного агониста PAR2 --- в крови, при водной и пищевой депривации на фоне введения СИТ. Однако влияние введение СИТ на гематологические показатели при различных формах депривации остаётся недостаточно изученным. В связи с этим, в данном исследовании показано действие СИТ на гематологические параметры у крыс при водной и пищевой депривации. Было выявлено, что при водной депривации на фоне дополнительного введения СИТ наблюдалось повышение уровня лейкоцитов на 38% (р˂0,05), гемоглобина на 13%, гематокрита на 11% и снижение количества тромбоцитов на 14%. В то же время при пищевой депривации происходили противоположные изменения, при которых прослеживалось снижение количества лейкоцитов на 20%, гемоглобина на 5%, гематокрита на 8% и тромбоцитов на 25% (р˂0,05). Таким образом, гематологические показатели являются значимыми информативными показателями при оценке компенсаторно-адаптационных процессов у крыс в условиях метаболического стресса (голод и жажда), а введение СИТ позволяет уменьшить его негативные последствия.
Литература
Zhao P., Metcalf M., Bunnett N.W. Biased signaling of protease-activated receptors // Front Endocrinol (Lausanne). 2014 May 13; 5: 67. https://doi.org/10.3389/fendo.2014.00067
Chandrabalan A., Ramachandran R. Molecular mechanisms regulating Proteinase-Activated Receptors (PARs) // FEBS J. 2021 Apr; 288(8): 2697-2726. https://doi.org/10.1111/febs.15829
Proteinase-activated receptors: transducers of proteinase-mediated signaling in inflammation and immune response / М. Steinhoff., J. Buddenkotte, V. Shpacovitch, [еt al.] // Endocr Rev. 2005 Feb; 26(1): 1-43. https:// doi.org/10.1210/er.2003-0025
Protease-Activated Receptors (PARs): Biology and Therapeutic Potential in Perioperative Stroke / Т. Mavridis, Т. Choratta, А. Papadopoulou [еt al.] // Transl Stroke Res. 2025 Jun;16(3):933-951. https://doi.org/10.1007/ s12975-024-01233-0
Lee H., Hamilton J.R. Physiology, pharmacology, and therapeutic potential of protease-activated receptors in vascular disease // Pharmacol Ther. 2012 May; 134(2): 246-59. https://doi.org/10.1016/j.pharmthera.2012.01.007
Protease-activated receptors in neuronal development, neurodegeneration, and neuroprotection: thrombin as signaling molecule in the brain / Т. Rohatgi, F. Sedehizade, K. G. Reymann [еt al.] // Neuroscientist. 2004 Dec; 10 (6): 501-12. https://doi.org/10.1177/1073858404269955
Proteinase-activated receptors (PARs) - focus on receptor-receptor-interactions and their physiological and pathophysiological impact / F. Gieseler, Н. Ungefroren, U. Settmacher [еt al.] // Cell Commun Signal. 2013 Nov; 11: 86. https://doi.org/10.1186/1478-811X-11-86
Activation of PAR2 promotes high-fat diet-induced renal injury by inducing oxidative stress and inflammation / S. Ha, Y. Yang, B.M. Kim [еt al.] // Biochim Biophys Acta Mol Basis Dis. 2022 Oct 1; 1868(10): 166474. https://doi.org/10.1016/j.bbadis.2022.166474
PAR2-mediated cellular senescence promotes inflammation and fibrosis in aging and chronic kidney disease / S. Ha, H. W. Kim, К. М. Kim [еt al.] // Aging Cell. 2024 Aug; 23(8): e14184. https://doi.org/10.1111/acel.14184
β-Arrestin-biased proteinase-activated receptor-2 antagonist C781 limits allergen-induced airway hyperresponsiveness and inflammation / H. V. Schiff, С. М. Rivas, W. P. Pederson [еt al.] // Br J Pharmacol. 2023 Mar; 180(5): 667-680. https://doi.org/ 10.1111/bph.15903
