Development of Neuroprotective Agents for the Treatment of Alzheimer's Disease using Conjugates of Serotonin with Sesquiterpene Lactones


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Abstract

Background:Sesquiterpene lactones are secondary plant metabolites with a wide variety of biological activities. The process of lactone conjugation to other pharmacophores can increase the efficacy and specificity of the conjugated agent effect on molecular targets in various diseases, including brain pathologies. Derivatives of biogenic indoles, including neurotransmitter serotonin, are of considerable interest as potential pharmacophores. Most of these compounds have neurotropic activity and, therefore, can be used in the synthesis of new drugs with neuroprotective properties.

Aim:The aim of this experimental synthesis was to generate potential treatment agents for Alzheimer's disease using serotonin conjugated with natural sesquiterpene lactones.

Methods:Three novel compounds were obtained via the Michael reaction and used for biological testing. The obtained conjugates demonstrated complex neuroprotective activities. Serotonin conjugated to isoalantolactone exhibited strong antioxidant and mitoprotective activities.

Results:The agent was also found to inhibit β-site amyloid precursor protein cleaving enzyme 1 (BACE-1), prevent the aggregation of β-amyloid peptide 1-42, and protect SH-SY5Y neuroblastoma cells from neurotoxins such as glutamate and H2O2. In a transgenic animal model of Alzheimer's disease (5xFAD line), the conjugated agent restored declined cognitive functions and improved learning and memory.

Conclusion:In conclusion, the obtained results indicate that serotonin conjugates to sesquiterpene lactones are promising agents for the treatment of symptoms associated with Alzheimer's disease.

About the authors

Margarita Neganova

Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University

Email: info@benthamscience.net

Junqi Liu

Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University

Email: info@benthamscience.net

Yulia Aleksandrova

, Institute of Physiologically Active Compounds of Russian Academy of Sciences

Email: info@benthamscience.net

Natalia Vasilieva

, Institute of Physiologically Active Compounds of Russian Academy of Sciences

Email: info@benthamscience.net

Alexey Semakov

, Institute of Physiologically Active Compounds of Russian Academy of Sciences

Email: info@benthamscience.net

Ekaterina Yandulova

, Institute of Physiologically Active Compounds of Russian Academy of Sciences

Email: info@benthamscience.net

Olga Sukocheva

Discipline of Health Sciences, College of Nursing and Health Sciences,, Flinders University

Author for correspondence.
Email: info@benthamscience.net

Konstantin Balakin

, Moscow Institute of Physics and Technology (National Research University)

Email: info@benthamscience.net

Sergey Klochkov

, Institute of Physiologically Active Compounds of Russian Academy of Sciences

Email: info@benthamscience.net

Ruitai Fan

Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University

Author for correspondence.
Email: info@benthamscience.net

References

  1. Hou, Y.; Dan, X.; Babbar, M.; Wei, Y.; Hasselbalch, S.G.; Croteau, D.L.; Bohr, V.A. Ageing as a risk factor for neurodegenerative disease. Nat. Rev. Neurol., 2019, 15(10), 565-581. doi: 10.1038/s41582-019-0244-7 PMID: 31501588
  2. Alzhimer’s Disease International. Dementia Statistics. Available from: https://www.alzint.org/about/dementia- facts-figures/dementia-statistics/
  3. Serrano-Pozo, A.; Growdon, J.H. Is Alzheimer’s disease risk modifiable? J. Alzheimers Dis., 2019, 67(3), 795-819. doi: 10.3233/JAD181028 PMID: 30776012
  4. Masters, C.L.; Bateman, R.; Blennow, K.; Rowe, C.C.; Sperling, R.A.; Cummings, J.L. Alzheimer’s disease. Nat. Rev. Dis. Primers, 2015, 1(1), 15056. doi: 10.1038/nrdp.2015.56 PMID: 27188934
  5. Weller, J.; Budson, A. Current understanding of Alzheimer’s disease diagnosis and treatment. F1000 Res., 2018, 7, 1161. doi: 10.12688/f1000research.14506.1 PMID: 30135715
  6. Gabr, M.T.; Ibrahim, M.M. Multitarget therapeutic strategies for Alzheimer’s disease. Neural Regen. Res., 2019, 14(3), 437-440. doi: 10.4103/1673-5374.245463 PMID: 30539809
  7. Pohanka, M. Oxidative stress in Alzheimer disease as a target for therapy. Bratisl. Med. J., 2018, 119(9), 535-543. doi: 10.4149/BLL_2018_097 PMID: 30226062
  8. Perez Ortiz, J.M.; Swerdlow, R.H. Mitochondrial dysfunction in Alzheimer’s disease: Role in pathogenesis and novel therapeutic opportunities. Br. J. Pharmacol., 2019, 176(18), 3489-3507. doi: 10.1111/bph.14585 PMID: 30675901
  9. Gallardo, G.; Holtzman, D.M. Amyloid-β and tau at the crossroads of Alzheimer’s disease. Adv. Exp. Med. Biol., 2019, 1184, 187-203. doi: 10.1007/978-981-32-9358-8_16 PMID: 32096039
  10. Neganova, M.E.; Klochkov, S.G.; Afanasieva, S.V.; Serkova, T.P.; Chudinova, E.S.; Bachurin, S.O.; Reddy, V.P.; Aliev, G.; Shevtsova, E.F. Neuroprotective effects of the securinine-analogues: Identification of allomargaritarine as a lead compound. CNS Neurol. Disord. Drug Targets, 2016, 15(1), 102-107. doi: 10.2174/1871527314666150821111812 PMID: 26295814
  11. Alghamdi, B.S. The neuroprotective role of melatonin in neurological disorders. J. Neurosci. Res., 2018, 96(7), 1136-1149. doi: 10.1002/jnr.24220 PMID: 29498103
  12. Yoo, J.M.; Lee, B.D.; Sok, D.E.; Ma, J.Y.; Kim, M.R. Neuroprotective action of N-acetyl serotonin in oxidative stress-induced apoptosis through the activation of both TrkB/CREB/BDNF pathway and Akt/Nrf2/Antioxidant enzyme in neuronal cells. Redox Biol., 2017, 11, 592-599. doi: 10.1016/j.redox.2016.12.034 PMID: 28110215
  13. Keller, S.; Polanski, W.H.; Enzensperger, C.; Reichmann, H.; Hermann, A.; Gille, G. 9-Methyl-β-carboline inhibits monoamine oxidase activity and stimulates the expression of neurotrophic factors by astrocytes. J. Neural Transm. (Vienna), 2020, 127(7), 999-1012. doi: 10.1007/s00702-020-02189-9 PMID: 32285253
  14. Schwarthoff, S.; Tischer, N.; Sager, H.; Schätz, B.; Rohrbach, M.M.; Raztsou, I.; Robaa, D.; Gaube, F.; Arndt, H.D.; Winckler, T. Evaluation of γ-carboline-phenothiazine conjugates as simultaneous NMDA receptor blockers and cholinesterase inhibitors. Bioorg. Med. Chem., 2021, 46, 116355. doi: 10.1016/j.bmc.2021.116355 PMID: 34391122
  15. Fatani, A.J.; Al-Hosaini, K.A.; Ahmed, M.M.; Abuohashish, H.M.; Parmar, M.Y.; Al-Rejaie, S.S. Carvedilol attenuates inflammatory biomarkers and oxidative stress in a rat model of ulcerative colitis. Drug Dev. Res., 2015, 76(4), 204-214. doi: 10.1002/ddr.21256 PMID: 26109469
  16. Liu, J.; Wang, M. Carvedilol protection against endogenous Aβ-induced neurotoxicity in N2a cells. Cell Stress Chaperones, 2018, 23(4), 695-702. doi: 10.1007/s12192-018-0881-6 PMID: 29435723
  17. Neganova, M.E.; Klochkov, S.G.; Petrova, L.N.; Shevtsova, E.F.; Afanasieva, S.V.; Chudinova, E.S.; Fisenko, V.P.; Bachurin, S.O.; Barreto, G.E.; Aliev, G. Securinine derivatives as potential anti-amyloid therapeutic approach. CNS Neurol. Disord. Drug Targets, 2017, 16(3), 351-355. doi: 10.2174/1871527315666161107090525 PMID: 27823572
  18. Skvortsova, V.I.; Bachurin, S.O.; Ustyugov, A.A.; Kukharsky, M.S.; Deikin, A.V.; Buchman, V.L.; Ninkina, N.N. Gamma-carbolines derivatives as promising agents for the development of pathogenic therapy for proteinopathy. Acta Nat. (Engl. Ed.), 2018, 10(4), 59-62. doi: 10.32607/20758251-2018-10-4-59-62 PMID: 30713762
  19. Li, Y.; Zhang, J.; Wan, J.; Liu, A.; Sun, J. Melatonin regulates Aβ production/clearance balance and Aβ neurotoxicity: A potential therapeutic molecule for Alzheimer’s disease. Biomed. Pharmacother., 2020, 132, 110887. doi: 10.1016/j.biopha.2020.110887 PMID: 33254429
  20. Shukla, M.; Govitrapong, P.; Boontem, P.; Reiter, R.J.; Satayavivad, J. Mechanisms of melatonin in alleviating Alzheimer’s disease. Curr. Neuropharmacol., 2017, 15(7), 1010-1031. PMID: 28294066
  21. Tang, J.J.; Huang, L.F.; Deng, J.L.; Wang, Y.M.; Guo, C.; Peng, X.N.; Liu, Z.; Gao, J.M. Cognitive enhancement and neuroprotective effects of OABL, a sesquiterpene lactone in 5xFAD Alzheimer’s disease mice model. Redox Biol., 2022, 50, 102229. doi: 10.1016/j.redox.2022.102229 PMID: 35026701
  22. Li, Q.; Wang, Z.; Xie, Y.; Hu, H. Antitumor activity and mechanism of costunolide and dehydrocostus lactone: Two natural sesquiterpene lactones from the Asteraceae family. Biomed. Pharmacother., 2020, 125, 109955. doi: 10.1016/j.biopha.2020.109955 PMID: 32014691
  23. Sims, N.R. Rapid isolation of metabolically active mitochondria from rat brain and subregions using Percoll density gradient centrifugation. J. Neurochem., 1990, 55(2), 698-707. doi: 10.1111/j.1471-4159.1990.tb04189.x PMID: 2164576
  24. Gornall, A.G.; Bardawill, C.J.; David, M.M. Determination of serum proteins by means of the biuret reaction. J. Biol. Chem., 1949, 177(2), 751-766. doi: 10.1016/S0021-9258(18)57021-6 PMID: 18110453
  25. Milackova, I.; Kovacikova, L.; Veverka, M.; Gallovic, J.; Stefek, M. Screening for antiradical efficiency of 21 semi-synthetic derivatives of quercetin in a DPPH assay. Interdiscip. Toxicol., 2013, 6(1), 13-17. doi: 10.2478/intox-2013-0003 PMID: 24170974
  26. Åkerman, K.E.O.; Wikström, M.K.F. Safranine as a probe of the mitochondrial membrane potential. FEBS Lett., 1976, 68(2), 191-197. doi: 10.1016/0014-5793(76)80434-6 PMID: 976474
