Targeting SIRT1 by Scopoletin to Inhibit XBB.1.5 COVID-19 Life
Cycle

Mohammadjavad      Sotoudeheian; Seyed-Mohamad-Sadegh      Mirahmadi; Mohammad      Pirhayati; Navid      Farahmandian; Reza      Azarbad; Hamidreza   Pazoki   Toroudi
Abstract

Natural products have historically driven pharmaceutical discovery, but their reliance has diminished with synthetic drugs. Approximately 35% of medicines originate from natural products. Scopoletin, a natural coumarin compound found in herbs, exhibits antioxidant, hepatoprotective, antiviral, and antimicrobial properties through diverse intracellular signaling mechanisms. Furthermore, it also enhances the activity of antioxidants. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes viral pneumonia through cytokine storms and systemic inflammation. Cellular autophagy pathways play a role in coronavirus replication and inflammation. The Silent Information Regulator 1 (SIRT1) pathway, linked to autophagy, protects cells via FOXO3, inhibits apoptosis, and modulates SIRT1 in type-II epithelial cells. SIRT1 activation by adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) enhances the autophagy cascade. This pathway holds therapeutic potential for alveolar and pulmonary diseases and is crucial in lung inflammation. Angiotensin-converting enzyme 2 (ACE-2) activation, inhibited by reduced expression, prevents COVID-19 virus entry into type-II epithelial cells. The coronavirus disease 2019 (COVID-19) virus binds ACE-2 to enter into the host cells, and XBB.1.5 COVID-19 displays high ACE-2-binding affinity. ACE-2 expression in pneumocytes is regulated by signal transducers and activators of transcription-3 (STAT3), which can increase COVID-19 virus replication. SIRT1 regulates STAT3, and the SIRT1/STAT3 pathway is involved in lung diseases. Therapeutic regulation of SIRT1 protects the lungs from inflammation caused by viral-mediated oxidative stress. Scopoletin, as a modulator of the SIRT1 cascade, can regulate autophagy and inhibit the entry and life cycle of XBB.1.5 COVID-19 in host cells.
Keywords: Gelseminic, coumarin, anti-inflammatory, antioxidant, autophagy, ACE2.
Graphical Abstract

[1]
Alhmoud E, Abdelsamad O, Soaly E, et al. Anticoagulation clinic drive-up service during COVID-19 pandemic in Qatar. J Thromb Thrombolysis  2021; 51: 297-300.
 [http://dx.doi.org/10.1007/s11239-020-02206-4]

[2]
Barnes GD, Burnett A, Allen A, et al. Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum. J Thromb Thrombolysis  2020; 50(1): 72-81.
 [http://dx.doi.org/10.1007/s11239-020-02138-z] [PMID:  32440883]

[3]
Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis  2020; 20(5): 533-4.
 [http://dx.doi.org/10.1016/S1473-3099(20)30120-1] [PMID:  32087114]

[4]
Aliabadi F, Ajami M, Pazoki-Toroudi H. Why does COVID‐19 pathology have several clinical forms? BioEssays  2020; 42(12): 2000198.
 [http://dx.doi.org/10.1002/bies.202000198] [PMID:  33174637]

[5]
Farasati Far B, Bokov D, Widjaja G, et al. Metronidazole, acyclovir and tetrahydrobiopterin may be promising to treat COVID-19 patients, through interaction with interleukin-12. J Biomol Struct Dyn  2023; 41(10): 4253-71.
 [http://dx.doi.org/10.1080/07391102.2022.2064917] [PMID:  35446232]

[6]
Ganesan A. The impact of natural products upon modern drug discovery. Curr Opin Chem Biol  2008; 12(3): 306-17.
 [http://dx.doi.org/10.1016/j.cbpa.2008.03.016] [PMID:  18423384]

[7]
Mishra BB, Tiwari VK. Natural products: An evolving role in future drug discovery. Eur J Med Chem  2011; 46(10): 4769-807.
 [http://dx.doi.org/10.1016/j.ejmech.2011.07.057] [PMID:  21889825]

[8]
Ren J, Yang L, Qiu S, Zhang AH, Wang XJ. Efficacy evaluation, active ingredients, and multitarget exploration of herbal medicine. Trends Endocrinol Metab  2023; 34(3): 146-57.
 [http://dx.doi.org/10.1016/j.tem.2023.01.005] [PMID:  36710216]

[9]
Calixto JB. The role of natural products in modern drug discovery. An Acad Bras Cienc  2019; 91 (Suppl. 3): e20190105.
 [http://dx.doi.org/10.1590/0001-3765201920190105] [PMID:  31166478]

[10]
Li Z, Kong D, Liu Y, Li M. Pharmacological perspectives and molecular mechanisms of coumarin derivatives against virus disease. Genes Dis  2022; 9(1): 80-94.
 [http://dx.doi.org/10.1016/j.gendis.2021.03.007] [PMID:  35005109]

