Potential Effects of Propolis Against Coronaviruses

Abstract

Throughout human history, many diseases are caused by viruses. Researchers are working on vaccines against viruses and these vaccines are widely used as protective material. Due to virus dynamics, new variants emerge as a result of mutations in different types of hosts from time to time. These variants can threaten human life by bypassing the unprepared immune system of the infected individual. Fortunately, our body has an immune system that can renew itself and works flawlessly against these viruses. The newly formed variant, which is not limited to the known, can also generate immunity against the genetic structure of the virus. In defense against viral infections, the limited effects of antivirals, the time-consuming need for vaccine production to be provided to the infected, and applications that strengthen the immune system come to the fore. In this context, if our immune system is supported and stimulated with natural, functional products such as propolis, it will be able to fight viruses more effectively. Propolis shows that it is a remarkable product in the fight against viruses with its modulations in the immune system against the SARS CoV-2 epidemic that swept the world, its PAK-1 blocker effect, early and higher immunity stimulation, increased antibody titers, and immunomodulatory effects such as prolonging the duration of immune protection. From this point of view, in this review article, we discussed the effects of propolis, known as a bee product that activates the immune system and facilitates the functioning of the immune system, against coronaviruses.

Keywords

• Coronavirus
• Propolis
• Immuno modulation

Propolisin Koronavirüslere Karşı Potansiyel Etkileri

Abstract

İnsanlık tarihi boyunca birçok hastalık virüs kaynaklı olarak meydana gelmektedir. Araştırmacılar virüslere karşı aşı çalışması yapmakta ve koruyucu materyal olarak bu aşılar yaygın olarak kullanılmaktadır. Virüs, dinamiği gereği farklı tür konaklarda zaman zaman mutasyona uğramaları sonucu yeni varyantlar ortaya çıkmaktadır. Bu varyantlar enfekte ettiği bireyin hazırlıksız olan bağışıklık sistemini atlatarak insan hayatını tehdit eder duruma gelebilmektedir. Neyse ki bu virüslere karşı, vücudumuzda kendini yenileyebilme özelliği olan ve kusursuz çalışan bir immün sistem vardır ki sadece bilinenle sınırlı kalmayan, yeni oluşan varyant virüsün genetik yapısına karşı da bağışıklık üretebilmektedir. Viral enfeksiyonlara karşı savunmada, antivirallerin sınırlı etkileri, aşı üretiminin enfekte olanlara sağlanmasının zaman alması, bağışıklık sistemini güçlendirici uygulamaları ön plana çıkartmaktadır. Bu bağlamda bağışıklık sistemimiz, propolis gibi doğal, fonksiyonel ürünler ile desteklenir ve uyarılırsa virüslere karşı daha etkili bir savaş verebilecektir. Propolis, Dünyayı saran SARS CoV-2 salgınına karşı immün sistemde yaptığı modülasyonlarla, PAK-1 bloker etkisi, erken ve daha yüksek bağışıklığın uyarılması, antikor titrelerinin yükseltilmesi, bağışıklık koruma süresinin uzatılması gibi immünmodülatör etkilere sahip olması ile virüslerle mücadelede dikkat çekici bir ürün olduğunu göstermektedir. Bu noktadan hareketle bu derleme makalesinde bağışıklık sistemini harekete geçiren ve bağışıklık sisteminin çalışmasını kolaylaştıran bir arı ürünü olarak bilinen propolisin kullanımında koronavirüslere karşı etkilerinin neler olabileceğini tartıştık.

