The role of exosomes in the mechanisms of inflammation development in patients with cardiovascular pathology and the contribution to therapeutic potential of stem cells

Authors

DOI:

https://doi.org/10.14739/2310-1210.2021.4.204886

Keywords:

exosomes, inflammation, cardiovascular diseases, stem cells

Abstract

The aim – based on the analysis of the scientific literature focused on understanding the role of exosomes in the mechanisms of inflammation development and application of stem cells for cellular therapy in different pathological conditions, to identify and substantiate the prospects of using the exosomes as prognostic markers of a disease progression and application of their therapeutic potential in cardiovascular pathology.

Global trends in the study of stem cells of different origins from the perspective of morphofunctional, molecular-genetic, cytogenetic, immunogenetic and cytological characteristics contribute significantly the development of regenerative medicine in the context of developing new methodological solutions for the use of stem cells and their components, particularly exosomes, for cell therapy of various pathological conditions. Studies show the indirect effect of exosomes on the immune response activation, coordination of cellular senescence processes and antigen presentation. There are also evidence of their impact on the structural and functional restoration of affected organs and blood vessels.

The application potential of exosomes in practical medicine, particularly in the area of new approaches development to synthesize the newer biopharmaceuticals and as markers of multifactorial pathology course in conjunction with studies on the mechanisms of exosome involvement into immune processes is discussed.

The study on the exosome-mediated mechanisms of inflammation in atherosclerosis is relevant, given the fact that their main physiological role is to implement the link between immunocompetent cells.

Conclusions. Improving knowledge of the molecular biological mechanisms of the exosome influence on immunological processes in patients with cardiovascular pathology allows to expand the range of diagnostic and prognostic criteria for the formation of immuno-inflammatory reactions and endothelial dysfunction and to outline ways to personify the choice of therapeutic programs, which, in turn, can open approaches to develop fundamentally newer pharmaceuticals.

Author Biographies

P. F. Muzychenko, Bogomolets National Medical University, Kyiv, Ukraine

Professor of the Department of Operative Surgery and Topographic Anatomy

Zh. M. Minchenko, SI “National Research Center for Radiation Medicine of the NAMS of Ukraine”, Kyiv

PhD, DSc, Professor, Head of the Laboratory of Immunogenetics

T. I. Havrylenko, SI “National Scientific Center “Institute of Cardiology named after M. D. Strazhesko” of the NAMS of Ukraine, Kyiv

PhD, DSc, Professor, Head of the Department of Immunology and Biochemistry

V. A. Cherniak, Taras Shevchenko National University, Kyiv, Ukraine

MD, PhD, DSc, Professor, Director of the University Clinic

S. V. Demidov, Taras Shevchenko National University, Kyiv, Ukraine

PhD, DSc, Professor, Head of the Department of General and Medical Genetics

N. O. Ryzhkova, SI “National Scientific Center "Institute of Cardiology named after M. D. Strazhesko” of the NAMS of Ukraine, Kyiv

MD, PhD, Senior Researcher of the Department of Immunology and Biochemistry

O. A. Pidhaina, SI “National Scientific Center "Institute of Cardiology named after M. D. Strazhesko” of the NAMS of Ukraine, Kyiv

MD, PhD, Senior Researcher of the Department of Immunology and Biochemistry

References

Sukhanov, Yu. V., Vorotelyak, E. A., Vasiliev, A. V., & Terskikh, V. V. (2018). 150 let kontseptsii «stvolovaya kletka» [150 yearsof concept of stem cell]. Rossiiskii fiziologicheskii zhurnal im. I. M. Sechenova, 104(1), 18-30. [in Russian].

Tiercy, J. M. (2016). How to select the best available related or unrelated donor of hematopoietic stem cells? Haematologica, 101(6), 680-687. https://doi.org/10.3324/haematol.2015.141119

Khomenko, V. I. (2018). Rol reiestriv donoriv hemopoetychnykh stovburovykh klityn dlia alohennoi transplantatsii [Role of the registries of hematopoietic stem cell donors in allogeneic transplantation]. Imunolohiia ta alerholohiia: nauka i praktyka, (1-2), 49-54. [in Ukrainian].

