Hi everybody, I want to share whit you a possible treatment for PFS than I found on a foreign forum. It is based on scientific literature and I want to try it as soon as possible because in my opinion is scientifically resonable. It is based in some substance that excert they effect on a epigenetic level.
Most of them are natural and only two are prescription drug but these latter two are foundamental for the action of the other because a synergestic effect between them. In my opinion is higly resonable and I will try it. These substances have to be taken everyday for at least one month in order to excert the effects.u
Looking for a cure for PFS
Everyone knows there is a theory about the pathogenesis of PFS: the persistent alteration of neurosteroid levels due to the induction of persistent epigenetic modification that lead to a modification of gene expression.
Essentially two mechanism regulate gene expression:
• Binding of chemical groups directly to DNA (covalently) that function as silencers or activators. The main inhibitor is the methyl group that, binding at particular points of the promoter sequences, silences gene expression. The protein that bind methyl groups to DNA is the DNMT.
• The other is the tangling of the DNA around proteins (called histones): if the DNA is wrapped on itself, the molecular machines that should read the instruction contained in the DNA, cannot bind the DNA because there isn’t sufficient space. The ability of a histone to compact a DNA molecules (and thus repress gene expression) depends on the presence of particular molecules bound to the histone. The main one is the acetate group: if it binds to histone, forces him to expand and so molecular machines can come in and gene expression is activated. The acetyl groups are linked to histone by HAT and detached from it by HDAC. Also histones can be methylated in some particular positions, and this has mixed effects on gene expression.
Finasteride activate epigenetic modification, such as gene silencing. Is there anyway to reset gene expression and then reverse epigenetic damage? The answer seems to be yes.
Firstly, we recall the main objectives:
• To promote the demethylation of DNA by inhibiting DNMT: the new synthesized DNA is less methylated and then whit an increased gene expression.
• Inhibit the deacetylation of histones, in particular inhibiting HDAC
• Encourage the acetylation of histones, in particular by increasing the activity of HAT
It has also been seen that the increase of histone acetylation is accompanied by a demethylation of DNA, that is, the two events have a synergistic effect. It 's important to note first of all that these effects are time and dose dependent, ie the effects are proportional to the dose taken and manifests itself after some time.
Several compounds can do this. Most of them are natural occuring compounds and found in green tea but this does not mean that they are little effective: some are very promising for the treatment of other diseases in which the gene expression change is crucial. Other are drugs are already used for other purposes. Unlucky, often they have a low biodisponibility and a short half-life, than high and multiple doses should be necessary. Most promising are listed for first.
EPIGALLOCATECHINE GALLATE (EPCG) One of most studied, well caracterized and most effective natural compound that influence gene expression. Is one of major component of green tea extract. It can easily cross blood-brain barrier and is demonstrated that directly bind DNA . It is DNMT1, DNMT3, HDAC1 inhibitor and a MeCP2 inhibitor using Mg2+ as cofactor. Increase amount of glutathione and indirectly the acetilation of histone H3 and H4. Unlucky it is also a weak inhibitor of HAT, has a very low biodisponibility and may be hepatotoxic. Has been demonstrated that minimum effective dose in order to induce genetic effect is 800 mg 2 times a day. The ingestion of high grade, dried green extract, which contains a lot of different catechine, gallate and flavonoid, is more effective then the ingestion of pure EPGC: all the “gallate” and “chatechin” compounds are generally HDAC and DNMT inhibitor and they have a synergistic effect. They’re generally recognized as safe.
QUERCITINE A flavonoid, is a strong enhancer of H3 and H4 histone acetylation, thus activates SIRT1 and SIRT6 mediated deacetylation; Inhibit DNMT and LSD1 (histone demethylating protein). It is also a weak MAOI. Was found to be active at a concentration of 75-100 um.
GENISTEINE (and less DAIDZEINE and BIOCIANINE A) They are phytoestrogens and belongs to the category of isoflavones. They are strong inhibitor of HDAC (mostly HDAC1) and DNMT (mostly DNMT1 and DNMT3); less strong inhibitor of MeCP2. Was proved to demethylate ipermethylated genomes without lead to ipomethylation. It has a strong and synergic effect whit other DNMT and HDAC inhibitor. It is an estrogen receptor agonist and then may produce non-hormonal effects.
SODIUM BUTIRRATE It is a strong and natural occurring HDAC inhibitor and one of most studied. It has a lot of other positive effects and has been demonstred to be neuroprotective.
VALPROATE and SULPIRIDE Valproate is an anticonvulsive and a mood stabilizer drug that act as a strong HDAC inhibitor and this may account of its anticonvulsive and mood stabilizing effects. Sulpiride is a very effective antidepressant (I want to recommend to everyone because is a fantastic drug whit a rapid onset and persisting effect specially on ruminative though, anxiety and bad feeling). It was found that a combination of the two drugs in clinically relevant doses activate brain demethylation. This effect was studied on GABA neurons but may occur also in other type of neurons .