[11]
Sotoudeheian M, Hoseini S, Mirahmadi SMS, Farahmandian N, Pazoki-Toroudi H. Oleuropein as a therapeutic agent for non-alcoholic fatty liver disease during hepatitis C. Rev Bras Farmacogn  2023; 33(4): 688-95.
 [http://dx.doi.org/10.1007/s43450-023-00396-5]

[12]
Zhu Y, Jiang Z, Liu L, et al. Scopoletin reactivates latent HIV-1 by inducing NF-κB expression without global T cell activation. Int J Mol Sci  2023; 24(16): 12649.
 [http://dx.doi.org/10.3390/ijms241612649] [PMID:  37628826]

[13]
Ajami M, Sotoudeheian M, Houshiar-Rad A, et al. Quercetin may reduce the risk of developing the symptoms of COVID-19. Avicenna J Phytomed 2023.
 [http://dx.doi.org/10.22038/AJP.2023.22920]

[14]
Abdelmohsen UR, Albohy A, Abdulrazik BS, et al. Natural coumarins as potential anti-SARS-CoV-2 agents supported by docking analysis. RSC Advances  2021; 11(28): 16970-9.
 [http://dx.doi.org/10.1039/D1RA01989A] [PMID:  35479715]

[15]
Mirzay-Razaz J, Hassanghomi M, Ajami M, Koochakpoor G, Hosseini-Esfahani F, Mirmiran P. Effective food hygiene principles and dietary intakes to reinforce the immune system for prevention of COVID-19: A systematic review. BMC Nutr  2022; 8(1): 53.
 [http://dx.doi.org/10.1186/s40795-022-00546-3] [PMID:  35655264]

[16]
Miller K, McGrath ME, Hu Z, et al. Coronavirus interactions with the cellular autophagy machinery. Autophagy  2020; 16(12): 2131-9.
 [http://dx.doi.org/10.1080/15548627.2020.1817280] [PMID:  32964796]

[17]
Diao F, Jiang C, Sun Y, et al. Porcine reproductive and respiratory syndrome virus infection triggers autophagy via ER stress-induced calcium signaling to facilitate virus replication. PLoS Pathog  2023; 19(3): e1011295.
 [http://dx.doi.org/10.1371/journal.ppat.1011295] [PMID:  36972295]

[18]
Jassey A, Jackson WT. Viruses and autophagy: Bend, but don’t break. Nat Rev Microbiol  2023; 1-13.
 [http://dx.doi.org/10.1038/s41579-023-00995-y] [PMID:  38102460]

[19]
Morris G, Athan E, Walder K, et al. Can endolysosomal deacidification and inhibition of autophagy prevent severe COVID-19? Life Sci  2020; 262: 118541.
 [http://dx.doi.org/10.1016/j.lfs.2020.118541] [PMID:  33035581]

[20]
Delorme-Axford E, Klionsky DJ. Highlights in the fight against COVID-19: Does autophagy play a role in SARS-CoV-2 infection?.  Taylor & Francis 2020; pp. 2123-7.
 [http://dx.doi.org/10.1080/15548627.2020.1844940]

[21]
Qu Y, Wang X, Zhu Y, et al. ORF3a-mediated incomplete autophagy facilitates severe acute respiratory syndrome coronavirus-2 replication. Front Cell Dev Biol  2021; 9: 716208.
 [http://dx.doi.org/10.3389/fcell.2021.716208] [PMID:  34386498]

[22]
Limanaqi F, Biagioni F, Gambardella S, Familiari P, Frati A, Fornai F. Promiscuous roles of autophagy and proteasome in neurodegenerative proteinopathies. Int J Mol Sci  2020; 21(8): 3028.
 [http://dx.doi.org/10.3390/ijms21083028] [PMID:  32344772]

[23]
Limanaqi F, Busceti CL, Biagioni F, et al. Cell clearing systems as targets of polyphenols in viral infections: Potential implications for COVID-19 pathogenesis. Antioxidants  2020; 9(11): 1105.
 [http://dx.doi.org/10.3390/antiox9111105] [PMID:  33182802]

[24]
Broussy S, Laaroussi H, Vidal M. Biochemical mechanism and biological effects of the inhibition of silent information regulator 1 (SIRT1) by EX-527 (SEN0014196 or selisistat). J Enzyme Inhib Med Chem  2020; 35(1): 1124-36.
 [http://dx.doi.org/10.1080/14756366.2020.1758691] [PMID:  32366137]

[25]
Yoo A, Narayan VP, Hong EY, Whang WK, Park T. Scopolin ameliorates high-fat diet induced hepatic steatosis in mice: potential involvement of SIRT1-mediated signaling cascades in the liver. Sci Rep  2017; 7(1): 2251.
 [http://dx.doi.org/10.1038/s41598-017-02416-6] [PMID:  28533555]

[26]
Alossaimi MA, Alzeer MA, Abdel Bar FM, ElNaggar MH. Pelargonium sidoides root extract: Simultaneous HPLC separation, determination, and validation of selected biomolecules and evaluation of SARS-CoV-2 inhibitory activity. Pharmaceuticals  2022; 15(10): 1184.
 [http://dx.doi.org/10.3390/ph15101184] [PMID:  36297296]

