Zhou Y, Wang F, Tang J, Nussinov R and Cheng F: Artificial intelligence in COVID-19 drug repurposing. Lancet Digit Heal. 2:e667–e676. 2020. View Article : Google Scholar

Konstantinidou S and Papanastasiou I: Repurposing current therapeutic regimens against SARS-CoV-2 (Review). Exp Ther Med. 2:1845–1855. 2020.

Sidiropoulou P, Docea AO, Nikolaou V, Katsarou MS, Spandidos DA, Tsatsakis A, Calina D and Drakoulis N: Unraveling the roles of vitamin D status and melanin during COVID-19 (Review). Int J Mol Med. 47:92–100. 2020. View Article : Google Scholar :

Zhang R, Wang X, Ni L, Di X, Ma B, Niu S, Liu C and Reiter RJ: COVID-19: Melatonin as a potential adjuvant treatment. Life Sci. 250:1175832020. View Article : Google Scholar : PubMed/NCBI

Turek FW and Gillette MU: Melatonin, sleep, and circadian rhythms: Rationale for development of specific melatonin agonists. Sleep Med. 5:523–532. 2004. View Article : Google Scholar : PubMed/NCBI

Zlotos DP: Recent advances in melatonin receptor ligands. Arch Pharm (Weinheim). 338:229–247. 2005. View Article : Google Scholar

Jahanban-Esfahlan R, Mehrzadi S, Reiter RJ, Seidi K, Majidinia M, Baghi HB, Khatami N, Yousefi B and Sadeghpour A: Melatonin in regulation of inflammatory pathways in rheumatoid arthritis and osteoarthritis: Involvement of circadian clock genes. Br J Pharmacol. 175:3230–3238. 2018. View Article : Google Scholar :

Kratz EM and Piwowar A: Melatonin, advanced oxidation protein products and total antioxidant capacity as seminal parameters of prooxidant-antioxidant balance and their connection with expression of metalloproteinases in context of male fertility. J Physiol Pharmacol. 68:659–668. 2017.

Olcese JM: Melatonin and female reproduction: An expanding universe. Front Endocrinol (Lausanne). 11:852020. View Article : Google Scholar

Hosseinzadeh A, Javad-Moosavi SA, Reiter RJ, Yarahmadi R, Ghaznavi H and Mehrzadi S: Oxidative/nitrosative stress, autophagy and apoptosis as therapeutic targets of melatonin in idiopathic pulmonary fibrosis. Expert Opin Ther Targets. 22:1049–1061. 2018. View Article : Google Scholar : PubMed/NCBI

Hosseinzadeh A, Javad-Moosavi SA, Reiter RJ, Hemati K, Ghaznavi H and Mehrzadi S: Idiopathic pulmonary fibrosis (IPF) signaling pathways and protective roles of melatonin. Life Sci. 201:17–29. 2018. View Article : Google Scholar : PubMed/NCBI

Luchetti F, Canonico B, Betti M, Arcangeletti M, Pilolli F, Piroddi M, Canesi L, Papa S and Galli F: Melatonin signaling and cell protection function. FASEB J. 24:3603–3624. 2010. View Article : Google Scholar : PubMed/NCBI

Hill SM, Belancio VP, Dauchy RT, Xiang S, Brimer S, Mao L, Hauch A, Lundberg PW, Summers W, Yuan L, et al: Melatonin: An inhibitor of breast cancer. Endocr Relat Cancer. 22:R183–R204. 2015. View Article : Google Scholar : PubMed/NCBI

Carlberg C: Gene regulation by melatonin. Ann N Y Acad Sci. 917:387–396. 2000. View Article : Google Scholar

Bahrampour Juybari K, Pourhanifeh MH, Hosseinzadeh A, Hemati K and Mehrzadi S: Melatonin potentials against viral infections including COVID-19: Current evidence and new findings. Virus Res. 287:1981082020. View Article : Google Scholar : PubMed/NCBI

Weaver SC, Ferro C, Barrera R, Boshell J and Navarro JC: Venezuelan equine encephalitis. Annu Rev Entomol. 49:141–174. 2004. View Article : Google Scholar

