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Id Subject Object Predicate Lexical cue
T1 0-9 Sentence denotes COVID-19:
T2 10-53 Sentence denotes Melatonin as a potential adjuvant treatment
T3 55-63 Sentence denotes Abstract
T4 64-187 Sentence denotes This article summarizes the likely benefits of melatonin in the attenuation of COVID-19 based on its putative pathogenesis.
T5 188-286 Sentence denotes The recent outbreak of COVID-19 has become a pandemic with tens of thousands of infected patients.
T6 287-585 Sentence denotes Based on clinical features, pathology, the pathogenesis of acute respiratory disorder induced by either highly homogenous coronaviruses or other pathogens, the evidence suggests that excessive inflammation, oxidation, and an exaggerated immune response very likely contribute to COVID-19 pathology.
T7 586-730 Sentence denotes This leads to a cytokine storm and subsequent progression to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and often death.
T8 731-869 Sentence denotes Melatonin, a well-known anti-inflammatory and anti-oxidative molecule, is protective against ALI/ARDS caused by viral and other pathogens.
T9 870-1089 Sentence denotes Melatonin is effective in critical care patients by reducing vessel permeability, anxiety, sedation use, and improving sleeping quality, which might also be beneficial for better clinical outcomes for COVID-19 patients.
T10 1090-1135 Sentence denotes Notably, melatonin has a high safety profile.
T11 1136-1272 Sentence denotes There is significant data showing that melatonin limits virus-related diseases and would also likely be beneficial in COVID-19 patients.
T12 1273-1358 Sentence denotes Additional experiments and clinical studies are required to confirm this speculation.
T13 1360-1378 Sentence denotes Graphical abstract
T14 1379-1436 Sentence denotes Melatonin as a potential adjuvant treatment for COVID-19.
T15 1438-1453 Sentence denotes 1 Introduction
T16 1454-1614 Sentence denotes Coronaviruses (CoVs) are RNA viruses infecting both human and animals; this infection involves the respiratory, gastrointestinal and central nervous system [1].
T17 1615-1819 Sentence denotes Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are infectious and lethal, and have caused thousands of deaths in the past two decades.
T18 1820-1955 Sentence denotes The recent outbreak was discovered in Wuhan, China; this highly contagious disease has spread throughout China and other countries [2].
T19 1956-2116 Sentence denotes Although antiviral therapy, corticosteroid therapy and mechanical respiratory support have been applied, there is lack of a specific treatment for COVID-19 [2].
T20 2117-2363 Sentence denotes Melatonin (N-acetyl-5-methoxytryptamine) is a bioactive molecule with an array of health-promoting properties; melatonin has been successfully used to treat sleep disorders, delirium, atherosclerosis, respiratory disease and viral infections [3].
T21 2364-2531 Sentence denotes Previous research has documented the positive effects of melatonin in alleviating acute respiratory stress induced by virus, bacteria, radiation, etc. [[4], [5], [6]].
T22 2532-2738 Sentence denotes Herein, we review the evidence indicating that melatonin will have supportive adjuvant utility in treating COVID-19 induced pneumonia, acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).
T23 2740-2803 Sentence denotes 2 Pathogenesis of COVID-19 and the rationale for melatonin use
T24 2804-2999 Sentence denotes Patients with COVID-19 (who were infected by SARS-CoV-2) are reported to present with fever, dry cough, myalgia, fatigue, and diarrhea, etc. with symptoms varying somewhat with the patients' age.
T25 3000-3168 Sentence denotes In some cases, the severe progression of the disease results in ALI/ARDS, respiratory failure, heart failure, sepsis, and sudden cardiac arrest within a few days [2,7].
T26 3169-3468 Sentence denotes The pathogenic examination of lung specimens from mild COVID-19 patients (who were retrospectively found to have COVID-19 at the time of lung cancer surgery) showed edema, proteinaceous exudate with globules, patchy inflammatory cellular infiltration and moderate formation of hyaline membranes [8].