Keywords

• Koronavirüs,
• propolis,
• İmmüno modülasyon

References

1. Li C, Zhao C, Bao J, Tang B, Wang Y, Gu B. Laboratory Diagnosis of Coronavirus Disease-2019 (COVID-19). Clin Chim Acta [Internet]. 2020 Jul [cited 2020 Jul 6]; Available from: https://linkinghub.elsevier.com/retrieve/pii/S0009898120303090
2. Masters PS. Coronavirus genomic RNA packaging. Vol. 537, Virology. Academic Press Inc.; 2019. p. 198–207.
3. Cui J, Li F, Shi ZL. Origin and evolution of pathogenic coronaviruses [Internet]. Vol. 17, Nature Reviews Microbiology. Nature Publishing Group; 2019 [cited 2020 Jul 6]. p. 181–92. Available from: /pmc/articles/PMC7097006/?report=abstract
4. Zhong NS, Zheng BJ, Li YM, Poon LLM, Xie ZH, Chan KH, et al. Epidemiology and cause of severe acute respiratory syndrome (SARS) in Guangdong, People’s Republic of China, in February, 2003. Lancet [Internet]. 2003 Oct 25 [cited 2020 Jul 6];362(9393):1353–8. Available from: /pmc/articles/PMC7112415/?report=abstract
5. Zaki AM, Van Boheemen S, Bestebroer TM, Osterhaus ADME, Fouchier RAM. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med [Internet]. 2012 Nov 8 [cited 2020 Jul 6];367(19):1814–20. Available from: https://pubmed.ncbi.nlm.nih.gov/23075143/
6. De Wit E, Van Doremalen N, Falzarano D, Munster VJ. SARS and MERS: Recent insights into emerging coronaviruses [Internet]. Vol. 14, Nature Reviews Microbiology. Nature Publishing Group; 2016 [cited 2020 Jul 7]. p. 523–34. Available from: www.nature.com/nrmicro
7. Su S, Wong G, Shi W, Liu J, Lai ACK, Zhou J, et al. Epidemiology, Genetic Recombination, and Pathogenesis of Coronaviruses [Internet]. Vol. 24, Trends in Microbiology. Elsevier Ltd; 2016 [cited 2020 Jul 7]. p. 490–502. Available from: /pmc/articles/PMC7125511/?report=abstract
8. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med [Internet]. 2020 Feb 20 [cited 2020 Jul 6];382(8):727–33. Available from: /pmc/articles/PMC7092803/?report=abstract

