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Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Loh et al., International Journal of Molecular Sciences, doi:10.3390/ijms23158122

Jul 2022

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Melatonin for COVID-19

11th treatment shown to reduce risk in December 2020, now with p = 0.0000002 from 18 studies.

Lower risk for mortality, ventilation, and recovery.

No treatment is 100% effective. Protocols combine treatments.

5,300+ studies for 116 treatments. c19early.org

Review of melatonin for viral infections and post-infection sequelae. The SARS-CoV-2 virus can cause oxidative stress, mitochondrial dysfunction, LINE1 derepression, and changes to m6A RNA modifications. These effects can increase viral replication and suppress host immune responses. Melatonin employs antioxidant and non-antioxidant mechanisms to modulate viral phase separation, restore mitochondrial function, suppress LINE1 derepression, and regulate m6A modifications. Through these diverse actions, melatonin may inhibit acute viral infection and replication, as well as prevent post-infection complications. The authors suggest melatonin could be an important therapeutic adjuvant for SARS-CoV-2 infection and post-infection recovery.

Reviews covering melatonin for COVID-19 include1-23.

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1. Sanduzzi Zamparelli et al., Immune-Boosting and Antiviral Effects of Antioxidants in COVID-19 Pneumonia: A Therapeutic Perspective, Life, doi:10.3390/life15010113.mdpi.com, doi.org.

2. Xie et al., The role of reactive oxygen species in severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection-induced cell death, Cellular & Molecular Biology Letters, doi:10.1186/s11658-024-00659-6.biomedcentral.com, doi.org.

3. Zhao et al., Melatonin Potentially Acts as a Widely-Acting Protective Tool in COVID-19, Medicine Research, doi:10.21127/yaoyimr20240006.medicineresearch.org, doi.org.

4. Yehia et al., Melatonin: a ferroptosis inhibitor with potential therapeutic efficacy for the post-COVID-19 trajectory of accelerated brain aging and neurodegeneration, Molecular Neurodegeneration, doi:10.1186/s13024-024-00728-6.biomedcentral.com, doi.org.

5. Chacin-Bonilla et al., Melatonin and viral infections: A review focusing on therapeutic effects and SARS-CoV-2, Melatonin Research, doi:10.32794/mr112500168.melatonin-research.net, doi.org.

6. Lempesis et al., A mid‑pandemic night's dream: Melatonin, from harbinger of anti‑inflammation to mitochondrial savior in acute and long COVID‑19 (Review), International Journal of Molecular Medicine, doi:10.3892/ijmm.2024.5352.spandidos-publications.com, doi.org.

7. Alomari et al., Assessing the antiviral potential of melatonin: A comprehensive systematic review, Reviews in Medical Virology, doi:10.1002/rmv.2499.wiley.com, doi.org.

8. Donzelli, A., Neglected Effective Early Therapies against COVID-19: Focus on Functional Foods and Related Active Substances. A Review, MDPI AG, doi:10.20944/preprints202312.1178.v1.preprints.org, doi.org.

9. Langen, M., Melatonin - the Hormone of Both Sun and Darkness - Protects Your Health and Can Save Your Life, Rounding The Earth, roundingtheearth.substack.com/p/melatonin-the-hormone-of-both-sun.substack.com.

10. Hosseinzadeh et al., Melatonin effect on platelets and coagulation: Implications for a prophylactic indication in COVID-19, Life Sciences, doi:10.1016/j.lfs.2022.120866.sciencedirect.com, doi.org.

11. Loh et al., Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19, International Journal of Molecular Sciences, doi:10.3390/ijms23158122.mdpi.com, doi.org.

12. Reiter et al., Melatonin: highlighting its use as a potential treatment for SARS-CoV-2 infection, Cellular and Molecular Life Sciences, doi:10.1007/s00018-021-04102-3.springer.com, doi.org.

13. Tan et al., Mechanisms and clinical evidence to support melatonin's use in severe COVID-19 patients to lower mortality, Life Sciences, doi:10.1016/j.lfs.2022.120368.sciencedirect.com, doi.org.

14. Behl et al., CD147-spike protein interaction in COVID-19: Get the ball rolling with a novel receptor and therapeutic target, Science of The Total Environment, doi:10.1016/j.scitotenv.2021.152072.sciencedirect.com, doi.org.

15. Castle et al., Implications for Systemic Approaches to COVID-19: Effect Sizes of Remdesivir, Tocilizumab, Melatonin, Vitamin D3, and Meditation, Journal of Inflammation Research, doi:10.2147/JIR.S323356.dovepress.com, doi.org.

16. Ramos et al., The Coronavirus Disease 2019 (COVID-19): Key Emphasis on Melatonin Safety and Therapeutic Efficacy, Antioxidants, doi:10.3390/antiox10071152.mdpi.com, doi.org.

17. Camp et al., Melatonin interferes with COVID-19 at several distinct ROS-related steps, Journal of Inorganic Biochemistry, doi:10.1016/j.jinorgbio.2021.111546.sciencedirect.com, doi.org.

18. Cross et al., Melatonin for the Early Treatment of COVID-19: A Narrative Review of Current Evidence and Possible Efficacy, Endocrine Practice, doi:10.1016/j.eprac.2021.06.001.sciencedirect.com, doi.org.

19. DiNicolantonio et al., Melatonin may decrease risk for and aid treatment of COVID-19 and other RNA viral infections, Open Heart, doi:10.1136/openhrt-2020-001568.bmj.com, doi.org.

