Quote from Hermes on November 9, 2021, 1:20 pm

This is a lot of information that goes over my head. Thank you for putting up the post and presenting the information in a graphic. It looks really neat. I haven't smoked for most of my life but picked up the habit when I was 29. In March 2019 I started with the low vitamin A diet, and there have been times I was smoking a lot, but the craving is still there today. I smoke a little less, but still enough that I could save quite some money without engaging in the habit.

User YH talks about his experience with smoking too in this thread [Long story short: Discovered my Vitamin A issues through smoking cigarettes.] and argues how beneficial it might be in the process of clearing RA. Not sure if this is in line with what you suggest above.

Quote from ggenereux on November 9, 2021, 7:11 pm

Hi @johannes2,

Thanks for putting together this analysis and sharing it here. Quite interesting. There are now three people who have reported an observed connection between smoking to their vitamin A intake.  But, it might be some other component rather than just nicotine that's beneficial.

One person (~ 60 yo man) was a longtime user of cannabis primarily to control his IBD symptoms. After about 2 years on a low vA diet says he no longer needs the cannabis. 

There’s also the HIV/AIDS study I mentioned a while back. When people with the disease stopped smoking cigarettes their chances of getting cancer in the following two years was significantly increased, not decreased as one might expect.

 

Quote from r on November 10, 2021, 1:21 am

Quote from Johannes on November 9, 2021, 10:18 am

A study exploring the relationship between growth hormone receptor (GHR) and retinol-binding protein 4 (RBP4) was recently published (Liu, Nie et al. 2021). The team revealed that GHR induces transcription of RBP4 by phosphorylation of tyrosine-protein kinase JAK2 (JAK2) and signal transducer and activator of transcription 5 (STAT5), which is the same pathway activated by holo-RBP4 and receptor for retinol uptake STRA6 (STRA6). The study therefore also apparently shows that RBP4 induces its own transcription when it activates STRA6/STAT5. Additionally GHR, by inducing hypoxia-inducible factor 1-alpha (HIF1A), promotes transcription of transthyretin (TTR), which forms a complex with and stabilizes RBP4.

While looking for GHR inhibitors I unexpectedly learned that nicotine inactivates both STAT5 and glucocorticoid receptor NR3C1 (Kobayashi, Tsugami et al. 2020), which I have recently shown to be highly correlated with retinol-related genes. STAT5 activation primarily results in weight gain, either by forming a heterodimer with peroxisome proliferator-activated receptor gamma (PPARG) (Dentelli, Trombetta et al. 2009) or by inhibiting transcriptional activity of PPAR alpha (Zhou and Waxman 1999).

Since STAT5 also controls transcription of RBP4, and nicotine inactivates STAT5, it appears that nicotine promotes elimination of retinol by preventing both its transport and esterification. This mechanism could explain why smoking prevents weight gain, and it could be linked to the occurrence of lung cancer. If STAT5 is inactivated, more retinol will be metabolized to retinoic acid (RA), and RA may cooperate synergistically with carcinogens in tobacco smoke to promote tumorigenesis. 

The SARS-CoV-2 spike protein (S) has recently been shown to bind to STRA6 (Mahmoud, Tamer et al. 2021), and this mechanism could also explain the decreased incidence of COVID-19 in smokers. Since both S and nicotine inhibit STAT5 activity, smokers will have already adapted to moderate STAT5 disruption and will be less affected by the additional disruption caused by S.

Inactivation of STAT5 could also explain why smoking is addictive, since it appears to provide temporary relief from vitamin A’s primary effects. Recall that STRA6 is a cytokine receptor, so the body naturally works to prevent its activation. If nicotine blocks its downstream effects, this would signal to the body that the pathogen has been defeated (even though there is no pathogen), and it would teach the adaptive immune system that pathogens can be defeated by smoking, even though there is still no pathogen, just vitamin A. It could even explain increased cravings for cigarettes after eating.

Finally, this theory would also predict an increased risk of NAFLD in smokers, because in smokers retinol is less likely to accumulate and more likely to be metabolized to retinoic acid. Indeed, this prediction is confirmed by a recent study, calculating an odds ratio (OR) of 1.11 for smokers and, interestingly, an OR of 1.38 for passive smokers (Akhavan Rezayat, Dadgar Moghadam et al. 2018).

I tried putting all the puzzle pieces together in the following graphic:

Edit: Teratogenicity of nicotine could also be explained by increased metabolism of retinol to RA.

Bibliography

Akhavan Rezayat, A., M. Dadgar Moghadam, M. Ghasemi Nour, M. Shirazinia, H. Ghodsi, M. R. Rouhbakhsh Zahmatkesh, M. Tavakolizadeh Noghabi, B. Hoseini and K. Akhavan Rezayat (2018). "Association between smoking and non-alcoholic fatty liver disease: A systematic review and meta-analysis." SAGE open medicine 6: 2050312117745223-2050312117745223.

