Early gene changes induced by isotretinoin in the skin provide clues to its mechanism of action

General Discussion
#1

Please take a moment to understand what I am talking about, I have taken the time with Propecia and everyones thoughts on here. Can those that have taken Propecia say the same?
Have you taken the time to understand my drug?

Im going to talk to the Accutane guys first and then I am going to make the possible connection with Finasteride while the recent study is fresh on everyone’s mind.

What some have you have been waiting on has already been around for over a decade with Accutane, and they did have a before and after.

This part is maybe important with Accutane, and I will throw in the words maybe and possibilities to not make absolute assumptions, but I think there is a chance for this.

Early gene changes induced by isotretinoin in the skin provide clues to its mechanism of action

Approximately half of the significantly changed genes affected by 13- cis RA contained consensus sequences for RAR or RXR receptors.

^Accutane does not bind to these receptors, it interferes with them.

Unlike tretinoin (all-trans retinoic acid), isotretinoin has little or no ability to bind to cellular retinol-binding proteins or retinoic acid nuclear receptors (RARs and RXRs)

Significant decreases in expression of genes that regulate lipid metabolism were noted after 8 weeks of isotretinoin therapy.

Gene array expression analysis was performed on patient skin biopsies at baseline and at 8 weeks of isotretinoin therapy in order to gain insight into putative pathways affected by 13- cis RA treatment. Using a false discovery rate (FDR) of 0.05 that corresponds to a 5% chance of false positive gene changes, 197 genes were significantly upregulated and 587 genes were significantly downregulated. Select genes that showed either an upregulation or downregulation of approximately two-fold or greater are listed in Table 2. For a complete listing of all significantly changed genes at 8 weeks, see Supplemental Data. The preponderance of genes that were downregulated at 8 weeks are involved in the metabolism of steroids, cholesterol and fatty acids, which is consistent with the known decreases in sebaceous gland lipid production induced by 13- cis RA. In comparison, the genes whose expression changed significantly after 1 week isotretinoin can be broadly categorized as tumor suppressors, protein processors and genes involved in the transfer or binding of ions, amino acids, lipids or retinoids.1

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#2

Regulation of gene expression by retinoids

At present, hundreds of genes are known to be regulated by retinoic acid. This regulation is very complex and is, in turn, regulated on many levels.

We have therefore evaluated published data from 1,191 papers covering 532 genes and have classified these genes into four categories according to the degree to which an hypothesis of direct versus indirect control is supported overall. We found 27 genes that are unquestionably direct targets of the classical pathway in permissive cellular contexts (Category 3 genes), plus 105 genes that appear to be candidates, pending the results of specific additional experiments (Category 2). Data on another 267 targets are not evocative of direct or indirect regulation either way, although control by retinoic acid through some mechanism is clear (Category 1). Most of the remaining 133 targets seem to be regulated indirectly, usually through a transcriptional intermediary, in the contexts studied so far (Category 0).

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#3

Link to top study seems broken?

#4

Ive posted this before, but this is an easier read then the pdf.

Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835911/#:~:text=The%20temporal%20changes%20in%20gene%20expression%20in%20patient%20skin%20noted,of%20lipid%20metabolizing%20enzymes%20and’

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#5

8 months will probably have different expression to 8 weeks aswell. Not enough information. Would be good if they did more studies years afterwards, as we know many people don’t have lasting clear skin

#6

This is where it gets more interesting with the Baylor study again showing AR overexpression.

Surprisingly, androgens can partially compensate for the loss of RA signaling, and we identify a link between the endocrine system and RA signaling:

Retinoic acid and androgen receptors combine to achieve tissue specific control of human prostatic transglutaminase expression: a novel regulatory network with broader significance

These data provide the first description of a prostate-specific gene where androgen plays a minor role in transcriptional regulation, raising the question of whether the classical transcriptional role of androgen–AR is sufficient as a mechanism to achieve prostate-specific expression. It also shows that RA might play an important role not only in prostate development but also in its function as a matured organ. Controlling the expression of prostatic genes and antagonizing the effects of androgen is important and perhaps necessary to control prostate gland homeostasis.

#7

I don’t really know what this means and probably most people here don’t either

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#8

I posted a study recently from Roche themselves where they hypothesized that acne may be caused by a problem with retinoic acid signaling. I’ve also posted studies that antiandrogens may alter vitamin a metabolism.
One of my points would be there was maybe already a vitamin a metabolism problem to begin with and Accutane was just a surface bandaid and could actually make things worse as it could further alter natural vit a metabolism.
I’ll get back to some of the rest.

#9

Let me word this differently,
Regulation of Androgen Receptor gene expression by Retinoic Acid.
My first point being what have you learned about retinoic acid?
Its functions, what it does.
I could rename this website
Accutanehelp.com and it would all read about the same.
Just replace your drug, receptors and molecules with mine and the theory that vitamin a dysfunction is the cause of everything.
Some Accutane guys have gravitated more to the thoughts of a couple key members on here like
Awor, Mew.
I said it when I first came on here, maybe it needed to be the other way around
you will learn from Accutane, retinoic acid, vitamin a, not antiandrogens.
You will learn from PAS not PFS.
Has anyone outside of PAS taken the time to learn?

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#10

Let me go back to this as an example as well, do you think he took one minute to try to understand what I was saying?
If you look at my post right before his, the thought is not that hard to comprehend, and this is a guy coming from Accutane!

Also please if your going to block my posts, just talk to me, I will listen.

#11

You can’t post study titles, grab random lines from it, add two sentences to it and expect people to understand what you’re getting at.

#12

I have intentionally tried to simplify most of my posts to begin over the course of years. I maybe have a different style on here then some. I try to say as much as possible using as few words as possible. No offense but im not spending all day on a post that people arent even reading or concerned about to begin with.