T27 3469-3682 Sentence denotes In a postmortem assessment of a COVID-19 patient with severe ARDS, specimens of infected lungs demonstrated bilateral diffuse alveolar damage with edema, pneumocyte desquamation and hyaline membrane formation [9].
T28 3683-3862 Sentence denotes Though these pathological reports were reported in only a small number of cases, the findings do resemble the pathological features found in SARS- and MERS-induced pneumonia [10].
T29 3863-3954 Sentence denotes SARS-CoVs, MERS-CoVs and SARS-CoV-2 are classified in beta-coronavirus family members [11].
T30 3955-4163 Sentence denotes 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.
T31 4164-4462 Sentence denotes In SARS-CoV and MERS-CoV infected animal model, marked inflammatory and immune responses may activate a “cytokine storm”, and apoptosis of epithelial cells and endothelial cells; subsequently, vascular leakage, abnormal T cell and macrophages responses ensue and induce ALI/ARDS or even death [13].
T32 4463-4610 Sentence denotes Based on genetic homology and pathologic features of the infected lung, we predicted that a cytokine storm also prevails in patients with COVID-19.
T33 4611-4882 Sentence denotes In the blood of patients with COVID-19, there was a marked increase in interleukin 1β (IL-1β), interferon γ (IFN-γ), interferon-inducible protein 10 (IP-10), and monocyte chemoattractant protein 1 (MCP-1), as well as IL-4 and IL-10 when compared to that of SARS patients.
T34 4883-4981 Sentence denotes This suggests some potential difference from SARS and MERS in the pathogenesis of coronavirus [2].
T35 4982-5154 Sentence denotes There is also a potential repressed immune function in COVID-19 patients with the hypo-albuminemia, lymphopenia, neutropenia, and decreased percentage of CD8+ T cell [2,7].
T36 5155-5325 Sentence denotes Recent reports suggest that in some COVID-19 patients, although being negative for the viral nucleic acid test, still sometimes present with a high level of inflammation.
T37 5326-5471 Sentence denotes A clinical trial using certolizumab pegol (a TNF blocker) along with other anti-virus therapies may have beneficial effects in COVID-19 patients.
T38 5472-5566 Sentence denotes Collectively, the finding indicates that inflammation is a major feature in COVID-19 patients.
T39 5567-5730 Sentence denotes Thus, we hypothesize that excessive inflammation, depressed immune system, and an activate cytokine storm substantially contribute to the pathogenesis of COVID-19.
T40 5731-6032 Sentence denotes 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-1β, IL-2, IL-6, IL-8, both IFN-α/β, tumor necrosis factor (TNF), C—C motif chemokine 3 (CCL3), CCL5, CCL2, and IP-10, etc.
T41 6033-6078 Sentence denotes These are under the control of immune system.
T42 6079-6199 Sentence denotes Thus, the overproduction of these cytokines and chemokines contributes to the development in disease [[14], [15], [16]].
T43 6200-6337 Sentence denotes IL-10, produced by T-helper-2 (Th2), is antiviral, with an infection of coronaviruses leading to a marked decrease in this agent [17,18].
T44 6338-6430 Sentence denotes Interestingly, COVID-19 patients sometimes have a significantly elevated level of IL-10 [2].
T45 6431-6529 Sentence denotes Whether this is a feature of the COVID-19 infection or the result of medical treatment is unknown.
T46 6530-6847 Sentence denotes The amplification of the inflammatory response would promote cellular apoptosis or necrosis of the affected cells, which would further fuel inflammation, followed by increasing permeability of blood vessels and the aberrant accumulation of inflammatory monocytes, macrophages and neutrophils in the lung alveoli [19].
T47 6848-7015 Sentence denotes This vicious circle would intensify the situation as the regulation of immune response is lost and cytokine storm is further activated, resulting in dire consequences.
T48 7016-7290 Sentence denotes This putative “cytokine storm” pathology associated with coronaviruses is also supported by experimental SARS-CoV models, one of which showed that the severity of ALI was accompanied by an elevated expression of inflammation-related genes rather than increased viral titers.
