Need ur guys help! important! possible demethylation treatment!

#1

Sorry guys closed because of privacy reasons.

I ask ur help in links/explanations why epigenetic silencing of genes is what is happening to us. A possible demethyating treatment may be tested by me in the future. Thanks in advance guys.

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#2

@awor What would u say? Thanks in advance, this is very important for me.

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#3

First of all, I find it very good of Dr. Healy to get involved in this proactive way. Also very positive is that you are not medicating yourself with some research chemicals, but having specialists treat and monitor you. I would not get into much theory discussions with Healy at this point, I don’t think that will be of much use, for various reasons. If he has any questions to me, he can freely contact me (he has my contacts).

Keep us posted on your exciting journey.

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#4

I don’t have much to add other than good luck
man, you are lucky to have found a doctor willing to do this with you.

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#5

Hey. It’s not i am going to discuss the theory with him specific. It’s more i need to make a paper to explain the theory so he can give that to the docs in Holland. Thats what i ask help with. I know u know a lot about it, so I ask if u maybe have some papers/explanations u think are usefull for me to write down? Thanks btw man, appreciated.

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#6

Best of luck.

#7

Just to chime in here and say Dr Healy’s a good guy. Maybe we can soon collaborate on some projects. I think we both want the same thing.

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#8

Good luck @AnhedonicApe and thanks for doing this.

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#9

Hear hear. Very very best of luck.

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#10

Hi @AnhedonicApe

It’s very interesting you’re going to trial this, but I must point out this is not to be taken lightly. To be even potentially effective, which we certainly cannot say it will be, you would likely need to be using this drug for a considerable time.

To provide context as I am not sure how familiar you are with epigenetics, methylation modifies chromatin and thus alters the access of proteins that bind to DNA. Methylation is a repressive modification that can be practically permanent as it is “copied” upon cell division by methyltransferase enzyme DNMT1, while the enzymed DMT3a and 3b establish new methylation. The base 5-methylcytosine is formed through the attachment of a methyl group to the 5th position of the cytosine ring in a CpG dinucleotide. More methylation in a CpG island means a more repressed gene - a “dimmer switch” if you like. Methylation is by its very nature a question of degrees, and provides compelling explanation for the vast difference in affected sites and severities between patients (e.g. why some have a functional impairment like anesthesia while others will experience severe atrophy), and why additional persistent symptoms develop in PFS/PSSD patients following further endocrine disruption.

Proven significant epigenetic differences in pfs patients with genital pain and atrophy (Di Loreto 2014) were averagely 5 years after cessation, and this would rule out transient modifications in severe cases. Traish’s 2018 paper, The Post-finasteride Syndrome: Clinical Manifestation of Drug-Induced Epigenetics Due to Endocrine Disruption, discusses this finding.

During cell division and replication, DNMT1 maintains existing methylation, and is thus the target of Decitabine. Decitabine’s relevant action is the inhibition of DMNT1, and the result is a reduced maintenance of existing methylation. To be clear, methylation is crucially important in like…not being a pile of soup…and 80% of mammalian CpG islands are methylated. This is very important to cell differentiation. The effects of inhibition are more significant in the frequent application of cancer, as cancer cells divide much faster than other somatic cells, so are vulnerable to the interruption of DNMT1. To use such a thing to address deleteriously methylated loci in somatic cells, it remains to be seen whether something this nonspecific could be taken for a long enough duration without adverse effects in the rest of the organism. It is also important to consider that adult neurons do not divide. Although DNMT enzymes are expressed in postmiotic neurons, it is not yet clear exactly how they mechanistically regulate neuronal transcription.

I hope that helps you make your decision, and I wish you luck if you go ahead with it. Please keep us informed if so.

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#11

Well explained. U are right, but I don’t see another way anymore tbh. How long do u think i would need to trial to see potential effect? Normal treatment for cancer is like a month i thought, they use 4 days with breaks of a week. Would u think i can’t take these breaks? How would u do it if u were me and u had to?

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#12

You can keep a blog of your story in this thread.

That’d be ultra cool.

I’d love to read that.

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#13

I think it’s more 2 weeks on, one week off for a 6 month course. It may vary depending on the delivery method and the drug being given.

#14

Duration wise, I don’t know, but I would imagine longer for the reasons stated. From what I have read the dosing involves short bursts over the cycle at lower doses as this has been seen to be more effective than continuous use, but you would have to ask your doctor for further details on the rationale of this dosing as I have not looked into it exhaustively. If I were to have to I can only say I’d probably approach it the way you are, with professional assistance, but it is very much uncharted waters.

Best

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#15

Is there possibly a way to enhance the effectiveness of decitibine that is safe/tested?

HDAC-inhibitors or HAT-inducers in combination?

Induction of histone demethylases such as LSD1?

Is there a way to promote active DNA demethylation at the same time and would that even be of benefit? Good, old-fashioned exercise, (shown to induce active demethylation in brain via TET1) if at all tolerable?

All rhetorical questions; and apologies for being non-specific about this, but this is a bit of a non-specific demethylation treatment, and I can’t think of any AR-related mechanism in particular to target with any certainty of the outcome.

Best guesses would be LSD1 and/or JHDM2A (KDM3A), since they have been found to act at AR-target gene promoters.

@AnhedonicApe, for your sake, don’t act on anything I say without consulting the professionals. Like Axolotl said, it is good you actually have the potential for professional help with this and I don’t want to be responsible for anything going wrong.

#16

@axolotl Yo dude. I found a study showing that the demethylating agent Azacytidine does promote active demethylation. What’s ur opinion on it? ‘’ It is well established that 5-AZA causes the reduction of the DNA methylation status by inhibiting DNMT through passive demethylation pathway [56]. Recently, the active demethylation of DNA through oxidation of 5mC to 5hmC mediated by TET proteins was discovered [9]. To our knowledge, our study is the first to demonstrate that 5-AZA reduces the methylation status of DNA not only by triggering the passive demethylation pathway of DNA [56] but also the active demethylation pathway through converting 5mC to 5hmC by inducing TET2 and TET3 proteins. However, our results showed that 5-AZA was unable to induce the 5hmC in TET2 knocked-down HCC cell lines suggesting a crucial role for TET2 in 5hmC induction and in the pathogenesis of HCC. This was further underlined by our findings that 5-AZA stopped HCC tumor cell growth through decline of 5mC and a strong increase of 5hmC. However, a detailed mechanism of how 5-AZA affects the expression and activity of TET proteins remains to be further elucidated.

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