Peptides of Laennec® preparation that contribute to the elimination of endotheliopathy
https://doi.org/10.17749/2070-4909/farmakoekonomika.2021.114
Abstract
Objective: identification of peptides in the composition of Laennec®, which can inhibit the development of endotheliopathy (endothelial dysfunction).
Material and methods. Hybrid mass spectrometry followed by data analysis based on topological recognition theory was performed. The analysis of the peptide composition of Laennec® included four stages: purification of the drug, chromatographic separation of peptides, determination of the multidimensional mass spectrum of the peptide fraction, and de novo sequencing of the isolated peptides.
Results. The preparation contains peptides-inhibitors of specific target proteins (PRKCZ, PKB, PKD1, MAPK14, IKKB, PDPK1) involved in the activation of the pro-inflammatory transcription factor NF-κB. Inhibition of CDK5 and SHC1 kinases helps to reduce endothelial cell apoptosis. The peptides of the drug also block enzymes involved in the synthesis and maturation of the tumor necrosis factor alpha (MAPKAPK2/3, ADAM17).
Conclusion. In the composition of Laennec®, peptides have been found that contribute to a complex pathogenetic action against endotheliopathy. Endothelial regeneration is especially important in the rehabilitation of patients who have recovered from COVID-19.
Supporting agencies: This work was financially supported by the Rhana company.
About the Authors
I. Yu. Torshin
Federal Research Center “Informatics and Management”, Russian Academy of Sciences
Russian Federation
Russian Federation
Ivan Yu. Torshin – PhD (Phys. Math.), PhD (Chem.), Senior Researcher
Wos ResearcherID: C-7683-2018
Scopus Author ID: 7003300274
RSCI SPIN-code: 1375-1114
4 Vavilov Str., Moscow 119333
О. А. Gromova
Federal Research Center “Informatics and Management”, Russian Academy of Sciences
Russian Federation
Russian Federation
Olga A. Gromova – Dr. Med. Sc., Professor, Research Supervisor
Wos ResearcherID: J-4946-2017
Scopus Author ID: 7003589812
RSCI SPIN-code: 6317-9833
4 Vavilov Str., Moscow 119333
V. G. Zgoda
Orekhovich Research Institute of Biomedical Chemistry, Center for Collective Use “Human Proteome”
Russian Federation
Russian Federation
Viktor G. Zgoda – Dr. Biol. Sc.
WoS ResearcherID: F-1791-2017
Scopus Author ID: 6602917155
RSCI SPIN-code: 7840-1330
10 bld. 8. Pogodinskaya Str., Moscow 119121
А. G. Chuchalin
Pirogov Russian National Research Medical University
Russian Federation
Russian Federation
Aleksandr G. Chuchalin – Dr. Med. Sc., Professor, Academician of RAS, Pulmonologist, Head of Chair of Hospital Therapy, Faculty of Pediatrics
RSCI SPIN-code: 7742-2054
16 Pervaya Leonov Str., Moscow 129226
V. А. Maksimov
Russian Medical Academy of Continuing Professional Education
Russian Federation
Russian Federation
Valeriy А. Maksimov – Dr. Med. Sc., Professor, Chair of Dietetics and Nutritionology
Scopus Author ID: 55901011200
2 bld. 1 Barrikadnaya Str., Moscow 123995
О. V. Tikhonova
Orekhovich Research Institute of Biomedical Chemistry, Center for Collective Use “Human Proteome”
Russian Federation
Russian Federation
Olga V. Tikhonova – PhD (Biol.)
WoS ResearcherID: F-5115-2017
Scopus Author ID: 57189102916
RSCI SPIN-code
10 bld. 8. Pogodinskaya Str., Moscow 119121
References
1. Puzik S.G. Endothelial dysfunction in the pathogenesis of arterial hypertension and the progression of atherosclerosis. Semeynaya meditsina / Family Medicine. 2018; 2: 69–74 (in Russ.).