Schoneboom BA, Lee JS and Grieder FB: Early expression of IFN-alpha/beta and iNOS in the brains of Venezuelan equine encephalitis virus-infected mice. J Interferon Cytokine Res. 20:205–215. 2000. View Article : Google Scholar : PubMed/NCBI

Schoneboom BA, Fultz MJ, Miller TH, McKinney LC and Glieder FB: Astrocytes as targets for Venezuelan equine encephalitis virus infection. J Neurovirol. 5:342–354. 1999. View Article : Google Scholar : PubMed/NCBI

Schoneboom BA, Catlin KMK, Marty AM and Grieder FB: Inflammation is a component of neurodegeneration in response to Venezuelan equine encephalitis virus infection in mice. J Neuroimmunol. 109:132–146. 2000. View Article : Google Scholar : PubMed/NCBI

Cain MD, Salimi H, Gong Y, Yang L, Hamilton SL, Heffernan JR, Hou J, Miller MJ and Klein RS: Virus entry and replication in the brain precedes blood-brain barrier disruption during intranasal alphavirus infection. J Neuroimmunol. 308:118–130. 2017. View Article : Google Scholar : PubMed/NCBI

Keck F, Kortchak S, Bakovic A, Roberts B, Agrawal N and Narayanan A: Direct and indirect pro-inflammatory cytokine response resulting from TC-83 infection of glial cells. Virulence. 9:1403–1421. 2018. View Article : Google Scholar : PubMed/NCBI

Valero N, Mosquera J, Alcocer S, Bonilla E, Salazar J and Álvarez-Mon M: Melatonin, minocycline and ascorbic acid reduce oxidative stress and viral titers and increase survival rate in experimental Venezuelan equine encephalitis. Brain Res. 1622:368–376. 2015. View Article : Google Scholar : PubMed/NCBI

Montiel M, Bonilla E, Valero N, Mosquera J, Espina LM, Quiroz Y and Álvarez-Mon M: Melatonin decreases brain apoptosis, oxidative stress, and CD200 expression and increased survival rate in mice infected by Venezuelan equine encephalitis virus. Antivir Chem Chemother. 24:99–108. 2015. View Article : Google Scholar

Valero N, MarinaEspina L, Bonilla E and Mosquera J: Melatonin decreases nitric oxide production and lipid peroxidation and increases interleukin-1 beta in the brain of mice infected by the Venezuelan equine encephalomyelitis virus. J Pineal Res. 42:107–112. 2007. View Article : Google Scholar : PubMed/NCBI

Valero N, Meleán E, Bonilla E, Arias J, Espina LM, Chacin-Bonilla L, Larreal Y, Maldonado M and Añez F: In vitro, melatonin treatment decreases nitric oxide levels in murine splenocytes cultured with the venezuelan equine encephalomyelitis virus. Neurochem Res. 30:1439–1442. 2005. View Article : Google Scholar : PubMed/NCBI

Tuñõn MJ, San-Miguel B, Crespo I, Laliena A, Vallejo D, Álvarez M, Prieto J and González-Gallego J: Melatonin treatment reduces endoplasmic reticulum stress and modulates the unfolded protein response in rabbits with lethal fulminant hepatitis of viral origin. J Pineal Res. 55:221–228. 2013. View Article : Google Scholar : PubMed/NCBI

Crespo I, Miguel BS, Laliena A, Álvarez M, Culebras JM, González-Gallego J and Tuñón MJ: Melatonin prevents the decreased activity of antioxidant enzymes and activates nuclear erythroid 2-related factor 2 signaling in an animal model of fulminant hepatic failure of viral origin. J Pineal Res. 49:193–200. 2010.PubMed/NCBI

Verdonschot J, Hazebroek M, Merken J, Debing Y, Dennert R, Brunner-La Rocca HP and Heymans S: Relevance of cardiac parvovirus B19 in myocarditis and dilated cardiomyopathy: Review of the literature. Eur J Heart Fail. 18:1430–1441. 2016. View Article : Google Scholar : PubMed/NCBI