20. Reiter (B) et al., Therapeutic Algorithm for Use of Melatonin in Patients With COVID-19, Frontiers in Medicine, doi:10.3389/fmed.2020.00226.frontiersin.org, doi.org.

21. Charaa et al., Prophylactic Treatment Protocol against the Severity of COVID-19 Using Melatonin, SSRN, doi:10.2139/ssrn.3601861.ssrn.com, doi.org.

22. Shneider et al., Can melatonin reduce the severity of COVID-19 pandemic?, International Reviews of Immunology, doi:10.1080/08830185.2020.1756284.tandfonline.com, doi.org.

23. Zhang et al., COVID-19: Melatonin as a potential adjuvant treatment, Life Sciences, doi:10.1016/j.lfs.2020.117583.sciencedirect.com, doi.org.

Loh et al., 23 Jul 2022, peer-reviewed, 2 authors. Contact: reiter@uthscsa.edu (corresponding author), lohdoris23@gmail.com.

This Paper Melatonin All

DOI record: { "DOI": "10.3390/ijms23158122", "ISSN": [ "1422-0067" ], "URL": "http://dx.doi.org/10.3390/ijms23158122", "abstract": "The relentless, protracted evolution of the SARS-CoV-2 virus imposes tremendous pressure on herd immunity and demands versatile adaptations by the human host genome to counter transcriptomic and epitranscriptomic alterations associated with a wide range of short- and long-term manifestations during acute infection and post-acute recovery, respectively. To promote viral replication during active infection and viral persistence, the SARS-CoV-2 envelope protein regulates host cell microenvironment including pH and ion concentrations to maintain a high oxidative environment that supports template switching, causing extensive mitochondrial damage and activation of pro-inflammatory cytokine signaling cascades. Oxidative stress and mitochondrial distress induce dynamic changes to both the host and viral RNA m6A methylome, and can trigger the derepression of long interspersed nuclear element 1 (LINE1), resulting in global hypomethylation, epigenetic changes, and genomic instability. The timely application of melatonin during early infection enhances host innate antiviral immune responses by preventing the formation of “viral factories” by nucleocapsid liquid-liquid phase separation that effectively blockades viral genome transcription and packaging, the disassembly of stress granules, and the sequestration of DEAD-box RNA helicases, including DDX3X, vital to immune signaling. Melatonin prevents membrane depolarization and protects cristae morphology to suppress glycolysis via antioxidant-dependent and -independent mechanisms. By restraining the derepression of LINE1 via multifaceted strategies, and maintaining the balance in m6A RNA modifications, melatonin could be the quintessential ancient molecule that significantly influences the outcome of the constant struggle between virus and host to gain transcriptomic and epitranscriptomic dominance over the host genome during acute infection and PASC.", "alternative-id": [ "ijms23158122" ], "author": [ { "ORCID": "http://orcid.org/0000-0002-1693-4081", "affiliation": [], "authenticated-orcid": false, "family": "Loh", "given": "Doris", "sequence": "first" }, { "ORCID": "http://orcid.org/0000-0001-6763-4225", "affiliation": [], "authenticated-orcid": false, "family": "Reiter", "given": "Russel J.", "sequence": "additional" } ], "container-title": "International Journal of Molecular Sciences", "container-title-short": "IJMS", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2022, 7, 25 ] ], "date-time": "2022-07-25T02:49:02Z", "timestamp": 1658717342000 }, "deposited": { "date-parts": [ [ 2022, 8, 3 ] ], "date-time": "2022-08-03T07:58:32Z", "timestamp": 1659513512000 }, "indexed": { "date-parts": [ [ 2023, 6, 28 ] ], "date-time": "2023-06-28T12:27:30Z", "timestamp": 1687955250909 }, "is-referenced-by-count": 2, "issue": "15", "issued": { "date-parts": [ [ 2022, 7, 23 ] ] }, "journal-issue": { "issue": "15", "published-online": { "date-parts": [ [ 2022, 8 ] ] } }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2022, 7, 23 ] ], "date-time": "2022-07-23T00:00:00Z", "timestamp": 1658534400000 } } ], "link": [ { "URL": "https://www.mdpi.com/1422-0067/23/15/8122/pdf", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "1968", "original-title": [], "page": "8122", "prefix": "10.3390", "published": { "date-parts": [ [ 2022, 7, 23 ] ] }, "published-online": { "date-parts": [ [ 2022, 7, 23 ] ] }, "publisher": "MDPI AG", "reference": [ { "DOI": "10.1056/NEJMc2119236", "doi-asserted-by": "publisher", "key": "ref1" }, { "DOI": "10.1111/febs.16379", "doi-asserted-by": "publisher", "key": "ref2" }, { "DOI": "10.1038/s41577-021-00662-4", "doi-asserted-by": "publisher", "key": "ref3" }, { "DOI": "10.1056/NEJMoa2109072", "doi-asserted-by": "publisher", "key": "ref4" }, { "DOI": "10.1016/j.eclinm.2021.101019", "doi-asserted-by": "publisher", "key": "ref5" }, { "DOI": "10.3389/fmed.2021.750378", "doi-asserted-by": "publisher", "key": "ref6" }, { "DOI": "10.3949/ccjm.88a.21010", "doi-asserted-by": "publisher", "key": "ref7" }, { "DOI": "10.1038/s41590-021-01104-y", "doi-asserted-by": "publisher", "key": "ref8" }, { "article-title": "NIH Launches New Initiative to Study “Long COVID.” National Institutes of Health (NIH)", "key": "ref9" }, { "key": "ref10", "unstructured": "The Impact of COVID Vaccination on Symptoms of Long Covid. 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