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As someone who's advocated for the ketogenic diet in this forum, I think I should add the following warning about it. But please bear with me, there is more to it.
The ketogenic diet (as a single therapy) can trigger viral reactivations.
Here are three papers for reference. The first one references various viruses that integrate histone deacetylation in their pathogenesis.
Epigenetic Regulation via Altered Histone Acetylation Results in Suppression of Mast Cell Function and Mast Cell-Mediated Food Allergic Responses (10.3389/fimmu.2018.02414)
Application of a patient-derived xenograft model in cytolytic viral activation therapy for nasopharyngeal carcinoma (10.18632/oncotarget.5544)
This post is about HDAC Inhibitors for the treatment of CFS/ME and MCAS. The ketogenesis produces β-hydroxybutyrate (BHB), which is a mild HDAC inhibitor. Other butyrate supplements are affected by this as well. But it also affects HDAC inhibitor medications such as SAHA (Vorinostat).
Reactivations aren't necessarily a bad thing though. They make infected cells susceptible to cytotoxicity. Under the normal circumstances of a CFS/ME pathology, I wouldn't expect positive outcomes. However, the viral reactivation mechanisms can be used against viruses themselves by combining them with the right kind of antiviral medications.
This very principle is also used by Joshua's New Hope protocol. But it's also used as an EBV-related anti-cancer therapy, as approached in the third reference, where they intentionally trigger EBV reactivation by use of Valproic Acid and damage the integrity of the replicated viruses with Ganciclovir. The first paper discusses similar approaches for other viruses, even including HIV.
Furthermore, other cell cycle-regulating drugs show similar effects on reactivations (10.1016/j.virusres.2017.11.021). While triggering apoptosis, they can also trigger viral reactivations.
By the way, Ivermectin is no potent gamma herpes antiviral. Its efficacy for gamma herpes viridae is based on its immunomodulating mechanism. I'm not sure yet if immune modulation has any use together with intentionally triggered viral reactivations.
Inducing viral reactivation using the HDAC inhibitor drug vorinostat has been tested as a possible HIV therapy.
The idea is to wipe out the latent reservoirs of HIV in the body, by reactivating HIV from latency, so that the immune system (along with the antiretroviral drugs) can then destroy the reactivated virus.
While HIV hides in a latent state, the immune system does not know where it is, so cannot tackle it. But once the virus is reactivated, it suddenly appears on the immune system's radar.
Interestingly, the chronic HIV infection of CD4 cells is not actually a latent infection, but an abortive infection. This is a little-known fact. Nearly all the infected CD4 cells contain an abortive HIV infection, not a latent infection.
So trying to induce viral reactivation in HIV patients will not help clear the CD4 cell infection directly. But it may help clear the reservoirs of latent HIV in other cell types.
It has also been proposed that the EBV and cytomegalovirus infections in ME/CFS patients are abortive infections, not latent infections. Dr Lerner first proposed this, and now the idea has been taken up by a research team at Ohio State University.
But how comes that reactivations happen so regularly then? I'm sure that these are reactivations and not new infections I'm talking about. There has to be a latent cell reservoir at least to a certain degree. Abortive reservoirs aren't uncommon, but usually, there is still a reactivation mechanism (10.1073/pnas.1910537117).
The idea is to wipe out the latent reservoirs of HIV in the body, by reactivating HIV from latency, so that the immune system (along with the antiretroviral drugs) can then destroy the reactivated virus.
I also found this. Not only for HIV, actually for many viruses. Since we don't know exactly which viridae are involved, we'd have to use one or multiple antivirals (not succession) parallel to an HDAC inhibitor. But which antivirals provide the best coverage and efficacy against all virus candidates? I'm not familiar with all the antiviral drugs and their mechanisms. It's important that the DNA/RNA of the virus is affected by the agent, and not only viral signaling. Ivermectin and HCQ are candidates for RNA viruses. I think we've already discussed this, as far as I remember. But what about DNA viruses? Which antiviral covers them all and which ones are also convenient to use (e.g. orally) and not too risky? Do you have any idea?
But how comes that reactivations happen so regularly then? I'm sure that these are reactivations and not new infections I'm talking about. There has to be a latent cell reservoir at least to a certain degree. Abortive reservoirs aren't uncommon, but usually, there is still a reactivation mechanism (10.1073/pnas.1910537117).
Interesting paper. I'll try to read it more thoroughly when I am less brain fogged. There is not much research on abortive infections, and I wonder if they play a greater role than we realize in chronic diseases of all sorts.
Is there any evidence for viral reactivations taking place in ME/CFS? I don't remember coming across any studies which suggest ME/CFS involves reactivations.
The exceptions being varicella zoster virus ME/CFS, which is rare, and involves VZV reactivation, and parvovirus B19 ME/CFS, which appears to be due to a regular productive active infection, which can be detected by blood PCR.