Bazyka, D., Sushko, V., Chumak, A., Chumak, V., & Yanovych, L. (Eds.). (2016). Chapter 9. Thirty years of experience in radiation immunogenetics since the Chornobyl accident. Health effects of the Chornobyl accident - thirty years aftermath (pp. 190-211). DIA. https://nrcrm.gov.ua/downloads/2017/monograph_last.pdf

Khaitov, R. M., Alekseev, L. P., Trofimov, D. Yu., Kofiadi, I. V., & Alekseeva, P. L. (2017). Immunogenetika i transplantatsiya krovetvornykh stvolovykh kletok [Immunogenetics and transplantation of hematopoietic stem cells]. Immunologiya, 38(4), 184-192. https://doi.org/10.18821/0206-4952-2017-38-4-184-192 [in Russian].

Khomenko, V. I. (2018) Transplantatsiia hemopoetychnykh stovburovykh klityn: systemno-istorychnyi aspekt [Transplantation of hematopoietic stem cells: historical aspects]. Klitynna ta orhanna transplantolohiia, 6(2), 112-117. https://doi.org/10.22494/cot.v6i2.85 [in Ukrainian].

Badierah, R. A., Uversky, V. N., & Redwan, E. M. (2021). Dancing with Trojan horses: an interplay between the extracellular vesicles and viruses. Journal of Biomolecular Structure and Dynamics, 39(8), 3034-3060. https://doi.org/10.1080/07391102.2020.1756409

Yáñez-Mó, M., Siljander, P. R., Andreu, Z., Zavec, A. B., Borràs, F. E., Buzas, E. I., Buzas, K., Casal, E., Cappello, F., Carvalho, J., Colás, E., Cordeiro-da Silva, A., Fais, S., Falcon-Perez, J. M., Ghobrial, I. M., Giebel, B., Gimona, M., Graner, M., Gursel, I., Gursel, M., … De Wever, O. (2015). Biological properties of extracellular vesicles and their physiological functions. Journal of Extracellular Vesicles, 4(1), Article 27066. https://doi.org/10.3402/jev.v4.27066

Jan, A. T., Rahman, S., Khan, S., Tasduq, S. A., & Choi, I. (2019). Biology, Pathophysiological Role, and Clinical Implications of Exosomes: A Critical Appraisal. Cells, 8(2), Article 99. https://doi.org/10.3390/cells8020099

Samoylova, E. M., Kalsin, V. A., Bespalova, V. A., Devichensky, V. M., & Baklaushev, V. P. (2017). Ekzosomy: ot biologii k klinike [Exosomes: from biology to clinics]. Geny i kletki, 12(24), 7-20. https://doi.org/10.23868/201707024 [in Russian].

McKelvey, K. J., Powell, K. L., Ashton, A. W., Morris, J. M., & McCracken, S. A. (2015). Exosomes: Mechanisms of Uptake. Journal of Circulating Biomarkers, 4, Article 7. https://doi.org/10.5772/61186

Hornung, S., Dutta, S., & Bitan, G. (2020). CNS-Derived Blood Exosomes as a Promising Source of Biomarkers: Opportunities and Challenges. Frontiers in Molecular Neuroscience, 13, Article 38. https://doi.org/10.3389/fnmol.2020.00038

Brown, R., Richardson, K. L., Kabir, T. D., Trinder, D., Ganss, R., & Leedman, P. J. (2020). Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology. Frontiers in Oncology, 10, Article 476. https://doi.org/10.3389/fonc.2020.00476

Zininga, T., Ramatsui, L., & Shonhai, A. (2018). Heat Shock Proteins as Immunomodulants. Molecules, 23(11), Article 2846. https://doi.org/10.3390/molecules23112846

Scalia, F., Marino Gammazza, A., Conway de Macario, E., Macario, A., & Cappello, F. (2019). Myelin Pathology: Involvement of Molecular Chaperones and the Promise of Chaperonotherapy. Brain Sciences, 9(11), Article 297. https://doi.org/10.3390/brainsci9110297

Federici, C., Shahaj, E., Cecchetti, S., Camerini, S., Casella, M., Iessi, E., Camisaschi, C., Paolino, G., Calvieri, S., Ferro, S., Cova, A., Squarcina, P., Bertuccini, L., Iosi, F., Huber, V., & Lugini, L. (2020). Natural-Killer-Derived Extracellular Vesicles: Immune Sensors and Interactors. Frontiers in Immunology, 11, Article 262. https://doi.org/10.3389/fimmu.2020.00262

