pmedpharmФармация и фармакологияPharmacy & Pharmacology2307-92662413-2241Pyatigorsk Medical and Pharmaceutical Institute - branch of Volgograd State Medical Univer10.19163/2307-9266-2021-9-5-346-355pmedpharm-932Research ArticleОБЗОРЫ, ЛЕКЦИИREVIEWS, LECTURESБЕЛОК ТЕПЛОВОГО ШОКА HSP70 – ПРЕДПОСЫЛКИ ИСПОЛЬЗОВАНИЯ В КАЧЕСТВЕ ЛЕКАРСТВЕННОГО СРЕДСТВАHEAT SHOCK PROTEIN HSP70: PREREQUISITES FOR USE AS A MEDICINAL PRODUCThttps://orcid.org/0000-0003-3138-2075ПокровскийВ. М.PokrovskyV. M.

студент 6-го курса Медицинского института

6th year student of the Medical Institute

vmpokrovsky@yandex.ruhttps://orcid.org/0000-0002-8415-4562ПатрахановЕ. А.PatrakhanovE. A.

Федеральное государственное автономное образовательное учреждение высшего образования «Белгородский государственный национальный исследовательский университет»308015, Россия, г. Белгород, ул. Победы, 85

6th year student of the Medical Institute

pateval7@gmail.comhttps://orcid.org/0000-0001-6439-2419АнциферовО. В.AntsiferovO. V.

старший преподаватель кафедры факультетской терапии 

Senior Lecturer, Department of Faculty Therapy

antsiferov@bsu.edu.ruКолесникИ. М.KolesnikI. M.

доцент кафедры фармакологии и клинической фармакологии 

Associate Professor of the Department of Pharmacology and Clinical Pharmacology

kolesnik_inga@mail.ruhttps://orcid.org/0000-0001-9737-6378БелашоваА. В.BelashovaA. V.

студентка 6-го курса Медицинского института

student of Medical Institute

belashova_av@mail.ruhttps://orcid.org/0000-0002-9970-4109СолдатоваВ. А.SoldatovaV. A.

аспирант кафедры фармакологии и клинической фармакологии 

postgraduate student of the Department of Pharmacology and Clinical Pharmacology

lorsoldatova@gmail.comПокопейкоО. Н.PokopeikoO. N.

студентка 4-го курса

4th year student

OPokopejko@mail.ruhttps://orcid.org/0000-0001-9440-5866КарагодинаА Ю.KaragodinaA. Yu.

студентка 6-го курса Медицинского института

6th year student, the Medical Institute, 

anastasiavolmedic@gmail.comhttps://orcid.org/0000-0001-9440-5866АрхиповИ. А.ArkhipovI. A.

студент 6-го курса Медицинского института

6th year student of the Medical Institute

iaarkhipovbsu@gmail.comВоронинаД. Г.VoroninaD. G.

младший научный сотрудник НИИ Фармакологии живых систем

Junior Researcher, Research Institute of Pharmacology of Living Systems

diana0085@inbox.ruСушковаД. Н.SushkovaD. N.

младший научный сотрудник НИИ Фармакологии живых систем

Junior Researcher, Research Institute of Pharmacology of Living Systems

maslova_d@bsu.edu.ruФедеральное государственное автономное образовательное учреждение высшего образования «Белгородский государственный национальный исследовательский университет» 308015, Россия, г. Белгород, ул. Победы, 85РоссияBelgorod State National Research University (NRU “BelSU”) 85, Pobeda St., Belgorod, Russia, 308015Russian Federationстудент 6-го курса Медицинского институтаРоссияBelgorod State National Research University (NRU “BelSU”) 85, Pobeda St., Belgorod, Russia, 308015Russian FederationФедеральное государственное автономное образовательное учреждение высшего образования  «Белгородский государственный национальный исследовательский университет» 308015, Россия, г. Белгород, ул. Победы, 85РоссияBelgorod State National Research University (NRU “BelSU”) 85, Pobeda St., Belgorod, Russia, 308015Russian FederationФедеральное государственное автономное образовательное учреждение высшего образования «Первый Московский государственный медицинский университет имени И.М. Сеченова» (Сеченовский Университет) 119991, Россия, г. Москва, ул. Трубецкая, 8/2РоссияFirst Moscow State Medical University n. a. I.M. Sechenov (Sechenov University) Bldg. 2, 8, Trubetskaya St., Moscow, Russia, 119991Russian Federation20212510202195346355Copyright © Покровский В.М., Патраханов Е.А., Анциферов О.В., Колесник И.М., Белашова А.В., Солдатова В.А., Покопейко О.Н., Карагодина А.Ю., Архипов И.А., Воронина Д.Г., Сушкова Д.Н., 20212021Покровский В.М., Патраханов Е.А., Анциферов О.В., Колесник И.М., Белашова А.В., Солдатова В.А., Покопейко О.Н., Карагодина А.Ю., Архипов И.А., Воронина Д.Г., Сушкова Д.Н.Pokrovsky V.M., Patrakhanov E.A., Antsiferov O.V., Kolesnik I.M., Belashova A.V., Soldatova V.A., Pokopeiko O.N., Karagodina A.Y., Arkhipov I.A., Voronina D.G., Sushkova D.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmpharm.ru/jour/article/view/932

Белок теплового шока Hsp70 является одним из основных компонентов цитопротекции при действии различных внешних раздражителей. Анализ литературных данных показывает, что на сегодняшний день исследователями сформированы многочисленные доказательства роли HSP70 в качестве биологической мишени для разработки лекарственных средств, однако, представления о его использовании в качестве лекарственного средства зачастую разнонаправлены.

