|
|
|
Citrus fruits are rich in flavonoids for immunoregulation and potential targeting ACE2 |
| Wenting Liu1, Weikang Zheng1, Liping Cheng1, Ming Li1, Jie Huang2, Shuzheng Bao3, Qiang Xu1, Zhaocheng Ma1 |
1 College of Horticulture and Forestry Sciences, Key Laboratory of Horticultural Plant Biology, Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China;
2 Network of Aquaculture Centres in Asia-Pacific, Bangkok 10903, Thailand;
3 China Association of Agricultural Science Societies, Beijing 100125, China |
|
|
|
|
Abstract The most recent outbreak of 2019 novel coronavirus, named as COVID-19, caused pneumonia epidemic in Wuhan with 2121 deaths cases as of February 20th 2020. Identification of effective antiviral agents to combat the novel coronavirus is urgently needed. Citrus fruit peel or wild citrus are rich in flavonoids, and clinically documented for roles in relief of cough and promotion of digestive health. Therefore, citrus fruits are assumed to possess antivirus activities or enhance the host immunity. A previous study found that hesperetin could act as a high potent inhibitor of SARS-CoV 3CLpro. We determined six flavonoid compounds' content in three citrus species by using LC-MS technique. The content of naringin and naringenin was at higher levels in pummelo. Hesperetin and hesperidin were highly accumulated in mandarin and sweet orange. The subsequent in vitro and in vivo experiments indicated that naringin could inhibit the expression of the proinflammatory cytokines (COX-2, iNOS, IL-1β and IL-6) induced by LPS in Raw macrophage cell line, and may restrain cytokine through inhibiting HMGB1 expression in a mouse model. The results revealed that naringin may have a potential application for preventing cytokine storm. We simulated molecular docking to predict the binding affinity of those flavonoids to bind Angiotensin-converting enzyme 2 (ACE 2), which is a receptor of the coronavirus. Consideration of the potential anti-coronavirus and anti-inflammatory activity of flavonoids, the citrus fruit or its derived phytochemicals are promising in the use of prevention and treatment of SARS-CoV-2 infection.
|
| Keywords
Citrus flavonoids
Naringin
Immunoregulation
ACE2
SARS-CoV-2
|
| Fund:The study was supported by the National Key Research and Development Program (2018YFD1000200), Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-D-202005), the Ability Establishment of Sustainable Use for Valuable Chinese Medicine Resources (2060302). |
|
Corresponding Authors:
Zhaocheng Ma
E-mail: mzhaocheng@mail.hzau.edu.cn
|
|
Issue Date: 12 March 2022
|
|
|
1. Huang W, Tang Y, Li L. HMGB1, a potent proinflammatory cytokine in sepsis. Cytokine. 2010;51:119-26. https://doi.org/10.1016/j.cyto.2010.02.021.
2. Liu X, Wang XJ. Potential inhibitors for 2019-nCoV coronavirus M protease from clinically approved medicines. J Genet Genomics. 2020;47:119-21. https://doi.org/10.1101/2020.01.29.924100.
3. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30:269-72. https://doi.org/10.1038/s41422-020-0282-0.
4. Chen H, Du Q. Potential natural compounds for preventing 2019-nCoV infection. Preprints. 2020, 2020010358. https://www.preprints.org/manuscript/202001.0358/v1.
5. Zumla A, Hui DS, Azhar EI, Memish ZA, Maeurer M. Reducing mortality from 2019-nCoV:host-directed therapies should be an option. Lancet. 2020;395:e35-6. https://doi.org/10.1016/S0140-6736(20)30305-6.
6. Yao K, Liu M, Li X, Huang J, Cai H. Retrospective clinical analysis on treatment of novel coronavirus-infected pneumonia with traditional. Chinese Medicine Lianhua Qingwen. Chin J Exp Trad Med Formulae. 2020. https://doi.org/10.13422/j.cnki.syfjx.20201099.
7. Lin CW, Tsai FJ, Tsai CH, Lai CC, Wan L, Ho TY, Hsieh CC, Chao PDL. Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds. AntiviralRes. 2005;68:36-42. https://doi.org/10.1016/j.antiviral.2005.07.002.
8. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020. https://doi.org/10.1016/S0140-6736(20)30183-5.
9. Dall'Asta M, Derlindati E, Curella V, Mena P, Calani L, Ray S, Zavaroni I, Brighenti F, Del RD. Effects of naringenin and its phase II metabolites on in vitro human macrophage gene expression. Int J Food Sci Nutr. 2013;64:843-9. https://doi.org/10.3109/09637486.2013.804039.
10. Feng S, Wang Y. Citrus phytochemicals and their potential effects on the prevention and treatment of obesity:review and progress of the past 10 years. J Food Bioact. 2018;4:99-106. https://doi.org/10.31665/JFB.2018.4165.