T49 7291-7499 Sentence denotes In another case, the ablation of IFN-α/β receptor or the depletion of inflammatory monocytes/macrophages caused a marked rise in the survival rate of coronaviruses host without a change in viral load [19,20].
T50 7500-7619 Sentence denotes Both situations suggest a potential amplifying mechanism involved in CoV-induced ALI/ARDS regardless of the viral load.
T51 7620-7788 Sentence denotes If a similar pathology also exists in COVID-19, the attenuation of the cytokine storm by targeting several key steps in the process could bring about improved outcomes.
T52 7789-7959 Sentence denotes Melatonin is not viricidal but it has indirect anti-viral actions [3] due to its anti-inflammation, anti-oxidation and immune enhancing features [[21], [22], [23], [24]].
T53 7960-8044 Sentence denotes There are situations in which melatonin suppresses the features of viral infections.
T54 8045-8226 Sentence denotes In mice whose central nervous system is infected by virus (e.g., encephalitis), the use of melatonin caused less viremia, reduced paralysis and death, and decreased virus load [25].
T55 8227-8408 Sentence denotes In previous respiratory syncytial virus models, melatonin caused down-regulation of acute lung oxidative injury, pro-inflammatory cytokine release and inflammatory cell recruitment.
T56 8409-8540 Sentence denotes These findings, along with those recently summarized by Reiter et al. [3], support a rationale for melatonin use in viral diseases.
T57 8541-8686 Sentence denotes Also, melatonin's anti-inflammation, anti-oxidation, immune enhancing actions supports its potential attenuation of COVID-19 infection (Fig. 1 ).
T58 8687-8759 Sentence denotes Fig. 1 Pathogenesis of COVID-19 and potential adjuvant use of melatonin.
T59 8760-8967 Sentence denotes We postulated that lungs infected by SARS-CoV-2, and a suppressed immune response, elevated inflammation and excessive oxidation stress proceed unabated, this results in the activation of the cytokine storm.
T60 8968-9098 Sentence denotes ALI/ARDS may ensue, accompanied by a series of complications, the outcomes of which vary according to the severity of the disease.
T61 9099-9292 Sentence denotes Melatonin may play a role of adjuvant medication in the regulation of immune system, inflammation and oxidation stress, and provide support for patients with ALI/ARDS and related complications.
T62 9293-9297 Sentence denotes ALI:
T63 9298-9322 Sentence denotes Acute lung injury; ARDS:
T64 9323-9359 Sentence denotes Acute respiratory distress syndrome.
T65 9361-9393 Sentence denotes 3 Melatonin & anti-inflammation
T66 9394-9462 Sentence denotes Melatonin exerts anti-inflammatory effects through various pathways.
T67 9463-9701 Sentence denotes Sirtuin-1 (SIRT1) may mediate the anti-inflammatory actions of melatonin by inhibiting high mobility group boxechromosomal protein 1 (HMGB1), and thus down-regulating the polarization of macrophages towards the pro-inflammatory type [26].
T68 9702-9860 Sentence denotes In sepsis-induced ALI, the proper regulation of SIRT1 attenuates lung injury and inflammation, in which the application of melatonin might be beneficial [27].
T69 9861-10008 Sentence denotes Nuclear factor kappa-B (NF-κB) is closely associated with pro-inflammatory and pro-oxidative responses while being an inflammatory mediator in ALI.
T70 10009-10112 Sentence denotes The anti-inflammatory effect of melatonin involves the suppression of NF-κB activation in ARDS [28,29].
T71 10113-10200 Sentence denotes Melatonin reportedly down-regulate NF-κB activation in T cells and lung tissue [30,31].
T72 10201-10292 Sentence denotes The stimulation of NF-E2-related factor 2 (Nrf2) is crucial in protecting lung from injury.
T73 10293-10431 Sentence denotes In related studies, melatonin induces the up-regulation of Nrf2 with therapeutic effects in hepatoprotection, cardioprotection, etc. [32].
