Melasma in PFS and raised DNMT1 in melasma, possible restoration of SERT with SIRT1

This is for hypothesis and even educated speculation.
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kpavel
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Melasma in PFS and raised DNMT1 in melasma, possible restoration of SERT with SIRT1

Unread post by kpavel »

Well, I poorly understand epigenetic theory, guys. But if this theory is reliable, here's my speculation.

Post-finasteride syndrome known symptoms list includes melasma (skin pigmentation disorder).
https://pubmed.ncbi.nlm.nih.gov/24719069/
Recent study found a significant increase in DNMT1 in melasma skin sample.
DNA Methyltransferases in Malar Melasma and Their Modification by Sunscreen in Combination With 4% Niacinamide, 0.05% Retinoic Acid, or Placebo
https://pubmed.ncbi.nlm.nih.gov/31143777/
Background: Malar melasma has a chronic and recurrent character that may be related to epigenetic changes.
Objective: To recognize the expression and DNA methylation of DNA methyltransferases (DNMTs) in malar melasma and perilesional skin, as well as the changes in DNMTs after their treatment with sunscreen in combination with 4% niacinamide, 0.05% retinoic acid, or placebo.
Methods: Thirty female patients were clinically evaluated for the expression of DNMT1 and DNMT3b using real-time PCR and immunofluorescence. These initial results were compared to results after eight weeks of treatment with sunscreen in combination with niacinamide, retinoic acid, or placebo.
Results: The relative expression of DNMT1 was significantly elevated in melasma compared with unaffected skin in all subjects, indicating DNA hypermethylation. After treatment, it was decreased in all groups: niacinamide (7 versus 1; p<0.01), retinoic acid (7 versus 2; p<0.05), and placebo (7 versus 3; p<0.05), which correlates with clinical improvement. DNMT3b was not overexpressed in lesional skin but reduced in all groups.
Conclusions: We found DNA hypermethylation in melasma lesions. Environmental factors such as solar radiation may induce cellular changes that trigger hyperpigmentation through the activation of pathways regulated by epigenetic modifications. However, limiting or decreasing DNA methylation through sunscreen, niacinamide, and retinoic acid treatments that provide photoprotection and genetic transcription can counteract this.
https://www.ncbi.nlm.nih.gov/pmc/articl ... gure/fig3/
https://pubmed.ncbi.nlm.nih.gov/3114377 ... re-4-uid-3
Since niacinamide is able to lighten skin it would be interesting to check how it decreases dnmt1. One of deacetylases called sirt1, known to be regulated by niacinamide (https://pubmed.ncbi.nlm.nih.gov/28417163/) seems to be able to deacetylate dnmt1.
SIRT1 Deacetylates the DNA Methyltransferase 1 (DNMT1) Protein and Alters Its Activitie
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3232929/
DNA methylation and histone acetylation/deacetylation are distinct biochemical processes that control gene expression. While DNA methylation is a common epigenetic signal that inhibits gene transcription, histone deacetylation similarly represses transcription but can be both an epigenetic and nonepigenetic phenomenon. Here we report that the histone deacetylase SIRT1 regulates the activities of DNMT1, a key enzyme responsible for DNA methylation. In mass spectrometry analysis, 12 new acetylated lysine sites were identified in DNMT1. SIRT1 physically associates with DNMT1 and can deacetylate acetylated DNMT1 in vitro and in vivo. Interestingly, deacetylation of different lysines on DNMT1 has different effects on the functions of DNMT1. For example, deacetylation of Lys1349 and Lys1415 in the catalytic domain of DNMT1 enhances DNMT1's methyltransferase activity, while deacetylation of lysine residues in the GK linker decreases DNMT1's methyltransferase-independent transcriptional repression function. Furthermore, deacetylation of all identified acetylated lysine sites in DNMT1 abrogates its binding to SIRT1 and impairs its capability to regulate cell cycle G2/M transition. Finally, inhibition of SIRT1 strengthens the silencing effects of DNMT1 on the expression of tumor suppressor genes ER-α and CDH1 in MDA-MB-231 breast cancer cells. Together, these results suggest that SIRT1-mediated deacetylation of DNMT1 is crucial for DNMT1's multiple effects in gene silencing.
At the end of Discussion section of this study there's the following paragraph.
In summary, we show that DNMT1 is acetylated at multiple lysines and that SIRT1 deacetylates DNMT1 in vitro and in vivo. Deacetylation of DNMT1 at specific lysines enhanced its methyltransferase activity, changed its transcription repression activity and cell cycle regulatory function, and impaired its capacity to silence TSGs. In contrast to class I HDACs, which boost the silencing effect of DNMT1 by chromatin modification or stabilization of DNMT1 (59, 81), SIRT1 directly modifies DNMT1 activity. Our study provides new insight into the posttranslational regulation of DNMT1 function and the functional diversity of SIRT1 in gene silencing.
Serotonin transporter can be repressed by HDAC1
Histone Deacetylase HDAC1 Downregulates Transcription of the Serotonin Transporter (5-HTT) Gene in Tumor Cells
https://pubmed.ncbi.nlm.nih.gov/26024595/
Serotonin (5-HT) has been reported to be involved in cancer progression by stimulating angiogenesis and cell growth. In this study, we examined the expression of the serotonin transporter (5-HTT) and the role of histone deacetylases (HDACs) in regulating the 5-HTT gene in tumor cells. The 5-HTT gene expression was almost silenced in chicken lymphoma DT40, myelomonocytic tumor HD11 and hepatoma DU249 cells, compared to their physiological counterpart. In contrast, HDAC1 mRNA expression was increased in these cell lines. Indeed, the pan-HDAC inhibitor trichostatin A (TSA) enhanced the 5-HTT mRNA expression in several tumor cell lines including the human cell lines HepG2 and THP-1 and increased the 5-HT uptake in HD11 cells. In addition, treatment with parthenolide (feverfew - herb with anti-serotonergic properties https://pubmed.ncbi.nlm.nih.gov/11603284/), which is capable of depleting HDAC1, and knockdown of HDAC1 using siRNA resulted in increased 5-HTT mRNA expression, confirming the role of HDAC1 in the down-regulation of 5-HTT in the tumor cells. Deletion analysis of the 5-HTT promoter and site-directed mutagenesis revealed that the transcription factor CCAAT/enhancer binding protein beta (C/EBPß), in interacting with the 5-HTT promoter, mediated both the inhibition of the 5-HTT expression by HDAC1 and the activation by CREB-binding protein (CBP). Using a chromatin immunoprecipitation assay, we found increased acetylation of histone H4 associated with the 5-HTT promoter in cells treated with TSA. Our results suggest that the 5-HTT gene is epigenetically downregulated by HDAC1 in several types of cancer.
Also, a very recent study, https://pubmed.ncbi.nlm.nih.gov/32446903/ , says directly that DNMT1 reduces SERT expression.
This makes me speculate SIRT1 positively regulates serotonin uptake.
Tree
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Re: Melasma in PFS and raised DNMT1 in melasma, possible restoration of SERT with SIRT1