[27]
Sun W, Shahrajabian MH. Therapeutic potential of phenolic compounds in medicinal plants—natural health products for human health. Molecules  2023; 28(4): 1845.
 [http://dx.doi.org/10.3390/molecules28041845] [PMID:  36838831]

[28]
He BT, Liu ZH, Li BZ, Yuan YJ. Advances in biosynthesis of scopoletin. Microb Cell Fact  2022; 21(1): 152.
 [http://dx.doi.org/10.1186/s12934-022-01865-7] [PMID:  35918699]

[29]
Firmansyah A, Winingsih W, Manobi JDY. Review of scopoletin: Isolation, analysis process, and pharmacological activity. Biointerface Res Appl Chem  2020; 11(4): 12006-19.
 [http://dx.doi.org/10.33263/BRIAC114.1200612019]

[30]
Khan NMU, Hossain MS. Scopoletin and  Î2-sitosterol glucoside from roots of Ipomoea digitata. J Pharmacogn Phytochem  2015; 4: 5-7.

[31]
Gnonlonfin GJB, Sanni A, Brimer L. Review scopoletin–a coumarin phytoalexin with medicinal properties. Crit Rev Plant Sci  2012; 31(1): 47-56.
 [http://dx.doi.org/10.1080/07352689.2011.616039]

[32]
Tripathi N, Singh R, Lepcha STS, et al. Isolation of scopoletin via LC-MS in roots of Girardinia diversifolia. Mater Today Proc  2023; 80: 363-6.
 [http://dx.doi.org/10.1016/j.matpr.2023.02.372]

[33]
PubChem Information NCfB  PubChem Compound Summary for CID 5280460, Scopoletin PubChem  Available from: 
          https://pubchem.ncbi.nlm.nih.gov/compound/Scopoletin

[34]
Parama D, Girisa S, Khatoon E, et al. An overview of the pharmacological activities of scopoletin against different chronic diseases. Pharmacol Res  2022; 179: 106202.
 [http://dx.doi.org/10.1016/j.phrs.2022.106202] [PMID:  35378275]

[35]
Zeng Y, Li S, Wang X, Gong T, Sun X, Zhang Z. Validated LC-MS/MS method for the determination of scopoletin in rat plasma and its application to pharmacokinetic studies. Molecules  2015; 20(10): 18988-9001.
 [http://dx.doi.org/10.3390/molecules201018988] [PMID:  26492227]

[36]
Wang Y, Xing X, Cao Y, et al. Development and application of an UHPLC-MS/MS method for comparative pharmacokinetic study of eight major bioactive components from yin chen hao tang in normal and acute liver injured rats. Evid Based Complement Alternat Med  2018; 2018: 1-12.
 [http://dx.doi.org/10.1155/2018/3239785] [PMID:  30519262]

[37]
Tabana YM, Hassan LEA, Ahamed MBK, et al. Scopoletin, an active principle of tree tobacco (Nicotiana glauca) inhibits human tumor vascularization in xenograft models and modulates ERK1, VEGF-A, and FGF-2 in computer model. Microvasc Res  2016; 107: 17-33.
 [http://dx.doi.org/10.1016/j.mvr.2016.04.009] [PMID:  27133199]

[38]
Bhanuvalli RS, Lotha R, Sivasubramanian A. Phenyl propanoid rich extract of edible plant Halosarcia indica exert diuretic, analgesic, and anti-inflammatory activity on Wistar albino rats. Nat Prod Res  2020; 34(11): 1616-20.
 [http://dx.doi.org/10.1080/14786419.2018.1521404] [PMID:  30394103]

[39]
Agarwal P, Sharma B, Alok S. Screening of anti-inflammatory and anti analgesic activity of Convolvulus pluricaulis Choisy. Int J Pharm Sci Res  2014; 5(6): 2458.
 [http://dx.doi.org/10.13040/IJPSR.0975-8232.5(6).2458-63]

[40]
Cottam EM, Maier HJ, Manifava M, et al. Coronavirus nsp6 proteins generate autophagosomes from the endoplasmic reticulum via an omegasome intermediate. Autophagy  2011; 7(11): 1335-47.
 [http://dx.doi.org/10.4161/auto.7.11.16642] [PMID:  21799305]

[41]
Cottam EM, Whelband MC, Wileman T. Coronavirus NSP6 restricts autophagosome expansion. Autophagy  2014; 10(8): 1426-41.
 [http://dx.doi.org/10.4161/auto.29309] [PMID:  24991833]

[42]
Kindrachuk J, Ork B, Hart BJ, Mazur S. Antiviral potential of ERK/MAPK and PI3K/AKT/mTOR signaling modulation for Middle East respiratory syndrome coronavirus infection as identified by temporal kinome analysis. agents chemother  2015; 59: 1088-99.
 [http://dx.doi.org/10.1128/AAC.03659-14]