T74 10432-10605 Sentence denotes Whether Nrf2 is involved in the CoV-induced ALI remains unknown, but the close interaction of SIRT1, NF-κB and Nrf2 suggests their participation in the CoV-induced ALI/ARDS.
T75 10606-10684 Sentence denotes As such, the data support the potential anti-inflammatory action of melatonin.
T76 10685-10847 Sentence denotes Inflammation is commonly associated with an elevated production of cytokines and chemokines, while melatonin causes a reduction in the pro-inflammatory cytokines.
T77 10848-10952 Sentence denotes TNF-α, IL-1β, IL-6, and IL-8, and an elevation in the level of anti-inflammatory cytokine IL-10 [33,34].
T78 10953-11237 Sentence denotes There may be, however, some 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-inflammatory cytokines, IL-1β, IL-2, IL-6, IL-12, TNF-α, and IFN-γ [35].
T79 11238-11343 Sentence denotes Conversely, in ALI infection models, melatonin presents with anti-inflammatory and protective action [6].
T80 11345-11374 Sentence denotes 4 Melatonin & anti-oxidation
T81 11375-11695 Sentence denotes The anti-oxidative effect of melatonin cooperates with its anti-inflammatory actions by up-regulating anti-oxidative enzymes (e.g. superoxide dismutase), down-regulating pro-oxidative enzymes (e.g. nitric oxide synthase), and it may also interact directly with free radicals, functioning as free radical scavenger [3,4].
T82 11696-11773 Sentence denotes Viral infections and their replication constantly generate oxidized products.
T83 11774-12015 Sentence denotes In a SARS-induced ALI model, the production of oxidized low density lipoprotein activates innate immune response by the overproduction of IL-6 alveolar macrophages via Toll-like receptor 4 (TLR4)/NF-kB signaling, thereby leading to ALI [36].
T84 12016-12115 Sentence denotes TLR4 is a receptor for the innate immune system, and it is also a therapeutic target for melatonin.
T85 12116-12268 Sentence denotes In brain ischemia, gastritis and periodontitis disease models, melatonin has documented anti-inflammation actions via TLR4 signaling [[37], [38], [39]].
T86 12269-12402 Sentence denotes The anti-oxidative effect of melatonin has also been confirmed in ALI caused by radiation, sepsis and ischemia-reperfusion [4,40,41].
T87 12403-12684 Sentence denotes In ALI/ARDS patients, especially when the disease is advanced and in patients treated in intense care units (ICUs), severe inflammation, hypoxemia and mechanical ventilation with high oxygen concentrations inevitably increases oxidant generation locally and systematically [42,43].
T88 12685-12772 Sentence denotes Accordingly, we speculate that excessive oxidation also is likely involved in COVID-19.
T89 12773-12978 Sentence denotes The extensive studies of Gitto et al. [44,45], who used melatonin to treat newborn infants with respiratory distress, has documented the anti-oxidant and anti-inflammatory actions of melatonin in the lung.
T90 12979-13131 Sentence denotes Thus, it is likely that the application of melatonin would be beneficial in controlling the inflammation and oxidation in coronavirus infected subjects.
T91 13133-13164 Sentence denotes 5 Melatonin & immunomodulation
T92 13165-13299 Sentence denotes When virus is inhaled and infects respiratory epithelial cells, dendritic cells phagocytose the virus and present antigens to T cells.
T93 13300-13474 Sentence denotes Effector T cell function by killing the infected epithelial cells, and cytotoxic CD8+ T cells produce and release pro-inflammatory cytokines which induce cell apoptosis [46].
T94 13475-13558 Sentence denotes Both the pathogen (CoV) and cell apoptosis trigger and amplify the immune response.
T95 13559-13742 Sentence denotes The exacerbation of cytokine production, excessive recruitment of immune cells and the uncontrollable epithelial damage generates a vicious circle for infection related ALI/ARDS [47].
T96 13743-13885 Sentence denotes The clinical characteristics of COVID-19 suggest that a reduced level of neutrophils, lymphocytes and CD8+ T cells in peripheral blood [7,48].
