if Sienes 250 (2020) 117583 ‘Contents lists available at ScienceDirect, Life Sciences ELSEVIER journal homepage: www.elsevier.comilecatellifescie Rui Zhang’, Xuebin Wang’, Leng Ni’, Xiao Di’, Baitao Ma, Shuai Niu’, Changwei Liu, Russel J. Reiter”*"* ‘pret of Ver Surge, eigen Medal Call Hop, hin ear of Mel Sea Peking Union Mobil Cole, Baie hina ° rpm of Cel Syms ont Astin, U7 Heh San Anan San Ani 7028, SA i SaRsco\-2 faticts. Bured on cinta features, pathology the pathorenesi of atte rexprtery divrder induced by eter Melton Fishly homogenous eorenaviruer or other pathogens, the evidence suger that exeerve infammalion,exi- oneonaecin Aston, and an exaggerated lnmaune rerponse very Ukelycontbute te COVID-I9 pathology. This leds to ee ‘olin stom and subvequentprogresion to acute hig injury (ALD /aeue eespcatory dlstens syndrome (ARDS) and often death, Mslatonn, «welliown ant-inlammatory and aat-oxidative molecule, protective sgulnst ALVARDS caused by vie and other pathogens. Melatonin is effective in cata cate patents Dy t= ducing vessel permeability anxiety sedtion use abd improving sleeping quali, which might le be beneficial for beter cea outcomes for COVID-19 patient. Notably, melatonin has a high safety prof. There is sf- ean data shoving that melatonin Hn vrwerelated dears and would als key Be Beneficial in COVID- 1. Introduction CCoconavicuses (CoV) are RNA viruses infecting both human and animals this infection involves the respiratory, gastrointestinal and ental nervous system [I]. Severe acute respiratory syndrome cor. fonavitus (SARS-CoV) and Middle ast respiratory syndrome cor- fonavirus (MERS.CoV) are infectious and lethal, and have eaused thousands of deaths inthe past two decades, The recent outbreak was discovered in Wuhan, China; ths highly contagious disease has spread throughout China and other countries 2), Although antiviral therapy, conticosteroid therapy and mechanical respiratory support have been applied, there is lack of a specific treatment for COVID-19 (21 “Melatonin (W-acetyl-S-methonytryptamine) isa bioactive molecule with an array of health-promoting properties; melatonin has been succesfully used to teat sleep disorders, delirium, atherosclerosis, re spiratory disease and viral infections (3. Previous research has docu: mented the postive effects of melatonin in alleviating acute respiratory stress induced by virus, bacteria, radiation, ete [6]. Herein, we re view the evidence indicating that melatonin will have supportive adjuvant uslity in resting COVID-19 induced pneumonia, acute lung Injury (ALD and acute respiratory distress syndrome (ARDS) 2. Pathogenesis of COVID-19 and the rationale for melatonin use Patients with COVID-19 (who were infected by SARS-CoV-2) are reported to present with fever, dry cough, myalgis, fatigue, and dar thea, ete with symptoms varying somewhat withthe pallens age. In some cases, the severe progression ofthe disease results in ALI/ARDS, respiratory failure, heart fallure, sepsis, and sudden cardiac arrest ‘within a few days [2,7] The pathogenic examination of ling specimens from mild COVID-19 patients (who were retrospectively found to have CCOVID-19 at the time of lung cancer surgery) showed edema, prote raccous exudate with globules, patchy inflammatory cellular infitra tion and moderate formation of hyaline membranes [8]. In a post- mortem assessment of a COVID-19 petient with severe ARDS, specimens of infected lungs demonstrated bilateral difuse alveolar damage with edema, pneumoeyte desquamation and hyaline membrane formation (9 Uaton Medica Cllege, No.1, Shusifayuar, Dongeneng Ditee, ihn 100730, China “Corespondence to: Russel J Reiter, Cel Biolog, Journal of Pineal Research, Melatonin Research, Thomson Reuters lit of Highly Cited Seen, Clarivate Aalyls lt of Highly Ged Scientist, Department of Cell Systems and Anatomy, "Bmal ares: Luci ivipsins com (G Li), rater @uthsess edu RJ Rte p//do ong/102036,3.4.2020 