Hansson, G. K., Libby, P., & Tabas, I. (2015). Inflammation and plaque vulnerability. Journal of Internal Medicine, 278(5), 483-493. https://doi.org/10.1111/joim.12406

Kozlov, V. A. (2019). Immunnaya paradigma i immunosupressornaya dominanta v patogeneze osnovnykh zabolevanii sovremennogo cheloveka [Immune paradigm and immunosuppressive dominance in the pathogenesis of major diseases of the modern man]. Byulleten' sibirskoi meditsiny, 18(1), 7-17. https://doi.org/10.20538/1682-0363-2019-1-7-17 [in Russian].

Weiberg, A., Bellinger, M. & Jin, H. (2015). Conversations between kingdoms: small RNAs. Current Opinion in Biotechnology, 32, 207-215. http://doi.org/10.1016/j.copbio.2014.12.025

Desd`ın-Mico, G. & Mittelbrunn, M. (2017). Role of exosomes in the protection of cellular homeostasis. Cell Adhesion & Migration, 11(2). 127-134. http://doi.org/10.1080/19336918.2016.1251000

El-Khoury, V., Pierson, S., Kaoma, T., Bernardin, F., & Berchem, G. (2016). Assessing cellular and circulating miRNA recovery: the impact of the RNA isolation method and the quantity of input material. Scientific Reports, 6, Article 19529. https://doi.org/10.1038/srep19529

Witwer, K. W., Van Balkom, B., Bruno, S., Choo, A., Dominici, M., Gimona, M., Hill, A. F., De Kleijn, D., Koh, M., Lai, R. C., Mitsialis, S. A., Ortiz, L. A., Rohde, E., Asada, T., Toh, W. S., Weiss, D. J., Zheng, L., Giebel, B., & Lim, S. K. (2019). Defining mesenchymal stromal cell (MSC)-derived small extracellular vesicles for therapeutic applications. Journal of Extracellular Vesicles, 8(1), Article 1609206. https://doi.org/10.1080/20013078.2019.1609206

Kunze-Schumacher, H., & Krueger, A. (2020). The Role of MicroRNAs in Development and Function of Regulatory T Cells - Lessons for a Better Understanding of MicroRNA Biology. Frontiers in Immunology, 11, Article 2185. https://doi.org/10.3389/fimmu.2020.02185

Hartmann, P., Schober, A., & Weber, C. (2015). Chemokines and microRNAs in atherosclerosis. Cellular and Molecular Life Sciences, 72(17), 3253-3266. https://doi.org/10.1007/s00018-015-1925-z

Higashimori, H., Schin, C. S., Chiang, M. S., Morel, L., Shoneye, T. A., Nelson, D. L., & Yang, Y. (2016). Selective Deletion of Astroglial FMRP Dysregulates Glutamate Transporter GLT1 and Contributes to Fragile X Syndrome Phenotypes In Vivo. The Journal of Neuroscience, 36(27), 7079-7094. https://doi.org/10.1523/JNEUROSCI.1069-16.2016

Yue, B., Yang, H., Wang, J., Ru, W., Wu, J., Huang, Y., Lan, X., Lei, C., & Chen, H. (2020). Exosome biogenesis, secretion and function of exosomal miRNAs in skeletal muscle myogenesis. Cell Proliferation, 53(7), Article e12857. https://doi.org/10.1111/cpr.12857

Peng, S., Gao, D., Gao, C., Wei, P., Niu, M., & Shuai, C. (2016). MicroRNAs regulate signaling pathways in osteogenic differentiation of mesenchymal stem cells (Review). Molecular Medicine Reports, 14(1), 623-629. https://doi.org/10.3892/mmr.2016.5335

Joyce, D. P., Kerin, M. J., & Dwyer, R. M. (2016). Exosome-encapsulated microRNAs as circulating biomarkers for breast cancer. International Journal of Cancer, 139(7), 1443-1448. https://doi.org/10.1002/ijc.30179

D'Asti, E., Chennakrishnaiah, S., Lee, T. H., & Rak, J. (2016). Extracellular Vesicles in Brain Tumor Progression. Cellular and Molecular Neurobiology, 36(3), 383-407. https://doi.org/10.1007/s10571-015-0296-1

