Сomponents of colostrum regulate the activity of the immune system in animals with liver fibrosis
Abstract
Regulation of the functional activity of the cellular component of the body's immune system against the background of var i ous liver pathologies, primarily fibrosis, represents a promising approach to developing treatment strategies for such altered fun c tional states. Low molecular weight protein components (LMW) obtained from whole cow colostrum were analysed as natural regulators of immune system activity. The effect of LMW on the number of cytotoxic components in blood serum, the activity of oxygen-dependent and oxygen-independent phagocytosis, and the number of circulating immune complexes in the blood of animals with Cu-induced liver fibrosis was determined. Liver fibrosis was induced in Wistar rats by 6 consecutive injections of copper sulphate at a dose of 1 mg/100 g body weight, and after 3 days one of the groups of animals was administered LMW at a dose of 0.1 mg/100 g body weight per os daily for 6 days. It was found that animals with Cu-induced liver fibrosis had a twofold increase in cytotoxic components in the body compared to the control group. This was accompanied by a twofold increase in the spontaneous level of phagocytic activity of neutrophils (without additional stimulation with zymosan), while the functional r e serve of neutrophils was depleted (there was no stimulation with zymosan); the ability of phagocytic cells to absorb foreign su b stances was increased by only 34%, while the number of circulating immune complexes was reduced by 33%. This immune status of animals with Cu-induced liver fibrosis can be defined as a risk factor for the developmen t of an autoimmune component. Administration of LMW to animals with liver fibrosis for 6 days at a dose of 1 mg/100 g of body weight led to a decrease in phagocytic activity to the level of control indicators, restoration of the reserve of oxygen-dependent phagocytosis of neutrophils and normalisation of oxygen-independent phagocytosis indicators, while the number of circulating immune complexes corre s ponded to the control values. The restoration of cellular parameters under the influence of LMW may prevent the chronic deve l opment of liver fibrosis and its transition to cirrhosis, and further systemic studies will allow the development of treatment tactics using natural LMW.References
Bao, Y., Wang, L., Pan, H., Zhang, T., Chen, Y., & Xu, S. (2021). Animal and organoid models of liver fibrosis. Frontiers in Physiology, 12, 666138.
Barouki, R., Samson, M., Blanc, E. B., Colombo, M., Zucman-Rossi, J., Lazaridis, K. N., Miller, G. W., & Coumoul, X. (2023). The exposome and liver disease – How environmental factors affect liver health. Journal of Hepatology, 79(2), 492–505.
Barzegar, F., Nabizadeh, S., Kamankesh, M., Ghasemi, J. B., & Mohammadi, A. (2023). Recent advances in natural product-based nanoemulsions as promising substitutes for hazardous synthetic food additives: A new revolution in food processing. Food and Bioprocess Technology, 17, 1087–1108.
Bozhkov, A. I., Novikova, A. V., Klimova, E. M., Ionov, I. A., Akzhyhitov, R. A., Kurhuzova, N. I., Bilovetska, S. G., Moskalov, V. B., & Haiovyi, S. S. (2024). Vitamin A reduces the mortality of animals with induced liver fibrosis by providing a multi-level body defense system. Journal of Clinical and Experimental Hepatology, 13(1), 48–63.
Bozhkov, A. I., Ohiienko, S. L., Bondar, A. Y., Ivanov, E. G., & Kurguzova, N. I. (2020). Low-molecular weight components of cow colostrum regulate bone marrow functions by modelling the redox-system of the organism. Regulatory Mechanisms in Biosystems, 11(2), 272–277.
Bozhkov, A. I., Ohiienko, S. L., Bondar, A. Y., Klimova, E. M., & Ivanov, E. G. (2019). Induced liver fibrosis is accompanied in young and old animals by age-dependent changes in bone marrow cells. Advances in Gerontology, 32(1–2), 45–54.
Bozhkov, A. I., Sidorov, V. I., Alboqai, O. K., Akzhyhitov, R. A., Kurguzova, N. I., Malyshev, A. B., Albegai, M. A. Y., & Gromovoi T. Y. (2021). The role of metallothioneins in the formation of hierarchical mechanisms of resistance to toxic compounds in young and old animals on the example of copper sulfate. Translational Medicine of Aging, 5, 62–74.
Buonocore, D., Seneci, A., Carrabetta, M. E., Pialorsi, F., Zurlo, M., Bottone, M. G., Veneroni, P., Verri, M., & Dossena, M. (2016). In vitro oxidative burst assay to evaluate the efficacy of Immune-G-matrix™, an innovative yeast-β-glucans, zinc and copper-based formulation. Nutrafoods, 15, 21–26.
Castaneda, D., Gonzalez, A. J., Alomari, M., Tandon, K., & Zervos, X. B. (2021). From hepatitis A to E: A critical review of viral hepatitis. World Journal of Gastroenterology, 27(16), 1691–1715.