Цель

Цель. Обобщить и проанализировать данные литературы об особенностях физиологических функций белка теплового шока Hsp 70 и обозначить возможности его применения с целью фармакологической коррекции различных патологических состояний. 

Материалы и методы

Материалы и методы. В процессе подбора материала для написания обзорной статьи использовали такие базы данных, как: Google Patents, Science Research Portal, Google Scholar, ScienceDirect, CiteSeer, Publications, ResearchIndex, Ingenta, PubMed, KEGG и др. Параметрами для отбора литературы были выбраны следующие слова и словосочетания: Hsp70, Hsp70 stroke, Hsp70 neuroprotection, Hsp70 cytoprotection, recombinant drugs.

Результаты

Результаты. В данном обзоре мы сфокусировались на фармакологии одного из ключевых представителей данного семейства – Hsp70. Литературный анализ подтверждает, что данная молекула является эндогенным регулятором многих физиологических процессов и демонстрирует тканезащитные эффекты при моделировании ишемических, нейродегенеративных и воспалительных процессов. Применение рекомбинантного экзогенного Hsp70 имитирует эндогенную функцию белка, свидетельствуя об отсутствии ряда типичных ограничений, характерных для фармакотерапии высокомолекулярными соединениями, таких как иммуногенность, быстрое разрушение протеазами или низкая степень прохождения через гистогематические барьеры.

Заключение

Заключение. Таким образом, Hsp70 может стать перспективным агентом для клинических испытаний в качестве препарата для лечения пациентов неврологического, иммунологического и кардиоваскулярного профилей.

Heat shock protein Hsp70 is one of the main cytoprotection components under the action of various external stimuli. The analysis of the literature data shows that nowadays, the researches’ overwhelming evidence has proven the role of Hsp70 as a biological target for the drug development; however, the ideas about its use as a drug are often multidirectional.

The aim of the article is to analyze and generalize the literature data on the features of the physiological functions of heat shock protein Hsp 70, and indicate the possibilities of its use for the pharmacological correction of various pathological conditions.

Materials and methods

Materials and methods. In the process of selecting material for writing this review article, such databases as Google Patents, Science Research Portal, Google Scholar, ScienceDirect, CiteSeer, Publications, ResearchIndex, Ingenta, PubMed, KEGG, etc. were used The following words and word combinations were selected as markers for identifying the literature: Hsp70, Hsp70 stroke, Hsp70 neuroprotection, Hsp70 cytoprotection, recombinant drugs.

Results

Results. In this review, the pharmacology of one of the key members of this family, Hsp70, was focused on. The literary analysis confirms that this molecule is an endogenous regulator of many physiological processes and demonstrates tissue protective effects in modeling ischemic, neurodegenerative and inflammatory processes. The use of recombinant exogenous Hsp70 mimics the endogenous function of the protein, indicating the absence of a number of typical limitations characteristic of pharmacotherapy with high molecular weight compounds, such as immunogenicity, a rapid degradation by proteases, or a low penetration of histohematogenous barriers.

Conclusion

Conclusion. Thus, Hsp70 may become a promising agent for clinical trials as a drug for the treatment of patients with neurological, immunological, and cardiovascular profiles.