  27. Phan, H.; Samarat, K.; Takamura, Y.; Azo-Oussou, A.; Nakazono, Y.; Vestergaard, M. Polyphenols modulate Alzheimer’s amyloid beta aggregation in a structure-dependent manner. Nutrients, 2019, 11(4), 756. doi: 10.3390/nu11040756 PMID: 30935135
  28. Präbst, K.; Engelhardt, H.; Ringgeler, S.; Hübner, H. Basic colorimetric proliferation assays: MTT, WST, and Resazurin. Methods Mol. Biol., 2017, 1601, 1-17. doi: 10.1007/978-1-4939-6960-9_1 PMID: 28470513
  29. Kraeuter, A.K.; Guest, P.C.; Sarnyai, Z. The open field test for measuring locomotor activity and anxiety-like behavior. Methods Mol. Biol., 2019, 1916, 99-103. doi: 10.1007/978-1-4939-8994-2_9 PMID: 30535687
  30. Morris, R. Developments of a water-maze procedure for studying spatial learning in the rat. J. Neurosci. Methods, 1984, 11(1), 47-60. doi: 10.1016/0165-0270(84)90007-4 PMID: 6471907
  31. Neganova, M.; Aleksandrova, Y.; Suslov, E.; Mozhaitsev, E.; Munkuev, A.; Tsypyshev, D.; Chicheva, M.; Rogachev, A.; Sukocheva, O.; Volcho, K.; Klochkov, S. Novel multitarget hydroxamic acids with a natural origin CAP group against Alzheimer’s disease: synthesis, docking and biological evaluation. Pharmaceutics, 2021, 13(11), 1893. doi: 10.3390/pharmaceutics13111893 PMID: 34834312
  32. Borgulya, J.; Bernauer, K. A practicable synthesis of 3-(2-aminoethyl)-1 h-indol-5-yl hydrogen sulfate (serotonin O-sulfate). Synthesis, 1983, 1983(1), 29-30. doi: 10.1055/s-1983-30205
  33. Semakov, A.V.; Anikina, L.V.; Pukhov, S.A.; Afanas’eva, S.V.; Klochkov, S.G. Conjugates of alantolactone with anthracycline antibiotics. Chem. Nat. Compd., 2016, 52, 695-696. doi: 10.1007/s10600-016-1744-y
  34. Chiurchiù, V.; Orlacchio, A.; Maccarrone, M. Is modulation of oxidative stress an answer? the state of the art of redox therapeutic actions in neurodegenerative diseases. Oxid. Med. Cell. Longev., 2016, 2016, 1-11. doi: 10.1155/2016/7909380 PMID: 26881039
  35. Luo, J.; Mills, K.; le Cessie, S.; Noordam, R.; van Heemst, D. Ageing, age-related diseases and oxidative stress: What to do next? Ageing Res. Rev., 2020, 57, 100982. doi: 10.1016/j.arr.2019.100982 PMID: 31733333
  36. Zhang, J.; Wang, X.; Vikash, V.; Ye, Q.; Wu, D.; Liu, Y.; Dong, W. ROS and ROS-mediated cellular signaling. Oxid. Med. Cell. Longev., 2016, 2016, 1-18. doi: 10.1155/2016/4350965 PMID: 26998193
  37. Singh, A.; Kukreti, R.; Saso, L.; Kukreti, S. Oxidative stress: a key modulator in neurodegenerative diseases. Molecules, 2019, 24(8), 1583. doi: 10.3390/molecules24081583 PMID: 31013638
  38. Neganova, M.E.; Aleksandrova, Y.R.; Nebogatikov, V.O.; Klochkov, S.; Ustyugov, A.A. Promising molecular targets for pharmacological therapy of neurodegenerative pathologies. Acta Nat. (Engl. Ed.), 2020, 12(3), 60-80. doi: 10.32607/actanaturae.10925 PMID: 33173597
  39. von Arnim, C.A.F.; Gola, U.; Biesalski, H.K. More than the sum of its parts? Nutrition in Alzheimer’s disease. Nutrition, 2010, 26(7-8), 694-700. doi: 10.1016/j.nut.2009.11.009 PMID: 20381316
  40. El-Bachá, R.S.; De-Lima-Filho, J.L.; Guedes, R.C.A. Dietary antioxidant deficiency facilitates cortical spreading depression induced by photoactivated riboflavin. Nutr. Neurosci., 1998, 1(3), 205-212. doi: 10.1080/1028415X.1998.11747230 PMID: 27406199
  41. Mandel, S.; Grünblatt, E.; Riederer, P.; Gerlach, M.; Levites, Y.; Youdim, M.B. Neuroprotective strategies in Parkinson’s disease: An update on progress. CNS Drugs, 2003, 17(10), 729-762. doi: 10.2165/00023210-200317100-00004 PMID: 12873156