2. Chuchalin A.G. A role of nitric oxide for the modern clinical practice: a scientific report at the 5th Pan-Russian Congress on pulmonary hypertension, December 13, 2017. Pulmonologiya. 2018; 28 (4): 503–11 (in Russ.). https://doi.org/10.18093/0869-0189-2018-28-4-503-511.
3. Panina I.Y., Petrichshtev N.N., Smirnov A.V., et al. Arterial hypertension and endothelial dysfunction in chronic kidney diseases. Arterial’naya gipertenziya / Arterial Hypertension. 2006; 12 (4): 352–7 (in Russ.). https://doi.org/10.18705/1607-419X-2006-12-4-352-357.
4. Sholkava M.V., Dotsenko E.A. Endothelial dysfunction in chronic obstructive pulmonary diseases. Emergency Cardiology and Cardiovascular Risks. 2019; 3 (1): 539–45 (in Russ.).
5. Liu C., Jiang Z.C., Shao C.X., Zhang H.G., et al. Preliminary study of the relationship between novel coronavirus pneumonia and liver function damage: a multicenter study. Zhonghua Gan Zang Bing Za Zhi. 2020; 28 (2): 148–52 (in Chinese). https://doi.org/10.3760/cma.j.issn.1007-3418.2020.02.003.
6. Tang N., Li D., Wang X., Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020; 18 (4): 844–7. https://doi.org/10.1111/jth.14768.
7. Jin X., Lian J.S., Hu J.H., et al. Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms. Gut. 2020; 69 (6): 1002–9. https://doi.org/10.1136/gutjnl-2020-320926.
8. Iba T., Connors J.M., Levy J.H. The coagulopathy, endotheliopathy, and vasculitis of COVID-19. Inflamm Res. 2020; 69 (12): 1181–9. https://doi.org/10.1007/s00011-020-01401-6.
9. Zhang J., McCullough P.A., Tecson K.M. Vitamin D deficiency in association with endothelial dysfunction: Implications for patients with COVID-19. Rev Cardiovasc Med. 2020; 21 (3): 339–44. https://doi.org/10.31083/j.rcm.2020.03.131.
10. Kang S., Tanaka T., Inoue H., et al. IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome. Proc Natl Acad Sci USA. 2020; 117 (36): 22351–6. https://doi.org/10.1073/pnas.2010229117.
11. McConnell M.J., Kawaguchi N., Kondo R., et al. Liver injury in COVID-19 and IL-6 trans-signaling-induced endotheliopathy. J Hepatol. 2021: 75 (3): 647–58. https://doi.org/10.1016/j.jhep.2021.04.050.
12. Philippe A., Chocron R., Gendron N., et al. Circulating Von Willebrand factor and high molecular weight multimers as markers of endothelial injury predict COVID-19 in-hospital mortality. Angiogenesis. 2021: 24 (3): 505–17. https://doi.org/10.1007/s10456-020-09762-6.
13. Syed F., Li W., Relich R.F., et al. Excessive matrix metalloproteinase-1 and hyperactivation of endothelial cells occurred in COVID-19 patients and were associated with the severity of COVID-19. medRxiv. 2021 Jan 20: 2021.01.19.21250115. https://doi.org/10.1101/2021.01.19.21250115.
14. Chioh F.W., Fong S.W., Young B.E., et al. Convalescent COVID-19 patients are susceptible to endothelial dysfunction due to persistent immune activation. Elife. 2021; 10: e64909. https://doi.org/10.7554/eLife.64909.
15. Pine A.B., Meizlish M.L., Goshua G., et al. Circulating markers of angiogenesis and endotheliopathy in COVID-19. Pulm Circ. 2020; 10 (4): 2045894020966547. https://doi.org/10.1177/2045894020966547.