[43]
Gassen NC, Papies J, Bajaj T, et al. Analysis of SARS-CoV-2-controlled autophagy reveals spermidine, MK-2206, and niclosamide as putative antiviral therapeutics. BioRxiv  2020; 2020.04.
 [http://dx.doi.org/10.1101/2020.04.15.997254]

[44]
Carmona-Gutierrez D, Bauer MA, Zimmermann A, et al. Digesting the crisis: Autophagy and coronaviruses. Microb Cell  2020; 7(5): 119-28.
 [http://dx.doi.org/10.15698/mic2020.05.715] [PMID:  32391393]

[45]
Kudchodkar SB, Levine B. Viruses and autophagy. Rev Med Virol  2009; 19(6): 359-78.
 [http://dx.doi.org/10.1002/rmv.630] [PMID:  19750559]

[46]
Jackson WT. Viruses and the autophagy pathway. Virology  2015; 479-480: 450-6.
 [http://dx.doi.org/10.1016/j.virol.2015.03.042] [PMID:  25858140]

[47]
Chude C, Amaravadi R. Targeting autophagy in cancer: Update on clinical trials and novel inhibitors. Int J Mol Sci  2017; 18(6): 1279.
 [http://dx.doi.org/10.3390/ijms18061279] [PMID:  28621712]

[48]
Fitzwalter BE, Towers CG, Sullivan KD, et al. Autophagy inhibition mediates apoptosis sensitization in cancer therapy by relieving FOXO3a turnover. Dev Cell  2018; 44: 555-65.
 [http://dx.doi.org/10.1016/j.devcel.2018.02.014]

[49]
Tompkins KD, Thorburn A. Regulation of apoptosis by autophagy to enhance cancer therapy. Biol Med  2019; 92(4): 707-18.
 [PMID:  31866785]

[50]
Zeh HJ, Bahary N, Boone BA, et al. A randomized phase II preoperative study of autophagy inhibition with high-dose hydroxychloroquine and gemcitabine/nab-paclitaxel in pancreatic cancer patients. Clin Cancer Res  2020; 26(13): 3126-34.
 [http://dx.doi.org/10.1158/1078-0432.CCR-19-4042] [PMID:  32156749]

[51]
Klionsky DJ, Abdelmohsen K, Abe A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. In: Autophagy.  3rd edition. 2016; 12: pp. 1-222.
 [http://dx.doi.org/10.1080/15548627.2015.1100356]

[52]
Axe EL, Walker SA, Manifava M, et al. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol  2008; 182(4): 685-701.
 [http://dx.doi.org/10.1083/jcb.200803137] [PMID:  18725538]

[53]
Lamb CA, Yoshimori T, Tooze SA. The autophagosome: Origins unknown, biogenesis complex. Nat Rev Mol Cell Biol  2013; 14(12): 759-74.
 [http://dx.doi.org/10.1038/nrm3696] [PMID:  24201109]

[54]
Tooze SA. Current views on the source of the autophagosome membrane. Essays Biochem  2013; 55: 29-38.
 [http://dx.doi.org/10.1042/bse0550029] [PMID:  24070469]

[55]
Gosert R, Kanjanahaluethai A, Egger D, Bienz K, Baker SC. RNA replication of mouse hepatitis virus takes place at double-membrane vesicles. J Virol  2002; 76(8): 3697-708.
 [http://dx.doi.org/10.1128/JVI.76.8.3697-3708.2002] [PMID:  11907209]

[56]
Knoops K, Kikkert M, Worm SHE, et al. SARS-coronavirus replication is supported by a reticulovesicular network of modified endoplasmic reticulum. PLoS Biol  2008; 6(9): e226.
 [http://dx.doi.org/10.1371/journal.pbio.0060226] [PMID:  18798692]

[57]
Ulasli M, Verheije MH, de Haan CA, Reggiori F. Qualitative and quantitative ultrastructural analysis of the membrane rearrangements induced by coronavirus. Cel microbiol  2010; 12: 844-61.
 [http://dx.doi.org/10.1111/j.1462-5822.2010.01437.x]

[58]
van den Worm SHE, Knoops K, Zevenhoven-Dobbe JC, et al. Development and RNA-synthesizing activity of coronavirus replication structures in the absence of protein synthesis. J Virol  2011; 85(11): 5669-73.
 [http://dx.doi.org/10.1128/JVI.00403-11] [PMID:  21430047]

[59]
Maier H, Britton P. Involvement of autophagy in coronavirus replication. Viruses  2012; 4(12): 3440-51.
 [http://dx.doi.org/10.3390/v4123440] [PMID:  23202545]

[60]
Kabeya Y, Mizushima N, Ueno T, et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J  2000; 19(21): 5720-8.
 [http://dx.doi.org/10.1093/emboj/19.21.5720] [PMID:  11060023]