11758 [Received 27 Febraary 2020; Rectived in revied form 16 March 2020; Accepted 20 UF Health San Antonio, San Antonio, TX 78228, USA March 2020Rang eat ye ane 2502000) 17588 Fig. 1. Pathogenesis of COVID-19 and potential adjuvant wie of melatonin. We postal tha lung infected by SARS-CV-2, anda suppressed Snmune response, ‘levated inflammation and excessive oidlin tress proceed uabeled, this el inthe aeivaton ofthe eyakine tam ALI/ARDS may env, accompanied by @ ‘eries of complications the outcomes of whieh vary according tothe seventy of the dsease. Melatonin may pla ale of adjuvant medication inthe elation of Immune system. inflammation an eidalion sess, snd provide suppor lor patents wilh AL/ARDS and related complication. ALI Aeut lung injury: ARDS: Acute respuatory dstesssyndrose ‘Trough these pathological reports were reported a small ‘number of cass, the findings do resemble the pathological features found in SARS- and MERS-induced pneumonia [10]-SARS-CoVs, MERS- (CoV and SARS-CoV-2 are clasified in beta-coronavirs family mem bers [11]. Recent published research suggests that SARS-CoV.2 shares 79.0% nucleotide Identity to SARS-CoV and 51.8% identity to MERS- CoV [12], indicating a high genetic homology among SARS.CoV-2, MERS.CoV and SARS-CoV. In SARS-CoV and MERS-CoV infected an. imal model, marked inflammatory and immune responses may activate a “eytokine storm’, and apoptosis of epithelial cells and endothelial, ‘els subsequently, vascular leakage, abnormal T cell and macrophages responses enste and indice ALI/ARDS or even death [12] Based on genetic homology and pathologic features ofthe infected lung, we predicted that a cytokine storm also prevails inpatients with ‘COVID-18. In the blood of patents wth COVID-18, there was a marked increase in intelevkin 1p (IL-1), interferon y (FN), interferon ducible protein 10 (P-10), and monocyte chemoattractant protein 1 (Q4CP-1, a¢ well as IL-4 and I1-10 when compared to that of SARS patiens. This suggests some potential diference from SARS and MERS in the pathogenesis of coronavirus [2]. There is also a potential re: pressed immune function in COVID-I9 patients with the hypo-album- ‘nemia, lymphopenia, neutropenia, and decreased percentegeof CD8* T cell [2,7]. Recent reports suggest that in some COVID-19 patients, a though being negative for the viral nucleic acid test, still sometimes present with a high level of inflammation. A clnial tral using certo- izumab pegol (@ TNE blocker) slong with other antivirus therapies may have beneficial effets in COVID-19 patients. Collectively, the finding indicates that inflammation is © major feature in COVID-18 patients. Thus, we hypothesize that exeessve inflammation, deprested {immune system, and an activate cytokine storm substantially contebute to the pathogenesis of COVID.18. In the early stages of coronaviruses infection, dendritic cells and epithelial cells are activated and express a cluster of pro-inflammatory cytokines and chemokines including IL-1p, IL-2, 1-6, I-8, both IFN-a/ 8, tumor necrosis factor (INF), CC motif chemokine $ (CCL3), CCLS, CCL2, and IP-10, etc. These are under the control of immune system. aus, the overproduction of these cytokines and chemokines con- tributes tothe development in disease [14-15] 11-10, produced by T-helper-2 (Th2) is antiviral, with an infection of coronaviruses leading to a marked decrease in this agent [17.18] Interestingly, COVID-I9 patients sometimes have a signficandy ele- vated level of I-10 [2]. Whether this isa feature of the COVID-19 in- fection ofthe result of medical treatment ie unknown. The amplifies: tion ofthe inflammatory response would promete cellular apoptosis ornecrosis ofthe affected ces, which would further fuel inflammation, followed by increasing permeability of blood vessels and the aberrant accumulation of inflammatory monocytes, macrophages and net trophils in the hung alveol (19) Ths vicious crete would intensify