#doris loh

I explored the molecular mechanisms for neurodegeneration in my last peer-reviewed paper “Melatonin regulation of phase separation in Neuro-PASC: out-maneuvering Janus-faced amyloids” [1]. As for cancer, the topic was discussed in my peer-reviewed paper on Long-COVID in 2022 [2].

A recently published peer-reviewed study that compared DNA damage in healthy, non-ICU, non-intubated ICU, and intubated-ICU COVID-19 patients, in order to determine if there is a relationship between COVID-19 infection and symptoms of Long-COVID [3].

The authors discovered that there is a distinct correlation in intensity of DNA damage with severity of COVID-19 disease. If you look at the chart below, you will see that severe infections result in higher DNA tail length and intensity [3]. What can cause these changes to DNA?

Increased DNA Tail Length and intensity -

The authors of the study employed the comet assay to assess DNA damage in COVID-19 patients. The DNA tail length refers to the distance DNA fragments migrate away from the main body of the nucleus when subjected to an electric field. It is a key parameter used to assess DNA damage, as longer tails generally indicate more extensive DNA damage. Whereas, the tail intensity refers to the proportion of DNA that migrates away from the cell's nucleus during electrophoresis, forming the "tail" in the comet-like image. Essentially, it quantifies the amount of DNA damage by measuring the fluorescence intensity of the tail relative to the overall fluorescence of the comet. A higher tail intensity indicates a greater extent of DNA damage.

The authors of the 2025 paper did not explain potential molecular mechanisms that can cause these DNA damages. But my 2022 paper presented LINE-1 derepression and hypomethylation as potential causes for DNA damage leading to genomic instability and disease [1].

Derepression of LINE-1, often observed in cancer, neurodegenerative disorders, and natural aging, can lead to increased DNA tail length and intensity due to their retrotransposition activity. This occurs because L1 elements, when not suppressed, can mobilize themselves through a process called target-primed reverse transcription (TPRT), which involves reverse transcribing an RNA copy of the L1 element into DNA and inserting it into a new genomic location. The inserted DNA often has a poly(A) tail and may be truncated at the 5' end, resulting in variable DNA tail lengths [4-6].

It is interesting to note that I am unable to find peer-reviewed reports on viruses that specifically cause LINE-1 derepression. Conversely, several peer-reviewed papers present evidence of LINE-1 derepression caused by the SARS-CoV-2 virus []7,8].

The important questions are, of course, can melatonin suppress LINE-1 derepression and attenuate potential DNA damages?

GOT MEL?” -Doris Loh

References

[1] Loh D, Reiter RJ. Melatonin regulation of phase separation in Neuro-PASC: out-maneuvering Janus-faced amyloids. Explor Neurosci. 2025;4:100678. https://doi.org/10.37349/en.2025.100678

[2] Loh, D.; Reiter, R. J. Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19. Int. J. Mol. Sci. 2022, 23 (15), 8122. https://doi.org/10.3390/ijms23158122.

[3] Abiri, E.; Abiri, A.; Daneshi, S.; Raesi, R. The Silent Legacy of COVID-19: Exploring Genomic Instability in Long-Term COVID-19 Survivors. BMC Infect. Dis. 2025, 25, 1–9.

[4] Morrish TA, Gilbert N, Myers JS, et al. DNA repair mediated by endonuclease-independent LINE-1 retrotransposition. Nat Genet. 2002;31(2):159-165. doi:10.1038/ng898

[5] Zhang X, Zhang R, Yu J. New Understanding of the Relevant Role of LINE-1 Retrotransposition in Human Disease and Immune Modulation. Front Cell Dev Biol. 2020;8:657. Published 2020 Aug 7. doi:10.3389/fcell.2020.00657

[6] Simon M, Van Meter M, Ablaeva J, et al. LINE1 Derepression in Aged Wild-Type and SIRT6-Deficient Mice Drives Inflammation. Cell Metab. 2019;29(4):871-885.e5. doi:10.1016/j.cmet.2019.02.014

[7] Zhang, L.; Richards, A.; Barrasa, M. I.; Hughes, S. H.; Young, R. A.; Jaenisch, R. Reverse-Transcribed SARS-CoV-2 RNA Can Integrate into the Genome of Cultured Human Cells and Can Be Expressed in Patient-Derived Tissues. Proc. Natl. Acad. Sci. U. S. A. 2021, 118.

[8] Zhang, Liguo, et al. "LINE1-mediated reverse transcription and genomic integration of SARS-CoV-2 mRNA detected in virus-infected but not in viral mRNA-transfected cells." Viruses 15.3 (2023): 629.

Why do all living organisms in the three domains of life -- archaea, eukarya, and prokarya -- all synthesize and utilize melatonin for possibly well over three billion years?

A new peer-reviewed article offers a glimpse into the vast, untapped world of phase separation where prion-like domains play critical roles in the organization and promotion of life at the most basic genetic, molecular level [1].

The authors reported that the "NANOG prion-like domain assembly is essential for specific DNA recognition and distant chromatin interactions". That means NANOG's ability to form prion-like assemblies via phase separation is the key to the cooperative and concerted DNA bridging mechanism that is essential for chromatin reorganization and pluripotency.

Since September of 2021, I have published two ground-breaking papers co-authored with the esteemed Dr. RJ Reiter on the ability of melatonin to not only regulate biomolecular condensate phase separation, but also exert regulatory control over physiological, pathological prions, and prion-like domains [2,3].

According to the current report on prion-like domains of NANOG, the ability to easily phase separate and form condensates is most important during early stages of pluripotency programming [1]. Thus the ability of melatonin to regulate LLPS to promote optimal condensate formation and prevent aberrant aggregation is potentially the holy grail to health and disease.

That is probably the reason why melatonin is effective for just about any condition you can think of. If you don't understand how melatonin regulates phase separation, I suggest you read this article now https://www.mdpi.com/2076-3921/10/9/1483#abstract

It will help you understand my next ground-breaking paper on melatonin and #Longcovid, which is of course, based on the principle of phase separation.

Have you had your MEL and AA today?*

* Disclaimer: These statements have not been evaluated by the Food and Drug Administration. Ascorbic acid, melatonin and any other product mentioned is not intended to diagnose, treat, cure or prevent any disease.

References

[1] Choi, K.-J.; Quan, M. D.; Qi, C.; Lee, J.-H.; Tsoi, P. S.; Zahabiyon, M.; Bajic, A.; Hu, L.; Prasad, B. V. V.; Liao, S.-C. J.; Li, W.; Ferreon, A. C. M.; Ferreon, J. C. NANOG Prion-like Assembly Mediates DNA Bridging to Facilitate Chromatin Reorganization and Activation of Pluripotency. Nat. Cell Biol. 2022, 24 (5), 737–747. https://doi.org/10.1038/s41556-022-00896-x.

[2] Loh, D.; Reiter, R. J. Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders. Antioxid. Redox Signal. 2021, 10 (9), 1483. https://doi.org/10.3390/antiox10091483.

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance