Friday Hope: Inhibition of LSD1: Significantly Dampen Cytokines While Minimally Impacting Interferon
Interestingly, inhibition of LSD1 is also a cancer therapeutic, and we deepen our understanding of the usual natural players (Curcumin, Melatonin, Resveratrol…).
Once again, we find a parallel between cancer therapy – and COVID therapy. In this case, it is the inhibition of a histone demethylase: LSD1.
First, what is LSD1 and how does it impact disease? Please note that I have repeatedly pointed out the Spike Protein induces the tumor microenvironment.
Lysine-specific demethylase 1 (LSD1) targets mono- or di-methylated histone H3K4 and H3K9 as well as non-histone substrates and functions in the regulation of gene expression as a transcriptional repressor or activator. This enzyme plays a pivotal role in various physiological processes, including development, differentiation, inflammation, thermogenesis, neuronal and cerebral physiology, and the maintenance of stemness in stem cells. LSD1 also participates in pathological processes, including cancer as the most representative disease. It promotes oncogenesis by facilitating the survival of cancer cells and by generating a pro-cancer microenvironment.
Roles of lysine-specific demethylase 1 (LSD1) in homeostasis and diseases
https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-021-00737-3
Now, let’s look at its role in COVID. LSD1 allows for enhanced Spike-ACE2 interaction.
Treatment options for COVID-19 remain limited, especially during the early or asymptomatic phase. Here, we report a novel SARS-CoV-2 viral replication mechanism mediated by interactions between ACE2 and the epigenetic eraser enzyme LSD1, and its interplay with the nuclear shuttling importin pathway. Recent studies have shown a critical role for the importin pathway in SARS-CoV-2 infection, and many RNA viruses hijack this axis to re-direct host cell transcription. LSD1 colocalized with ACE2 at the cell surface to maintain demethylated SARS-CoV-2 spike receptor-binding domain lysine 31 to promote virus-ACE2 interactions.
Targeting novel LSD1-dependent ACE2 demethylation domains inhibits SARS-CoV-2 replication
https://www.nature.com/articles/s41421-021-00279-w
Again, as I have repeatedly observed, stop the Spike, stop the pathology. Additionally, targeting LSD1 also dampens cytokine expression while minimally impacting antiviral interferon response.
We showed that the nuclear factor κB–dependent inflammatory response to viral infection was selectively inhibited by loss of the lysine demethylase LSD1, which was previously implicated in innate immune responses to cancer, with negligible effects on the antiviral IFN response. LSD1 ablation also enhanced an IFN-independent antiviral response, blocking viral egress through the lysosomal pathway.
Inhibition of the lysine demethylase LSD1 modulates the balance between inflammatory and antiviral responses against coronaviruses
https://www.science.org/doi/10.1126/scisignal.ade0326
Fortunately, there are ways to naturally inhibit the expression of LSD1, and, fascinatingly, they are some of the starting lineup we have been using all along. This gives us further understanding of the mechanisms by which these natural compounds help us in our fight against SARS-CoV-2 and its Spike Protein:
Resveratrol
The inhibitory activity of resveratrol against LSD1 was independent on its antioxidant properties and was specific, not through SIRT1 activation. For myogenic differentiation of C2C12 fibroblasts, LSD1 is required61. The authors found that in C2C12 cells, resveratrol effectively inhibited myocyte formation and myosin heavy chain (MHC) expression. Finally, they speculated that resveratrol bound to LSD1 to inhibit its demethylase activity. The data may suggest that resveratrol would be a good starting point for designing new LSD1 inhibitors.
Curcumin
In 2013, Abdulla et al.60 first reported that curcumin inactivated LSD1 independent on its antioxidant property. Curcumin effectively suppressed myocyte formation of cell differentiation and the expression of both myogenin and MHC. Very recently, Zhao and co-workers71 reported that curcumin inactivated LSD1 (IC50 = 9.6 μmol/L), further structure-based modifications of curcumin gave cinnamamides as new LSD1 inhibitors, of which WB07 demonstrated the best potency (IC50 = 0.8 μmol/L) and was selective over MAO-A/B (IC50 > 50 μmol/L).
Melatonin
In 2017, Yang et al.81 revealed that melatonin showed therapeutic potential in patient-derived tumor xenograft (PDTX) models bearing oral cancer cells via suppressing LSD1. After treatment for 42 days, melatonin inhibited tumor growth and weight significantly without observed toxicities. In contrast to the control group, LSD1 expression was significantly lower in the melatonin-treated group.
Olive Oil
As a natural phenolic secoiridoid found in extra virgin olive oil (EVOO), oleacein directly inhibited LSD1 (IC50 = 2.5 μmol/L) in the alpha-screen-based in vitro assays. Besides, oleacein completely suppressed the expression of sex determining region Y-box 2 (SOX2) in cancer stem-like and induced pluripotent stem (iPS) cells. Oleacein could be potentially used as a hit compound to design new secoiridoid-based LSD1 inhibitors.
Natural products as LSD1 inhibitors for cancer therapy
https://www.sciencedirect.com/science/article/pii/S221138352030616X
I highly recommend reading the quoted paper in its entirety, as it is extremely educational.
The above is a work of medical research and not medical advice. As with all medications and supplements, consult your primary care provider before use.
There is hope. There are tools we can use to fight against the damage that the Spike Protein causes. I will continue to work to uncover more understanding and healing. Thank you for your readership and support.
Thank you Walter. We are all much better off because of your research.
Thank u so much Walter . This essay caused me to look up the Pacific Yew . We learned about this in medical school regarding Taxol , chemo drug used in ovarian cancer treatment. There are so much God put on this earth to help us and heal us .