Today: Jun 24, 2024
Last update: May 3, 2024
Molecular Mechanisms of Proteins — Targets for SARS-CоV-2 (Review)

Molecular Mechanisms of Proteins — Targets for SARS-CоV-2 (Review)

Morgun A.V., Salmin V.V., Boytsova E.B., Lopatina O.L., Salmina A.B.
Key words: coronavirus infection; SARS-CoV-2; brain damage in COVID-19; blood-brain barrier; neuroinflammation; ACE2; CD147.
2020, volume 12, issue 6, page 98.

Full text

html pdf

The rapidly accumulating information about the new coronavirus infection and the ambiguous results obtained by various authors necessitate further research aiming at prevention and treatment of this disease. At the moment, there is convincing evidence that the pathogen affects not only the respiratory but also the central nervous system (CNS).

The aim of the study is to provide an insight into the molecular mechanisms underlying the damage to the CNS caused by the new coronavirus SARS-CoV-2.

Results. By analyzing the literature, we provide evidence that the brain is targeted by this virus. SARS-CoV-2 enters the body with the help of the target proteins: angiotensin-converting enzyme 2 (ACE2) and associated serine protease TMPRSS2 of the nasal epithelium. Brain damage develops before the onset of pulmonary symptoms. The virus spreads through the brain tissue into the piriform cortex, basal ganglia, midbrain, and hypothalamus. Later, the substantia nigra of the midbrain, amygdala, hippocampus, and cerebellum become affected. Massive death of neurons, astrogliosis and activation of microglia develop at the next stage of the disease. By day 4, an excessive production of proinflammatory cytokines in the brain, local neuroinflammation, breakdown of the blood-brain barrier, and impaired neuroplasticity are detected. These changes imply the involvement of a vascular component driven by excessive activity of matrix metalloproteinases, mediated by CD147. The main players in the pathogenesis of COVID-19 in the brain are products of angiotensin II (AT II) metabolism, largely angiotensin 1-7 (AT 1-7) and angiotensin IV (AT IV). There are conflicting data regarding their role in damage to the CNS in various diseases, including the coronavirus infection.

The second participant in the pathogenesis of brain damage in COVID-19 is CD147 — the inducer of extracellular matrix metalloproteinases. This molecule is expressed on the endothelial cells of cerebral microvessels, as well as on leukocytes present in the brain during neuroinflammation. The CD147 molecule plays a significant role in maintaining the structural and functional integrity of the blood-brain barrier by controlling the basal membrane permeability and by mediating the astrocyte-endothelial interactions. Via the above mechanisms, an exposure to SARS-CoV-2 leads to direct damage to the neurovascular unit of the brain.

  1. Alenina N., Bader M. ACE2 in brain physiology and pathophysiology: evidence from transgenic animal models. Neurochem Res 2019; 44(6): 1323–1329,
  2. Li H., Xue Q., Xu X. Involvement of the nervous system in SARS-CoV-2 infection. Neurotox Res 2020; 38(1): 1–7,
  3. Heurich A., Hofmann-Winkler H., Gierer S., Liepold T., Jahn O., Pöhlmann S. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J Virol 2014; 88(2): 1293–1307,
  4. Ulrich H., Pillat M.M. CD147 as a target for COVID-19 treatment: suggested effects of azithromycin and stem cell engagement. Stem Cell Rev Rep 2020; 16(3): 434–440,