Van Giau, V., & An, S. S. (2016). Emergence of exosomal miRNAs as a diagnostic biomarker for Alzheimer's disease. Journal of the Neurological Sciences, 360, 141-152. https://doi.org/10.1016/j.jns.2015.12.005

Coleman, B. M., & Hill, A. F. (2015). Extracellular vesicles - Their role in the packaging and spread of misfolded proteins associated with neurodegenerative diseases. Seminars in Cell & Developmental Biology, 40, 89-96. https://doi.org/10.1016/j.semcdb.2015.02.007

Perez-Hernandez, J., & Cortes, R. (2015). Extracellular Vesicles as Biomarkers of Systemic Lupus Erythematosus. Disease Markers, 2015, Article 613536. https://doi.org/10.1155/2015/613536

Mel'nikov, P. A., Baklaushev, V. P., Gabashvili, A. N., Nukolova, N. V., Kuznetsov, I. I., Cherepanov, S. A., Koshkin, F. A., Leopol'd, A. V., & Chekhonin, V. P. (2017). Internalization of Vectorized Liposomes Loaded with Plasmid DNA in C6 Glioma Cells. Bulletin of Experimental Biology and Medicine, 163(1), 114-122. https://doi.org/10.1007/s10517-017-3750-x

Baklaushev, V. P., Nukolova, N. N., Khalansky, A. S., Gurina, O. I., Yusubalieva, G. M., Grinenko, N. P., Gubskiy, I. L., Melnikov, P. A., Kardashova, K., Kabanov, A. V., & Chekhonin, V. P. (2015). Treatment of glioma by cisplatin-loaded nanogels conjugated with monoclonal antibodies against Cx43 and BSAT1. Drug Delivery, 22(3), 276-285. https://doi.org/10.3109/10717544.2013.876460

Ren, J., He, W., Zheng, L., & Duan, H. (2016). From structures to functions: insights into exosomes as promising drug delivery vehicles. Biomaterials Science, 4(6), 910-921. https://doi.org/10.1039/c5bm00583c

Schmidt, A. H., Sauter, J., Baier, D. M., Daiss, J., Keller, A., Klussmeier, A., Mengling, T., Rall, G., Riethmüller, T., Schöfl, G., Solloch, U. V., Torosian, T., Means, D., Kelly, H., Jagannathan, L., Paul, P., Giani, A. S., Hildebrand, S., Schumacher, S., Markert, J., … Schetelig, J. (2020). Immunogenetics in stem cell donor registry work: The DKMS example (Part 1). International Journal of Immunogenetics, 47(1), 13-23. https://doi.org/10.1111/iji.12471

Butts, J. C., McCreedy, D. A., Martinez-Vargas, J. A., Mendoza-Camacho, F. N., Hookway, T. A., Gifford, C. A., Taneja, P., Noble-Haeusslein, L., & McDevitt, T. C. (2017). Differentiation of V2a interneurons from human pluripotent stem cells. Proceedings of the National Academy of Sciences of the United States of America, 114(19), 4969-4974. https://doi.org/10.1073/pnas.1608254114

Gomzikova, M. O., & Rizvanov, A. A. (2017). Current Trends in Regenerative Medicine: From Cell to Cell-Free Therapy. BioNanoScience, 7, 240-245. https://doi.org/10.1007/s12668-016-0348-0

Teng, X., Chen, L., Chen, W., Yang, J., Yang, Z., & Shen, Z. (2015). Mesenchymal Stem Cell-Derived Exosomes Improve the Microenvironment of Infarcted Myocardium Contributing to Angiogenesis and Anti-Inflammation. Cellular Physiology and Biochemistry, 37(6), 2415-2424. https://doi.org/10.1159/000438594

Hu, G. W., Li, Q., Niu, X., Hu, B., Liu, J., Zhou, S. M., Guo, S. C., Lang, H. L., Zhang, C. Q., Wang, Y., & Deng, Z. F. (2015). Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells attenuate limb ischemia by promoting angiogenesis in mice. Stem Cell Research & Therapy, 6(1), Article 10. https://doi.org/10.1186/scrt546

Chalasani, A., Ji, K., Sameni, M., Mazumder, S. H., Xu, Y., Moin, K., & Sloane, B. F. (2017). Live-Cell Imaging of Protease Activity: Assays to Screen Therapeutic Approaches. In O. Schilling (Ed.), Protein Terminal Profiling (1st ed, Vol. 1574, 215-225). Methods in molecular biology. https://doi.org/10.1007/978-1-4939-6850-3_16