Kühl U, Pauschinger M, Seeberg B, Lassner D, Noutsias M, Poller W and Schultheiss HP: Viral persistence in the myocardium is associated with progressive cardiac dysfunction. Circulation. 112:1965–1970. 2005. View Article : Google Scholar : PubMed/NCBI

Ouyang H, Zhong J, Lu J, Zhong Y, Hu Y and Tan Y: Inhibitory effect of melatonin on Mst1 ameliorates myocarditis through attenuating ER stress and mitochondrial dysfunction. J Mol Histol. 50:405–415. 2019. View Article : Google Scholar : PubMed/NCBI

Sang Y, Gu X, Pan L, Zhang C, Rong X, Wu T, Xia T, Li Y, Ge L, Zhang Y and Chu M: Melatonin ameliorates coxsackievirus B3-induced myocarditis by regulating apoptosis and autophagy. Front Pharmacol. 9:13842018. View Article : Google Scholar : PubMed/NCBI

Simko F, Hrenak J, Dominguez-Rodriguez A and Reiter RJ: Melatonin as a putative protection against myocardial injury in COVID-19 infection. Expert Rev Clin Pharmacol. 13:921–924. 2020. View Article : Google Scholar : PubMed/NCBI

Junaid A, Tang H, van Reeuwijk A, Abouleila Y, Wuelfroth P, van Duinen V, Stam W, van Zonneveld AJ, Hankemeier T and Mashaghi A: Ebola hemorrhagic shock Syndrome-on-a-Chip. iScience. 23:1007652020. View Article : Google Scholar :

Martín Giménez VM, Inserra F, Tajer CD, Mariani J, Ferder L, Reiter RJ and Manucha W: Lungs as target of COVID-19 infection: Protective common molecular mechanisms of vitamin D and melatonin as a new potential synergistic treatment. Life Sci. 254:1178082020. View Article : Google Scholar : PubMed/NCBI

Hill-Batorski L, Halfmann P, Neumann G and Kawaoka Y: The cytoprotective enzyme heme Oxygenase-1 suppresses ebola virus replication. J Virol. 87:13795–13802. 2013. View Article : Google Scholar : PubMed/NCBI

Hazra S, Chaudhuri AG, Tiwary BK and Chakrabarti N: Matrix metallopeptidase 9 as a host protein target of chloroquine and melatonin for immunoregulation in COVID-19: A network-based meta-analysis. Life Sci. 257:1180962020. View Article : Google Scholar : PubMed/NCBI

Habtemariam S, Daglia M, Sureda A, Selamoglu Z, Fuat Gulhan M and Mohammad Nabavi S: Melatonin and respiratory diseases: A review. Curr Top Med Chem. 17:467–488. 2016. View Article : Google Scholar : PubMed/NCBI

Shim DW, Shin HJ, Han JW, Ji YE, Jang CH, Koppula S, Kang TB and Lee KH: A novel synthetic derivative of melatonin, 5-hydroxy-2'-isobutyl-streptochlorin (HIS), inhibits inflammatory responses via regulation of TRIF-dependent signaling and inflammasome activation. Toxicol Appl Pharmacol. 284:227–235. 2015. View Article : Google Scholar : PubMed/NCBI

Reiter RJ, Sharma R, Ma Q, Dominquez-Rodriguez A, Marik PE and Abreu-Gonzalez P: Melatonin inhibits COVID-19-induced cytokine storm by reversing aerobic glycolysis in immune cells: A mechanistic analysis. Med Drug Discov. 6:1000442020. View Article : Google Scholar : PubMed/NCBI

Bouhafs RKL and Jarstrand C: Effects of antioxidants on surfactant peroxidation by stimulated human polymorphonuclear leukocytes. Free Radic Res. 36:727–734. 2002. View Article : Google Scholar : PubMed/NCBI

Zhang Y and Li X, Grailer JJ, Wang N, Wang M, Yao J, Zhong R, Gao GF, Ward PA, Tan DX and Li X: Melatonin alleviates acute lung injury through inhibiting the NLRP3 inflammasome. J Pineal Res. 60:405–414. 2016. View Article : Google Scholar : PubMed/NCBI