9. Docea AO, Tsatsakis A, Albulescu D, Cristea O, Zlatian O, Vinceti M, et al. A new threat from an old enemy: Re-emergence of coronavirus (Review) [Internet]. Vol. 45, International Journal of Molecular Medicine. Spandidos Publications; 2020 [cited 2020 Jul 9]. p. 1631–43. Available from: https://pubmed.ncbi.nlm.nih.gov/32236624/
10. Madabhavi I, Sarkar M, Kadakol N. CoviD-19: A review [Internet]. Vol. 90, Monaldi Archives for Chest Disease. PAGEPress Publications; 2020 [cited 2020 Jul 7]. p. 248–58. Available from: https://www.monaldi archives.org/index.php/macd/article/view/1298
11. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet [Internet]. 2020 Feb 15 [cited 2020 Jul 7];395(10223):507–13. Available from: /pmc/articles/PMC7135076/?report=abstract
12. Huleihel M, Ishano V. Effect of propolis extract on malignant cell transformation by Moloney murine sarcoma virus. Arch Virol [Internet]. 2001 [cited 2020 Jul 13];146(8):1517–26. Available from: https://pubmed.ncbi.nlm.nih.gov/11676414/
13. Gekker G, Hu S, Spivak M, Lokensgard JR, Peterson PK. Anti-HIV-1 activity of propolis in CD4+ lymphocyte and microglial cell cultures. J Ethnopharmacol. 2005 Nov 14;102(2):158–63.
14. Sforcin JM. Biological Properties and Therapeutic Applications of Propolis [Internet]. Vol. 30, Phytotherapy Research. John Wiley and Sons Ltd; 2016 [cited 2020 Jul 8]. p. 894–905. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/ptr.5605
15. Kurek-Górecka A, Górecki M, Rzepecka-Stojko A, Balwierz R, Stojko J. Bee Products in Dermatology and Skin Care. Molecules [Internet]. 2020 Jan 28 [cited 2020 Jul 9];25(3):556. Available from: https://www.mdpi.com/1420-3049/25/3/556
16. Pascoal A, Feás X, Dias T, Dias LG, Estevinho LM. The Role of Honey and Propolis in the Treatment of Infected Wounds. In: Microbiology for Surgical Infections: Diagnosis, Prognosis and Treatment. Elsevier Inc.; 2014. p. 221–34.
17. Toreti VC, Sato HH, Pastore GM, Park YK. Recent progress of propolis for its biological and chemical compositions and its botanical origin. Evidence-based Complement Altern Med. 2013;2013.
18. Salatino A, Teixeira ÉW, Negri G, Message D. Origin and chemical variation of Brazilian propolis. Evidence-based Complement Altern Med. 2005;2(1):33–8.
19. Maksimova-Todorova V, Manolova N, Gegova G, Serkedzhieva I, Uzunov S. [Antiviral action of fractions isolated from propolis]. Acta Microbiol Bulg [Internet]. 1985 Jan 1 [cited 2020 Jul 13];17:79–85. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3834770
20. J Starzyk, S Scheller, J Szaflarski, M Moskwa AS. Biological Properties and Clinical Application of Propolis. II. Studies on the Antiprotozoan Activity of Ethanol Extract of Propolis. Arzneimittelforschung. 1977;27(6)(Biological Properties and Clinical Application of Propolis. II. Studies on the Antiprotozoan Activity of Ethanol Extract of Propolis):1198–9.
21. Fokt H, Pereira a, Ferreira a M, Cunha a, Aguiar C. How do bees prevent hive infections ? The antimicrobial properties of propolis. Appl Microbiol. 2010;481–93.
22. Henry K. The Propolis Book. 2012;(January):1–15.
23. Búfalo MC, Figueiredo AS, De Sousa JPB, Candeias JMG, Bastos JK, Sforcin JM. Anti-poliovirus activity of Baccharis dracunculifolia and propolis by cell viability determination and real-time PCR. J Appl Microbiol [Internet]. 2009 Nov [cited 2020 Jul 13];107(5):1669–80. Available from: /pmc/articles/PMC7197736/?report=abstract
24. Amoros M, Sauvager F, Girre L, Cormier M. In vitro antiviral activity of propolis. Apidologie [Internet]. 1992 [cited 2020 Jul 8];23(3):231–40. Available from: http://www.apidologie.org/10.1051/apido:19920306