  42. Yu, Y.C.; Kuo, C.L.; Cheng, W.L.; Liu, C.S.; Hsieh, M. Decreased antioxidant enzyme activity and increased mitochondrial DNA damage in cellular models of Machado-Joseph disease. J. Neurosci. Res., 2009, 87(8), 1884-1891. doi: 10.1002/jnr.22011 PMID: 19185026
  43. Shevtsova, E.; Vinogradova, D.; Neganova, M.; Shevtsov, P.; Lednev, B.; Bachurin, S. Mitochondria are an important target in the search for new drugs for the treatment of Alzheimer′s disease and senile dementia. Biomed. Chem., 2018, 1(3), e00058.
  44. Lin, M.T.; Simon, D.K.; Ahn, C.H.; Kim, L.M.; Beal, M.F. High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer’s disease brain. Hum. Mol. Genet., 2002, 11(2), 133-145. doi: 10.1093/hmg/11.2.133 PMID: 11809722
  45. Su, B.; Wang, X.; Bonda, D.; Perry, G.; Smith, M.; Zhu, X. Abnormal mitochondrial dynamics-a novel therapeutic target for Alzheimer’s disease? Mol. Neurobiol., 2010, 41(2-3), 87-96. doi: 10.1007/s12035-009-8095-7 PMID: 20101529
  46. Reddy, P.H.; Reddy, T.P. Mitochondria as a therapeutic target for aging and neurodegenerative diseases. Curr. Alzheimer Res., 2011, 8(4), 393-409. doi: 10.2174/156720511795745401 PMID: 21470101
  47. Swerdlow, R.H.; Khan, S.M. A "mitochondrial cascade hypothesis" for sporadic Alzheimer’s disease. Med. Hypotheses, 2004, 63(1), 8-20. doi: 10.1016/j.mehy.2003.12.045 PMID: 15193340
  48. Bradley-Whitman, M.A.; Lovell, M.A. Epigenetic changes in the progression of Alzheimer’s disease. Mech. Ageing Dev., 2013, 134(10), 486-495. doi: 10.1016/j.mad.2013.08.005 PMID: 24012631
  49. Jodeiri Farshbaf, M.; Ghaedi, K.; Megraw, T.L.; Curtiss, J.; Shirani Faradonbeh, M.; Vaziri, P.; Nasr-Esfahani, M.H. Does PGC1α/FNDC5/BDNF elicit the beneficial effects of exercise on neurodegenerative disorders? Neuromol. Med., 2016, 18(1), 1-15. doi: 10.1007/s12017-015-8370-x PMID: 26611102
  50. Yan, M.H.; Wang, X.; Zhu, X. Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease. Free Radic. Biol. Med., 2013, 62, 90-101. doi: 10.1016/j.freeradbiomed.2012.11.014 PMID: 23200807
  51. Yao, P.J.; Eren, E.; Goetzl, E.J.; Kapogiannis, D. Mitochondrial electron transport chain protein abnormalities detected in plasma extracellular vesicles in Alzheimer’s disease. Biomedicines, 2021, 9(11), 1587. doi: 10.3390/biomedicines9111587 PMID: 34829816
  52. Long, J.; He, P.; Shen, Y.; Li, R. New evidence of mitochondria dysfunction in the female Alzheimer’s disease brain: deficiency of estrogen receptor-β. J. Alzheimers Dis., 2012, 30(3), 545-558. doi: 10.3233/JAD-2012-120283 PMID: 22451324
  53. Damiano, M.; Diguet, E.; Malgorn, C.; D’Aurelio, M.; Galvan, L.; Petit, F.; Benhaim, L.; Guillermier, M.; Houitte, D.; Dufour, N.; Hantraye, P.; Canals, J.M.; Alberch, J.; Delzescaux, T.; Déglon, N.; Beal, M.F.; Brouillet, E. A role of mitochondrial complex II defects in genetic models of Huntington’s disease expressing N-terminal fragments of mutant huntingtin. Hum. Mol. Genet., 2013, 22(19), 3869-3882. doi: 10.1093/hmg/ddt242 PMID: 23720495
  54. Ohta, S.; Ohsawa, I. Dysfunction of mitochondria and oxidative stress in the pathogenesis of Alzheimer’s disease: On defects in the cytochrome c oxidase complex and aldehyde detoxification. J. Alzheimers Dis., 2006, 9(2), 155-166. doi: 10.3233/JAD-2006-9208 PMID: 16873963