16. Nicosia R.F., Ligresti G., Caporarello N., et al. COVID-19 vasculopathy: mounting evidence for an indirect mechanism of endothelial injury. Am J Pathol. 2021; 191 (8): 1374–84. https://doi.org/10.1016/j.ajpath.2021.05.007.
17. Fedin A.I., Starykh E.P., Parfenov A.S., et al. Pharmacotherapy of endothelial dysfunction in patients with atherosclerotic brain ischemia. S.S. Korsakov’s Journal of Neurology and Psychiatry. 2013; 113 (10): 45–8 (in Russ.).
18. Filippov E.V. Possibilities for correcting endothelial dysfunction in patients with arterial hypertension and coronary heart disease. Meditsinskiy sovet / Medical Council. 2019; 5: 64–7 (in Russ.). https://doi.org/10.21518/2079-701X-2019-5-64-67.
19. Torshin I.Yu., Gromova O.A. Micronutrients against coronaviruses. Мoscow: GEOTAR-Media; 2020: 112 pp. (in Russ.).
20. Maksimov V.A., Torshin I.Yu., Chuchalin A.G., et al. An experience of using Laennec in patients at high risk of a cytokine storm with COVID-19 and hyperferritinemia. Pulmonologiya. 2020; 30 (5): 587–98 (in Russ.). https://doi.org/10.18093/0869-0189-2020-30-5-587-598.
21. Gromova O.A., Torshin I.Yu., Maksimov V.A., et al. Peptides contained in the composition of Laennec that contribute to the treatment of hyperferritinemia and iron overload disorders.FARMAKOEKONOMIKA. Sovremennaya farmakoekonomika i farmakoepidemiologiya / FARMAKOEKONOMIKA. Modern Pharmacoeconomics and Pharmacoepidemiology. 2020; 13 (4): 413–25 (in Russ.). https://doi.org/10.17749/2070-4909/farmakoekonomika.2020.070.
22. Torshin I.Y., Gromova O.A., Dibrova E.A., et al. Peptides in the composition of Laennec that show antiviral effects in the therapy of atopic dermatitis and herpes infection. Russian Journal of Allergy. 2018; 15 (1): 82–90 (in Russ.). https://doi.org/10.36691/rja191.
23. Torshin I.Y., Rudakov K.V. Combinatorial analysis of the solvability properties of the problems of recognition and completeness of algorithmic models. Part 1: Factorization approach. Pattern Recognit Image Anal. 2017; 27 (1): 16–28. https://doi.org/10.1134/S1054661817010151.
24. Torshin I.Yu., Rudakov K.V. Combinatorial analysis of the solvability properties of the problems of recognition and completeness of algorithmic models. Part 2: Metric approach within the framework of the theory of classification of feature values. Pattern Recognit Image Anal. 2017; 27 (2): 184–99. https://doi.org/10.1134/S1054661817020110.
25. Torshin I.Y. Optimal dictionaries of the final information on the basis of the solvability criterion and their applications in bioinformatics. Pattern Recognit Image Anal. 2013; 23 (2): 319–27. https://doi.org/10.1134/S1054661813020156.
26. Torshin I.Yu., Rudakov K.V. On the procedures of generation of numerical features over partitions of sets of objects in the problem of predicting numerical target variables. Pattern Recognit Image Anal. 2019; 29 (4): 654–67. https://doi.org/10.1134/S1054661819040175.
27. Torshin I.Y., Rudakov K.V. On the application of the combinatorial theory of solvability to the analysis of chemographs. Part 1: Fundamentals of modern chemical bonding theory and the concept of the chemograph. Pattern Recognit Image Anal. 2014; 24 (1): 11–23. https://doi.org/10.1134/S1054661814010209.
28. Torshin I.Yu., Gromova O.A. Worldwide experience of the therapeutic use of the human placental hydrolytes. Experimental and Clinical Gastroenterology. 2019; 170 (10): 79–89 (in Russ.). https://doi.org/10.31146/1682-8658-ecg-170-10-79-89.