Liang, B., He, X., Zhao, Y. X., Zhang, X. X., & Gu, N. (2020). Advances in Exosomes Derived from Different Cell Sources and Cardiovascular Diseases. BioMed Research International, 2020, Article 7298687. https://doi.org/10.1155/2020/7298687

Patil, M., Henderson, J., Luong, H., Annamalai, D., Sreejit, G., & Krishnamurthy, P. (2019). The Art of Intercellular Wireless Communications: Exosomes in Heart Disease and Therapy. Frontiers in Cell and Developmental Biology, 7, Article 315. https://doi.org/10.3389/fcell.2019.00315

Nouraee, N., & Mowla, S. J. (2015). miRNA therapeutics in cardiovascular diseases: promises and problems. Frontiers in Genetics, 6, Article 232. https://doi.org/10.3389/fgene.2015.00232

Chistiakov, D. A., Orekhov, A. N., & Bobryshev, Y. V. (2016). Cardiac Extracellular Vesicles in Normal and Infarcted Heart. International Journal of Molecular Sciences, 17(1), Article 63. https://doi.org/10.3390/ijms17010063

Yuan, M. J., Maghsoudi, T., & Wang, T. (2016). Exosomes Mediate the Intercellular Communication after Myocardial Infarction. International Journal of Medical Sciences, 13(2), 113-116. https://doi.org/10.7150/ijms.14112

Hoefer, I. E., Steffens, S., Ala-Korpela, M., Bäck, M., Badimon, L., Bochaton-Piallat, M. L., Boulanger, C. M., Caligiuri, G., Dimmeler, S., Egido, J., Evans, P. C., Guzik, T., Kwak, B. R., Landmesser, U., Mayr, M., Monaco, C., Pasterkamp, G., Tuñón, J., Weber, C., & ESC Working Group Atherosclerosis and Vascular Biology. (2015). Novel methodologies for biomarker discovery in atherosclerosis. European Heart Journal, 36(39), 2635-2642. https://doi.org/10.1093/eurheartj/ehv236

Cypryk, W., Nyman, T. A., & Matikainen, S. (2018). From Inflammasome to Exosome - Does Extracellular Vesicle Secretion Constitute an Inflammasome-Dependent Immune Response? Frontiers in Immunology, 9, Article 2188. https://doi.org/10.3389/fimmu.2018.02188

Gao, W., Liu, H., Yuan, J., Wu, C., Huang, D., Ma, Y., Zhu, J., Ma, L., Guo, J., Shi, H., Zou, Y., & Ge, J. (2016). Exosomes derived from mature dendritic cells increase endothelial inflammation and atherosclerosis via membrane TNF-α mediated NF-κB pathway. Journal of Cellular and Molecular Medicine, 20(12), 2318-2327. https://doi.org/10.1111/jcmm.12923

Barnes, B. J., & Somerville, C. C. (2020). Modulating Cytokine Production via Select Packaging and Secretion From Extracellular Vesicles. Frontiers in Immunology, 11, Article 1040. https://doi.org/10.3389/fimmu.2020.01040

Zeng, Y., Yao, X., Liu, X., He, X., Li, L., Liu, X., Yan, Z., Wu, J., & Fu, B. M. (2019). Anti-angiogenesis triggers exosomes release from endothelial cells to promote tumor vasculogenesis. Journal of Extracellular Vesicles, 8(1), Article 1629865. https://doi.org/10.1080/20013078.2019.1629865

Nakata, R., Shimada, H., Fernandez, G. E., Fanter, R., Fabbri, M., Malvar, J., Zimmermann, P., & DeClerck, Y. A. (2017). Contribution of neuroblastoma-derived exosomes to the production of pro-tumorigenic signals by bone marrow mesenchymal stromal cells. Journal of Extracellular Vesicles, 6(1), Article 1332941. https://doi.org/10.1080/20013078.2017.1332941

Vilgelm, A. E., & Richmond, A. (2019). Chemokines Modulate Immune Surveillance in Tumorigenesis, Metastasis, and Response to Immunotherapy. Frontiers in Immunology, 10, Article 333. https://doi.org/10.3389/fimmu.2019.00333