  5. Hoffmann M., Kleine-Weber H., Schroeder S., Krüger N., Herrler T., Erichsen S., Schiergens T.S., Herrler G., Wu N.H., Nitsche A., Müller M.A., Drosten C., Pöhlmann S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181(2): 271–280.e8,
  6. Chen Z., Mi L., Xu J., Yu J., Wang X., Jiang J., Xing J., Shang P., Qian A., Li Y., Shaw P.X., Wang J., Duan S., Ding J., Fan C., Zhang Y., Yang Y., Yu X., Feng Q., Li B., Yao X., Zhang Z., Li L., Xue X., Zhu P. Function of HAb18G/CD147 in invasion of host cells by severe acute respiratory syndrome coronavirus. J Infect Dis 2005; 191(5): 755–760,
  7. Mao L., Jin H., Wang M., Hu Y., Chen S., He Q., Chang J., Hong C., Zhou Y., Wang D., Miao X., Li Y., Hu B. Neurologic manifestations of hospitalized patients with Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol 2020; 77(6): 683–690,
  8. Li Y.C., Bai W.Z., Hashikawa T. Response to commentary on “The neuroinvasive potential of SARS-CoV-2 may play a role in the respiratory failure of COVID-19 patients”. J Medic Virol 2020; 92(7): 707–709,
  9. Pranata R., Huang I., Lim M.A., Wahjoepramono P.E.J., July J. Impact of cerebrovascular and cardiovascular diseases on mortality and severity of COVID-19 — systematic review, meta-analysis, and meta-regression. J Stroke Cerebrovasc Dis 2020; 29(8): 104949,
  10. Afshar H., Yassin Z., Kalantari S., Aloosh O., Lotfi T., Moghaddasi M., Sadeghipour A., Emamikhah M. Evolution and resolution of brain involvement associated with SARS-CoV2 infection: a close clinical — paraclinical follow up study of a case. Mult Scler Relat Disord 2020; 43: 102216,
  11. Lai C.C., Ko W.C., Lee P.I., Jean S.S., Hsueh P.R. Extra-respiratory manifestations of COVID-19. Int J Antimicrob Agents 2020; 56(2): 106024,
  12. Matías-Guiu J., Gomez-Pinedo U., Montero-Escribano P., Gomez-Iglesias P., Porta-Etessam J., Matias-Guiu J.A. Should we expect neurological symptoms in the SARS-CoV-2 epidemic? Neurologia 2020; 35(3): 170–175,
  13. Netland J., Meyerholz D.K., Moore S., Cassell M., Perlman S. Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J Virol 2008; 82(15): 7264–7275,
  14. Yamashita M., Yamate M., Li G.M., Ikuta K. Susceptibility of human and rat neural cell lines to infection by SARS-coronavirus. Biochem Biophys Res Commun 2005; 334(1): 79–85,
  15. Brann D.H., Tsukahara T., Weinreb C., Lipovsek M., Van den Berge K., Gong B., Chance R., Macaulay I.C., Chou H.J., Fletcher R., Das D., Street K., Bezieux H., Choi Y.G., Risso D., Dudoit S., Purdom E., Mill J., Hachem R.A., Matsunami H., Logan D.W., Goldstein B.J., Grubb M.S., Ngai J., Datta S.R. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia: preprint. Sci Adv 2020; 6(31): eabc5801,
  16. Li Y.C., Bai W.Z., Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Medic Virol 2020; 92(6): 552–555,
  17. Baig A.M., Khaleeq A., Ali U., Syeda H. Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci 2020; 11(7): 995–998,
  18. Giacomelli A., Pezzati L., Conti F., Bernacchia D., Siano M., Oreni L., Rusconi S., Gervasoni C., Ridolfo A.L., Rizzardini G., Antinori S., Galli M. Self-reported olfactory and taste disorders in SARS-CoV-2 patients: a cross-sectional study. Clin Infect Dis 2020; 71(15): 889–890,
  19. Butowt R., Bilinska K. SARS-CoV-2: olfaction, brain infection, and the urgent need for clinical samples allowing earlier virus detection. ACS Chem Neurosci 2020; 11(9): 1200–1203,