29. Torshin I.Yu., Gromova O.A. Expert data analysis in molecular pharmacology. Мoscow: MTsNMO; 2012: 748 pp. (in Russ.).
30. Xu S., Yan Y., Yan Z., et al. Septic serum mediates inflammatory injury in human umbilical vein endothelial cells via reactive oxygen species, mitogen activated protein kinases and nuclear factor-κB. Int J Mol Med. 2021; 47 (1): 267–75. https://doi.org/10.3892/ijmm.2020.4785.
31. Vrints C.J., Krychtiuk K.A., Van Craenenbroeck E.M., et al. Endothelialitis plays a central role in the pathophysiology of severe COVID-19 and its cardiovascular complications. Acta Cardiol. 2021; 76 (2): 109–24. https://doi.org/10.1080/00015385.2020.1846921.
32. Pan Y., Wang Y., Xu J., et al. TG and VLDL cholesterol activate NLRP1 inflammasome by Nuclear Factor-κB in endothelial cells. Int J Cardiol. 2017; 234: 103. https://doi.org/10.1016/j.ijcard.2016.12.156.
33. Baer J.T., Du Laney T.V., Wyrick P.B., et al. Nuclear factor-kappaB activation in endothelium by Chlamydia pneumoniae without active infection. J Infect Dis. 2003; 188 (8): 1094–7. https://doi.org/10.1086/378564.
34. Song D., Ye X., Xu H., Liu S.F. Activation of endothelial intrinsic NF- {kappa}B pathway impairs protein C anticoagulation mechanism and promotes coagulation in endotoxemic mice. Blood. 2009; 114 (12): 2521–9. https://doi.org/10.1182/blood-2009-02-205914.
35. Morita M., Yano S., Yamaguchi T., Sugimoto T. Advanced glycation end products-induced reactive oxygen species generation is partly through NF-kappa B activation in human aortic endothelial cells. J Diabetes Complications. 2013; 27 (1): 11–5. https://doi.org/10.1016/j.jdiacomp.2012.07.006.
36. Pan W., Yu H., Huang S., Zhu P. Resveratrol protects against TNF-α-induced injury in human umbilical endothelial cells through promoting sirtuin-1-induced repression of NF-KB and p38 MAPK. PLoS One. 2016; 11 (1): e0147034. https://doi.org/10.1371/journal.pone.0147034.
37. Dong H.J., Shang C.Z., Peng D.W., et al. Curcumin attenuates ischemia-like injury induced IL-1β elevation in brain microvascular endothelial cells via inhibiting MAPK pathways and nuclear factor-κB activation. Neurol Sci. 2014; 35 (9): 1387–92. https://doi.org/10.1007/s10072-014-1718-4.
38. Hu W., Zhang Q., Yang X., et al. Puerarin inhibits adhesion molecule expression in tnf-alpha-stimulated human endothelial cells via modulation of the nuclear factor kappaB pathway. Pharmacology. 2010; 85 (1): 27–35. https://doi.org/10.1159/000264938.
39. Ohkita M., Takaoka M., Shiota Y., et al. A nuclear factor-kappaB inhibitor BAY 11-7082 suppresses endothelin-1 production in cultured vascular endothelial cells. Jpn J Pharmacol. 2002; 89 (1): 81–4. https://doi.org/10.1254/jjp.89.81.
40. Guo G., Cheng X., Fu R. Losartan inhibits nuclear factor-κB activation induced by small, dense LDL cholesterol particles in human umbilical vein endothelial cells. Curr Ther Res Clin Exp. 2013; 76: 17–20. https://doi.org/10.1016/j.curtheres.2013.11.006.
41. Zhou S.J., Bai L., Lv L., et al. Liraglutide ameliorates renal injury in streptozotocin-induced diabetic rats by activating endothelial nitric oxide synthase activity via the downregulation of the nuclear factor-κB pathway. Mol Med Rep. 2014; 10 (5): 2587–94. https://doi.org/10.3892/mmr.2014.2555.