Dentelli, P., A. Trombetta, G. Togliatto, A. Zeoli, A. Rosso, B. Uberti, F. Orso, D. Taverna, L. Pegoraro and M. F. Brizzi (2009). "Formation of STAT5/PPARγ Transcriptional Complex Modulates Angiogenic Cell Bioavailability in Diabetes." Arteriosclerosis, Thrombosis, and Vascular Biology 29(1): 114-120.

Kobayashi, K., Y. Tsugami, N. Suzuki, T. Suzuki and T. Nishimura (2020). "Nicotine directly affects milk production in lactating mammary epithelial cells concurrently with inactivation of STAT5 and glucocorticoid receptor in vitro." Toxicol In Vitro 63: 104741.

Liu, J., C. Nie, L. Xue, Y. Yan, S. Liu, J. Sun, M. Fan, H. Qian, H. Ying, L. Wang and Y. Li (2021). "Growth hormone receptor disrupts glucose homeostasis via promoting and stabilizing retinol binding protein 4." Theranostics 11(17): 8283-8300.

Mahmoud, E., H. Tamer, A.-A. Yousry Esam-Eldin, S. Heba, M. S. Israa, F. A. E. M. Mohammed and A. Amr (2021). "STRA6, as A Novel Binding Receptor of COVID-19, A Breakthrough That could Explain COVID-19 Symptoms with Unknown Aetiology." Research Square.

Zhou, Y. C. and D. J. Waxman (1999). "STAT5b down-regulates peroxisome proliferator-activated receptor alpha transcription by inhibition of ligand-independent activation function region-1 trans-activation domain." J Biol Chem 274(42): 29874-29882.

"Inactivation of STAT5 could also explain why smoking is addictive, since it appears to provide temporary relief from vitamin A’s primary effects. "

I am a Vitamin A toxic person ( ingested cod liver oil and supplements + sweet potatoes / carrots ). I am a smoker , but stopeed smoking recently for a while ( it messed up my stomach acid ) . I Do confirm that smoking does cause some effect on Vitamin A in the body , but it wasn't a relief in symptoms , but rather my symptoms would flare up for a while ? Maybe more Vitamin A was released to the blood from Liver ?

I really can't say how much smoking has helped me to reduce my vitamin A level , but it does have some effect on Vitamin A for sure 
can't say positive or negative 

Quote from Armin on November 10, 2021, 7:46 am

Interesting stuff.

It does seem that tobacco is used as a palliative for ones with chronic illness. The Marshall Protocol's take on this is that nicotine lowers immune system potency and therefore symptoms and the chlorogenic acid in "foods" like tobacco/coffee are potent innate immune system modulators. 

Chronic inflammation causes the brain to downregulate dopamine in an attempt to conserve energy and heal. Like a sick/wounded cat/dog hiding under the deck or in the garage after a fight, the body wants the organism to rest. The problem with this in modern life is that we don't have months/years to sit on our asses and recover.

So, these compounds in tobacco and coffee have 2 fold effects. It reduces immune symptoms and increases dopamine, giving ones motivation to operate in the world as they fight off illness.

Currently, by body does not tolerate coffee. It does ok on caffeine but coffee messes me up (feeling of being drunk/in a haze) and doesn't blunt any current symptoms. Nicotine/tobacco seems to aid more so. 

Quote from Hermes on November 10, 2021, 8:39 am

Interesting how you mention that tobacco both reduces immune symptoms and increases dopamine. For me, coffee is a no-go too. It messes with my sleep and makes me nervous. Maybe I'll come back to it again because I really like the taste of it. Tobacco on the other hand makes me alert without the jitters. I actually enjoy smoking a cigarette.

Quote from Johannes on November 11, 2021, 6:43 am

Thanks for sharing those stories Christian and Grant, it’s always reassuring to see predictions get confirmed by real-life experiences. The topic of cannabis is also very interesting, since RBP2 was shown to transport not just retinol but also the most abundant endocannabinoid 2-arachidonoylglycerol (2-AG), which is the ester of arachidonic acid and glycerol (reviewed by Blaner, Brun et al. 2020). I’ve been meaning to post about it for a while, but I still don’t really understand what functionally distinguishes RBP1 from RBP2 (apart from the fact that RBP2 is only expressed in the small intestine), and I want to learn some more about that before I post. For example, cellular retinoic acid-binding protein 1 (CRABP1) is believed to channel RA to enzymes for elimination whereas CRABP2 is believe to channel RA to the nucleus for transcriptional activation, but it appears that no such distinction can be made for RBP1 and RBP2. (Napoli 2016) provides a detailed, albeit complex review, and I’m currently working to resolve the logical inconsistencies arising from conflicting results in some of the referenced studies. Napoli’s work appears sincere, since he admits that in many past studies “the minimum vitamin A content [in rodent chow] was sixfold greater than the amount of vitamin A recommended for rodents”.