  20. Lu R., Zhao X., Li J., Niu P., Yang B., Wu H., Wang W., Song H., Huang B., Zhu N., Bi Y., Ma X., Zhan F., Wang L., Hu T., Zhou H., Hu Z., Zhou W., Zhao L., Chen J., Meng Y., Wang J., Lin Y., Yuan J., Xie Z., Ma J., Liu W.J., Wang D., Xu W., Holmes E.C., Gao G.F., Wu G., Chen W., Shi W., Tan W. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 2020; 395(10224): 565–574,
  21. Lan J., Ge J., Yu J., Shan S., Zhou H., Fan S., Zhang Q., Shi X., Wang Q., Zhang L., Wang X. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 2020; 581(7807): 215–220,
  22. Chen I.Y., Moriyama M., Chang M.F., Ichinohe T. Severe acute respiratory syndrome coronavirus viroporin 3a activates the NLRP3 inflammasome. Front Microbiol 2019; 10: 50,
  23. Shi C.S., Nabar N.R., Huang N.N., Kehrl J.H. SARS-coronavirus open reading frame-8b triggers intracellular stress pathways and activates NLRP3 inflammasomes. Cell Death Discov 2019; 5: 101,
  24. Luo C., Luo H., Zheng S., Gui C., Yue L., Yu C., Sun T., He P., Chen J., Shen J., Luo X., Li Y., Liu H., Bai D., Shen J., Yang Y., Li F., Zuo J., Hilgenfeld R., Pei G., Chen K., Shen X., Jiang H. Nucleocapsid protein of SARS coronavirus tightly binds to human cyclophilin A. Biochem Biophys Res Commun 2004; 321(3): 557–565,
  25. Kuba K., Imai Y., Rao S., Gao H., Guo F., Guan B., Huan Y., Yang P., Zhang Y., Deng W., Bao L., Zhang B., Liu G., Wang Z., Chappell M., Liu Y., Zheng D., Leibbrandt A., Wada T., Slutsky A.S., Liu D., Qin C., Jiang C., Penninger J.M. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med 2005; 11(8): 875–879,
  26. de Wilde A.H., Pham U., Posthuma C.C., Snijder E.J. Cyclophilins and cyclophilin inhibitors in nidovirus replication. Virology 2018; 522: 46–55,
  27. von Brunn A., Ciesek S., von Brunn B., Carbajo-Lozoya J. Genetic deficiency and polymorphisms of cyclophilin A reveal its essential role for Human Coronavirus 229E replication. Curr Opin Virol 2015; 14: 56–61,
  28. Tian L., Liu W., Sun L. Role of cyclophilin A during coronavirus replication and the antiviral activities of its inhibitors. Sheng Wu Gong Cheng Xue Bao 2020; 36(4): 605–611,
  29. Zehendner C.M., White R., Hedrich J., Luhmann H.J. A neurovascular blood-brain barrier in vitro model. Methods Mol Biol 2014; 1135: 403–413,
  30. Mel’nikova Yu.S., Makarova T.P. Endothelial dysfunction as the key link of chronic diseases pathogenesis. Kazanskij medicinskij zurnal 2015; 96(4): 659–665.
  31. Jullienne A., Badaut J. Molecular contributions to neurovascular unit dysfunctions after brain injuries: lessons for target-specific drug development. Future Neurol 2013; 8(6): 677–689,
  32. Morgun A.V., Kuvacheva N.V., Khilazheva E.D., Pozhilenkova E.A., Salmina A.B. Research of the metabolic conjugation and intercellular interactions on the model of neurovascular unit in vitro. Sibirskoe meditsinskoe obozrenie 2015; 1: 28–31.
  33. Boytsova E.В., Morgun A.V., Martynova G.P., Tohidpour A., Pisareva N.V., Ruzaeva V.A., Salmina A.B. GPR81 lactate receptors in the regulation of cell functional activity. Sibirskoe meditsinskoe obozrenie 2016; 5: 15–23.
  34. Uspenskaya Yu.A., Komleva Yu.K., Gorina Ya.V., Pozhilenkova E.A., Belova O.A., Salmina A.B. CD147 polyfunctionality and new diagnostic and therapy opportunities. Sibirskoe meditsinskoe obozrenie 2018; 4: 22–30.