CURCUMINE Strong inhibitor of HDAC, HAT, DNMT, MeCP2. Has been shown to be able to induce demetilation of hypermethylated zone of DNA, in a stronger way than genisteine. Because its potent HAT inhibitor activity it may be a second line treatment or can be used to prevent ssri’s induced modification of genetic expression.
LUTEOLINE Luteolin is a flavone, a type of flavonoid. Increase histone acetylation, particularly H3 e H4, inhibiting their HDAC and activating SIRT6-mediated deacetylation; Inhibit DNMT and LSD1 (histone demetylating protein). Thus, weak diminish phosporylation on H3 and H4 and is a weak indirect antagonist of DNMT.
APIGENINE A flavone, is a HDAT inhibitor (soprattuto H1 and H3) and weak activator of SIRT6 mediated deacetylation. Apigenin may also stimulate adult neurogenesis. Concentration over 5-10 um are not recommended because gaba agonism and other central effects. It is a weak MAOI.
DIALLIL SULFIDE, ANACARDIC ACID and GARLIC A lot of compounds in garlic and broccoli are HDAC and DNMT inhibitor, then high grade dried garlic extract and to eat broccoli may be strongly recommended.
SAM, vitamins B and ZINC S-Adenosil-Methionine is the natural transporter of methyl groups and work in a synergic way whit DNMT, than induce methylation. Its natural counterpart is S-Adenosil-Omocisteine, a strong demethylating agent which expression increase during the use of HDAC inhibitor: this mean that there’s a synergistic effect between increase of acetylation and the activation of demethylation. For this reason, the supplement of SAMe is not recommended. The vitamins of group B are used to carrier and bind methyl group, then supplementation of high amount of B vitamins is not recommended if the increase of demethylation is wanted. The Zn2+ ion is he natural cofactor of HDAC, then the uses of Zn2+ supplements may increase their activities.
Here the right dosage for each components, obtained form the ones used in the studios and the name of the commercial form of this that you can find on Amazon:
-EPGC 600 mg, 3 times a day (Piping Rock Health Products - EGCG Green Tea 600 mg Standardized Extract, standardized in 30% in EGCG)
-Quercitine 600 mg, 3 times a day (MegaQuercitin, Solaray)
-Genisteine 800mg, 4 times a day (Vital Nutrients - Genistein)
-Apigenine 30 mg, 3 times a day (Swanson Ultra, Apigenin)
-Luteoline 300 mg, 3 times a day(Swanson Ultra, Luteolin Complex)
-Sodium Butyrrate 600 mg, 3 times a day (BodyBio/E-Lyte - Sodium Butyrate)
-Sulpiride 100 mg, 2 times a day
-Valproate 200mg, 3 times a day
The most important are EPCG, quercitine, butirrate, valproate, sulpiride and genisteine that have to take togheter everyday for at least one month. Luteoline and apigenine are desiderable but not necessary because are the less effective.
List of citations
12- Histone deacetylase inhibitors reverse CpG methylation by regulating DNMT1 through ERK signaling, Sarkar S
13- Green tea polyphenols for prostate cancer chemoprevention: A translational perspective J.J. Johnson
14- Flavonoids Influence Epigenetic-Modifying Enzyme Activity: Structure-Function Relationships and the Therapeutic Potential for Cancer Gilbert, E.R.; Liu, D.P
15- Epigenetic activities of flavonoids in the prevention and treatment of cancer, Christian Busch
17- Epigenome, Cancer Prevention and Flavonoids and Curcumin, Višnja Stepanić
18- Dietary Polyphenols May Affect DNA Methylation, Mingzhu Fang
19- Bioactive Nutraceuticals and Dietary Supplements in Neurological and Brain disease, Ronald Ross Watson,Victor R. Preedy
20- Mechanisms for the Inhibition of DNA Methyltransferases by Tea Catechins and Bioflavonoids, Won Jun Lee
21- The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells, Zhu WG
22- Epigenetic changes induced by curcumin and other natural compounds, Simone Reuter
23- Green Tea Polyphenols in drug discovery - a success or failure?, Thomas J. Smith
24- Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and polyphenon E, Chow HH
25- Molecular targets of (-)-epigallocatechin-3-gallate (EGCG): specificity and interaction with membrane lipid rafts, Patra SK
26- Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation, Dong E
27- Selective DNA Methylation of BDNF Promoter in Bipolar Disorder: Differences Among Patients with BDI and BDII, D’Addario C.
28- Valproate induces DNA demethylation in nuclear extracts from adult mouse brain, Erbo Don