Whereas for enterovirus ME/CFS and EBV/CMV/HHV-6 ME/CFS, blood PCR is usually negative, indicating that there is not much productive infection going on.
In Dr Lerner's model of ME/CFS, he proposed there were low-level productive herpesvirus infections (which could be producing new viral particles, or could be in a dormant latent state, or a bit of both), as well as abortive herpesvirus infections existing in parallel. He theorized that the new viruses created by the productive infection would re-seed the abortive infection.
I am confused by the paper you cited, as my understanding is that abortive infections can never produce viral particles. Yet if I read it right, that paper says abortively infected cells can sometimes return to normal productive infection, and create viral particles.
By definition, an abortive infection is where a virus has entered a cell which does not possess the necessary internal machinery or conditions to support viral replication. The virus can survive in the cell, but it cannot fully complete its replicative lifecycle. So in the cell, the virus is forever trying to replicate, but forever failing to do so. That's an abortive infection: there is viral activity in the cells, but no new viruses are produced.
So if a cell does not possess the necessary internal conditions to support replication, it's hard to understand how that cell can suddenly change, and provide the virus with the right conditions to replicate.
Whereas for enterovirus ME/CFS and EBV/CMV/HHV-6 ME/CFS, blood PCR is usually negative, indicating that there is not much productive infection going on.
Not that I know, but there is a PR post with a poll on viral PCRs. It seems like quite a fraction of users have abnormal results for other viral infections.
Whereas for enterovirus ME/CFS and EBV/CMV/HHV-6 ME/CFS, blood PCR is usually negative, indicating that there is not much productive infection going on.
PCR is useless as soon as antibodies exist. If there are reactivations, then they are lytic and early productive, which can only be properly detected by EA, which isn't normally tested.
In Dr Lerner's model of ME/CFS, he proposed there were low-level productive herpesvirus infections (which could be producing new viral particles, or could be in a dormant latent state, or a bit of both), as well as abortive herpesvirus infections existing in parallel. He theorized that the new viruses created by the productive infection would re-seed the abortive infection.
So if a cell does not possess the necessary internal conditions to support replication, it's hard to understand how that cell can suddenly change, and provide the virus with the right conditions to replicate.
Only free viral particles show up on PCRs. Large amounts of viral particles become free during productive replication or when cells are destroyed in substantial numbers, as during the mid- to late phase of COVID-19. Intracellular viral infections, their proteins, any latent-lytic and abortive infections don't show up on PCRs or antibody tests. It's normal to have a certain amount of latent virus reservoir from the latent viruses that we've had previously. This includes early childhood infections, some of them also from the herpes family. This is why parents should vaccinate their children against these. It has a risk, but it's better than having the disease with its long-term consequences.
I guess there could some be global change to the internal cellular environment induced by an external factor outside the cell, a factor like hormones, etc.
If the cell interior is changed by such a factor so that the virus can now complete its lifecycle in the cell, then I guess it might change from an abortive to a productive infection.
But I have not previously come across any research indicating that a non-permissive cell (this is defined as one which does not allow a productive infection, and so can lead to an abortive infection) can turn into a permissive cell (one which can host a productive viral infection).
The virus itself has no control over the permissiveness of the cell.
This is different to a latent infection, where the virus is in control regarding whether it replicates or not.
In a latent infection, it is the virus itself which decides to stop replicating, in order to hide away from the immune system. And it is the virus itself which is programmed to wake up from latency under certain conditions (like when the host immune system is weak).
If it is going to help the virus survive, a latent infection must take place within a permissive cell; it has to be permissive, otherwise the virus could not wake up from latency to start reproducing, which then would defeat the object of latency (the object being to hide away in order to come back to fight another day).
Do you mean the rapamycin paper you linked to? Interestingly, some ME/CFS patients made substantial improvements with rapamycin after about a month or so. See this post. But it is anyone's guess as to why rapamycin helped.
I think that paper is just saying that EBV uses methylation as a mechanism to switch off its production of viral proteins, when this virus wants to "go to sleep" and enter a dormant latent state, hiding away in a cell.
So for EBV, methylation is like "sleep dust" which the virus uses to put itself to sleep.
Do you mean the rapamycin paper you linked to? Interestingly, some ME/CFS patients made substantial improvements with rapamycin after about a month or so. See this post. But it is anyone's guess as to why rapamycin helped.
No. I don't mean the combination therapy. You'd have to combine Rapamycin and HDAC inhibitors with an antiviral. I mean normal antivirals against herpes viruses and other DNA viruses. Like Tenofovir.
I also found this. Not only for HIV, actually for many viruses. Since we don't know exactly which viridae are involved, we'd have to use one or multiple antivirals (not succession) parallel to an HDAC inhibitor. But which antivirals provide the best coverage and efficacy against all virus candidates? I'm not familiar with all the antiviral drugs and their mechanisms. It's important that the DNA/RNA of the virus is affected by the agent, and not only viral signaling. Ivermectin and HCQ are candidates for RNA viruses. I think we've already discussed this, as far as I remember. But what about DNA viruses? Which antiviral covers them all and which ones are also convenient to use (e.g. orally) and not too risky? Do you have any idea?