25. Ma X, Guo Z, Zhang Z, Li X, Wang X, Liu Y, et al. Ferulic acid isolated from propolis inhibits porcine parvovirus replication potentially through Bid-mediate apoptosis. Int Immunopharmacol. 2020 Jun 1;83:106379.
26. Bachevski D, Damevska K, Simeonovski V, Dimova M. Back to the basics: Propolis and COVID ‐19. Dermatol Ther [Internet]. 2020 Jul 3 [cited 2020 Jul 13]; Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/dth.13780
27. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell [Internet]. 2020 Apr 16 [cited 2020 Jul 27];181(2):271-280.e8. Available from: https://pubmed.ncbi.nlm.nih.gov/32142651/
28. Maruta H, He H. PAK1-blockers: Potential Therapeutics against COVID-19. Med Drug Discov. 2020 Jun 1;6:100039.
29. Nguyen BCQ, Yoshimura K, Kumazawa S, Tawata S, Maruta H. Frondoside A from sea cucumber and nymphaeols from Okinawa propolis: Natural anti-cancer agents that selectively inhibit PAK1 <i>in vitro </i> Drug Discov Ther [Internet]. 2017 May 30 [cited 2020 Jul 13];11(2):110–4. Available from: https://www.jstage.jst.go.jp/article/ddt/11/2/11_2017.01011/_article
30. Taira N, Nguyen BCQ, Be Tu PT, Tawata S. Effect of Okinawa Propolis on PAK1 Activity, Caenorhabditis elegans Longevity, Melanogenesis, and Growth of Cancer Cells. J Agric Food Chem [Internet]. 2016 Jul 13 [cited 2020 Jul 13];64(27):5484–9. Available from: https://pubs.acs.org/sharingguidelines
31. Xu JW, Ikeda K, Kobayakawa A, Ikami T, Kayano Y, Mitani T, et al. Downregulation of Rac1 activation by caffeic acid in aortic smooth muscle cells. Life Sci. 2005 Apr 29;76(24):2861–72.
32. Maruta H. Herbal therapeutics that block the oncogenic kinase PAK1: A practical approach towards PAK1-dependent diseases and longevity. Vol. 28, Phytotherapy Research. John Wiley and Sons Ltd; 2014. p. 656–72.
33. González-Búrquez MDJ, González-Díaz FR, García-Tovar CG, Carrillo-Miranda L, Soto-Zárate CI, Canales-Martínez MM, et al. Comparison between in Vitro Antiviral Effect of Mexican Propolis and Three Commercial Flavonoids against Canine Distemper Virus. Evidence-based Complement Altern Med. 2018;2018.
34. Syed S, Saleem A. Severe Acute Respiratory Syndrome Epidemiology and Control. Lab Med [Internet]. 2004 Feb 1 [cited 2020 Jul 9];35(2):112–6. Available from: https://academic.oup.com/labmed/article-abstract/35/2/112/2504364
35. Debiaggi M, Tateo F, Pagani L, Luini M, Romero E. Effects of propolis flavonoids on virus infectivity and replication. Microbiologica. 1990;13(3):207–13.
36. Yu MS, Lee J, Lee JM, Kim Y, Chin YW, Jee JG, et al. Identification of myricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase, nsP13. Bioorganic Med Chem Lett [Internet]. 2012 Jun 15 [cited 2020 Jul 21];22(12):4049–54. Available from: /pmc/articles/PMC7127438/?report=abstract
37. Kumova U, Korkmaz A, Avcı BC, Ceyran G. Kö Ş E Yazilari Önemlİ Bİ R Ari Ürünü : Propolİ S Derleme ( Review ). Uludag Bee J. 2002;(May):10–23.
38. Lin Y, Ren N, Li S, Chen M, Pu P. Novel anti-obesity effect of scutellarein and potential underlying mechanism of actions. Biomed Pharmacother [Internet]. 2019 Sep 1 [cited 2020 Jul 21];117. Available from: https://pubmed.ncbi.nlm.nih.gov/31228804/
39. Ryu YB, Jeong HJ, Kim JH, Kim YM, Park JY, Kim D, et al. Biflavonoids from Torreya nucifera displaying SARS-CoV 3CLpro inhibition. Bioorganic Med Chem [Internet]. 2010 Nov 15 [cited 2020 Jul 21];18(22):7940–7. Available from: https://pubmed.ncbi.nlm.nih.gov/20934345/
40. Coskun I, Duymaz GM, Dastan T, Sonmezer OE, Acar S, et al. The Characterization and Bioactive Composition of Turkish Propolis [Internet]. Vol. 1, Journal of Apitherapy and Nature/Apiterapi ve Doğa Dergisi. 2018 Dec [cited 2020 Jul 21]. Available from: www.dergipark.gov.tr/jan