Hsp 70цитопротекцияшапероннейропротекциярекомбинантные препаратыHsp 70cytoprotectionchaperoneneuroprotectionrecombinant drugsДанное исследование поддержано грантом Белгородской области на оказание государственной поддержки внедрения в производство инновационных технологий в рамках технологических проектов полного цикла.This study was supported by a grant from the Belgorod Region for the government support implementation of innovative technologies into promotion, within the framework of full-cycle technological projects.ReferencesSchlesinger M.J. Heat Shock Proteins // The Journal of biological chemistry. – 1990. – Vol. 265, No. 21. – P. 12111–12114.Schlesinger M.J. Heat shock proteins. J Biol Chem. 1990 Jul 25;265(21):12111-4.Ferat-Osorio E., Sánchez-Anaya A., Gutiérrez-Mendoza M., Boscó-Gárate I., Wong-Baeza I., Pastelin-Palacios R., Pedraza-Alva G., Bonifaz L.C., Cortés-Reynosa P., Pérez-Salazar E., Arriaga-Pizano L., López-Macías C., Rosenstein Y., Isibasi A. Heat shock protein 70 down-regulates the production of toll-like receptor-induced pro-inflammatory cytokines by a heat shock factor-1/constitutive heat shock element-binding factor-dependent mechanism // J Inflamm (Lond). – 2014. – Vol. 11. – Art. No.19. DOI: 10.1186/1476-9255-11-19.Ferat-Osorio E, Sánchez-Anaya A, Gutiérrez-Mendoza M, Boscó-Gárate I, Wong-Baeza I, Pastelin-Palacios R, Pedraza-Alva G, Bonifaz LC, Cortés-Reynosa P, Pérez-Salazar E, Arriaga-Pizano L, López-Macías C, Rosenstein Y, Isibasi A. Heat shock protein 70 down-regulates the production of toll-like receptor-induced pro-inflammatory cytokines by a heat shock factor-1/constitutive heat shock element-binding factor-dependent mechanism. J Inflamm (Lond). 2014 Jul 12;11:19. DOI: 10.1186/1476-9255-11-19.Meng W., Clerico E.M., McArthur N., Gierasch L.M. Allosteric landscapes of eukaryotic cytoplasmic Hsp70s are shaped by evolutionary tuning of key interfaces. Proceedings of the National Academy of Sciences. – 2018. – Vol. 115, No.47. – P. 11970–11975. DOI: 10.1073/pnas.1811105115.Meng W, Clerico EM, McArthur N, Gierasch L. M. Allosteric landscapes of eukaryotic cytoplasmic Hsp70s are shaped by evolutionary tuning of key interfaces. Proceedings of the National Academy of Sciences. 2018 Nov; 115(47):11970–75; DOI: 10.1073/pnas.1811105115.Fernández-Fernández M.R., Gragera M., Ochoa-Ibarrola L., Quintana-Gallardo L., Valpuesta J.M. Hsp70 – a master regulator in protein degradation // FEBS Lett. – 2017. – Vol. 591, No.17 – P. 2648–2660. DOI: 10.1002/1873-3468.12751.Fernández-Fernández MR, Gragera M, Ochoa-Ibarrola L, Quintana-Gallardo L, Valpuesta JM. Hsp70 – a master regulator in protein degradation. FEBS Lett. 2017 Sep;591(17):2648–60. DOI: 10.1002/1873-3468.12751.Acebron S.P., Fernandez-Saiz V., Taneva S.G., Moro F., Muga A. DnaJ recruits DnaK to protein aggregates // J Biol Chem. – 2008. – Vol. 283, No.3. – P. 1381–1390. DOI: 10.1074/jbc.M706189200.Acebrón SP, Fernández-Sáiz V, Taneva SG, Moro F, Muga A. DnaJ recruits DnaK to protein aggregates. J Biol Chem. 2008 Jan 18;283(3):1381–90. DOI: 10.1074/jbc.M706189200.Оценка Прогноза социально-экономического развития Российской Федерации на период 2019–2024 годов // Финансы: теория и практика. – 2018. – Т. 22, № 6. – С. 153–156. DOI: 10.26794/2587-5671-2018-22-6-153-156.Assessment of Socio-Economic Development Forecast for the Russian Federation in 2019–2024. Finance: Theory and Practice. 2018;22(6):153–6. DOI: 10.26794/2587-5671-2018-22-6-153-156. RussianMitragotri S., Burke P.A., Langer R. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies // Nat Rev Drug Discov. – 2014. – Vol. 13, No.9. – P. 655-672. DOI: 10.1038/nrd4363.Mitragotri S, Burke PA, Langer R. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat Rev Drug Discov. 2014 Sep;13(9):655–72. DOI: 10.1038/nrd4363.Craik D.J., Fairlie D.P., Liras S., Price D. The future of peptide-based drugs // Chem Biol Drug Des. – 2013. – Vol. 81, No.1. – P. 136–147. DOI: 10.1111/cbdd.12055.Craik DJ, Fairlie DP, Liras S, Price D. The future of peptide-based drugs. Chem Biol Drug Des. 2013 Jan;81(1):136–47. DOI: 10.1111/cbdd.12055.Brocchieri L., de Conway M.E., Macario A.J. Hsp70 genes in the human genome: conservation and differentiation patterns predict a wide array of overlapping and specialized functions // BMC Evol Biol. – 2008. – Vol. 8 – Art. No.19. DOI: 10.1186/1471-2148-8-19.Brocchieri L, Conway de Macario E, Macario AJ. Hsp70 genes in the human genome: Conservation and differentiation patterns predict a wide array of overlapping and specialized functions. BMC Evol Biol. 2008 Jan 23;8:19. DOI: 10.1186/1471-2148-8-19.Daugaard M., Jäättelä M, Rohde M. Hsp70-2 is required for tumor cell growth and survival // Cell Cycle. – 2005. – Vol. 4, Issue 7. – P. 877–880. DOI: 10.4161/cc.4.7.1838.Daugaard M, Jäättelä M, Rohde M. Hsp70-2 is required for tumor cell growth and survival. Cell Cycle. 