  35. Morgun A.V., Osipova E.D., Boytsova E.B., Lopatina O.L., Gorina Ya.V., Pozhilenkova E.A., Salmina A.B. Vascular component of neuroinflammation in experimental Alzheimer’s disease. Tsitologiia 2020; 62(1): 16–23.
  36. Bostancıklıoğlu M. SARS-CoV2 entry and spread in the lymphatic drainage system of the brain. Brain Behav Immun 2020; 87: 122–123,
  37. Bostancıklıoğlu M. Temporal correlation between neurological and gastrointestinal symptoms of SARS-CoV-2. Inflamm Bowel Dis 2020; 26(8): e89-e91,
  38. Cabirac G.F., Murray R.S., McLaughlin L.B., Skolnick D.M., Hogue B., Dorovini-Zis K., Didier P.J. In vitro interaction of coronaviruses with primate and human brain microvascular endothelial cells. Adv Exp Med Biol 1995; 380: 79–88,
  39. Bleau C., Filliol A., Samson M., Lamontagne L. Brain invasion by mouse hepatitis virus depends on impairment of tight junctions and beta interferon production in brain microvascular endothelial cells. J Virol 2015; 89(19): 9896–9908,
  40. South A.M., Diz D.I., Chappell M.C. COVID-19, ACE2, and the cardiovascular consequences. Am J Physiol Heart Circ Physiol 2020; 318(5): H1084–H1090,
  41. Magrone T., Magrone M., Jirillo E. Focus on receptors for coronaviruses with special reference to angiotensin-converting enzyme 2 as a potential drug target — a perspective. Endocr Metab Immune Disord Drug Targets 2020; 20(6): 807–811,
  42. Zangrillo A., Landoni G., Beretta L., Morselli F., Serpa Neto A., Bellomo R; COVID-BioB Study Group. Angiotensin II infusion in COVID-19-associated vasodilatory shock: a case series. Crit Care 2020; 24(1): 227,
  43. Xia H., Lazartigues E. Angiotensin-converting enzyme 2 in the brain: properties and future directions. J Neurochem 2008; 107(6): 1482–1494,
  44. Clarke N.E., Turner A.J. Angiotensin-converting enzyme 2: the first decade. Int J Hypertens 2012; 2012: 307315,
  45. Moccia F., Gerbino A., Lionetti V., Miragoli M., Munaron L.M., Pagliaro P., Pasqua T., Penna C., Rocca C., Samaja M., Angelone T. COVID-19-associated cardiovascular morbidity in older adults: a position paper from the Italian Society of Cardiovascular Researches. Geroscience 2020; 42(4): 1021–1049,
  46. Perez S.E., Nadeem M., Malek-Ahmadi M.H., He B., Mufson E.J. Frontal cortex and hippocampal γ-secretase activating protein levels in prodromal Alzheimer disease. Neurodegener Dis 2017; 17(6): 235–241,
  47. Vickers C., Hales P., Kaushik V., Dick L., Gavin J., Tang J., Godbout K., Parsons T., Baronas E., Hsieh F., Acton S., Patane M., Nichols A., Tummino P. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem 2002; 277(17): 14838–14843,
  48. Guignabert C., de Man F., Lombès M. ACE2 as therapy for pulmonary arterial hypertension: the good outweighs the bad. Eur Respir J 2018; 51(6): 1800848,
  49. Bader M., Alenina N., Young D., Santos R.A.S., Touyz R.M. The meaning of Mas. Hypertension 2018; 72(5): 1072–1075,
  50. Ohishi M., Yamamoto K., Rakugi H. Angiotensin (1–7) and other angiotensin peptides. Curr Pharm Des 2013; 19(17): 3060–3064,