Coskun, M., Kayis, T., Yilmaz, M., Dursun, O., & Emre, I. (2021). Copper and zinc impact on stress biomarkers and growth parameters in a model organism, Galleria mellonella larvae. Biometals, 34(6), 1263–1273.
Dallio, M., Sangineto, M., Romeo, M., Villani, R., Romano, A. D., Loguercio, C., Serviddio, G., & Federico, A. (2021). Immunity as cornerstone of non-alcoholic fatty liver disease: The contribution of oxidative stress in the disease progression. International Journal of Molecular Sciences, 22(1), 436.
Devarbhavi, H., Asrani, S. K., Arab, J. P., Nartey, Y. A., Pose, E., & Kamath, P. S. (2023). Global burden of liver disease: 2023 update. Journal of Hepatology, 79(2), 516–537.
El-Fattah, A. M. A., Rabo, F. H. R. A., El-Dieb, S. M., & El-Kashef, H. A. (2012). Changes in composition of colostrum of Egyptian buffaloes and Holstein cows. BMC Veterinary Research, 8, 19.
Ghosh, S., & Iacucci, M. (2021). Diverse immune effects of bovine colostrum and benefits in human health and disease. Nutrients, 13(11), 3798.
Ginès, P., Krag, A., Abraldes, J. G., Solà, E., Fabrellas, N., & Kamath, P. S. (2021). Liver cirrhosis. The Lancet, 398(10308), 1359–1376.
Hayashida, M., Matsuura, T., Saeki, I., Yanagi, Y., Yoshimaru, K., Nishimoto, Y., Takahashi, Y., Fujita, K., Takada, N., Taguchi, S., Uesugi, T., Hirose, R., Nakamura, M., Nakao, M. & Taguchi, T. (2021). Association of lymphocyte crossmatch and the outcome of intestinal transplantation in swine. Pediatric Surgery International, 27(3), 279–281.
Ivanov, E. G., Lebid-Biletska, K. M., Bozhkov, A., & Nikitchenko, Y. V. (2024). Copper sulfate and carbon tetrachloride induces a uniform response at the level of the redox system and the nature of this response depends on age. Regulatory Mechanisms in Biosystems, 15(3), 496–503.
Ivanov, I., Goltvjansky, A., Bozhkov, A., & Gromovoy, T. (2024). Selective-integrative technology for the separation of colostrum into components and the possibilities of obtaining protein substances from different sources. Innovative Biosystems and Bioengineering, 8(3), 60–67.
Ivanov, I., Kozheshkurt, V., Bozhkov, A., Goltvjansky, A., Katrich, V., Sidorov, V., & Gromovoy, T. (2021). Low-molecular components of colostrum as a regulator of the organism redox-system and biological antidote. Eureka: Life Sciences, 2, 56–64.
Jiang, L., Liu, W., Xu, J., Gao, X., Zhao, H., Li, S. H., Huang, W., Yang, Z., & Wei, Z. (2022). CuO-NPs-triggered heterophil extracellular traps exacerbate liver injury in chicks by promoting oxidative stress and inflammatory responses. Archives of Toxicology, 96(11), 2913–2926.
Khan, T. S., Akram, N., Faisal, Z., Saeed F, Rasheed, A., Ahmed, F., & Afzaal, M. (2024). Bovine colostrum: Therapeutic potential and clinical evidence. International Dairy Journal, 157, 105996.
Khudan, R., Bandas, I., Mykolenko, A., Svanishvili, N., & Krynytska, I. (2021). The influence of chronic hyperhomocysteinemia on phagocytic and metabolic activity of peripheral blood neutrophils in case of lipopolysaccharide-induced periodontitis. Georgian Medical News, (321), 119–125.
Klimova, E. M., Bozhkov, A. I., Boyko, V. V., Drozdova, L. A., Lavinskaya, E. V., & Skok, M. V. (2016). Endogenic cytotoxic compounds and formation of the clinic forms of myasthenia. Translational Biomedicine, 7(3), 84.
Klimova, E. M., Bozhkov, A. I., Lavinska, O. V., Drozdova, L. A., & Kurhuzova, N. I. (2022). Low molecular weight cytotoxic components (DAMPs) form the post-COVID-19 syndrome. Immunobiology, 228(1), 152316.
Kovaleva, M. K., Menzyanova, N. G., Jain, A., Yadav, A., Flora, S. J. S., & Bozhkov, A. I. (2012). Effect of hormesis in Dunaliella viridis Teodor. (Chlorophyta) under the influence of copper sulfate. International Journal on Algae, 14(2), 44–61.
Kusumaningrum, C. E., Widyasari, E. M., Sriyani, M. E., & Wongso, H. (2021). Pharmacological activities and potential use of bovine colostrum for peptide-based radiopharmaceuticals: A review. Pharmacia, 68(2), 471–477.
Le, M. J. (2023). A review of liver fibrosis and cirrhosis regression. Journal of Pathology and Translational Medicine, 57(4), 189–195.
Li, P., & Chang, M. (2021). Roles of PRR-mediated signaling pathways in the regulation of oxidative stress and inflammatory diseases. International Journal of Molecular Sciences, 22(14), 7688.