Habibi A., Ruf W., Schurgers L. Protease-activated receptors in vascular smooth muscle cells: a bridge between thrombo-inflammation and vascular remodeling // Cell Commun Signal. 2025 Jan; 31: 23(1): 57. https:// doi.org/ 10.1186/s12964-025-02066-6
Expression of Proteinase-Activated Receptor 2 During Colon Volvulus in the Horse / С. Lambertini, А. Zannoni, N. Romagnoli [еt al.] // Front Vet Sci. 2020 Nov 27;7:589367. https://doi.org/ 10.3389/fvets.2020.589367
The expression of protease-activated receptor 2 and 4 in the colon of irritable bowel syndrome patients. / J. H. Zhao, L. Dong, H. T. Shi [еt al.] // Dig Dis Sci. 2012 Jan; 57(1): 58-64. https://doi.org/10.1007/s10620-011-1827-3
Immune tolerance regulation is critical to immune homeostasis / L. Han, Т. Wu, Q. Zhang [еt al.] // J. Immunol. Res. 2025; 2025: 5006201. DOI: https://doi.org/10.1155/jimr/5006201
Nutrition and immune system: from the Mediterranean diet to dietary supplementary through the microbiota / L. Barrea, G. Muscogiuri, Е. Frias-Toral [еt al.] // Crit Rev Food Sci Nutr. 2021; 61(18): 3066-3090. https:// doi.org/10.1080/10408398.2020.1792826
Berrio J. P., Hestehave S., Kalliokoski O. Reliability of sucrose preference testing following short or no food and water deprivation-a Systematic Review and Meta-Analysis of rat models of chronic unpredictable stress // Transl Psychiatry. 2024 Jan 19; 14(1): 39. https://doi.org/ 10.1038/s41398-024-02742-0
Kuzmina I. V., Ovchinnikova N. V., Tolpygo S. M. Activity of the proteolytic enzyme trypsin in rat serum under conditions of water and food deprivation // Bulletin of Experimental Biology and Medicine. 2023; 175 (5): 540--544. https://doi.org/10.47056/0365-9615-2023-175-5-540-544
Кислова И. В., Овчинникова Н. В., Толпыго С. М. Показатели периферической крови у крыс в условиях жажды и голода // Патогенез. 2022. Т. 20. №3. С. 96-97 https://doi.org/10.25557/2310-0435.2022.03.96-97
Neutrophils as critical orchestrators of chronic inflammation / К. Torfs, G. Vermeersch, М. Gouwy [еt al.] // Cell Mol Immunol. 2026 Feb; 23(2): 123-149. https://doi.org/10.1038/s41423-025-01380-w
Targeting neutrophil serine proteases in bronchiectasis / J. D. Chalmers, М. А. Mall, S. H. Chotirmall [еt al.] // Eur Respir J. 2025 Jan 2; 65(1): 2401050. https://doi.org/10.1183/13993003.01050-2024
Zavasnik-Bergant T. Cystatin protease inhibitors and immune functions // Front. Biosci. 2008. Vol. 1. № 13. P. 4625-4637. https://doi.org/10.2741/3028
Trypsin inhibitors: promising candidate satietogenic proteins as complementary treatment for obesity and metabolic disorders? / V. Cristina Oliveira de Lima, G. Piuvezam, В. Leal Lima Maciel [еt al.] // J Enzyme Inhib Med Chem. 2019 Dec; 34(1): 405-419. https://doi.org/10.1080/14756366.2018.1542387.
Effect of Soybean Trypsin Inhibitor on Biochemical Parameters of the Blood under Conditions of Water and Food Deprivation in Rats / I. V. Kuzmina, S. M. Tolpygo, В. В. Shoibonov [еt al.] // Bull Exp Biol Med. 2025 Jan; 178(3): 319-322. https://doi.org/10.1007/s10517-025-06329-7
Gironacci M.M., Bruna-Haupt E. Unraveling the crosstalk between renin-angiotensin system receptors // Acta Physiol (Oxf). 2024 May; 240(5): e14134. https://doi.org/ 10.1111/apha.14134.