2005; 4 (Issue 7): 877–80. DOI: 10.4161/cc.4.7.1838.Taylor I.R., Ahmad A., Wu T., Nordhues B.A., Bhullar A., Gestwicki J.E., Zuiderweg E.R.P. The disorderly conduct of Hsc70 and its interaction with the Alzheimer’s-related Tau protein. // J Biol Chem. – 2018. – Vol. 293, No.27. – P. 10796–10800. DOI:10.1074/jbc.RA118.002234.Taylor IR, Ahmad A, Wu T, Nordhues BA, Bhullar A, Gestwicki JE, Zuiderweg ERP. The disorderly conduct of Hsc70 and its interaction with the Alzheimer’s-related Tau protein. J Biol Chem. 2018 Jul 6;293(27):10796–80. DOI: 10.1074/jbc.RA118.002234.Doyle S.M., Genest O., Wickner S. Protein rescue from aggregates by powerful molecular chaperone machines // Nat Rev Mol Cell Biol – 2013. – Vol. 14. – P. 617–629. DOI: 10.1038/nrm3660.Doyle SM, Genest O, Wickner S. Protein rescue from aggregates by powerful molecular chaperone machines. Nat Rev Mol Cell Biol. 2013 Oct;14(10):617–29. DOI: 10.1038/nrm3660.Acebron S.P., Fernandez-Saiz V., Taneva S.G., Moro F., Muga A. DnaJ recruits DnaK to protein aggregates // J Biol Chem. – 2008. – Vol. 283, No.3. – P. 1381–1390. DOI: 10.1074/jbc.M706189200.Acebrón SP, Fernández-Sáiz V, Taneva SG, Moro F, Muga A. DnaJ recruits DnaK to protein aggregates. J Biol Chem. 2008 Jan 18;283(3):1381–90. DOI: 10.1074/jbc.M706189200.Ahmad A., Bhattacharya A., McDonald R.A., Cordes M, Ellington B, Bertelsen EB, Zuiderweg ER. Heat shock protein 70 kDa chaperone / DnaJ cochaperone complex employs an unusual dynamic interface // Proc Natl Acad Sci USA. – 2011. – Vol. 108, No.47. – P. 18966–18971. DOI: 10.1073/pnas.1111220108.Ahmad A, Bhattacharya A, McDonald RA, Cordes M, Ellington B, Bertelsen EB, Zuiderweg ER. Heat shock protein 70 kDa chaperone/DnaJ cochaperone complex employs an unusual dynamic interface. Proc Natl Acad Sci U S A. 2011 Nov 22;108(47):18966–71. DOI: 10.1073/pnas.1111220108.Bracher A., Verghese J. The nucleotide exchange factors of Hsp70 molecular chaperones // Front Mol Biosci. – 2015. – Vol. 2. – Art. No.10. DOI: 10.3389/fmolb.2015.00010.Bracher A, Verghese J. The nucleotide exchange factors of Hsp70 molecular chaperones. Front Mol Biosci. 2015 Apr 7;2:10. DOI: 10.3389/fmolb.2015.00010.Gao T., Newton A.C. The turn motif is a phosphorylation switch that regulates the binding of Hsp70 to protein kinase C // J Biol Chem. – 2002. – Vol. 277, No.35. – P. 31585–31592. DOI: 10.1074/jbc.M204335200.Gao T, Newton AC. The turn motif is a phosphorylation switch that regulates the binding of Hsp70 to protein kinase C. J Biol Chem. 2002 Aug 30;277(35):31585–92. DOI: 10.1074/jbc.M204335200.Wang M.L., Tuli R., Manner P.A., Sharkey P.F., Hall D.J., Tuan R.S. Direct and indirect induction of apoptosis in human mesenchymal stem cells in response to titanium particles // J Orthop Res. – 2003. – Vol. 21, No.4. – P. 697–707. DOI: 10.1016/S0736-0266(02)00241-3.Wang ML, Tuli R, Manner PA, Sharkey PF, Hall DJ, Tuan RS. Direct and indirect induction of apoptosis in human mesenchymal stem cells in response to titanium particles. J Orthop Res. 2003 Jul;21(4):697–707. DOI: 10.1016/S0736-0266(02)00241-3.Zhao H., Michaelis M.L., Blagg B.S. Hsp90 modulation for the treatment of Alzheimer’s disease // Adv Pharmacol. – 2012. – Vol. 64. – P. 1–25. DOI: 10.1016/B978-0-12-394816-8.00001-5.Zhao H, Michaelis ML, Blagg BS. Hsp90 modulation for the treatment of Alzheimer’s disease. Adv Pharmacol. 2012;64:1–25. DOI: 10.1016/B978-0-12-394816-8.00001-5.Lanneau D., Wettstein G., Bonniaud P., Garrido C. Heat shock proteins: cell protection through protein triage // ScientificWorldJournal. – 2010. – Vol. 10. – P. 1543–1552. DOI: 10.1100/tsw.2010.152.Lanneau D, Wettstein G, Bonniaud P, Garrido C. Heat shock proteins: cell protection through protein triage. ScientificWorldJournal. 