Liu, Y. B., & Chen, M. K. (2022). Epidemiology of liver cirrhosis and associated complications: Current knowledge and future directions. World Journal of Gastroenterology, 28(41), 5910–5930.
Makri, E., Goulas, A., & Polyzos, S. A. (2021). Epidemiology, pathogenesis, diagnosis and emerging treatment of nonalcoholic fatty liver disease. Archives of Medical Research, 52(1), 25–37.
Paternostro, R., & Trauner, M. (2022). Current treatment of non-alcoholic fatty liver disease. Journal of Internal Medicine, 292(2), 190–204.
Pellicano, R., Ferro, A., Cicerchia, F., Mattivi, S., Fagoonee, S., & Durazzo, M. (2023). Autoimmune hepatitis and fibrosis. Journal of Clinical Medicine, 12(5), 1979.
Playford, R., & Weiser, M. (2021). Bovine colostrum: Its constituents and uses. Nutrients, 13(1), 265.
Poonia, A., & Shiva (2022). Bioactive compounds, nutritional profile and health benefits of colostrum: A review. Food Production, Processing and Nutrition, 4, 26.
Powell, E. E., Wong, V. W. S., & Rinella, M. (2021). Non-alcoholic fatty liver disease. The Lancet, 397(10290), 2212–2224.
Puppel, K., Gołębiewski, M., Grodkowski, G., Slósarz, J., Kunowska-Slósarz, M., Solarczyk, P., Łukasiewicz, M., Balcerak, M., & Przysucha, T. (2019). Composition and factors affecting quality of bovine colostrum: A review. Animals, 9(12), 1070.
Qiuling, L., Qilin, Y., Cheng, Y., Minping, Z., Kangning, W., & Enhua, X. (2023). The application of a novel platform of multiparametric magnetic resonance imaging in a bioenvironmental toxic carbon tetrachloride-induced mouse model of liver fibrosis. Environmental Research, 238(1), 117130.
Riha, I., Haskova, V., Kaslik, J., Maierova, M., & Stransky, J. (1979). The use of polyethylene glycol for immune complex detection in human sera. Molecular Immunology, 16(7), 489–493.
Sadiq, Z. (2023). Free radicals and oxidative stress: Signaling mechanisms, redox basis for human diseases, and cell cycle regulation. Current Molecular Medicine, 23(1), 13–35.
Scheibner, K. A., Lutz, M. A., Boodoo, S., Fenton, M. J., Powell, J. D., & Horton, M. R. (2006). Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. Journal of Immunology, 177(2), 1272–1281.
Struff, W. G., & Sprotte, G. (2008). Bovine colostrum as a biologic in clinical medicine: A review – Part II. International Journal of Clinical Pharmacology and Therapeutics, 46(5), 211–225.
Tretter, V., Hochreiter, B., Zach, M. L., Krenn, K., & Klein, K. U. (2021). Understanding cellular redox homeostasis: A challenge for precision medicine. International Journal of Molecular Sciences, 23(1), 106.
Unsal, V., Cicek, M., & Sabancilar, İ. (2020). Toxicity of carbon tetrachloride, free radicals and role of antioxidants. Reviews on Environmental Health, 36(2), 279–295.
Valko, M., Jomova, K., Rhodes, C. J., Kuča, K., & Musílek, K. (2016). Redox- and non-redox-metal-induced formation of free radicals and their role in human disease. Archives of Toxicology, 90, 1–37.
Wąsowska, E., & Puppel, K. (2018). Changes in the content of immunostimulating components of colostrum obtained from dairy cows at different levels of production. Journal of the Science of Food and Agriculture, 98(13), 5062–5068.
Yalçıntaş, Y. M., Duman, H., Rocha, J. M., Bartkiene, E., Karav, S., & Ozogul, F. (2024). Role of bovine colostrum against various diseases. Food Bioscience, 61, 104818.
Yan, M., Huo, Y., Yin, S., & Hu, H. (2018). Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions. Redox Biology, 17, 274–283.
Yanko, N. V., Kaskova, L. F., Kulai, O. O., Khmil, O. V., & Novikova, S. C. (2022). Neutrophil activities in adolescents with type I diabetes mellitus depending on periodontal state. Wiadomości Lekarskie, 75(11), 2826–2830.
Yao, Q.-Y., Feng, Y.-D., Han, P., Yang, F., & Song, G.-Q. (2020). Hepatic microenvironment underlies fibrosis in chronic hepatitis B patients. World Journal of Gastroenterology, 26(27), 3917–3928.
Zheng, J., Zhao, L., Dong, J., Chen, H., Li, D., Zhang, X., Hassan, M. M., Steck, S. E., Li, X., Xiang, Y.-B., & Wang, H. (2022). The role of dietary factors in nonalcoholic fatty liver disease to hepatocellular carcinoma progression: A systematic review. Clinical Nutrition, 41(10), 2295–2307.
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons «Attribution» 4.0 License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.