R, what you describe in fact appears to further support the theory, and I think I didn’t explain it as well as I could have. It’s important to distinguish between two different responses caused by vitamin A. In the first response, which I have previously referred to as “primary effects”, retinol is esterified for long-term storage and this process is mediated by STRA6/STAT5. These effects are similar to the effects produced by growth hormone. Apart from the first response there is also the terminal response, which occurs when the body tries to eliminate retinol. The terminal response includes oxidation to retinoic acid and culminates in formation of a metabolite like (4R)-OH-retinoyl glucuronide that is soluble enough to be eliminated in feces.

The precise kinetics of both responses are still very uncertain. In my opinion the purpose of the first response is to delay/slow down the terminal response to a great enough extent that minimal toxicity occurs, kind of like “flatten the curve”. When, for a number of different reasons, the terminal response is accelerated, the phenomenon we call “VA toxicity” occurs. Some of these reasons include

- No more available capacity for storage of retinyl esters

- Opportunistic hydrolization of retinyl esters by bacteria

- Alcohol consumption, although the precise mechanism for this is ill-defined

- As I mentioned in the original post, nicotine and SARS-CoV-2 spike protein

Conversely, I believe citral inhibits the terminal response and promotes the first response which is why it is anti-inflammatory.

If the terminal response is already occurring at a high rate, smoking will cause formation of even more retinoic acid, and even though that is a good thing in principle (because the retinoic acid is ultimately eliminated) it can cause symptoms to flare up. The COVID-19 spike protein and vaccines partially or completely inhibit the first response, which is why they can produce severe inflammation and death.

I also want to point out that user YH mentioned they were suffering from depression and that this was relieved by smoking. Since depression is linked to weight gain, and weight gain occurs during the first response, it is possible that the first response induces depression, and that therefore smoking could relieve depression symptoms. Unfortunately, throughout scientific literature not much care has been taken to distinguish between the effects of retinol and retinoic acid, which can sometimes make it difficult to discern what is causing what.

To summarize, nicotine appears to be beneficial if for some reason the terminal response isn’t happening as fast as it could be happening, but detrimental if the terminal response is already proceeding as fast as it can without causing overt toxicity.

Armin, you make some good points, and I’ve also been meaning to look at the relationship between stimulants and vitamin A more closely. Hopefully I’ll get around to it sometime soon.

Bibliography

Blaner, W. S., P.-J. Brun, R. M. Calderon and M. Golczak (2020). "Retinol-binding protein 2 (RBP2): biology and pathobiology." Critical reviews in biochemistry and molecular biology 55(2): 197-218.

Napoli, J. L. (2016). "Functions of Intracellular Retinoid Binding-Proteins." Sub-cellular biochemistry 81: 21-76.

Quote from ggenereux on November 11, 2021, 7:45 am

Just linking a few prior forum comments regarding smoking:

From @tim-2,

https://ggenereux.blog/discussion/topic/smoking-and-va/

From YH

https://ggenereux.blog/discussion/topic/long-story-short-discovered-my-vitamin-a-issues-through-smoking-cigarettes/#postid-253

https://ggenereux.blog/discussion/topic/nearly-7-months-progress/

I have completely stopped smoking cigarettes because I don't crave them at all. Cravings for many junk foods are gone.

Maybe somewhat related, YH's experience with the reduced appleal of coffee is about the same as mine.

 

 

Quote from Armin on November 12, 2021, 8:31 am

Looking back on my history of vices such as smoking, drinking alchohol/coffee, etc, I can't help but wonder what was really going on.

My illnesses started well before I drank coffee, smoked, drank alcohol, etc. I did find it interesting that when I was started doing these things after my illnesses cropped up, I was reminded by "health experts" that doing these things depleted nutrients. The logical conclusion is that I needed to increase my intake of "healthy" foods full of nutrients to counterbalance the negatives of what I was doing. I even worked at a health food store and tried everything in there and nothing really made a difference. "Eat more greens, colored vegetables, PUFAs". In hindsight, these were just making things much worse.

That doubly goes for working out. "Since you are taxing your body with exercise, make sure you get more nutrients". For me it was a recipe for disaster.

We have been blaming the wrong things. I don't absolve these vices as harmless but the combination may be the lynchpin. People back in the 50s/60s smoked and drank and their health wasn't nearly as bad as ours.

Quote from r on November 12, 2021, 8:37 am

http://www.anaturalhealingcenter.com/documents/Thorne/articles/bowel_disease8-3.pdf

 

 

Epidemiological data have found smoking may confer some level of protection from UC. Thirty newly diagnosed UC patients were matched for age, sex, and marital and economic status with healthy controls. Patients with UC were three times less likely to smoke but seven times more likely to have quit smoking an average of 27 months prior to diagnosis.