2010 Aug 3;10:1543–52. DOI: 10.1100/tsw.2010.152.Alberti S., Demand J., Esser C., Emmerich N., Schild H., Hohfeld J. Ubiquitylation of BAG-1 suggests a novel regulatory mechanism during the sorting of chaperone substrates to the proteasome // J Biol Chem. – 2002. – Vol. 277, No.48. – P. 45920–45927. DOI: 10.1074/jbc.M204196200.Alberti S, Demand J, Esser C, Emmerich N, Schild H, Hohfeld J. Ubiquitylation of BAG-1 suggests a novel regulatory mechanism during the sorting of chaperone substrates to the proteasome. J Biol Chem. 2002 Nov 29;277(48):45920–7. DOI: 10.1074/jbc.M204196200.Okafor C.C., Haleem-Smith H., Laqueriere P., Manner P.A., Tuan R.S. Particulate endocytosis mediates biological responses of human mesenchymal stem cells to titanium wear debris // J Orthop Res. – 2006. – Vol. 24, No.3. – P. 461–473. DOI: 10.1002/jor.20075.Okafor CC, Haleem-Smith H, Laqueriere P, Manner PA, Tuan RS. Particulate endocytosis mediates biological responses of human mesenchymal stem cells to titanium wear debris. J Orthop Res. 2006 Mar;24(3):461–73. DOI: 10.1002/jor.20075.Kobayashi S.D., Voyich J.M., Whitney A.R., DeLeo F.R. Spontaneous neutrophil apoptosis and regulation of cell survival by granulocyte macrophage-colony stimulating factor // J Leukoc Biol. – 2005. – Vol. 78, No.6. – P. 1408–1418. DOI: 10.1189/jlb.0605289.Kobayashi SD, Voyich JM, Whitney AR, DeLeo FR. Spontaneous neutrophil apoptosis and regulation of cell survival by granulocyte macrophage-colony stimulating factor. J Leukoc Biol. 2005 Dec;78(6):1408–18. DOI: 10.1189/jlb.0605289.Lavrik I.N., Golks A., Krammer P.H. Caspases: pharmacological manipulation of cell death // J Clin Invest. – 2005. – Vol. 115, No.10. – P. 2665–2672. DOI: 10.1172/JCI26252.Lavrik IN, Golks A, Krammer PH. Caspases: pharmacological manipulation of cell death. J Clin Invest. 2005 Oct;115(10):2665–72. DOI: 10.1172/JCI26252.24 Schmitt E., Parcellier A., Gurbuxani S., Cande C., Hammann A., Morales M.C., Hunt C.R., Dix D.J., Kroemer R.T., Giordanetto F., Jäättelä M., Penninger J.M., Pance A., Kroemer G., Garrido C. Chemosensitization by a non-apoptogenic heat shock protein 70-binding apoptosis-inducing factor mutant // Cancer Res. – 2003. – Vol. 63, No.23. – P. 8233–8240.Schmitt E, Parcellier A, Gurbuxani S, Cande C, Hammann A, Morales MC, Hunt CR, Dix DJ, Kroemer RT, Giordanetto F, Jäättelä M, Penninger JM, Pance A, Kroemer G, Garrido C. Chemosensitization by a non-apoptogenic heat shock protein 70-binding apoptosis-inducing factor mutant. Cancer Res. 2003 Dec 1;63(23):8233–40.Matsumori Y., Northington F.J., Hong S.M., Kayama T., Sheldon R.A., Vexler ZS, et al. Reduction of caspase-8 and -9 cleavage is associated with increased c-FLIP and increased binding of Apaf-1 and Hsp70 after neonatal hypoxic/ischemic injury in mice overexpressing Hsp70 // Stroke – 2006. – Vol. 37 – P. 507–512. DOI: 10.1161/01.STR.0000199057.00365.20.Matsumori Y, Northington FJ, Hong SM, Kayama T, Sheldon RA, Vexler ZS, et al. Reduction of caspase-8 and -9 cleavage is associated with increased c-FLIP and increased binding of Apaf-1 and Hsp70 after neonatal hypoxic/ischemic injury in mice overexpressing Hsp70. Stroke 2006; 37 (Issue 2): 507–12. DOI: 10.1161/01.STR.0000199057.00365.20.Guo F., Sigua C., Bali P., George P., Fiskus W., Scuto A., Annavarapu S., Mouttaki A., Sondarva G., Wei S., Wu J., Djeu J., Bhalla K. Mechanistic role of heat shock protein 70 in Bcr-Abl-mediated resistance to apoptosis in human acute leukemia cells // Blood. – 2005. – Vol. 105, No.3. – P. 1246–1255. DOI: 10.1182/blood-2004-05-2041.Guo F, Sigua C, Bali P, George P, Fiskus W, Scuto A, Annavarapu S, Mouttaki A, Sondarva G, Wei S, Wu J, Djeu J, Bhalla K. Mechanistic role of heat shock protein 70 in Bcr-Abl-mediated resistance to apoptosis in human acute leukemia cells. Blood. 2005 Feb 1;105(3):1246–55. DOI: 10.1182/blood-2004-05-2041.Joly A.L., Wettstein G., Mignot G., Ghiringhelli F., Garrido C. Dual role of heat shock proteins as regulators of apoptosis and innate immunity // J Innate Immun. – 2010. – Vol. 2, No.3. – P. 238–247. DOI: 10.1159/000296508.Joly AL, Wettstein G, Mignot G, Ghiringhelli F, Garrido C. Dual role of heat shock proteins as regulators of apoptosis and innate immunity. J Innate Immun. 2010;2(3):238–47. DOI: 10.1159/000296508.Pitti R.M., Marsters S.A., Ruppert S., Donahue C.J., Moore A., Ashkenazi A. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family // J Biol Chem. – 1996. – Vol.271, No.22. – P. 12687–12690. DOI: 10.1074/jbc.271.22.12687.Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem. 1996 May 31;271(22):12687–90. DOI: 10.1074/jbc.271.22.12687.Pang Q., Keeble W., Christianson T.A., Faulkner G.R., Bagby G.C. FANCC interacts with Hsp70 to protect hematopoietic cells from IFN-gamma/TNF-alpha-mediated cytotoxicity // EMBO J. – 2001. – Vol. 20, No.16. – P. 4478–4489. DOI: 10.1093/emboj/20.16.4478.Pang Q, Keeble W, Christianson TA, Faulkner GR, Bagby GC. FANCC interacts with Hsp70 to protect hematopoietic cells from IFN-gamma/TNF-alpha-mediated cytotoxicity. EMBO J. 2001 Aug 15;20(16):4478–89. DOI: 10.1093/emboj/20.16.4478.Pang Q., Christianson T.A., Keeble W., Koretsky T., Bagby G.C. The anti-apoptotic function of Hsp70 in the interferon-inducible double-stranded RNA-dependent protein kinase-mediated death signaling