Neutrophils preserve energy storage in sympathetically activated adipocytes / S. Son, С. Xu, Н. Fu [еt al.] // Nature. 2026 Feb; 650(8102): 718-726. https://doi.org/ 10.1038/s41586-025-09839-6
Kettritz R. Neutral serine proteases of neutrophils // Immunol Rev. 2016 Sep; 273(1): 232-48. https:// doi.org/10.1111/imr.12441
Meyer-Hoffert U., Wiedow O. Neutrophil serine proteases: mediators of innate immune responses // Curr Opin Hematol. 2011 Jan; 18(1): 19-24. https://doi.org/10.1097/MOH.0b013e32834115d1
Neutrophil-derived serine proteases induce FOXA2-mediated autophagy dysfunction and exacerbate colitis-associated carcinogenesis via protease activated receptor 2 / J. Yuan, J. Ma, F. Zhang, Т. Wang [еt al.] // Autophagy. 2025 Oct; 21(10): 2130-2147. https://doi.org/ 10.1080/15548627.2025.2489335
PAR2 (Protease-Activated Receptor 2) Deficiency Attenuates Atherosclerosis in Mice / S. M. Jones, А. Mann, К. Conrad [еt al.] // Arterioscler Thromb Vasc Biol. 2018 Jun; 38(6): 1271-1282. https://doi.org/10.1161/ ATVBAHA.117.3100822.
Zhao P, Metcalf M, Bunnett NW. Biased signaling of protease-activated receptors. Front Endocrinol (Lausanne). 2014; May 13. 5. 67 p. https://doi.org/10.3389/fendo.2014.00067
Chandrabalan A, Ramachandran R. Molecular mechanisms regulating Proteinase-Activated Receptors (PARs). FEBS J. 2021; Apr. 288(8). 2697-2726 p. https://doi.org/10.1111/febs.15829
Steinhoff М, Buddenkotte J, Shpacovitch V. Proteinase-activated receptors: transducers of proteinase-mediated signaling in inflammation and immune response. Endocr Rev. 2005; Feb. 26(1). 1-43 p. https://doi.org/10.1210/er.2003-0025
Mavridis Т, Choratta Т, Papadopoulou А. Protease-Activated Receptors (PARs): Biology and therapeutic potential in perioperative stroke. Transl Stroke Res. 2025. Jun. 16(3). 933-951 p. https://doi.org/10.1007/s12975-024-01233-0
Lee H, Hamilton JR. Physiology, pharmacology, and therapeutic potential of protease-activated receptors in vascular disease. Pharmacol Ther. 2012 May. 134(2). 246-59 p. https://doi.org/10.1016/j.pharmthera.2012.01.007
Rohatgi Т, Sedehizade F, Reymann KG. Protease-activated receptors in neuronal development, neurodegeneration and neuroprotection: thrombin as signaling molecule in the brain. Neuroscientist. 2004; Dec. 10(6). 501-12 p. https:// doi.org/10.1177/1073858404269955
Gieseler F, Ungefroren Н, Settmacher U. Proteinase-activated receptors (PARs) - focus on receptor-receptor-interactions and their physiological and pathophysiological impact. Cell Commun Signal. 2013; Nov. 11. 86 p. https:// doi.org/10.1186/1478-811X-11-86
Ha S, Yang Y, Kim BM. Activation of PAR2 promotes high-fat diet-induced renal injury by inducing oxidative stress and inflammation. Biochim Biophys Acta Mol Basis Dis. 2022; Oct 1. 1868(10). 166474 p. https://doi.org/10.1016/ j.bbadis.2022.166474
Ha S, Kim HW, Kim КМ. PAR2-mediated cellular senescence promotes inflammation and fibrosis in aging and chronic kidney disease. Aging Cell. 2024; Aug. 23(8). e14184 p. https://doi.org/10.1111/acel.14184
Schiff HV, Rivas СМ, Pederson WP. β-Arrestin-biased proteinase-activated receptor-2 antagonist C781 limits allergen-induced airway hyperresponsiveness and inflammation. Br J Pharmacol. 2023; Mar. 180(5). 667-680 p. https:// doi.org/ 10.1111/bph.15903
Habibi A, Ruf W, Schurgers L. Protease-activated receptors in vascular smooth muscle cells: a bridge between thrombo-inflammation and vascular remodeling. Cell Commun Signal. 2025; Jan. 31. 23(1). 57 p. https://doi.org/ 10.1186/ s12964-025-02066-6
Lambertini С, Zannoni А, Romagnoli N. Expression of Proteinase-Activated Receptor 2 during colon volvulus in the horse. Front Vet Sci. 2020; Nov 27. 7. 589367 p. https://doi.org/ 10.3389/fvets.2020.589367