Soussia I Ben, Mies F, Naeije R and Shlyonsky V: Melatonin down-regulates volume-sensitive chloride channels in fibroblasts. Pflugers Arch. 464:273–285. 2012. View Article : Google Scholar : PubMed/NCBI

Farhood B, Aliasgharzadeh A, Amini P, Rezaeyan A, Tavassoli A, Motevaseli E, Shabeeb D, Musa AE and Najafi M: Mitigation of radiation-induced lung pneumonitis and fibrosis using metformin and melatonin: A histopathological study. Medicina (Kaunas). 55:4172019. View Article : Google Scholar

Hong S, Kim CY, Lee JE and Seong GJ: Agmatine protects cultured retinal ganglion cells from tumor necrosis factor-alpha-induced apoptosis. Life Sci. 84:28–32. 2009. View Article : Google Scholar

Bosco AD, Schedler FB, Colares JR, Schemitt EG, Hartmann RM, Forgiarini Junior LA, Dias AS and Marroni NP: Melatonin effects on pulmonary tissue in the experimental model of hepatopulmonary syndrome. J Bras Pneumol. 45:e201701642019.In English, Portuguese. View Article : Google Scholar : PubMed/NCBI

Pita R, Marco-Contelles J, Ramos E, Del Pino J and Romero A: Toxicity induced by chemical warfare agents: Insights on the protective role of melatonin. Chem Biol Interact. 206:134–142. 2013. View Article : Google Scholar : PubMed/NCBI

Macit E, Yaren H, Aydin I, Kunak ZI, Yaman H, Onguru O, Uysal B, Korkmaz A, Turel S and Kenar L: The protective effect of melatonin and S-methylisothiourea treatments in nitrogen mustard induced lung toxicity in rats. Environ Toxicol Pharmacol. 36:1283–1290. 2013. View Article : Google Scholar : PubMed/NCBI

Llinàs L, Peinado VI, Ramon Goñi J, Rabinovich R, Pizarro S, Rodriguez-Roisin R, Barberà JA and Bastos R: Similar gene expression profiles in smokers and patients with moderate COPD. Pulm Pharmacol Ther. 24:32–41. 2011. View Article : Google Scholar

Al-Rasheed NM, Fadda L, Attia HA, Sharaf IA, Mohamed AM and Al-Rasheed NM: Pulmonary prophylactic impact of melatonin and/or quercetin: A novel therapy for inflammatory hypoxic stress in rats. Acta Pharm. 67:125–135. 2017. View Article : Google Scholar : PubMed/NCBI

Jin H, Wang Y, Zhou L, Liu L, Zhang P, Deng W and Yuan Y: Melatonin attenuates hypoxic pulmonary hypertension by inhibiting the inflammation and the proliferation of pulmonary arterial smooth muscle cells. J Pineal Res. 57:442–450. 2014. View Article : Google Scholar : PubMed/NCBI

Hardeland R: Aging, melatonin, and the pro-and anti-inflammatory networks. Int J Mol Sci. 20:12332019. View Article : Google Scholar

Sehirli AO, Sayiner S and Serakinci N: Role of melatonin in the treatment of COVID-19; as an adjuvant through cluster differentiation 147 (CD147). Mol Biol Rep. 47:8229–8233. 2020. View Article : Google Scholar : PubMed/NCBI

Wu GC, Peng CK, Liao WI, Pao HP, Huang KL and Chu SJ: Melatonin receptor agonist protects against acute lung injury induced by ventilator through up-regulation of IL-10 production. Respir Res. 21:652020. View Article : Google Scholar : PubMed/NCBI

Al-Zaqri N, Pooventhiran T, Alsalme A, Warad I, John AM and Thomas R: Structural and physico-chemical evaluation of melatonin and its solution-state excited properties, with emphasis on its binding with novel coronavirus proteins. J Mol Liq. 318:1140822020. View Article : Google Scholar : PubMed/NCBI

Kleszczyński K, Slominski AT, Steinbrink K and Reiter RJ: Clinical trials for use of melatonin to fight against COVID-19 are urgently needed. Nutrients. 12:25612020. View Article : Google Scholar