T97 13886-14144 Sentence denotes Melatonin exerts regulatory actions on the immune system and directly enhances the immune response by improving proliferation and maturation of natural killing cells, T and B lymphocytes, granulocytes and monocytes in both bone marrow and other tissues [49].
T98 14145-14348 Sentence denotes In macrophages, antigen presentation is also augmented after the application of melatonin, where the up-regulation of complement receptor 3, MHC class I and class II, and CD4 antigens were detected [50].
T99 14349-14450 Sentence denotes NOD-like receptor 3 (NLRP3) inflammasome is part of the innate immune response during lung infection.
T100 14451-14569 Sentence denotes The pathogen, including a virus (CoVs has not yet been tested), triggers NLRP3 activation to amplify the inflammation.
T101 14570-14658 Sentence denotes There is probably a balance of the protective and damaging actions of NLRP3 in the lung.
T102 14659-14852 Sentence denotes Thus, in a mouse experiment, inhibition of NLRP3 in the early phase of infection increased mortality, whereas suppression of NLRP3 at the peak of infection allowed for a protective effect [51].
T103 14853-14933 Sentence denotes This supports the use of melatonin in ALI/ARDS when inflammation is most severe.
T104 14934-15083 Sentence denotes Inflammasome NLRP3 is correlated to lung diseases caused by infection, including influenza A virus, syncytial virus, and bacteria [[51], [52], [53]].
T105 15084-15413 Sentence denotes The efficacy of melatonin in regulating NLRP3 has been proven in radiation-induced lung injury, allergic airway inflammation and oxygen-induced ALI and LPS-induced ALI models, in which melatonin reduced the infiltration of macrophages and neutrophils into the lung in ALI due to the inhibition of NLRP3 inflammasome [4,28,54,55].
T106 15415-15463 Sentence denotes 6 Melatonin effects in cytokine levels in human
T107 15464-15740 Sentence denotes Although there is obviously no report related to the use of melatonin in COVID-19 patients, in subjects with other diseases and an increased level of inflammation, the application of melatonin showed promising results regarding the attenuation of circulating cytokines levels.
T108 15741-15968 Sentence denotes In a randomized controlled trial, 8-week oral intake of 6 mg/d melatonin caused a significant decrease in serum levels of IL-6, TNF-α and hs-C-reactive protein (hs-CRP) in patients with diabetes mellitus and periodontitis [56].
T109 15969-16188 Sentence denotes In another trial of patients suffering with severe multiple sclerosis, orally 25 mg/d of melatonin for 6 months also promoted a significant reduction in serum concentrations of TNF-α, IL-6, IL-1β and lipoperoxides [57].
T110 16189-16461 Sentence denotes 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 5 mg/d of melatonin for less than 5 days induced a reduced level of pro-inflammatory cytokines.
T111 16462-16651 Sentence denotes A recent meta-analysis of a total of 22 randomized controlled trials suggested that a supplementary use of melatonin is associated with a significant reduction of TNF-α and IL-6 level [61].
T112 16652-16871 Sentence denotes This clinical evidence suggests that the use of melatonin as a supplement may effectively reduce the levels of circulating cytokines, and may potentially also lower pro-inflammatory cytokine levels in COVID-19 patients.
T113 16873-16921 Sentence denotes 7 Melatonin & other supportive adjuvant effects
T114 16922-17022 Sentence denotes The integrity of the vascular endothelial barrier is crucial in the immunoregulation within alveoli.
T115 17023-17244 Sentence denotes Severe inflammation 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.
T116 17245-17359 Sentence denotes Experimental evidence suggests that melatonin mediates the suppression of VEGF in vascular endothelial cells [62].
T117 17360-17494 Sentence denotes Based on clinical reports of COVID-19, patients with severe ALI/ARDS may also have an increased risk of sepsis and cardiac arrest [2].
T118 17495-17615 Sentence denotes Published reports indicate that the application of melatonin may ameliorate the septic shock via the NLRP3 pathway [63].