Unread post by Tree »

Interesting, thanks for the good research.

Ssri's inhibit sert function by reduction of sert binding sites. A reduction in sert mrna gene expression doesn't reduce sert binding sites induced by ssri. An increase in sert mrna expression, however, may possibly upregulate sert binding density.

Chronic amitriptyline administration increases serotonin transporter binding sites.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6758131/

https://pubmed.ncbi.nlm.nih.gov/10081979/
Sb919
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Re: Melasma in PFS and raised DNMT1 in melasma, possible restoration of SERT with SIRT1

Unread post by Sb919 »

These guys say regular nicotinamide inhibits sirt1, but nicotinamide riboside and nicotinamide mononucleotide raise it? Not sure what to make of it...

What do you think the best form to take would be?

https://www.longecity.org/forum/topic/1 ... r-w-nrnmn/
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kpavel
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Re: Melasma in PFS and raised DNMT1 in melasma, possible restoration of SERT with SIRT1

Unread post by kpavel »

Sb919 wrote: Fri Apr 23, 2021 12:20 pm These guys say regular nicotinamide inhibits sirt1, but nicotinamide riboside and nicotinamide mononucleotide raise it? Not sure what to make of it...

What do you think the best form to take would be?

https://www.longecity.org/forum/topic/1 ... r-w-nrnmn/
Perhaps, I would agree with those who mention salvage/nampt in the thread. AMPK, I read, boosts nampt. And no need to eat more than 1g of NAM imho.
Anyway it was topical NAM which inhibited dnmt1/dnmt3b better than retinoic acid in that experiment.
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kpavel
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Re: Melasma in PFS and raised DNMT1 in melasma, possible restoration of SERT with SIRT1

Unread post by kpavel »

Tree wrote: Thu Apr 22, 2021 7:53 pm Interesting, thanks for the good research.

Ssri's inhibit sert function by reduction of sert binding sites. A reduction in sert mrna gene expression doesn't reduce sert binding sites induced by ssri. An increase in sert mrna expression, however, may possibly upregulate sert binding density.

Chronic amitriptyline administration increases serotonin transporter binding sites.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6758131/

https://pubmed.ncbi.nlm.nih.gov/10081979/
I'm not sure, why people lose anxiety and that seem to be severe cases. Also some lose their ocd. Some research
https://pubmed.ncbi.nlm.nih.gov/15936877/
https://pubmed.ncbi.nlm.nih.gov/24013013/
https://pubmed.ncbi.nlm.nih.gov/30700759/
https://pubmed.ncbi.nlm.nih.gov/29210107/
https://pubmed.ncbi.nlm.nih.gov/19717141/
https://pubmed.ncbi.nlm.nih.gov/18354388/
One pro-anxiety and pro-ocd protein is guess what - nNOS.
nNOS and SERT interact,
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