[61]
Prentice E, McAuliffe J, Lu X, Subbarao K, Denison MR. Identification and characterization of severe acute respiratory syndrome coronavirus replicase proteins. J Virol  2004; 78(18): 9977-86.
 [http://dx.doi.org/10.1128/JVI.78.18.9977-9986.2004] [PMID:  15331731]

[62]
Menon MB, Dhamija S. Beclin 1 phosphorylation – at the center of autophagy regulation. Front Cell Dev Biol  2018; 6: 137.
 [http://dx.doi.org/10.3389/fcell.2018.00137] [PMID:  30370269]

[63]
Limanaqi F, Biagioni F, Busceti CL, et al. Phytochemicals bridging autophagy induction and alpha-synuclein degradation in parkinsonism. Int J Mol Sci  2019; 20(13): 3274.
 [http://dx.doi.org/10.3390/ijms20133274] [PMID:  31277285]

[64]
Lystad AH, Carlsson SR, Simonsen A. Toward the function of mammalian ATG12–ATG5-ATG16L1 complex in autophagy and related processes. Autophagy  2019; 15(8): 1485-6.
 [http://dx.doi.org/10.1080/15548627.2019.1618100] [PMID:  31122169]

[65]
Sanchez-Wandelmer J, Reggiori F. Amphisomes: Out of the autophagosome shadow? EMBO J  2013; 32(24): 3116-8.
 [http://dx.doi.org/10.1038/emboj.2013.246] [PMID:  24219988]

[66]
Limanaqi F, Biagioni F, Gambardella S, Ryskalin L, Fornai F. Interdependency between autophagy and synaptic vesicle trafficking: Implications for dopamine release. Front Mol Neurosci  2018; 11: 299.
 [http://dx.doi.org/10.3389/fnmol.2018.00299] [PMID:  30186112]

[67]
Lin Y, Wu C, Wang X, et al. Glucosamine promotes hepatitis B virus replication through its dual effects in suppressing autophagic degradation and inhibiting MTORC1 signaling. Autophagy  2020; 16(3): 548-61.
 [http://dx.doi.org/10.1080/15548627.2019.1632104] [PMID:  31204557]

[68]
Gassen NC, Niemeyer D, Muth D, et al. SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection. Nat Commun  2019; 10(1): 5770.
 [http://dx.doi.org/10.1038/s41467-019-13659-4] [PMID:  31852899]

[69]
Ou X, Liu Y, Lei X, et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun  2020; 11(1): 1620.
 [http://dx.doi.org/10.1038/s41467-020-15562-9] [PMID:  32221306]

[70]
Chen X, Wang K, Xing Y, et al. Coronavirus membrane-associated papain-like proteases induce autophagy through interacting with Beclin1 to negatively regulate antiviral innate immunity. Protein Cell  2014; 5(12): 912-27.
 [http://dx.doi.org/10.1007/s13238-014-0104-6] [PMID:  25311841]

[71]
Chen M, Yi L, Jin X, et al. Resveratrol attenuates vascular endothelial inflammation by inducing autophagy through the cAMP signaling pathway. Autophagy  2013; 9(12): 2033-45.
 [http://dx.doi.org/10.4161/auto.26336] [PMID:  24145604]

[72]
Gurusamy N, Lekli I, Mukherjee S, et al. Cardioprotection by resveratrol: A novel mechanism via autophagy involving the mTORC2 pathway. Cardiovasc Res  2010; 86(1): 103-12.
 [http://dx.doi.org/10.1093/cvr/cvp384] [PMID:  19959541]

[73]
Wang B, Yang Q, Sun Y, et al. Resveratrol‐enhanced autophagic flux ameliorates myocardial oxidative stress injury in diabetic mice. J Cell Mol Med  2014; 18(8): 1599-611.
 [http://dx.doi.org/10.1111/jcmm.12312] [PMID:  24889822]

[74]
Kim YH, Bae JU, Kim IS, Chang CL, Oh SO, Kim CD. SIRT1 prevents pulmonary thrombus formation induced by arachidonic acid via downregulation of PAF receptor expression in platelets. Platelets  2016; 27(8): 735-42.
 [http://dx.doi.org/10.1080/09537104.2016.1190005] [PMID:  27275930]

[75]
Guixé-Muntet S, de Mesquita FC, Vila S, et al. Cross-talk between autophagy and KLF2 determines endothelial cell phenotype and microvascular function in acute liver injury. J Hepatol  2017; 66(1): 86-94.
 [http://dx.doi.org/10.1016/j.jhep.2016.07.051] [PMID:  27545498]

[76]
Lin YF, Lee YH, Hsu YH, et al. Resveratrol-loaded nanoparticles conjugated with kidney injury molecule-1 as a drug delivery system for potential use in chronic kidney disease. Nanomedicine  2017; 12(22): 2741-56.
 [http://dx.doi.org/10.2217/nnm-2017-0256] [PMID:  28884615]

[77]
Huang FC, Kuo HC, Huang YH, Yu HR, Li SC, Kuo HC. Anti-inflammatory effect of resveratrol in human coronary arterial endothelial cells via induction of autophagy: Implication for the treatment of Kawasaki disease. BMC Pharmacol Toxicol  2017; 18(1): 3.
 [http://dx.doi.org/10.1186/s40360-016-0109-2] [PMID:  28069066]