  51. Ziegler C.G.K., Allon S.J., Nyquist S.K., Mbano I.M., Miao V.N., Tzouanas C.N., Cao Y., Yousif A.S., Bals J., Hauser B.M., Feldman J., Muus C., Wadsworth M.H.  II, Kazer S.W., Hughes T.K., Doran B., Gatter G.J., Vukovic M., Taliaferro F., Mead B.E., Guo Z., Wang J.P., Gras D., Plaisant M., Ansari M., Angelidis I., Adler H., Sucre J.M.S., Taylor C.J., Lin B., Waghray A., Mitsialis V., Dwyer D.F., Buchheit K.M., Boyce J.A., Barrett N.A., Laidlaw T.M., Carroll S.L., Colonna L., Tkachev V., Peterson C.W., Yu A., Zheng H.B., Gideon H.P., Winchell C.G., Lin P.L., Bingle C.D., Snapper S.B., Kropski J.A., Theis F.J., Schiller H.B., Zaragosi L.E., Barbry P., Leslie A., Kiem H.P., Flynn J.L., Fortune S.M., Berger B., Finberg R.W., Kean L.S., Garber M., Schmidt A.G., Lingwood D., Shalek A.K., Ordovas-Montanes J.; HCA Lung Biological Network. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell 2020; 181(5): 1016–1035.e19,
  52. Peña Silva R.A., Chu Y., Miller J.D., Mitchell I.J., Penninger J.M., Faraci F.M., Heistad D.D. Impact of ACE2 deficiency and oxidative stress on cerebrovascular function with aging. Stroke 2012; 43(12): 3358–3363,
  53. Nautiyal M., Arnold A.C., Chappell M.C., Diz D.I. The brain renin-angiotensin system and mitochondrial function: influence on blood pressure and baroreflex in transgenic rat strains. Int J Hypertens 2013; 2013: 136028,
  54. Wu J., Zhao D., Wu S., Wang D. Ang-(1–7) exerts protective role in blood-brain barrier damage by the balance of TIMP-1/MMP-9. Eur J Pharmacol 2015; 748: 30–36,
  55. Li X., Wang X., Xie J., Liang B., Wu J. Suppression of angiotensin-(1–7) on the disruption of blood-brain barrier in rat of brain glioma. Pathol Oncol Res 2019; 25(1): 429–435,
  56. Wang J., Chen S., Bihl J. Exosome-mediated transfer of ACE2 (angiotensin-converting enzyme 2) from endothelial progenitor cells promotes survival and function of endothelial cell. Oxid Med Cell Longev 2020; 2020: 4213541,
  57. Labandeira-Garcia J.L., Costa-Besada M.A., Labandeira C.M., Villar-Cheda B., Rodríguez-Perez A.I. Insulin-like growth factor-1 and neuroinflammation. Front Aging Neurosci 2017; 9: 365,
  58. Wright J.W., Harding J.W. Contributions by the brain renin-angiotensin system to memory, cognition, and Alzheimer’s disease. J Alzheimers Dis 2019; 67(2): 469–480,
  59. Stragier B., De Bundel D., Sarre S., Smolders I., Vauquelin G., Dupont A., Michotte Y., Vanderheyden P. Involvement of insulin-regulated aminopeptidase in the effects of the renin-angiotensin fragment angiotensin IV: a review. Heart Fail Rev 2008; 13(3): 321–337,
  60. Gard P.R. Cognitive-enhancing effects of angiotensin IV. BMC Neurosci 2008; 9(Suppl 2): S15,
  61. Zhang M.Y., Beyer C.E. Measurement of neurotransmitters from extracellular fluid in brain by in vivo microdialysis and chromatography-mass spectrometry. J Pharm Biomed Anal 2006; 40(3): 492–499,
  62. Hamming I., Timens W., Bulthuis M.L., Lely A.T., Navis G., van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 2004; 203(2): 631–637,