Zhao JH, Dong L, Shi HT. The expression of protease-activated receptor 2 and 4 in the colon of irritable bowel syndrome patients. Dig Dis Sci. 2012; Jan. 57(1). 58-64 p. https://doi.org/10.1007/s10620-011-1827-3
Han L, Wu Т, Zhang Q. Immune tolerance regulation is critical to immune homeostasis. J. Immunol. Res. 2025; 5006201 p. DOI: https://doi.org/10.1155/jimr/5006201
Barrea L, Muscogiuri G, Frias-Toral Е. Nutrition and immune system: from the Mediterranean diet to dietary supplementary through the microbiota. Crit Rev Food Sci Nutr. 2021; 61(18). 3066-3090 p. https:// doi.org/10.1080/10408398.2020.1792826
Berrio JP, Hestehave S, Kalliokoski O. Reliability of sucrose preference testing following short or no food and water deprivation-a Systematic Review and Meta-Analysis of rat models of chronic unpredictable stress. Transl Psychiatry. 2024; Jan 19. 14(1). 39 p. https://doi.org/ 10.1038/s41398-024-02742-0
Kuzmina IV, Ovchinnikova NV, Tolpygo SM. Activity of the proteolytic enzyme trypsin in rat serum under conditions of water and food deprivation. Bulletin of Experimental Biology and Medicine. 2023; 175 (5). 540-544 p. https:// doi.org/10.47056/0365-9615-2023-175-5-540-544
Kislova IV, Ovchinnikova NV, Tolpygo SM. [Peripheral blood parameters of rats under conditions of thirst and hunger]. Patogenez. 2022; Vol.20. 3. 96-97 p. https://doi.org/10.25557/2310-0435.2022.03.96-97
Torfs К, Vermeersch G, Gouwy М. Neutrophils as critical orchestrators of chronic inflammation. Cell Mol Immunol. 2026; Feb. 23(2). 123-149 p. https://doi.org/10.1038/s41423-025-01380-w
Chalmers JD, Mall МА, Chotirmall SH. Targeting neutrophil serine proteases in bronchiectasis. Eur Respir J. 2025; Jan 2. 65(1). 2401050 p. https://doi.org/10.1183/13993003.01050-2024
Zavasnik-Bergant T. Cystatin protease inhibitors and immune functions. Front. Biosci. 2008; Vol.1. 13. 4625-4637 p. https://doi.org/10.2741/3028
Cristina Oliveira de Lima V, Piuvezam G, Leal Lima Maciel В. Trypsin inhibitors: promising candidate satietogenic proteins as complementary treatment for obesity and metabolic disorders? J Enzyme Inhib Med Chem. 2019; Dec. 34 (1). 405-419 p. https://doi.org/10.1080/14756366.2018.1542387.
Kuzmina IV, Tolpygo SM, Shoibonov ВВ. Effect of soybean trypsin inhibitor on biochemical parameters of the blood under conditions of water and food deprivation in rats. Bull Exp Biol Med. 2025; Jan. 178(3). 319-322 p. https:// doi.org/10.1007/s10517-025-06329-7
Gironacci MM, Bruna-Haupt E. Unraveling the crosstalk between renin-angiotensin system receptors. Acta Physiol (Oxf). 2024; May. 240 (5). e14134. https://doi.org/ 10.1111/apha.14134.
Son S, Xu С, Fu Н. Neutrophils preserve energy storage in sympathetically activated adipocytes. Nature. 2026; Feb. 650(8102). 718-726 p. https://doi.org/ 10.1038/s41586-025-09839-6
Kettritz R. Neutral serine proteases of neutrophils. Immunol Rev. 2016; Sep. 273(1). 232-48 p. https:// doi.org/10.1111/imr.12441
Meyer-Hoffert U, Wiedow O. Neutrophil serine proteases: mediators of innate immune responses. Curr Opin Hematol. 2011; Jan. 18(1). 19-24 p. https://doi.org/10.1097/MOH.0b013e32834115d1
Yuan J, Ma J, Zhang F, Wang Т. Neutrophil-derived serine proteases induce FOXA2-mediated autophagy dysfunction and exacerbate colitis-associated carcinogenesis via protease activated receptor 2. Autophagy. 2025; Oct. 21 (10). 2130-2147 p. https://doi.org/ 10.1080/15548627.2025.2489335
Jones SM, Mann А, Conrad К. PAR2 (Protease-Activated Receptor 2) deficiency attenuates atherosclerosis in mice. Arterioscler Thromb Vasc Biol. 2018; Jun. 38 (6): 1271-1282 p. https://doi.org/10.1161/ATVBAHA.117.3100822.