[78]
Guo D, Xie J, Zhao J, Huang T, Guo X, Song J. Resveratrol protects early brain injury after subarachnoid hemorrhage by activating autophagy and inhibiting apoptosis mediated by the Akt/mTOR pathway. Neuroreport  2018; 29(5): 368-79.
 [http://dx.doi.org/10.1097/WNR.0000000000000975] [PMID:  29360689]

[79]
Al Azzaz J, Rieu A, Aires V, et al. Resveratrol-induced xenophagy promotes intracellular bacteria clearance in intestinal epithelial cells and macrophages. Front immun  2019; 9: 3149.
 [http://dx.doi.org/10.3389/fimmu.2018.03149]

[80]
Yang QB, He YL, Zhong XW, Xie WG, Zhou JG. Resveratrol ameliorates gouty inflammation via upregulation of sirtuin 1 to promote autophagy in gout patients. Inflammopharmacology  2019; 27(1): 47-56.
 [http://dx.doi.org/10.1007/s10787-018-00555-4] [PMID:  30600470]

[81]
Le K, Chibaatar Daliv E, Wu S, et al. SIRT1-regulated HMGB1 release is partially involved in TLR4 signal transduction: A possible anti-neuroinflammatory mechanism of resveratrol in neonatal hypoxic-ischemic brain injury. Int Immunopharmacol  2019; 75: 105779.
 [http://dx.doi.org/10.1016/j.intimp.2019.105779] [PMID:  31362164]

[82]
Xing J, Liu H, Yang H, Chen R, Chen Y, Xu J. Upregulation of Unc-51-like kinase 1 by nitric oxide stabilizes SIRT1, independent of autophagy. PLoS One  2014; 9(12): e116165.
 [http://dx.doi.org/10.1371/journal.pone.0116165] [PMID:  25541949]

[83]
Rahman I, Kinnula VL, Gorbunova V, Yao H. SIRT1 as a therapeutic target in inflammaging of the pulmonary disease. Prev Med  2012; 54(Suppl)(Suppl): S20-8.
 [http://dx.doi.org/10.1016/j.ypmed.2011.11.014] [PMID:  22178470]

[84]
Arabian M, Aboutaleb N, Soleimani M, Mehrjerdi FZ, Ajami M, Pazoki-Toroudi H. Role of morphine preconditioning and nitric oxide following brain ischemia reperfusion injury in mice. Iran J Basic Med Sci  2015; 18(1): 14-21.
 [http://dx.doi.org/10.22038/ijbms.2015.3881] [PMID:  25810871]

[85]
Potente M, Dimmeler S. NO targets SIRT1: A novel signaling network in endothelial senescence. Am Heart Assoc  2008; 28: 1577-9.
 [http://dx.doi.org/10.1161/ATVBAHA.108.173682]

[86]
Liu X, Yang T, Sun T, Shao K. SIRT1-mediated regulation of oxidative stress induced by Pseudomonas aeruginosa lipopolysaccharides in human alveolar epithelial cells. Mol Med Rep  2017; 15(2): 813-8.
 [http://dx.doi.org/10.3892/mmr.2016.6045] [PMID:  28000862]

[87]
Azad MB, Chen Y, Gibson SB. Regulation of autophagy by reactive oxygen species (ROS): Implications for cancer progression and treatment. Antioxid Redox Signal  2009; 11(4): 777-90.
 [http://dx.doi.org/10.1089/ars.2008.2270] [PMID:  18828708]

[88]
Javedan G, Shidfar F, Davoodi SH, et al. Conjugated linoleic acid rat pretreatment reduces renal damage in ischemia/reperfusion injury: Unraveling antiapoptotic mechanisms and regulation of phosphorylated mammalian target of rapamycin. Mol Nutr Food Res  2016; 60(12): 2665-77.
 [http://dx.doi.org/10.1002/mnfr.201600112] [PMID:  27466783]

[89]
Sotoudeheian M, Soleimani M, Farahmandian N. Molecular pathways disturbances during COVID-19 lead to cardiomyocyte necroptosis. Preprints  2023; 4: 8-82.
 [http://dx.doi.org/10.20944/preprints202304.0882.v1]

[90]
Nam H, Kim MM. Scopoletin has a potential activity for anti-aging via autophagy in human lung fibroblasts. Phytomedicine  2015; 22(3): 362-8.
 [http://dx.doi.org/10.1016/j.phymed.2015.01.004] [PMID:  25837273]

[91]
Narasimhan KKS, Jayakumar D, Velusamy P, et al. Morinda citrifolia and its active principle scopoletin mitigate protein aggregation and neuronal apoptosis through augmenting the DJ-1/Nrf2/ARe signaling pathway. Oxid Med Cell Longev  2019; 2019: 1-13.
 [http://dx.doi.org/10.1155/2019/2761041] [PMID:  31191797]