the situation as the regulation of immune response i lost and cytokine storm is further activated, resulting in die consequences, Tis putative “cytokine storm” pathology associated with cox onavirwses i also supported by experimental SARS-CoV models, one of ‘which showed thatthe severity of ALI was accompanied by an elevated expression of inflammationzelated genes rather than increased viral titers. In another case, the ablation of TFN-2/B receptor or the depletion of inflammatory monocytes/macrophages caused a marked rise in the survival rate of coronaviruses hort without @ change in viral load 19,20). Both situations suggest a potential amplifying mechanism in- volved in CoV-induced ALU/ARDS regardless of the viral load. If 2si- ila pathology also exes in COVID-I9, the attenuation ofthe cytokine storm by targeting several key steps in the process could bring about improved outcomes. “Melatonin is not vireidal but it has indirect anti-viral actions [3] due to its antvinflammation, anti-oxidation and immune enhancing features [21-24]. Thee are situations in which melatonin suppresses the features of vital infections. In mice whose central nervous system is infected by virus (eg. encephalitis), the use of melatonin caused less ceria, reduced paralysis and death, and decreased vieus load (25]. In previous respiratory syncyUal vicus models, melatonin caused doven- Fequlation of acute lung oxidative injury, proinflammatory cytokine release and inflammatory cell recruitment, These findings, along sith those recently summarized by Reiter etal [3], support a rationale for relatonin use in viral diseases, Also, melatonin's antinflammation, anti-oxidation, Immune enhancing actions suppors its potential at- tenuation of COVID-18 infection (Fig. 1). 3, Melatonin & ant‘-inflammation Melatonin exerts ant-inlammatory effects through various path- ‘ways. Siuin-1 (SIRTI) may mediate the ant-inflammatory actions of melatonin by inhibiting high mobility group boxechromosomal protein 1 (MGB, and thus doven-regulating the polarization of macrophoges towards the pro-inflammatory type [25]. In sepsicinduced ALL, the proper regulation of SIRT! attenuates lung injury and inflammtion, in ‘hich the application of melatonin might be beneficial [27]. Nuclear factor kapps-B (NF-xB) is losely associated with proinflammatory and pre-oxidative responses while being an inflammatory mediator in ALL The ant-inflarmatory effect of melatonin involves the suppression of [Fox aetvation in ARDS (25,28). Melatonin reportedly down-regulate [NP-xB activation in eels an hing tse [30,31]. The stimulation of [NE2-telated factor 2 (Nt2) is crucial in protecting lug from injury. In related studies, melatonin indsees the up-regulation of Nef2 with therapeutic effects in hepatoprotection, eardioproteetion, ete. (521. ‘whether Nef is involved in the CoV-induced AL remains unknown, byt the close interaction of SIRTI, NFa and Nrf2 suggests thei por Leipatio inthe CoV-induced ALVARDS. As such, the data support the potential antiinflammatory action of melatonin. Inflammation is commonly asvociated with an elevated proguction of cytokines and chemokines, while melatonin causes a reduction in the provi flammatory cytokines. TNF-, IL-1f, IL-6, nd IL-8, and an elevation in the level of antiinflammatory cytokine IL-10 [33,54]. There may be, however, ome concerns about the potential pro-inflammatory actions of melatonin when used in very high doses or under suppressed immune conditions where it may induce an increase production of pro-in- flammatory cytokines, I-IB, 1-2, 1, I-12, TNF-a, and IPN [35] Conversely, in ALI infection modes, melatonin presente with antiin flammatory and protective action (5) ye ane 2502000) 17588 4. Melatonin & anti-oxidation The ant-oxidative effect of melatonin cooperates with its anttin- ‘lammatory actions by up-regulating anti-oxidaive enzymes (eg. s- peroxide dismutase), doven-regulating pro-xidative enzymes (©. nic {rie oxide synthase), an it may also interact directly with fee radicals, fanetioning as fee radical scavenger [3,4]. Viral infections and their replication constantly generate oxidized products. In a SARS-induced [ALI model, the production of oxidized low density lipoprotein activates innate immune response by the overproduction of IL-6 alveolar mac- rophages via Tollltke receptor 4 (TLR4)/NF-EB signaling, thereby leading to ALI [35]. TIR4 is a receptor for the innate immune system, and it is also a therapeutic target for melatonin. In brain ischemia, gastritis and periodontitis disease models, melatonin has documented anti-inflammation actions via TLR4 signaling [37-39]. The ant-oxida tive effect of melatonin has also been confirmed in ALI caused by ra- ation, sepsis end ischemia-reperfusion (,40,41]. In ALVARDS pa tients, especially when the disease is advanced and in patients treated in intense care units (ICUs), severe inflammation, hypoxemia and me- chanical ventilation with high oxygen concentrations inevitably in creases oxidant generation locally and systematically [12,43]. Accord ingly, we speculate that excessive oxidation also is likely involved in COVID-18, The extensive studies of Gitto et al. [445], who used melatonin to treat newborn infants with respiratory distress, has ocumented the anti-oxidant snd ant-inflammatory actions of mela- tonin in the Teng. Thus, i slikely thatthe appliation of melatonin would be beneficial in contrlling the inflammation and oxidation in coronavirs infected subjects 5. Melatonin & immunomodulation ‘When virus is inhaled and infects respiratory epithelial cells, den- Gritic cells phagocytose the virus and present antigens to T cell Effector Teall function by killing the infeced epithelial eels, and ey~ totorie Cb8 + T eels produce and release pro-inflammatory cytokines hich indoce cell apoptosis [6]. Both the pathogen (CoV) and cell apoptosis trigger and amplify the immune response. The exacerbation of eytokine production, excessive recruitment of immune cells and the _unconsrollable epithelia! damage generates a vicious cirle fr infection related ALW/ARDS [7]. The elnieal characteristics of COVID-19 sug- {gest that a reduced level of neutrophil, Iymphoeytes and CD8 + T ells In peripheral blood [7,8]. Melatonin exerts regulatory aetions on the immune system and directly enhances the immune response by in proving proliferation and maturation of natural killing cells, T and B Iymphoeytes, granulocytes and monoeytes in both bone marrow snd other tissues [79]. In macrophages, antigen presentation is also aug mented after the application of melatonin, where the up-regulation of complement receptor 3, MIG class I and elas I, and CD‘ antigens were Aetected (50) Noble receptor 3 (NLRP3) inflammasome is part of the innate fmmune response during lung infection. The pathogen, including a virus (CoVs has not yet been tested), triggers NLRPS activation to amplify the inflammation. There is probably a balance ofthe protective ‘nd damaging actions of NLRP3 inthe lung. Thus, in a mouse experi- rent, inhibition of NLRPS in the early phase of infection increased mortality, whereas suppression of NLRPS at the peak of infection al lowed fora protective effect {51]. Tis supports the use of melatonin in ALI/ARDS when inflammation is most severe. Inflammasome NLRPS is correlated to lung diseases eaused by infection, including infuenza. A virus, syneytial virus, and bacteria (51-53). The efficacy of melatonin {in regulating NLRP3 has been proven in radiation-indueed lung injury, allergic airway inflammation and oxygen-induced AL! and LPS-induced [ALI models in which melatonin reduced the infiltration of macro- phages and neutrophils into the Tung in ALI due to the inhibition of NLRPS inflammasome [4,28,54,35}.Ramune eat (6. Melatonin effects in eytokine levels in human Although there is obviously no ceport related to the use of melatonin in