T119 17616-17764 Sentence denotes Specifically, melatonin may a have preventive effect against sepsis-induced renal injury, septic cardiomyopathy and liver injury [[64], [65], [66]].
T120 17765-18014 Sentence denotes It was also reported that melatonin had benefits in patients with myocardial infarction, cardiomyopathy, hypertensive heart diseases and pulmonary hypertension, and probably functions via the TLR4/survivor activating factor enhancement pathway [67].
T121 18015-18213 Sentence denotes Moreover, melatonin exerts neurological protection by reducing the cerebral inflammatory response, cerebral edema and brain-blood barrier permeability under a number of experimental conditions [68].
T122 18214-18398 Sentence denotes In the ICU, deep sedation is associated with increased long-term mortality, and the application of melatonin reduces sedation use and the frequency of pain, agitation, anxiety [69,70].
T123 18399-18501 Sentence denotes Also, a recent meta-analysis showed that melatonin improves sleep quality in patients in the ICU [71].
T124 18502-18753 Sentence denotes Thus, the rationale for the use of melatonin in COVID-19 patients not only focuses on the attenuation of the infection-induced respiratory disorders, but also on an overall improvement and prevention of patients' wellbeing and potential complications.
T125 18755-18776 Sentence denotes 8 Melatonin & safety
T126 18777-18900 Sentence denotes When considering the use of melatonin to treat COVID-19, the safety of the melatonin is of utmost significance to consider.
T127 18901-19155 Sentence denotes As reviewed previously, short-term use of melatonin is safe, even in those given high doses, and the reported adverse effects are limited to occasional dizziness, headache, nausea and sleepiness; in general melatonin's safety in humans is very high [72].
T128 19156-19313 Sentence denotes In clinical trials, doses of 3 mg, 6 mg and 10 mg of melatonin oral intake by patients in ICU showed satisfactory safety when compared to placebo [70,73,74].
T129 19314-19442 Sentence denotes Also, even when melatonin was given to humans at dose of 1 g/d for a month, there were no adverse reports of the treatment [75].
T130 19443-19554 Sentence denotes Finally, there were no adverse effects recorded after the use of melatonin in ALI/ARDS animal studies [3,4,28].
T131 19555-19749 Sentence denotes While the safety of melatonin has been verified in many human studies, its effect when given to COVID-19 patients should be carefully monitored despite the very high safety profile of melatonin.
T132 19751-19764 Sentence denotes 9 Conclusion
T133 19765-20018 Sentence denotes The possible beneficial effects of melatonin as adjuvant use in COVID-19 in anti-inflammation, anti-oxidation, immune response regulation has been repeatedly demonstrated in respiratory disorder models induced by infections and associated complications.
T134 20019-20055 Sentence denotes Melatonin has a high safety profile.
T135 20056-20326 Sentence denotes Although the direct evidence of melatonin application in COVID-19 is unclear, both its use in experimental animal models and in studies on humans has continuously documented its efficacy and safety and its use by COVID-19 patients predictably would be highly beneficial.
T136 20328-20368 Sentence denotes CRediT authorship contribution statement
T137 20369-20632 Sentence denotes Rui Zhang:Resources, Writing - original draft.Xuebin Wang:Writing - original draft.Leng Ni:Writing - review & editing, Supervision.Xiao Di:Visualization.Baitao Ma:Writing - review & editing.Shuai Niu:Resources.Changwei Liu:Conceptualization, Supervision.Russel J.
T138 20633-20667 Sentence denotes Reiter:Writing - review & editing.
T139 20669-20684 Sentence denotes Acknowledgement
T140 20685-20808 Sentence denotes We thank all the doctors, nurses, and researchers who have fought against the virus on the frontline of 2019-nCoV epidemic.
T141 20809-20911 Sentence denotes We thank everyone who has given great and selfless support to the fight against this deadly infection.
T142 20912-21034 Sentence denotes This research did not receive a specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
T143 21036-21069 Sentence denotes Declaration of competing interest
T144 21070-21130 Sentence denotes The authors declare that there are no conflicts of interest.