Wang R, Hozumi Y, Yin C and Wei GW: Mutations on COVID-19 diagnostic targets. Genomics. 112:5204–5213. 2020. View Article : Google Scholar : PubMed/NCBI

Shariare MH, Parvez MAK, Karikas GA and Kazi M: The growing complexity of COVID-19 drug and vaccine candidates: Challenges and critical transitions. J Infect Public Health. 14:214–220. 2021. View Article : Google Scholar : PubMed/NCBI

Shneider A, Kudriavtsev A and Vakhrusheva A: Can melatonin reduce the severity of COVID-19 pandemic? Int Rev Immunol. 39:153–162. 2020. View Article : Google Scholar : PubMed/NCBI

Shi J, Xiao Y, Zhang Y, Geng D, Cong D, Shi KX and Knapp RJ: Challenges of drug development during the COVID-19 pandemic: Key considerations for clinical trial designs. Br J Clin Pharmacol. Oct 29–2020.Epub ahead of print. View Article : Google Scholar : PubMed/NCBI

Parvathaneni V and Gupta V: Utilizing drug repurposing against COVID-19-Efficacy, limitations, and challenges. Life Sci. 259:1182752020. View Article : Google Scholar

Acuña-Castroviejo D, Escames G, Figueira JC, de la Oliva P, Borobia AM and Acuña-Fernández C: Clinical trial to test the efficacy of melatonin in COVID-19. J Pineal Res. 69:e126832020. View Article : Google Scholar : PubMed/NCBI

Bourne RS, Mills GH and Minelli C: Melatonin therapy to improve nocturnal sleep in critically ill patients: Encouraging results from a small randomised controlled trial. Crit Care. 12:R522008. View Article : Google Scholar : PubMed/NCBI

Mistraletti G, Umbrello M, Sabbatini G, Miori S, Taverna M, Cerri B, Mantovani ES, Formenti P, Spanu P, D'Agostino A, et al: Melatonin reduces the need for sedation in ICU patients: A randomized controlled trial. Minerva Anestesiol. 81:1298–1310. 2015.PubMed/NCBI

Mistraletti G, Sabbatini G, Taverna M, Figini MA, Umbrello M, Magni P, Ruscica M, Dozio E, Esposti R, DeMartini G, et al: Pharmacokinetics of orally administered melatonin in critically ill patients. J Pineal Res. 48:142–147. 2010. View Article : Google Scholar : PubMed/NCBI

Nordlund JJ and Lerner AB: The effects of oral melatonin on skin color and on the release of pituitary hormones. J Clin Endocrinol Metab. 45:768–774. 1977. View Article : Google Scholar : PubMed/NCBI

Biancatelli RMLC, Berrill M, Mohammed YH and Marik PE: Melatonin for the treatment of sepsis: The scientific rationale. J Thorac Dis. 12(Suppl 1): S54–S65. 2020. View Article : Google Scholar

Herrera EA and González-Candia A: Comment on melatonin as a potential adjuvant treatment for COVID-19. Life Sci. 253:1177392020. View Article : Google Scholar : PubMed/NCBI

Moghadam SO: A review on currently available potential therapeutic options for covid-19. Int J Gen Med. 13:443–467. 2020. View Article : Google Scholar

Barchas J, DaCosta F and Spector S: Acute Pharmacology of melatonin. Nature. 214:919–920. 1967. View Article : Google Scholar : PubMed/NCBI

Papavasiliou PS, Cotzias GC, Duby SE, Steck AJ, Bell M and Lawrence WH: Melatonin and Parkinsonism. JAMA. 221:881972. View Article : Google Scholar : PubMed/NCBI

Pandi-Perumal SR, Cardinali DP, Reiter RJ and Brown GM: Low melatonin as a contributor to SARS-CoV-2 disease. Melatonin Res. 3:558–576. 2020. View Article : Google Scholar

Öztürk G, Akbulut KG and Güney Ş: Melatonin, aging, and COVID-19: Could melatonin be beneficial for COVID-19 treatment in the elderly? Turkish J Med Sci. 50:1504–1512. 2020. View Article : Google Scholar

EU Clinical Trials Register: Eudract_number: 2020-001808-42. https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001808-42/ES. Accessed December 5, 2020.