  63. Elased K.M., Cunha T.S., Marcondes F.K., Morris M. Brain angiotensin-converting enzymes: role of angiotensin-converting enzyme 2 in processing angiotensin II in mice. Exp Physiol 2008; 93(5): 665–675,
  64. Tikellis C., Thomas M.C. Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease. Int J Pept 2012; 2012: 256294,
  65. Evans C.E., Miners J.S., Piva G., Willis C.L., Heard D.M., Kidd E.J., Good M.A., Kehoe P.G. ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer’s disease. Acta Neuropathol 2020; 139(3): 485–502,
  66. Wright J.W., Kawas L.H., Harding J.W. A role for the brain RAS in Alzheimer’s and Parkinson’s diseases. Front Endocrinol (Lausanne) 2013; 4: 158,
  67. Gironacci M.M. Angiotensin-(1–7): beyond its central effects on blood pressure. Ther Adv Cardiovasc Dis 2015; 9(4): 209–216,
  68. Kehoe P.G., Wong S., Al Mulhim N., Palmer L.E., Miners J.S. Angiotensin-converting enzyme 2 is reduced in Alzheimer’s disease in association with increasing amyloid-β and tau pathology. Alzheimers Res Ther 2016; 8(1): 50,
  69. Miners J.S., Ashby E., Van Helmond Z., Chalmers K.A., Palmer L.E., Love S., Kehoe P.G. Angiotensin-converting enzyme (ACE) levels and activity in Alzheimer’s disease, and relationship of perivascular ACE-1 to cerebral amyloid angiopathy. Neuropathol Appl Neurobiol 2008; 34(2): 181–193,
  70. Liu S., Liu J., Miura Y., Tanabe C., Maeda T., Terayama Y., Turner A.J., Zou K., Komano H. Conversion of Aβ43 to Aβ40 by the successive action of angiotensin-converting enzyme 2 and angiotensin-converting enzyme. J Neurosci Res 2014; 92(9): 1178–1186,
  71. Liu S., Ando F., Fujita Y., Liu J., Maeda T., Shen X., Kikuchi K., Matsumoto A., Yokomori M., Tanabe-Fujimura C., Shimokata H., Michikawa M., Komano H., Zou K. A clinical dose of angiotensin-converting enzyme (ACE) inhibitor and heterozygous ACE deletion exacerbate Alzheimer’s disease pathology in mice. J Biol Chem 2019; 294(25): 9760–9770,
  72. Chappell M.C., Marshall A.C., Alzayadneh E.M., Shaltout H.A., Diz D.I. Update on the angiotensin converting enzyme 2-angiotensin (1-7)-Mas receptor axis: fetal programing, sex differences, and intracellular pathways. Front Endocrinol (Lausanne) 2014; 4: 201,
  73. Wilson B.A., Nautiyal M., Gwathmey T.M., Rose J.C., Chappell M.C. Evidence for a mitochondrial angiotensin-(1–7) system in the kidney. Am J Physiol Renal Physiol 2016; 310(7): 637–645,
  74. Yu C., Tang W., Wang Y., Shen Q., Wang B., Cai C., Meng X., Zou F. Downregulation of ACE2/Ang-(1–7)/Mas axis promotes breast cancer metastasis by enhancing store-operated calcium entry. Cancer Lett 2016; 376(2): 268–277,
  75. Li Z., Mo N., Li L., Cao Y., Wang W., Liang Y., Deng H., Xing R., Yang L., Ni C., Chui D., Guo X. Surgery-induced hippocampal angiotensin II elevation causes blood-brain barrier disruption via MMP/TIMP in aged rats. Front Cell Neurosci 2016; 10: 105,
  76. Xu J., Sriramula S., Lazartigues E. Excessive glutamate stimulation impairs ACE2 activity through adam17-mediated shedding in cultured cortical neurons. Cell Mol Neurobiol 2018; 38(6): 1235–1243,