[92]
Zhao P, Dou Y, Chen L, et al. SC-III3, a novel scopoletin derivative, induces autophagy of human hepatoma HepG2 cells through AMPK/mTOR signaling pathway by acting on mitochondria. Fitoterapia  2015; 104: 31-40.
 [http://dx.doi.org/10.1016/j.fitote.2015.05.002] [PMID:  25964188]

[93]
Sotoudeheian M, Hoseini S. Therapeutic properties of polyphenols affect AMPK molecular pathway in hyperlipidemia. Preprints 2023.
 [http://dx.doi.org/10.20944/preprints202301.0528.v1]

[94]
Chattree V, Singh K, Singh K, Goel A, Maity A, Lone A. A comprehensive review on modulation of SIRT1 signaling pathways in the immune system of COVID ‐19 patients by phytotherapeutic melatonin and epigallocatechin‐3‐gallate. J Food Biochem  2022; 46(12): e14259.
 [http://dx.doi.org/10.1111/jfbc.14259] [PMID:  35662052]

[95]
Khan H, Patel S, Majumdar A. Role of NRF2 and Sirtuin activators in COVID-19. Clin Immunol  2021; 233: 108879.
 [http://dx.doi.org/10.1016/j.clim.2021.108879] [PMID:  34798239]

[96]
Clarke NE, Belyaev ND, Lambert DW, Turner AJ. Epigenetic regulation of angiotensin-converting enzyme 2 (ACE2) by SIRT1 under conditions of cell energy stress. Clin Sci  2014; 126(7): 507-16.
 [http://dx.doi.org/10.1042/CS20130291] [PMID:  24147777]

[97]
Pinto BGG, Oliveira AER, Singh Y, et al. ACE2 expression is increased in the lungs of patients with comorbidities associated with severe COVID-19. J Infect Dis  2020; 222(4): 556-63.
 [http://dx.doi.org/10.1093/infdis/jiaa332] [PMID:  32526012]

[98]
Sahu S, Patil CR, Kumar S, Apparsundaram S, Goyal RK. Role of ACE2-Ang (1–7)-Mas axis in post-COVID-19 complications and its dietary modulation. Mol Cell Biochem  2022; 477(1): 225-40.
 [http://dx.doi.org/10.1007/s11010-021-04275-2] [PMID:  34655418]

[99]
Shamir I, Abutbul-Amitai M, Abbas-Egbariya H, Pasmanik-Chor M, Paret G, Nevo-Caspi Y. STAT3 isoforms differentially affect ACE2 expression: A potential target for COVID‐19 therapy. J Cell Mol Med  2020; 24(21): 12864-8.
 [http://dx.doi.org/10.1111/jcmm.15838] [PMID:  32949179]

[100]
Liang L, Wang D, Yu H, et al. Transcriptional regulation and small compound targeting of ACE2 in lung epithelial cells. Acta Pharmacol Sin  2022; 43(11): 2895-904.
 [http://dx.doi.org/10.1038/s41401-022-00906-6] [PMID:  35468992]

[101]
Karbasforooshan H, Roohbakhsh A, Karimi G. SIRT1 and microRNAs: The role in breast, lung and prostate cancers. Exp Cell Res  2018; 367(1): 1-6.
 [http://dx.doi.org/10.1016/j.yexcr.2018.03.023] [PMID:  29574020]

[102]
Xu G, Cai J, Wang L, et al. MicroRNA-30e-5p suppresses non-small cell lung cancer tumorigenesis by regulating USP22-mediated Sirt1/JAK/STAT3 signaling. Exp Cell Res  2018; 362(2): 268-78.
 [http://dx.doi.org/10.1016/j.yexcr.2017.11.027] [PMID:  29174979]

[103]
Zhuo Y, Zhang S, Li C, Yang L, Gao H, Wang X. Resolvin D1 promotes SIRT1 expression to counteract the activation of STAT3 and NF-κB in mice with septic-associated lung injury. Inflammation  2018; 41(5): 1762-71.
 [http://dx.doi.org/10.1007/s10753-018-0819-2] [PMID:  30014231]

[104]
Zhou Y, Zhang F, Ding J. As a modulator, multitasking roles of SIRT1 in respiratory diseases. Immune Netw  2022; 22(3): e21.
 [http://dx.doi.org/10.4110/in.2022.22.e21] [PMID:  35799705]

[105]
Jafarzadeh A, Nemati M, Jafarzadeh S. Contribution of STAT3 to the pathogenesis of COVID-19. Microb Pathog  2021; 154: 104836.
 [http://dx.doi.org/10.1016/j.micpath.2021.104836] [PMID:  33691172]

[106]
Hennighausen L, Lee HK. Activation of the SARS-CoV-2 receptor Ace2 by cytokines through pan JAK-STAT enhancers. BioRxiv 2020.