  55. Mohamed, T.M.; Youssef, M.A.M.; Bakry, A.A.; El-Keiy, M.M. Alzheimer’s disease improved through the activity of mitochondrial chain complexes and their gene expression in rats by boswellic acid. Metab. Brain Dis., 2021, 36(2), 255-264. doi: 10.1007/s11011-020-00639-7 PMID: 33159653
  56. Mosconi, L.; Andrews, R.D.; Matthews, D.C. Comparing brain amyloid deposition, glucose metabolism, and atrophy in mild cognitive impairment with and without a family history of dementia. J. Alzheimers Dis., 2013, 35(3), 509-524. doi: 10.3233/JAD-121867 PMID: 23478305
  57. Faizi, M.; Seydi, E.; Abarghuyi, S.; Salimi, A.; Nasoohi, S.; Pourahmad, J. A search for mitochondrial damage in Alzheimer’s disease using isolated rat brain mitochondria. Iran. J. Pharm. Res., 2016, 15(Suppl.), 185-195. PMID: 28228816
  58. Emmerzaal, T.L.; Rodenburg, R.J.; Tanila, H.; Verweij, V.; Kiliaan, A.J.; Kozicz, T. Age-dependent decrease of mitochondrial complex II activity in a familial mouse model for alzheimer’s disease. J. Alzheimers Dis., 2018, 66(1), 75-82. doi: 10.3233/JAD-180337 PMID: 30248054
  59. Blennow, K.; Zetterberg, H. Biomarkers for Alzheimer’s disease: current status and prospects for the future. J. Intern. Med., 2018, 284(6), 643-663. doi: 10.1111/joim.12816 PMID: 30051512
  60. Viola, K.L.; Klein, W.L. Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis. Acta Neuropathol., 2015, 129(2), 183-206. doi: 10.1007/s00401-015-1386-3 PMID: 25604547
  61. Takahashi, R.H.; Nagao, T.; Gouras, G.K. Plaque formation and the intraneuronal accumulation of β-amyloid in Alzheimer’s disease. Pathol. Int., 2017, 67(4), 185-193. doi: 10.1111/pin.12520 PMID: 28261941
  62. Simonian, N.A.; Coyle, J.T. Oxidative stress in neurodegenerative diseases. Annu. Rev. Pharmacol. Toxicol., 1996, 36(1), 83-106. doi: 10.1146/annurev.pa.36.040196.000503 PMID: 8725383
  63. Schubert, D.; Piasecki, D. Oxidative glutamate toxicity can be a component of the excitotoxicity cascade. J. Neurosci., 2001, 21(19), 7455-7462. doi: 10.1523/JNEUROSCI.21-19-07455.2001 PMID: 11567035
  64. Gardner, A.M.; Xu, F.; Fady, C.; Jacoby, F.J.; Duffey, D.C.; Tu, Y.; Lichtenstein, A. Apoptotic vs. nonapoptotic cytotoxicity induced by hydrogen peroxide. Free Radic. Biol. Med., 1997, 22(1-2), 73-83. doi: 10.1016/S0891-5849(96)00235-3 PMID: 8958131
  65. Yu, J.; Ye, J.; Liu, X.; Han, Y.; Wang, C. Protective effect of L-carnitine against H2O2 -induced neurotoxicity in neuroblastoma (SH-SY5Y) cells. Neurol. Res., 2011, 33(7), 708-716. doi: 10.1179/1743132810Y.0000000028 PMID: 21756550
  66. Oakley, H.; Cole, S.L.; Logan, S.; Maus, E.; Shao, P.; Craft, J.; Guillozet-Bongaarts, A.; Ohno, M.; Disterhoft, J.; Van Eldik, L.; Berry, R.; Vassar, R. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J. Neurosci., 2006, 26(40), 10129-10140. doi: 10.1523/JNEUROSCI.1202-06.2006 PMID: 17021169
  67. Charisis, S.; Ntanasi, E.; Yannakoulia, M.; Anastasiou, C.A.; Kosmidis, M.H.; Dardiotis, E.; Hadjigeorgiou, G.; Sakka, P.; Veskoukis, A.S.; Kouretas, D.; Scarmeas, N. Plasma GSH levels and Alzheimer’s disease. A prospective approach.: Results from the HELIAD study. Free Radic. Biol. Med., 2021, 162, 274-282. doi: 10.1016/j.freeradbiomed.2020.10.027 PMID: 33099001

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