  77. Mo J., Enkhjargal B., Travis Z.D., Zhou K., Wu P., Zhang G., Zhu Q., Zhang T., Peng J., Xu W., Ocak U., Chen Y., Tang J., Zhang J., Zhang J.H. AVE 0991 attenuates oxidative stress and neuronal apoptosis via Mas/PKA/CREB/UCP-2 pathway after subarachnoid hemorrhage in rats. Redox Biol 2019; 20: 75–86,
  78. Cao X., Lu X.M., Tuo X., Liu J.Y., Zhang Y.C., Song L.N., Cheng Z.Q., Yang J.K., Xin Z. Angiotensin-converting enzyme 2 regulates endoplasmic reticulum stress and mitochondrial function to preserve skeletal muscle lipid metabolism. Lipids Health Dis 2019; 18(1): 207,
  79. Arroja M.M.C., Reid E., Roy L.A., Vallatos A.V., Holmes W.M., Nicklin S.A., Work L.M., McCabe C. Assessing the effects of Ang-(1–7) therapy following transient middle cerebral artery occlusion. Sci Rep 2019; 9(1): 3154,
  80. Grass G.D., Toole B.P. How, with whom and when: an overview of CD147-mediated regulatory networks influencing matrix metalloproteinase activity. Biosci Rep 2015; 36(1): e00283,
  81. Uspenskaya Yu.A., Morgun A.V., Osipova E.D., Semyachkina-Glushkovskaya O.V., Malinovskaya N.A. Glycoprotein CD147 as a new molecular target for pharmacotherapy in oncology. Eksperimental’naya i klinicheskaya farmakologiya 2019; 82(3): 36–44,
  82. Kaushik D.K., Hahn J.N., Yong V.W. EMMPRIN, an upstream regulator of MMPs, in CNS biology. Matrix Biol 2015; 44–46: 138–146,
  83. Agrawal S.M., Silva C., Tourtellotte W.W., Yong V.W. EMMPRIN: a novel regulator of leukocyte transmigration into the CNS in multiple sclerosis and experimental autoimmune encephalomyelitis. J Neurosci 2011; 31(2): 669–677,
  84. Kanyenda L.J., Verdile G., Boulos S., Krishnaswamy S., Taddei K., Meloni B.P., Mastaglia F.L., Martins R.N. The dynamics of CD147 in Alzheimer’s disease development and pathology. J. Alzheimers Dis 2011; 26(4): 593–605,
  85. Nahalkova J., Volkmann I., Aoki M., Winblad B., Bogdanovic N., Tjernberg L.O., Behbahani H. CD147, a γ-secretase associated protein is upregulated in Alzheimer’s disease brain and its cellular trafficking is affected by presenilin-2. Neurochem Int 2010; 56(1): 67–76,
  86. Zhou S., Zhou H., Walian P.J., Jap B.K. Regulation of γ-secretase activity in Alzheimer’s disease. Biochemistry 2007; 46(10): 2553–2563,
  87. Zhou S., Zhou H., Walian P.J., Jap B.K. CD147 is a regulatory subunit of the gamma-secretase complex in Alzheimer’s disease amyloid β-peptide production. Proc Natl Acad Sci U S A 2005; 102(21): 7499–7504,
  88. Satoh J., Tabunoki H., Ishida T., Saito Y., Arima K. Immunohistochemical characterization of γ-secretase activating protein expression in Alzheimer’s disease brains. Neuropathol Appl Neurobiol 2012; 38(2): 132–141,
  89. Xie J., Li X., Zhou Y., Wu J., Tan Y., Ma X., Zhao Y., Liu X., Zhao Y. Resveratrol abrogates hypoxia-induced up-regulation of exosomal amyloid-β partially by inhibiting CD147. Neurochem Res 2019; 44(5): 1113–1126,
  90. Muri L., Leppert D., Grandgirard D., Leib S.L. MMPs and ADAMs in neurological infectious diseases and multiple sclerosis. Cell Mol Life Sci 2019; 76(16): 3097–3116,