[107]
Gottschalk G, Knox K, Roy A. ACE2: At the crossroad of COVID-19 and lung cancer. Gene Rep  2021; 23: 101077.
 [http://dx.doi.org/10.1016/j.genrep.2021.101077] [PMID:  33723522]

[108]
Yue C, Song W, Wang L, et al. ACE2 binding and antibody evasion in enhanced transmissibility of XBB.1.5. Lancet Infect Dis  2023; 23(3): 278-80.
 [http://dx.doi.org/10.1016/S1473-3099(23)00010-5] [PMID:  36746173]

[109]
Callaway E. Is coronavirus variant XBB. 1.5 a global threat. Nature  2023; 613: 222-3.
 [http://dx.doi.org/10.1038/d41586-023-00014-3] [PMID:  36624320]

[110]
Atanasoff KE, Brambilla L, Adelsberg DC, et al. An in vitro experimental pipeline to characterize the epitope of a SARS-CoV-2 neutralizing antibody. MBio  2023; e02477-23.
 [http://dx.doi.org/10.1128/mbio.02477-23] [PMID:  38054729]

[111]
Eurosurveillance editorial team. Using the rear-view mirror to look forward. Euro Surveill  2023; 28(2): 220112e.
 [http://dx.doi.org/10.2807/1560-7917.ES.2023.28.2.220112e]

[112]
Graham F. Daily briefing: Is subvariant XBB. 1.5 a global threat? Nature  2023.  Available from: 
          https://www.nature.com/articles/d41586-023-00052-x
     Accessed 20 January 2023.

[113]
Shi Z, Li N, Chen C, et al. Novel NO-releasing scopoletin derivatives induce cell death via mitochondrial apoptosis pathway and cell cycle arrest. Eur J Med Chem  2020; 200: 112386.
 [http://dx.doi.org/10.1016/j.ejmech.2020.112386] [PMID:  32438251]

[114]
Modanwal S, Mishra N. Rejuvenation of traditional medicine in the twenty-first century against SARS-CoV-2. Nat Singap  2023; 115-36.
 [http://dx.doi.org/10.1007/978-981-99-3664-9_5]

[115]
Ikanovic T, Sehercehajic E, Saric B, et al. In silico analysis of scopoletin interaction with potential SARS-CoV-2 target. International Conference “New Technologies, Development and Applications”: NT.  897-903.
 [http://dx.doi.org/10.1007/978-3-030-75275-0_99]

[116]
Gay NH, Suwanjang W, Ruankham W, et al. Butein, isoliquiritigenin, and scopoletin attenuate neurodegeneration via antioxidant enzymes and SIRT1/ADAM10 signaling pathway. RSC Advances  2020; 10(28): 16593-606.
 [http://dx.doi.org/10.1039/C9RA06056A] [PMID:  35498835]

[117]
Zhang T, Xu L, Guo X, et al. The potential of herbal drugs to treat heart failure: The roles of Sirt1/AMPK. J Pharm Anal 2023.
 [http://dx.doi.org/10.1016/j.jpha.2023.09.001]

[118]
Yan T, Zheng R, Li Y, et al. Epidemiological insights into the omicron outbreak via meltarray-assisted real-time tracking of SARS-CoV-2 variants. Viruses  2023; 15(12): 2397.
 [http://dx.doi.org/10.3390/v15122397] [PMID:  38140638]

[119]
Parums DV. Editorial: The XBB.1.5 (‘Kraken’) subvariant of omicron SARS-CoV-2 and its rapid global spread. Med Sci Monit  2023; 29: e939580.
 [http://dx.doi.org/10.12659/MSM.939580] [PMID:  36722047]

[120]
Devasundaram S, Terpos E, Rosati M, et al. XBB. 1.5 neutralizing antibodies upon bivalent COVID ‐19 vaccination are similar to XBB but lower than BQ. 1.1. Am J Hematol  2023; 98(5): E123-6.
 [http://dx.doi.org/10.1002/ajh.26887] [PMID:  36810791]

[121]
van Werkhoven H, Valk A-W, Smagge B, et al. Early COVID-19 vaccine effectiveness of XBB. 1.5 vaccine against hospitalization and ICU admission, the Netherlands. medRxiv  12.
 [http://dx.doi.org/10.1101/2023.12.12.23299855]

[122]
Uraki R, Ito M, Kiso M, et al. Antiviral and bivalent vaccine efficacy against an omicron XBB.1.5 isolate. Lancet Infect Dis  2023; 23(4): 402-3.
 [http://dx.doi.org/10.1016/S1473-3099(23)00070-1] [PMID:  36773622]

[123]
Baggieri M, Gioacchini S, Borgonovo G, et al. Antiviral, virucidal and antioxidant properties of Artemisia annua against SARS-CoV-2. Biomed Pharmacother  2023; 168: 115682.
 [http://dx.doi.org/10.1016/j.biopha.2023.115682] [PMID:  37832410]
Cite As
Current Reviews in Clinical and Experimental Pharmacology

Targeting SIRT1 by Scopoletin to Inhibit XBB.1.5 COVID-19 Life Cycle

Abstract

Graphical Abstract