COVID-19 patients, in subjects with other diseases and an increased level ofinlammation, the application of melatonin showed promising resulte regarding the attenuation of circulating cytokines Teves. In a randomized controled tril, Sweek oral intake of 6 mg/€ melatonin ‘caused a significant decrease in serum levels of IL-6, TNF-a and hs-C- reactive protein (hs-CRP) in patients with diabetes mellitus and per ‘odontitis (58). In another trial of patients suifring with severe multiple sclerosis, orally 25 mg/d of melatonin for § months also promoted a significant reduction in serum concentrations of TNF-a, 1-6, 1-1 and lipoperoxides (57). In the acute phase of inflammation, including during surgical stress (58), brain reperfusion [59], and coronary artery reperfusion (60], melatonin intake of 10 mg/d, 6 mg/d and S mg/d of ‘melatonin for less than 5 days induced a reduced level of pro- flammatory cytokines. A recent meta-analysis ofa total of 22 rando- ‘mized controlled trials suggested that a supplementary ute of melatonin is associated with a significant reduction of TNF-a and 1-6 level [61] ‘This elinieal evidence suggests thatthe use of melatonin asa supple ment may effectively reduce the levels of circulating cytokines, and may potentially also lower pro-inflammatory eytokne levels in COVID- 19 patients, 7. Melatonin & other supportive adjuvant effects ‘The integrity of the vascular endothelial barier is erucial in the immunoregulation within alveol, Severe jalammation and immune responses induce epithelial and endothelial cell apoptosis, as well as Increasing the production of VEGF, which aggravates edema and the ‘extravasation of the immune cells from blood vessels. Experimental ‘evidence suggests that melatonin mediates the suppression of VEGP in vascular endothelial ells (62). Based on clinical reports of COVID-19, patients with severe ALI/ARDS may also have an increased risk of sepsis ‘and cardiac arrest [2], Published reports indicate that the application of| ‘melatonin may ameliorate the septic shock via the NLRPS pathway (03). Specifically, melatonin may have preventive effect ageinst sepsis induced renal injury, septic cardiomyopathy and liver injury [64-65]. It was also reported that melatonin had benefits in patients ‘with myocardial infareton, cardiomyopathy, hypertensive heart dis ‘eases and pulmonary hypertension, and probably functions vis the ‘TLRA/survivor activating fator enhancement pathway [57]. Moreover, melatonin exerts neurological protection by redueing the cerebral in- flammatory response, cerebral ema and brain-blood barrier perme: ability under a number of experimental conditions (58). In the 1CU, ‘deep sedation is associated with increased long-term morality, and the application of melatonin reduces sedation use and the feequeney of pain, agitation, anxiety [59,70]. Also, a recent meta-analysis showed that melatonin improves sleep quality inpatients in the ICU [71]. Ths, the rationale forthe ise of melatonin in COVID-19 patients not only Tocuses on the attentation of the infecion-indiced respiratory dis ‘orders, but also on an overall improvement and prevention of patients ‘wellbeing and potential complications ye ane 2502000) 17588 i i a 3 CCRedit authorship contribution statement yurees, Writing - original Wang:Writing - original draftLeng NiWriing - review & editing Supervision Xiao Di:Visuslization Baitae MaWriting ~ review & eciting Shuai Niu:Resources.changwei Liu:Conceptuslizatin, Supervision Russel J, Relter Writing - review & editing Acknowledgement We thank all dhe doctors, nurses, and researchers who have fought agains the virus on the frontline of 2019-nCoV epidemic, We thank everyone who bas given great and selfless support to the fight against ‘hie deadly infection, This research di not receive a specific rant from fonding agencies in the public, commercial, o not-for-profit sectors. 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