Tang, N., Sun, B., Gupta, A., Rempel, H., & Pulliam, L. (2016). Monocyte exosomes induce adhesion molecules and cytokines via activation of NF-κB in endothelial cells. FASEB journal, 30(9), 3097-3106. https://doi.org/10.1096/fj.201600368RR

Black, L. V., Saunderson, S. C., Coutinho, F. P., Muhsin-Sharafaldine, M. R., Damani, T. T., Dunn, A. C., & McLellan, A. D. (2016). The CD169 sialoadhesin molecule mediates cytotoxic T-cell responses to tumour apoptotic vesicles. Immunology & Cell Biology, 94(5), 430-438. https://doi.org/10.1038/icb.2015.111

Grabowska, J., Lopez-Venegas, M. A., Affandi, A. J., & den Haan, J. (2018). CD169+ Macrophages Capture and Dendritic Cells Instruct: The Interplay of the Gatekeeper and the General of the Immune System. Frontiers in Immunology, 9, Article 2472. https://doi.org/10.3389/fimmu.2018.02472

Rudenko, A., Gavrilenko, T., Rasputnyak, O., Lomakovsky, A., Rizhkova, N., & Podgaynaya, E. (2017). Vliyanie immunopatologicheskikh reaktsii na remodelirovanie miokarda i razvitie sistolicheskoi disfunktsii serdtsa u patsientov s ishemicheskoi kardiomiopatiei [Influence of immunopathological reactions on myocardial remodeling and development of systolic dysfunction of the heart in patients with ischemic cardiomyopathy]. Laboratornaya diagnostika. Vostochnaya Evropa, 6(3), 418-428. [in Russian].

Kovalenko, V. N., Gavrilenko, T. I., Ryzhkova, N. A., Parkhomenko, A. N., Ilienko, I. N., & Lomakovsky, A. N. (2015). Retseptory vrozhdennogo immuniteta pri ateroskleroze i revmatoidnom artrite (obzor literatury) [Receptors of innate immunity at atherosclerosis and rheumatoid arthritis (review of literature)]. Zhurnal NAMN Ukrainy, 21(2), 170-180. [in Russian].

Podgaynaya, E., Gavrilenko, T., Lomakovsky, A., Rizhkova, N., & Yakushko, L. (2016). Immunnye markery riska razvitiya serdechno-sosudistykh sobytii u patsientov so stabil'noi ishemicheskoi bolezn'yu serdtsa [Immune markers of the risk of cardiovascular events in patients with stable cardiac ischemia]. Laboratornaya diagnostika. Vostochnaya Evropa, 5(3), 441-449. [in Russian].

Libby, P., Nahrendorf, M., & Swirski, F. K. (2016). Leukocytes Link Local and Systemic Inflammation in Ischemic Cardiovascular Disease: An Expanded "Cardiovascular Continuum". Journal of the American College of Cardiology, 67(9), 1091-1103. https://doi.org/10.1016/j.jacc.2015.12.048

Swirski, F. K., Nahrendorf, M., & Libby, P. (2016). Mechanisms of Myeloid Cell Modulation of Atherosclerosis. Microbiology Spectrum, 4(4). https://doi.org/10.1128/microbiolspec.MCHD-0026-2015

Gavrilenko, T. I., Ryzhkova, N.O., Parkhomenko, O. M., & Dovgan, N. V. (2019). Rol faktora rostu endoteliiu sudyn pry hostrykh formakh ishemichnoi khvoroby sertsia [Physiological significance of vascular endothelial growth factor in patients with acute forms of coronary artery disease]. Fiziolohichnyi zhurnal, 65(5), 33-39. https://doi.org/10.15407/fz65.05.033 [in Ukrainian].

Published

2021-07-01

How to Cite

1.
Muzychenko PF, Minchenko ZM, Havrylenko TI, Cherniak VA, Demidov SV, Ryzhkova NO, Pidhaina OA. The role of exosomes in the mechanisms of inflammation development in patients with cardiovascular pathology and the contribution to therapeutic potential of stem cells. Zaporozhye Medical Journal [Internet]. 2021Jul.1 [cited 2024Dec.5];23(4):566-74. Available from: http://zmj.zsmu.edu.ua/article/view/204886

Issue

Section

Review