11. Yan X, Li H, Liu J, Jiang Y, Zhang H. Effects of dexamethasone on inflammatory reaction and glucocorticoid receptors level in ALI rats induced by different factors. Int J Respir. 2006;10:724-7.
12. Ramos-Benitez MJ, Ruiz-Jimenez C, Rosado-Franco JJ, Ramos-Pérez WD, Mendez LB, Osuna A, Espino AM. Fh15 Blocks the lipopolysaccharideinduced cytokine storm while modulating peritoneal macrophage migration and CD38 expression within spleen macrophages in a mouse model of septic shock. mSphere. 2018;3:e00548-e1518. https://doi.org/10.1128/mSphere.00548-18.
13. Chtourou Y, Aouey B, Aroui S, Kebieche M, Fetoui H. Anti-apoptotic and anti-inflammatory effects of naringin on cisplatin-induced renal injury in the rat. Chem Biol Interact. 2016;243:1-9. https://doi.org/10.1016/j.cbi.2015.11.019.
14. Ulloa L, Messmer D. High-mobility group box 1 (HMGB1) protein:friend and foe. Cytokine Growth Factor Rev. 2006;17:189-201. https://doi.org/10.1016/j.cytogfr. 2006.01.003.
15. Wang H, Yang H, Tracey KJ. Extracellular role of HMGB1 in inflammation and sepsis. J Intern Med. 2004;255:320-31. https://doi.org/10.1111/j.1365-2796.2003.01302.x.
16. Park JS, Arcaroli J, Yum HK, Yang H, Wang H, Yang KY, Choe KH, Strassheim D, Pitts TM, Tracey KJ, Abraham E. Activation of gene expression in human neutrophils by high mobility group box 1 protein. Am J Physiol Cell Physiol. 2003;284:C870-9. https://doi.org/10.1152/ajpcell.00322.2002.
17. Kim VY, Batty A, Li J, Kirk SG, Jin SA, Tang Y, Zhang J, Rogers J, Deng LK, Nelin HX, Liu LDY. Glutathione reductase promotes fungal clearance and suppresses inflammation during systemic Candida albicans infection in mice. J Immunol. 2019;203:2239-51. https://doi.org/10.4049/jimmunol.1701686.
18. Wu J, Han Y, Zou X, Zhu K, Wang Z, Ye X, Liu Y, Dong S, Chen X, Liu D, Wen Z, Wang Y, Huang S, Zhou Z, Zeng C, Huang C, Zheng S, Du X, Huang X, Zhang B, Jing C, Yang G. Silica nanoparticles as an enhancer in the IL-1β-induced inflammation cycle of A549 cells. Immunopharmacol Immunotoxicol. 2019;41:199-206. https://doi.org/10.1080/08923973.2019.1569046.
19. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, Wang W, Song H, Huang B, Zhu N. Genomic characterisation and epidemiology of 2019 novel coronavirus:implications for virus origins and receptor binding. Lancet. 2020;395:565-74. https://doi.org/10.1016/S0140-6736(20)30251-8.
20. Xu X, Chen P, Wang J, Feng J, Zhou H, Li X, Zhong W, Hao P. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Sci China Life Sci. 2020;63:457-60. https://doi.org/10.1007/s11427-020-1637-5.
21. Kuhn JH, Radoshitzky SR, Li W, Wong SK, Choe H, Farzan M. The SARS Coronavirus receptor ACE 2 A potential target for antiviral therapy. New Concepts Antiviral Therapy. 2006. https://doi.org/10.1007/978-0-387-31047-3_15.
22. Letko MC, Munster V. Functional assessment of cell entry and receptor usage for lineage B β-coronaviruses, including 2019-nCoV. bioRxiv. 2020. https://doi.org/10.1101/2020.01.22.915660.
23. Chen F, Chan K, Jiang Y, Kao R, Lu H, Fan K, Cheng V, Tsui W, Hung I, Lee T. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J Clin Virol. 2004;31:69-75. https://doi.org/10.1016/j.jcv.2004.03.003.
24. Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005;2:69. https://doi.org/10.1186/1743-422X-2-69.
25. Cheng L, Zheng W, Li M, Huang J, Bao S, Xu Q, Ma Z. Citrus fruits are rich in flavonoids for immunoregulation and potential targeting ACE2. Preprints (2020) https://www.preprints.org/manuscript/202002.0313/v1. |
|
Viewed |
|
|
|
Full text
|
|
|
|
|
Abstract
|
|
|
|
|
Cited |
|
|
|
|
| |
Shared |
|
|
|
|
| |
Discussed |
|
|
|
|