pathway requires the Fanconi anemia protein, FANCC // J Biol Chem. – 2002. – Vol. 277, No.51. – P. 49638–49643. DOI: 10.1074/jbc.M209386200.Pang Q, Christianson TA, Keeble W, Koretsky T, Bagby GC. The anti-apoptotic function of Hsp70 in the interferon-inducible double-stranded RNA-dependent protein kinase-mediated death signaling pathway requires the Fanconi anemia protein, FANCC. J Biol Chem. 2002 Dec 20;277(51):49638–43. DOI: 10.1074/jbc.M209386200.Thirstrup K., Sotty F., Montezinho L.C., Badolo L., Thougaard A., Kristjánsson M., Jensen T., Watson S., Nielsen S.M. Linking HSP90 target occupancy to HSP70 induction and efficacy in mouse brain // Pharmacol Res. – 2016. – Vol. 104. – P. 197–205. DOI: 10.1016/j.phrs.2015.12.028.Thirstrup K, Sotty F, Montezinho LC, Badolo L, Thougaard A, Kristjánsson M, Jensen T, Watson S, Nielsen SM. Linking HSP90 target occupancy to HSP70 induction and efficacy in mouse brain. Pharmacol Res. 2016 Feb;104:197–205. DOI: 10.1016/j.phrs.2015.12.028.Purandhar K., Jena P.K., Prajapati B., Rajput P., Seshadri S. Understanding the role of heat shock protein isoforms in male fertility, aging and apoptosis // World J Mens Health. – 2014. – Vol. 32, No.3. – P. 123–132. DOI: 10.5534/wjmh.2014.32.3.123.Purandhar K, Jena PK, Prajapati B, Rajput P, Seshadri S. Understanding the role of heat shock protein isoforms in male fertility, aging and apoptosis. World J Mens Health. 2014 Dec;32(3):123–32. DOI: 10.5534/wjmh.2014.32.3.123.Jiang B., Liang P., Deng G., Tu Z., Liu M., Xiao X. Increased stability of Bcl-2 in HSP70-mediated protection against apoptosis induced by oxidative stress // Cell Stress Chaperones. – 2011. – Vol. 16, No.2. – P. 143–152. DOI: 10.1007/s12192-010-0226-6.Jiang B, Liang P, Deng G, Tu Z, Liu M, Xiao X. Increased stability of Bcl-2 in HSP70-mediated protection against apoptosis induced by oxidative stress. Cell Stress Chaperones. 2011 Mar;16(2):143–52. DOI: 10.1007/s12192-010-0226-6.Crowe D.L., Sinha U.K. p53 apoptotic response to DNA damage dependent on bcl2 but not bax in head and neck squamous cell carcinoma lines // Head Neck. – 2006. – Vol. 28, No.1. – P. 15–23. DOI: 10.1002/hed.20319.Crowe DL, Sinha UK. p53 apoptotic response to DNA damage dependent on bcl2 but not bax in head and neck squamous cell carcinoma lines. Head Neck. 2006 Jan;28(1):15–23. DOI: 10.1002/hed.20319.Akakura S., Yoshida M., Yoneda Y., Horinouchi S. A role for Hsc70 in regulating nucleocytoplasmic transport of a temperature-sensitive p53 (p53Val-135) // J Biol Chem. – 2001. – Vol. 276, No.18. – P. 14649–14657. DOI: 10.1074/jbc.M100200200.Akakura S, Yoshida M, Yoneda Y, Horinouchi S. A role for Hsc70 in regulating nucleocytoplasmic transport of a temperature-sensitive p53 (p53Val-135). J Biol Chem. 2001 May 4;276(18):14649–57. DOI: 10.1074/jbc.M100200200.Tsukahara F., Maru Y. Identification of novel nuclear export and nuclear localization-related signals in human heat shock cognate protein 70 // J Biol Chem. – 2004. – Vol. 279, No.10. – P. 8867–8872. DOI: 10.1074/jbc.M308848200.Tsukahara F, Maru Y. Identification of novel nuclear export and nuclear localization-related signals in human heat shock cognate protein 70. J Biol Chem. 2004 Mar 5;279(10):8867–72. DOI: 10.1074/jbc.M308848200.Lu D., Xu A., Mai H., Zhao J., Zhang C., Qi R., Wang H., Lu D., Zhu L. The synergistic effects of heat shock protein 70 and ginsenoside Rg1 against tert-butyl hydroperoxide damage model in vitro // Oxid Med Cell Longev. – 2015. – Vol. 2015. – Art. No.437127. DOI: 10.1155/2015/437127.Lu D, Xu A, Mai H, Zhao J, Zhang C, Qi R, Wang H, Lu D, Zhu L. The synergistic effects of heat shock protein 70 and ginsenoside Rg1 against tert-butyl hydroperoxide damage model in vitro. Oxid Med Cell Longev. 2015;2015:437127. DOI: 10.1155/2015/437127.Manucha W., Carrizo L., Ruete C., Vallés P.G. Apoptosis induction is associated with decreased NHE1 expression in neonatal unilateral ureteric obstruction // BJU Int. – 2007. – Vol. 100, No.1. – P. 191–198. DOI: 10.1111/j.1464-410X.2007.06840.x.Manucha W, Carrizo L, Ruete C, Vallés PG. Apoptosis induction is associated with decreased NHE1 expression in neonatal unilateral ureteric obstruction. BJU Int. 2007 Jul;100(1):191–8. DOI: 10.1111/j.1464-410X.2007.06840.x.Manucha W., Kurbán F., Mazzei L., Benardón M.E., Bocanegra V., Tosi M.R., Vallés P. eNOS/Hsp70 interaction on rosuvastatin cytoprotective effect in neonatal obstructive nephropathy // Eur J Pharmacol. – 2011. – Vol. 650, No.2–3. – P. 487–495. DOI: 10.1016/j.ejphar.2010.09.059.Manucha W, Kurbán F, Mazzei L, Benardón ME, Bocanegra V, Tosi MR, Vallés P. eNOS/Hsp70 interaction on rosuvastatin cytoprotective effect in neonatal obstructive nephropathy. Eur J Pharmacol. 