41. Gao W, Wu J, Wei J, Pu L, Guo C, Yang J, et al. Brazilian green propolis improves immune function in aged mice. J Clin Biochem Nutr [Internet]. 2014 [cited 2020 Jul 14];55(1):7–10. Available from: http://jlc.jst.go.jp/DN/JST.JSTAGE/jcbn/13-70?lang=en&from=CrossRef&type=abstract
42. Bachiega TF, Orsatti CL, Pagliarone AC, Sforcin JM. The effects of propolis and its isolated compounds on cytokine production by murine macrophages. Phyther Res [Internet]. 2012 Sep [cited 2020 Jul 13];26(9):1308–13. Available from: https://pubmed.ncbi.nlm.nih.gov/22275284/
43. Conti BJ, Santiago KB, Cardoso EO, Freire PP, Carvalho RF, Golim MA, et al. Propolis modulates miRNAs involved in TLR-4 pathway, NF-κB activation, cytokine production and in the bactericidal activity of human dendritic cells. J Pharm Pharmacol [Internet]. 2016 Dec 1 [cited 2020 Jul 14];68(12):1604–12. Available from: http://doi.wiley.com/10.1111/jphp.12628
44. Ivanovska N, Neychev H, Stefanova Z, Bankova V, Popov S. Influence of cinnamic acid on lymphocyte proliferation, cytokine release and Klebsiella infection in mice. Apidologie [Internet]. 1995 [cited 2020 Jul 17];26(2):73–81. Available from: http://www.apidologie.org/10.1051/apido:19950201
45. Da Silva SS, Thomé GDS, Cataneo AHD, Miranda MM, Felipe I, Andrade CGTDJ, et al. Brazilian propolis antileishmanial and immunomodulatory effects. Evidence-based Complement Altern Med. 2013;2013.
46. Sá-Nunes A, Faccioli LH, Sforcin JM. Propolis: Lymphocyte proliferation and IFN-γ production. J Ethnopharmacol. 2003 Jul 1;87(1):93–7.
47. Orsatti CL, Missima F, Pagliarone AC, Bachiega TF, BÃofalo MC, AraÃojo JP, et al. Propolis immunomodulatory action in vivo on Toll-like receptors 2 and 4 expression and on pro-inflammatory cytokines production in mice. Phyther Res [Internet]. 2009 Aug 1 [cited 2020 Jul 13];24(8):n/a-n/a. Available from: http://doi.wiley.com/10.1002/ptr.3086
48. Wang LC, Lin YL, Liang YC, Yang YH, Lee JH, Yu HH, et al. The effect of caffeic acid phenethyl ester on the functions of human monocyte-derived dendritic cells. BMC Immunol [Internet]. 2009 Jul 16 [cited 2020 Jul 16];10:39. Available from: /pmc/articles/PMC2724478/?report=abstract
49. Murad JM, Calvi SA, Soares AMVC, Bankova V, Sforcin JM. Effects of propolis from Brazil and Bulgaria on fungicidal activity of macrophages against Paracoccidioides brasiliensis. J Ethnopharmacol. 2002;79(3):331–4.
50. SFORCIN JM, KANENO R, FUNARI SRC. ABSENCE OF SEASONAL EFFECT ON THE IMMUNOMODULATORY ACTION OF BRAZILIAN PROPOLIS ON NATURAL KILLER ACTIVITY. J Venom Anim Toxins [Internet]. 2002 [cited 2020 Jul 13];8(1):19–29. Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0104-79302002000100003&lng=en&nrm=iso&tlng=en
51. Fischer G, Conceição FR, Leite FPL, Dummer LA, Vargas GDA, Hübner S de O, et al. Immunomodulation produced by a green propolis extract on humoral and cellular responses of mice immunized with SuHV-1. Vaccine. 2007 Jan 26;25(7):1250–6.
52. Shen Z, Medicine YY. Propolis, a new adjuvant. Chinese J Prev Vet Med. 1989;5:55–7.
53. Chu WH. Adjuvant effect of propolis on immunisation by inactivated Aeromonas hydrophila in carp (Carassius auratus gibelio). Fish Shellfish Immunol. 2006 Jul 1;21(1):113–7.
54. Sforcin JM, Orsi RO, Bankova V. Effect of propolis, some isolated compounds and its source plant on antibody production. J Ethnopharmacol. 2005 Apr 26;98(3):301–5.
55. Park JH, Lee JK, Kim HS, Chung ST, Eom JH, Kim KA, et al. Immunomodulatory effect of caffeic acid phenethyl ester in Balb/c mice. Int Immunopharmacol. 2004 Mar 1;4(3):429–36.
56. Márquez N, Sancho R, Macho A, Calzado MA, Fiebich BL, Muñoz E. Caffeic Acid Phenethyl Ester Inhibits T-Cell Activation by Targeting Both Nuclear Factor of Activated T-Cells and NF-κB Transcription Factors. J Pharmacol Exp Ther [Internet]. 2004 Mar 1 [cited 2020 Jul 17];308(3):993–1001. Available from: http://jpet.aspetjournals.org/content/308/3/993