  91. Rosenberg G.A., Estrada E.Y., Mobashery S. Effect of synthetic matrix metalloproteinase inhibitors on lipopolysaccharide-induced blood–brain barrier opening in rodents: differences in response based on strains and solvents. Brain Research 2007; 1133(1): 186–192,
  92. Salmina A.B., Kuvacheva N.V., Morgun A.V., Komleva Yu.K., Pozhilenkova E.A., Lopatina O.L., Gorina Y.V., Taranushenko T.E., Petrova L.L. Glycolysis-mediated control of blood-brain barrier development and function. Int J Biochem Cell Biol 2015; 64: 174–184,
  93. Curtin K.D., Meinertzhagen I.A., Wyman R.J. Basigin (EMMPRIN/CD147) interacts with integrin to affect cellular architecture. J Cell Sci 2005; 118(Pt 12): 2649–2660,
  94. Higashida H., Salmina A.B., Olovyannikova R.Y., Hashii M., Yokoyama S., Koizumi K., Jin D., Liu H.X., Lopatina O., Amina S., Islam M.S., Huang J.J., Noda M. Cyclic ADP-ribose as a universal calcium signal molecule in the nervous system. Neurochem Int 2007; 51(2–4): 192–199,
  95. Buckley C., Wilson C., McCarron J.G. FK506 regulates Ca2+ release evoked by inositol 1,4,5-trisphosphate independently of FK-binding protein in endothelial cells. Br J Pharmacol 2020; 177(5): 1131–1149,
  96. Liu S., Jin R., Xiao A.Y., Zhong W., Li G. Inhibition of CD147 improves oligodendrogenesis and promotes white matter integrity and functional recovery in mice after ischemic stroke. Brain Behav Immun 2019; 82: 13–24,
  97. Kim M.S., Lee G.H., Kim Y.M., Lee B.W., Nam H.Y., Sim U.C., Choo S.J., Yu S.W., Kim J.J., Kim Kwon Y., Who Kim S. Angiotensin II causes apoptosis of adult hippocampal neural stem cells and memory impairment through the action on AMPK-PGC1α signaling in heart failure. Stem Cells Transl Med 2017; 6(6): 1491–1503,
  98. Jin Z.G., Melaragno M.G., Liao D.F., Yan C., Haendeler J., Suh Y.A., Lambeth J.D., Berk B.C. Cyclophilin A is a secreted growth factor induced by oxidative stress. Circ Res 2000; 87(9): 789–796,
  99. Bell R.D., Winkler E.A., Singh I., Sagare A.P., Deane R., Wu Z., Holtzman D.M., Betsholtz C., Armulik A., Sallstrom J., Berk B.C., Zlokovic B.V. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 2012; 485(7399): 512–516,
  100. Halliday M.R., Rege S.V., Ma Q., Zhao Z., Miller C.A., Winkler E.A., Zlokovic B.V. Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease. J Cereb Blood Flow Metab 2016; 36(1): 216–227,
  101. Halliday M.R., Pomara N., Sagare A.P., Mack W.J., Frangione B., Zlokovic B.V. Relationship between cyclophilin a levels and matrix metalloproteinase 9 activity in cerebrospinal fluid of cognitively normal apolipoprotein e4 carriers and blood-brain barrier breakdown. JAMA Neurol 2013; 70(9): 1198–1200,
  102. Tohidpour A., Morgun A.V., Boitsova E.B., Malinovskaya N.A., Martynova G.P., Khilazheva E.D., Kopylevich N.V., Gertsog G.E., Salmina A.B. Neuroinflammation and infection: molecular mechanisms associated with dysfunction of neurovascular unit. Front Cell Infect Microbiol 2017; 7: 276,
Morgun A.V., Salmin V.V., Boytsova E.B., Lopatina O.L., Salmina A.B. Molecular Mechanisms of Proteins — Targets for SARS-CоV-2 (Review). Sovremennye tehnologii v medicine 2020; 12(6): 98,

Journal in Databases