Rodríguez-Rubio M, Figueira JC, Acuña-Castroviejo D, Borobia AM, Escames G and de La Oliva P: A phase II, single-center, double-blind, randomized placebo-controlled trial to explore the efficacy and safety of intravenous melatonin in patients with COVID-19 admitted to the intensive care unit (MelCOVID study): A structured summary of a study protocol for a randomized controlled trial. Trials. 21:6992020. View Article : Google Scholar

EU Clinical Trials Register: Eudract_number: 2020-001530-35. https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001530-35/ES. Accessed December 5, 2020.

ClinicalTrials.gov: Safety and Efficacy of Melatonin in Outpatients Infected With COVID-19. https://clinicaltrials.gov/ct2/show/NCT04474483?term=melatonin&cond=Covid19&draw=2&rank=1. Accessed December 5, 2020.

ClinicalTrials.gov: Selective Estrogen Modulation and Melatonin in Early COVID-19. https://clinicaltrials.gov/ct2/show/NCT04531748?term=melatonin&cond=Covid19&draw=2&rank=2. December 5, 2020.

ClinicalTrials.gov: Evaluation of Therapeutic Effects of Melatonin by Inhibition of NLRP3 Inflammasome in COVID19 Patients. https://clinicaltrials.gov/ct2/show/NCT04409522?term=melatonin&cond=Covid19&draw=1&rank=3. Accessed December 5, 2020.

ClinicalTrials.gov: Efficacy of Intravenous Melatonin on Mortality in Adult Patients Admitted to the Intensive Care Unit With COVID-19. https://clinicaltrials.gov/ct2/show/NCT04568863?term=melatonin&cond=Covid19&draw=1&rank=4. Accessed December 5, 2020.

ClinicalTrials.gov: The Effect of Melatonin and Vitamin C on COVID-19. https://clinicaltrials.gov/ct2/show/NCT04530539?term=melatonin&cond=Covid19&draw=1&rank=5. Accessed December 5, 2020.

ClinicalTrials.gov: Melatonin Agonist on Hospitalized Patients With Confirmed or Suspected COVID-19. https://clinicaltrials.gov/ct2/show/NCT04470297?term=melatonin&cond=Covid19&draw=1&rank=6. Accessed December 5, 2020.

ClinicalTrials.gov: Efficacy of Melatonin in the Prophylaxis of Coronavirus Disease 2019 (COVID-19) Among Healthcare Workers. https://clinicaltrials.gov/ct2/show/NCT04353128?term=melatonin&cond=Covid19&draw=1&rank=7. Accessed December 5, 2020.

Zhou Y, Hou Y, Shen J, Mehra R, Kallianpur A, Culver DA, Gack MU, Farha S, Zein J, Comhair S, et al: A network medicine approach to investigation and population-based validation of disease manifestations and drug repurposing for COVID-19. PLoS Biol. 18:e30009702020. View Article : Google Scholar : PubMed/NCBI

ClinicalTrials.gov: Antioxidants as Adjuvant Therapy to Standard Therapy in Patients With COVID-19. https://clinicaltrials.gov/ct2/show/NCT04570254?term=melatonin&cond=Covid19&draw=1&rank=8. Accessed December 5, 2020.

Hassaniazad M, Bazram A, Hassanipour S and Fathalipour M: Evaluation of the efficacy and safety of favipiravir and interferon compared to lopinavir/ritonavir and interferon in moderately ill patients with COVID-19: A structured summary of a study protocol for a randomized controlled trial. Trials. 21:8862020. View Article : Google Scholar : PubMed/NCBI

ClinicalTrials.gov: Search of: Melatonin|Covid19-List Results. https://clinicaltrials.gov/ct2/results?recrs=&cond=Covid19&term=melatonin&cntry=&state=&city=&dist=. Accessed December 5, 2020.

EU Clinical Trials Register: Search for covid-19 and melatonin. https://www.clinicaltrialsregister.eu/ctr-search/search?query=covid-19+and+melatonin. Accessed December 5, 2020.