If you just glanced at this thread from top to bottom I dont think my point is that hard to come across.
One guy got it, he just happened to come from another drug.

If I posted a study on Fin would that spark some more interest?
You know it would.

If a person really doesnt understand what im saying and cared to begin with, id say take a guess, ask a question.
Im not sure how I could explain some of this further and again this has been over the course of years.

If your not around for days,weeks or not even really reading my posts any criticism isnt really going to bother me much.

This is the same guy that told me “just eat sauerkraut” after I had extensively talked about the possible importance of bacteria and the microbiome in all of this.
I came from a drug thats purpose was to permanently alter or eradicate bacteria so it never came back.
Thats one difference between Fin and Accutane, its effects were made to be permanent.

I guess maybe my brain works differently then some, lets take this study title,

Retinoic acid and androgen receptors combine to achieve tissue specific control of human prostatic transglutaminase expression: a novel regulatory network with broader significance

^ I dont even need to read the rest to see the possibility, but I have.

#13

I’m sorry but it is an entirely unreasonable expectation to expect people to read your posts for months on end to make sense of them. What is the point that you are trying to make?

You’ve posted a study that says that isotretinoin treatment changes gene expression in the skin of people WHILE they are on it. The Baylor study looked at gene expression in the penile tissue of people who were experiencing side effects WELL PAST their usage of Finasteride. How are these the same to you?

#14

Idk I have a feeling you only went back and read some of this after I said something. Reading my posts for months on end is not quite what I was saying. I think maybe you are choosing to argue over listen. I’m just saying if I was going to try to sum up my thoughts in every individual post it would be pages not paragraphs and who in the hell is going to read that.

You’ve also had a few studies now on fin of side effects that persisted after the drug, I just requoted one yesterday. Isn’t that what routers was about as well? I think some of these clues about changes in gene expression could very much be valid.

I’ve also posted a study about 5 times now on persistent side effects 20 years after Accutane.
Did you happen to catch that one?

I will say you got some momentum right now with these researchers looking at fin.

#15

Have you heard of KISS?
Keep it simple stupid.
Its an engineering philosophy.

Im going to add to some of this, I was on my lunch break earlier.

Oral isotretinoin (13-cis-retinoic acid) therapy in severe acne …

https://pubmed.ncbi.nlm.nih.gov › …
(https://pubmed.ncbi.nlm.nih.gov/2943822/)

The results suggest that isotretinoin therapy interferes with the endogenous vitamin A metabolism in the skin. Publication types. Clinical Trial;

Effects of pharmacological retinoids on several vitamin A-metabolizing enzymes

13-cis-retinoic acid, and all-trans-retinoic acid are vitamin A derivatives used in the treatment of cancer and severe acne. Patients taking these drugs often show side effects resembling the symptoms of hypovitaminosis A, namely, night blindness and decreased plasma retinol levels. A dietary vitamin A deficiency is not suspected in these patients; therefore, interference with normal vitamin A metabolism seems likely.

^So this could possibly be the case both internally and externally.

So what gene changes were we seeing again @borax?

Approximately half of the significantly changed genes affected by 13- cis RA contained consensus sequences for RAR or RXR receptors.

What are some of these genes involved in?
The preponderance of genes that were downregulated at 8 weeks are involved in the metabolism of steroids, cholesterol and fatty acids,

This was that study from yesterday, I thought this was actually pretty good seeing this again.

Effects of Subchronic Finasteride Treatment and Withdrawal on Neuroactive Steroid Levels and Their Receptors in the Male Rat Brain

One month after the last treatment (i.e., withdrawal period), some of these effects persisted (i.e., the upregulation of the androgen receptor in the cerebral cortex, an increase of dihydroprogesterone in the cerebellum, a decrease of dihydrotestosterone in plasma).

You can see how this is already getting a little messy so im going to end it right here for now.
Plus I just got off work and want to grab a beer.
I’ll be done here real soon.

#16

I took it for longer than 3 months, so it seem blood levels seem to deviate from skin, so I wonder if blood levels are not a good reflection of organ or tissue levels?

#17

This is something to remember. This is the probiotic Align in the States and Aflorex overseas.
Bifido Longum strain 35624.
This will get you back into video games.

promotion of retinoic acid metabolism by B. infantis was a key regulatory feature of this bacterium [21]. In this report, we demonstrate that B. infantis feeding to mice results in increased CD103+RALDH+ dendritic cells within the mucosa

Male microbiota-associated metabolite protects

Male mice treated with flutamide exhibited increased disease incidence and severity, and decreased CD103DC function including a decreased ability to induce conversion of Tregs in vitro and decreased expression of RALDH2 mRNA

If anyone was wondering that means antiandrogens (and im sure you could put Finasteride in this category) could alter vitamin a metabolism.

#18

Just thinking about the skin study, I remember around the 3 month mark, skin dryness and peeling was chronic at 6 not so. So is retinol still high in skin at 6 month mark?

What I’m trying to say is if skin retinol drops, off treatment and on at 6 month mark, where does it go?

#19

Vitamin A supplements gave me eye floaters, thats a fact.
There could be an issue with metabolism of dietary vit a (or supplements) to its active form retinoic acid.

Gut dysbiosis could play a major role in this.

"Recent studies show that both commensal and pathogenic bacteria drastically alter vitamin A metabolism in the host."

One potential pathogen that comes to mind is p.acnes. A very common bacteria. Accutane only treated this on the skin.
Remember this patent I posted?

Propionibacterium inhibits apoptosis of keratinocytes, and increase the expression of internal androgen receptor.

#20

I really don’t think p.acnes is gone, vitamin deficiency could be making people think it has.