2011 Jan 15;650(2-3):487–95. DOI: 10.1016/j.ejphar.2010.09.059.Mansilla M.J., Costa C., Eixarch H., Tepavcevic V., Castillo M., Martin R., Lubetzki C., Aigrot M.S., Montalban X., Espejo C. Hsp70 regulates immune response in experimental autoimmune encephalomyelitis // PLoS One. – 2014. – Vol. 9, No.8. – e105737. DOI: 10.1371/journal.pone.0105737.Mansilla MJ, Costa C, Eixarch H, Tepavcevic V, Castillo M, Martin R, Lubetzki C, Aigrot MS, Montalban X, Espejo C. Hsp70 regulates immune response in experimental autoimmune encephalomyelitis. PLoS One. 2014 Aug 25;9(8):e105737. DOI: 10.1371/journal.pone.0105737.Mazzei L., Docherty N.G., Manucha W. Mediators and mechanisms of heat shock protein 70 based cytoprotection in obstructive nephropathy // Cell Stress Chaperones. – 2015. – Vol. 20, No.6. – P. 893–906. DOI: 10.1007/s12192-015-0622-z.Mazzei L, Docherty NG, Manucha W. Mediators and mechanisms of heat shock protein 70 based cytoprotection in obstructive nephropathy. Cell Stress Chaperones. 2015 Nov;20(6):893–906. DOI: 10.1007/s12192-015-0622-z.Sharp F.R., Lu A., Tang Y., Millhorn D.E. Multiple molecular penumbras after focal cerebral ischemia // J Cereb Blood Flow Metab. – 2000. – Vol. 20, No.7. – P. 1011–1032. DOI: 10.1097/00004647-200007000-00001.Sharp FR, Lu A, Tang Y, Millhorn DE. Multiple molecular penumbras after focal cerebral ischemia. J Cereb Blood Flow Metab. 2000 Jul;20(7):1011–32. DOI: 10.1097/00004647-200007000-00001.Doeppner T.R., Nagel F., Dietz G.P., Weise J., Tönges L., Schwarting S., Bähr M. TAT-Hsp70-mediated neuroprotection and increased survival of neuronal precursor cells after focal cerebral ischemia in mice // J Cereb Blood Flow Metab. – 2009. – Vol. 29, No.6. – P. 1187–1196. DOI: 10.1038/jcbfm.2009.44.Doeppner TR, Nagel F, Dietz GP, Weise J, Tönges L, Schwarting S, Bähr M. TAT-Hsp70-mediated neuroprotection and increased survival of neuronal precursor cells after focal cerebral ischemia in mice. J Cereb Blood Flow Metab. 2009 Jun;29(6):1187–96. DOI: 10.1038/jcbfm.2009.44.Hulina A., Grdić Rajković M., Jakšić Despot D., Jelić D., Dojder A., Čepelak I., Rumora L. Extracellular Hsp70 induces inflammation and modulates LPS/LTA-stimulated inflammatory response in THP-1 cells // Cell Stress Chaperones. – 2018. – Vol. 23, No.3. – P. 373–384. DOI: 10.1007/s12192-017-0847-0.Hulina A, Grdić Rajković M, Jakšić Despot D, Jelić D, Dojder A, Čepelak I, Rumora L. Extracellular Hsp70 induces inflammation and modulates LPS/LTA-stimulated inflammatory response in THP-1 cells. Cell Stress Chaperones. 2018 May;23(3):373–84. DOI: 10.1007/s12192-017-0847-0.Zhan X., Ander B.P., Liao I.H., Hansen J.E., Kim C., Clements D., Weisbart R.H., Nishimura R.N., Sharp F.R. Recombinant Fv-Hsp70 protein mediates neuroprotection after focal cerebral ischemia in rats // Stroke. – 2010. – Vol. 41, No.3. – P. 538–543. DOI: 10.1161/STROKEAHA.109.572537.Zhan X, Ander BP, Liao IH, Hansen JE, Kim C, Clements D, Weisbart RH, Nishimura RN, Sharp FR. Recombinant Fv-Hsp70 protein mediates neuroprotection after focal cerebral ischemia in rats. Stroke. 2010 Mar;41(3):538–43. DOI: 10.1161/STROKEAHA.109.572537.Supko J.G., Hickman R.L., Grever M.R., Malspeis L. Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent // Cancer Chemother Pharmacol. – 1995. – Vol. 36, No.4. – P. 305–315. DOI: 10.1007/BF00689048.Supko JG, Hickman RL, Grever MR, Malspeis L. Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother Pharmacol. 1995;36(4):305–15. DOI: 10.1007/BF00689048.Porter J.R., Fritz C.C., Depew K.M. Discovery and development of Hsp90 inhibitors: a promising pathway for cancer therapy // Curr Opin Chem Biol. – 2010. – Vol. 14, No.3. – P. 412–420. DOI: 10.1016/j.cbpa.2010.03.019.Porter JR, Fritz CC, Depew KM. Discovery and development of Hsp90 inhibitors: a promising pathway for cancer therapy. Curr Opin Chem Biol. 2010 Jun;14(3):412–20. DOI: 10.1016/j.cbpa.2010.03.019.Doeppner T.R., Ewert T.A., Tönges L., Herz J., Zechariah A., ElAli A., Ludwig A.K., Giebel B., Nagel F., Dietz G.P., Weise J., Hermann D.M., Bähr M. Transduction of neural precursor cells with TAT-heat shock protein 70 chaperone: therapeutic potential against ischemic stroke after intrastriatal and systemic transplantation // Stem Cells. – 2012. – Vol. 30, No.6. – P. 1297–1310. DOI: 10.1002/stem.1098.Doeppner TR, Ewert TA, Tönges L, Herz J, Zechariah A, ElAli A, Ludwig AK, Giebel B, Nagel F, Dietz GP, Weise J, Hermann DM, Bähr M. Transduction of neural precursor cells with TAT-heat shock protein 70 chaperone: therapeutic potential against ischemic stroke after intrastriatal and systemic transplantation. Stem Cells. 