57. Okamoto Y, Hara T, Ebato T, Fukui T, Masuzawa T. Brazilian propolis ameliorates trinitrobenzene sulfonic acid-induced colitis in mice by inhibiting Th1 differentiation. Int Immunopharmacol. 2013 Jun 1;16(2):178–83.
58. Missima F, Sforcin JM. Green Brazilian propolis action on macrophages and lymphoid organs of chronically stressed mice. Evidence-based Complement Altern Med. 2008;5(1):71–5.
59. Búfalo MC, Bordon-Graciani AP, Conti BJ, de Assis Golim M, Sforcin JM. The immunomodulatory effect of propolis on receptors expression, cytokine production and fungicidal activity of human monocytes. J Pharm Pharmacol [Internet]. 2014 Oct 1 [cited 2020 Jul 21];66(10):1497–504. Available from: http://doi.wiley.com/10.1111/jphp.12279
60. Sforcin J. The effect of propolis on pro-inflammatory cytokines produced by melanoma-bearing mice submitted to chronic stress. J ApiProduct ApiMedical Sci. 2009;1(1):11–5.
61. Búfalo MC, Sforcin JM. The modulatory effects of caffeic acid on human monocytes and its involvement in propolis action. J Pharm Pharmacol [Internet]. 2015 May 1 [cited 2020 Jul 23];67(5):740–5. Available from: http://doi.wiley.com/10.1111/jphp.12364
62. Conti BJ, Búfalo MC, Golim MDA, Bankova V, Sforcin JM. Cinnamic acid is partially involved in propolis immunomodulatory action on human monocytes. Evidence-based Complement Altern Med. 2013;2013:1–8.
63. ORSI RO, FUNARI SRC, SOARES AMVC, CALVI SA, OLIVEIRA SL, SFORCIN JM, et al. Immunomodulatory action of propolis on macrophage activation. J Venom Anim Toxins [Internet]. 2000 [cited 2020 Jul 23];6(2):205–19. Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0104-79302000000200006&lng=en&nrm=iso&tlng=en
64. Syamsudin, Dewi RM. Immunomodulatory and In vivo Antiplasmodial Activities of Propolis Extracts Research and Development Center for Pharmacy and Biomedicine , Jakarta , Jl Percetakan Negara , Jakarta , Indonesia Department of Pathology , Faculty of Medicine , University of I. Am J Pharmacol Toxicol. 2009;4(3):75–9.
65. Girgin G, Baydar T, Ledochowski M, Schennach H, Bolukbasi DN, Sorkun K, et al. Immunomodulatory effects of Turkish propolis: Changes in neopterin release and tryptophan degradation. Immunobiology. 2009 Feb 1;214(2):129–34.
66. Ding S, Jiang H, Fang J. Regulation of Immune Function by Polyphenols. J Immunol Res [Internet]. 2018 [cited 2020 Jul 8];2018. Available from: /pmc/articles/PMC5925142/?report=abstract
67. del Cornò M, Scazzocchio B, Masella R, Gessani S. Regulation of Dendritic Cell Function by Dietary Polyphenols. Crit Rev Food Sci Nutr [Internet]. 2016 Apr 3 [cited 2020 Jul 8];56(5):737–47. Available from: https://pubmed.ncbi.nlm.nih.gov/24941314/
68. Propolis: Uses, Side Effects, Interactions, Dosage, and Warning [Internet]. [cited 2020 Jul 27]. Available from: https://www.webmd.com/vitamins/ai/ingredientmono-390/propolis
69. The Use of Brazilian Green Propolis Extract (EPP-AF) in Patients Affected by COVID-19. - Full Text View - ClinicalTrials.gov [Internet]. [cited 2020 Jul 27]. Available from: https://clinicaltrials.gov/ct2/show/study/NCT04480593#moreinfo
70. Pobiega K, Kraśniewska K, Gniewosz M. Application of propolis in antimicrobial and antioxidative protection of food quality – A review. Vol. 83, Trends in Food Science and Technology. Elsevier Ltd; 2019. p. 53–62.
71. Gao W, Wu J, Wei J, Pu L, Guo C, Yang J, et al. Brazilian green propolis improves immune function in aged mice. J Clin Biochem Nutr [Internet]. 2014 [cited 2020 Jul 14];55(1):7–10. Available from: http://jlc.jst.go.jp/DN/JST.JSTAGE/jcbn/13-70?lang=en&from=CrossRef&type=abstract