42. Lei L., Huaiyong C., Qi W., et al. The role of nuclear factor-κB in endothelial cell inflammatory injury by intermittent hypoxia in rat with emphysema. Zhonghua Jie He He Hu Xi Za Zhi. 2015; 38 (3): 196–201 (in Chinese).
43. Bian Y., Song C., Cheng K., et al. An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J Proteomics. 2014; 96: 253–62. https://doi.org/10.1016/j.jprot.2013.11.014.
44. Song P., Xie Z., Wu Y., et al. Protein kinase Czeta-dependent LKB1 serine 428 phosphorylation increases LKB1 nucleus export and apoptosis in endothelial cells. J Biol Chem. 2008; 283 (18): 12446–55. https://doi.org/10.1074/jbc.M708208200.
45. Hurov J.B., Watkins J.L., Piwnica-Worms H. Atypical PKC phosphorylates PAR-1 kinases to regulate localization and activity. Curr Biol. 2004; 14 (8): 736–41. https://doi.org/10.1016/j.cub.2004.04.007.
46. Preuss K.D., Pfreundschuh M., Fadle N., et al. Hyperphosphorylation of autoantigenic targets of paraproteins is due to inactivation of PP2A. Blood. 2011; 118 (12): 3340–6. https://doi.org/10.1182/blood-2011-04-351668.
47. Tsuchiya Y., Asano T., Nakayama K., et al. Nuclear IKKbeta is an adaptor protein for IkappaBalpha ubiquitination and degradation in UVinduced NF-kappaB activation. Mol Cell. 2010; 39 (4): 570–82. https://doi.org/10.1016/j.molcel.2010.07.030.
48. Serra R.W., Fang M., Park S.M., et al. A KRAS-directed transcriptional silencing pathway that mediates the CpG island methylator phenotype. Elife. 2014; 3: e02313. https://doi.org/10.7554/eLife.02313.
49. Xu P., Derynck R. Direct activation of TACE-mediated ectodomain shedding by p38 MAP kinase regulates EGF receptor-dependent cell proliferation. Mol Cell. 2010; 37 (4): 551–66. https://doi.org/10.1016/j.molcel.2010.01.034.
50. Reinhardt H.C., Hasskamp P., Schmedding I., et al. DNA damage activates a spatially distinct late cytoplasmic cell-cycle checkpoint network controlled by MK2-mediated RNA stabilization. Mol Cell. 2010; 40 (1): 34–49. https://doi.org/10.1016/j.molcel.2010.09.018.
51. Werz O., Szellas D., Steinhilber D., Rådmark O. Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPKactivated protein kinase 2 (MK2). J Biol Chem. 2002; 277 (17): 14793– 800. https://doi.org/10.1074/jbc.M111945200.
52. Gimm T., Wiese M., Teschemacher B., et al. Hypoxia-inducible protein 2 is a novel lipid droplet protein and a specific target gene of hypoxia-inducible factor-1. FASEB J. 2010; 24 (11): 4443–58. https://doi.org/10.1096/fj.10-159806.
53. Tanimoto K., Makino Y., Pereira T., Poellinger L. Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von HippelLindau tumor suppressor protein. EMBO J. 2000; 19 (16): 4298–309. https://doi.org/10.1093/emboj/19.16.4298.
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Torshin I.Yu., Gromova О.А., Zgoda V.G., Chuchalin А.G., Maksimov V.А., Tikhonova О.V. Peptides of Laennec® preparation that contribute to the elimination of endotheliopathy. FARMAKOEKONOMIKA. Modern Pharmacoeconomics and Pharmacoepidemiology. 2021;14(4):468-479. (In Russ.) https://doi.org/10.17749/2070-4909/farmakoekonomika.2021.114
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