Quote from Johannes on December 22, 2021, 8:22 am

I also don’t know much about RAR agonists, but logic would suggest that since retinoic acid is an RAR ligand, other RAR agonists would similarly not be beneficial. Pharmacologically, the following classes of substances are most likely to be beneficial:

• Prostaglandin G/H synthase (PTGS) inhibitors like ibuprofen; of these low-dose aspirin seems to be the safest to take long term, and it may also be more effective than ibuprofen since it targets the constitutively expressed PTGS1 and not the inducible PTGS2
• Any treatment that works against COVID-19 also appears to prevent vitamin A toxicity: ivermectin completely inhibits bacterial RBP4 and around 15% of hepatic RBP4 in rodents (Sani and Vaid 1988) while hydroxychloroquine blocks the uptake of retinol into human embryonic kidney cells (Nicolò, Ferro Desideri et al. 2021); in my opinion the reason these treatments are demonized so much is not because they work against COVID-19 but because they work against vitamin A toxicity! The people in charge don’t care whether you die from COVID-19 or not, but they care very much that everyone gets their daily dose of retinoids; if everyone started taking these substances prophylactically against COVID-19, people might accidentally “wake up” and stop believing all of their propaganda!
• CYP26A1 inhibitors should theoretically be safe to use in women, as they are likely to promote anti-inflammatory, pro-estrogenic metabolism of retinoic acid; similarly aromatase inducers may be beneficial in women
• Zinc and possibly calcium to increase intracellular pH, and also because zinc is a co-factor for both the synthesis and functionality of a number of enzymes
• STAT5/IL6/JAK2 inhibitors could theoretically lead to a transient increase in the severity of symptoms (since they prevent storage of retinol and therefore promote oxidative metabolism), but that could be beneficial if the goal is to totally “purge” vitamin A from tissues
• Conversely, aldehyde dehydrogenase (ALDH) inhibitors such as citral/lemongrass oil appear to transiently attenuate symptoms, but I’m not sure how desirable that is since it also prevents elimination of retinol
• Supplementing with certain anti-inflammatory lipids like palmitic acid or docosahexaenoic acid looks to be beneficial on paper, but great care must be taken when choosing the right lipid, since very subtle chemical differences seem to determine whether a lipid is pro- or anti-inflammatory; for example (5R)-OH-ETE is anti-inflammatory whereas (5S)-OH-ETE is pro-inflammatory, and I think this is also the reason why fish oil supplements are so controversial in scientific literature

In general, I have quite a few reservations about pharmacological treatments, since a) it is very rare that a substance specifically interacts with just one target enzyme/protein, and b) even if a substance is highly specific, our genes are not, and they often perform different functions based on the cellular context or even localization (the PRKCs are a great example of this). In general, sunlight appears to be the most beneficial of any supplement, since it prevents illness (less colds/illnesses in summer) and because it causes isomerization (and/or decomposition) of all-trans-retinoic acid to the slightly less inflammatory 13-cis-RA; however I suspect that it may also induce isomerization to 9-cis-RA, which is almost undetectable in humans because it is rapidly consumed/eliminated as soon as it’s formed. Because we know so little about 9-cis-RA, it is quite possible that 9-cis-RA is significantly less toxic than the other retinoids.

Bibliography

Nicolò, M., L. Ferro Desideri, M. Bassetti and C. E. Traverso (2021). "Hydroxychloroquine and chloroquine retinal safety concerns during COVID-19 outbreak." International ophthalmology 41(2): 719-725.

Sani, B. P. and A. Vaid (1988). "Specific interaction of ivermectin with retinol-binding protein from filarial parasites." The Biochemical journal 249(3): 929-932.