2012 Jun;30(6):1297–310. DOI: 10.1002/stem.1098.Liu T., Zhang L., Joo D., Sun S.C. NF-κB signaling in inflammation // Signal Transduct Target Ther. – 2017. – Vol. 2. – Art. No.17023. DOI: 10.1038/sigtrans.2017.23.Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017;2:17023. DOI: 10.1038/sigtrans.2017.23.Christian F., Smith E.L., Carmody R.J. The Regulation of NF-κB Subunits by Phosphorylation // Cells. – 2016. – Vol. 5, No.1. – Art. No.12. DOI: 10.3390/cells5010012.Christian F, Smith EL, Carmody RJ. The Regulation of NF-κB Subunits by Phosphorylation. Cells. 2016 Mar 18;5(1):12. DOI: 10.3390/cells5010012.Hoesel B., Schmid J.A. The complexity of NF-κB signaling in inflammation and cancer // Mol. Cancer. – 2013. – Vol. 12. – Art. No.86. DOI: 10.1186/1476-4598-12-86.Hoesel B, Schmid JA. The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer. 2013;12:86. DOI: 10.1186/1476-4598-12-86.Wang C.H., Chou P.C., Chung F.T. et al. Heat shock protein70 is implicated in modulating NF-κB activation in alveolar macrophages of patients with active pulmonary tuberculosis // Sci Rep. – 2017. – Vol. 7. – Art. No.1214. DOI: 10.1038/s41598-017-01405-zWang CH, Chou PC, Chung FT. et al. Heat shock protein70 is implicated in modulating NF-κB activation in alveolar macrophages of patients with active pulmonary tuberculosis. Sci Rep. 2017;7:1214. DOI: 10.1038/s41598-017-01405-z.Hulina-Tomašković A., Somborac-Bačura A., Grdić Rajković M., Bosnar M., Samaržija M., Rumora L. Effects of extracellular Hsp70 and cigarette smoke on differentiated THP-1 cells and human monocyte-derived macrophages // Mol Immunol. – 2019. – Vol. 111. – P. 53–63. DOI: 10.1016/j.molimm.2019.04.002.Hulina-Tomašković A, Somborac-Bačura A, Grdić Rajković M, Bosnar M, Samaržija M, Rumora L. Effects of extracellular Hsp70 and cigarette smoke on differentiated THP-1 cells and human monocyte-derived macrophages. Mol Immunol. 2019 Jul;111:53–63. DOI: 10.1016/j.molimm.2019.04.002.Somensi N., Brum P.O., de Miranda Ramos V., Gasparotto J., Zanotto-Filho A., Rostirolla D.C., da Silva Morrone M., Moreira J.C.F., Pens Gelain D. Extracellular HSP70 Activates ERK1/2, NF-kB and Pro-Inflammatory Gene Transcription Through Binding with RAGE in A549 Human Lung Cancer Cells // Cell Physiol Biochem. – 2017. – Vol. 42, No.6. – P. 2507–2522. DOI: 10.1159/000480213.Somensi N, Brum PO, de Miranda Ramos V, Gasparotto J, Zanotto-Filho A, Rostirolla DC, da Silva Morrone M, Moreira JCF, Pens Gelain D. Extracellular HSP70 Activates ERK1/2, NF-kB and Pro-Inflammatory Gene Transcription Through Binding with RAGE in A549 Human Lung Cancer Cells. Cell Physiol Biochem. 2017;42(6):2507–2522. DOI: 10.1159/000480213.Luo X., Zuo X., Zhou Y., Zhang B., Shi Y., Liu M., Wang K., McMillian D.R., Xiao X. Extracellular heat shock protein 70 inhibits tumour necrosis factor-alpha induced proinflammatory mediator production in fibroblast-like synoviocytes // Arthritis Res Ther. – 2008. – Vol. 10, No.2. – R41. DOI: 10.1186/ar2399.Luo X, Zuo X, Zhou Y, Zhang B, Shi Y, Liu M, Wang K, McMillian DR, Xiao X. Extracellular heat shock protein 70 inhibits tumour necrosis factor-alpha induced proinflammatory mediator production in fibroblast-like synoviocytes. Arthritis Res Ther. 2008;10(2):R41. DOI: 10.1186/ar2399.Mortaz E., Redegeld F.A., Nijkamp F.P., Wong H.R., Engels F. Acetylsalicylic acid-induced release of HSP70 from mast cells results in cell activation through TLR pathway // Exp Hematol. – 2006. – Vol. 34, No.1. – P. 8–18. DOI: 10.1016/j.exphem.2005.10.012.Mortaz E, Redegeld FA, Nijkamp FP, Wong HR, Engels F. Acetylsalicylic acid-induced release of HSP70 from mast cells results in cell activation through TLR pathway. Exp Hematol. 2006 Jan;34(1):8–18. DOI: 10.1016/j.exphem.2005.10.012.Gurskiy Y.G., Garbuz D.G., Soshnikova N.V., Krasnov A.N., Deikin A., Lazarev V.F., Sverchinskyi D., Margulis B.A., Zatsepina O.G., Karpov V.L., Belzhelarskaya S.N., Feoktistova E., Georgieva S.G., Evgen’ev M.B. The development of modified human Hsp70 (HSPA1A) and its production in the milk of transgenic mice // Cell Stress Chaperones. – 2016. – Vol. 21, No.6. – P. 1055–1064. DOI: 10.1007/s12192-016-0729-x.Gurskiy YG, Garbuz DG, Soshnikova NV, Krasnov AN, Deikin A, Lazarev VF, Sverchinskyi D, Margulis BA, Zatsepina OG, Karpov VL, Belzhelarskaya SN, Feoktistova E, Georgieva SG, Evgen’ev MB. The development of modified human Hsp70 (HSPA1A) and its production in the milk of transgenic mice. Cell Stress Chaperones. 2016 Nov;21(6):1055–1064. DOI: 10.1007/s12192-016-0729-x.

The authors declare that there are no conflicts of interest present.