By the way. Rapamycin single therapy, i.e. without any antivirals, doesn't help to clear out all viral reservoirs. Viral pathology (e.g. via Bcl-2) supersedes mTOR signaling, so apoptosis remains suppressed in these infected cells. Rapamycin can clear out senescent cells though. Maybe this is why it helps. Maybe it also helps with abortive infections. It depends on what viral pathology remains in abortively infected cells.
For ME/CFS linked to EBV, CMV and/or HHV-6, ME/CFS doctors such as Lerner and Montoya have used Valtrex (if the only infection is EBV), or Valcyte (if you have CMV or HHV-6). See this post for details of their studies treating ME/CFS patients with these two antivirals.
Treatment takes a long time (a year or more). Dr Lerner said it takes a long time because these antivirals do not work for the abortive infection be believed was causing ME/CFS, they only work indirectly, by targeting the parallel productive infection.
Lerner said once you get the productive infection under control, it stops re-seeding the abortive infection, and in that way, the abortive infection is eventually controlled. But this is all theory, because no studies have been done which demonstrate the existence of an abortive herpesvirus infection in ME/CFS.
Some ME/CFS patients have done well on drugs like Valcyte, but Stanford recently stopped using Valcyte for treating ME/CFS, which I guess means the success rate was low.
Dr Chia uses tenofovir, but I am not sure which viruses he finds it effective for. He normally treats enterovirus ME/CFS patients, rather than herpesvirus ME/CFS patients.
Interferon is a highly effective antiviral/immunomodulator to treat enterovirus ME/CFS, and often allows severe bedbound patients to return to work. But relapse occurs after 4 to 14 months, so unfortunately this is not a permanent cure for enterovirus ME/CFS.
If you check my roadmap, it covers all the important antivirals and immunomodulators that are used by ME/CFS doctors.
Thank you. This is exactly what I was hoping for. So many options. I will have to look through them and figure out what combines best with "reactivation therapy".
Treatment takes a long time (a year or more). Dr Lerner said it takes a long time because these antivirals do not work for the abortive infection be believed was causing ME/CFS, they only work indirectly, by targeting the parallel productive infection.
This is where reactivation is so helpful. SAHA does not only force latent cells to reactivate, it alternatively pushes latent and abortive cells into apoptosis or autophagy. The chances that viral pathology supersedes this are smaller than with mTOR inhibitors because this drug directly interacts with the Bcl-2 pathway, which is a common target for viruses. This is translatable for butyrates and the ketogenic diet, of course (pmid: 10757447).
Dr Chia uses tenofovir, but I am not sure which viruses he finds it effective for. He normally treats enterovirus ME/CFS patients, rather than herpesvirus ME/CFS patients.
It seems to work against EBV as well, according to this study (10.1073/pnas.2002392117). I have only read the abstract though.
Against CMV, they used Ganciclovir in the HDAC combination trial, but they needed very large doses (10.18632/oncotarget.5544). I'm not sure why they chose Ganciclovir among all the choices.
Interferon is a highly effective antiviral/immunomodulator to treat enterovirus ME/CFS, and often allows severe bedbound patients to return to work. But relapse occurs after 4 to 14 months, so unfortunately this is not a permanent cure for enterovirus ME/CFS.
Just like Ivermectin, this is only efficacious against DNA viruses via immune modulation. Immune modulation is unlikely to synergize with reactivation therapy. In fact, some might even block the reactivation process of HDAC inhibitors so that the combination only treats the functional disease and not the causality.
It would certainly be interesting to experiment with herpesvirus antivirals combined with latency reactivators as a herpesvirus ME/CFS treatment. Possibly the latency reactivators could shorten treatment time considerably.
Yes, that's an interesting study which I saw before.
It is an in vitro study, though, so we cannot immediately tell if tenofovir will have any antiviral effects against EBV in vivo. It will only work in vivo if the drug concentrations used in vitro can be obtained in the bloodstream or tissues, and that depends on the pharmacokinetics of tenofovir in the body.
However, using this tenofovir EBV study, a simple pharmacokinetic calculation I did a while ago showed that blood concentrations of tenofovir are sufficient, and so I suspect tenofovir does have some moderate antiviral effects in vivo, when taken at the normal dose.
But to put it in perspective, my pharmacokinetic calculation showed the in vivo antiviral potency of tenofovir for EBV is around 10 times less than that of Valcyte or Valtrex.
Tenofovir however also does other useful things that may benefit ME/CFS: it is a potent immunomodulator, which reduces Th2 cytokines and increases Th1 cytokines, which may then help clear viral infection. The oxymatrine that Dr Chia uses for enterovirus works in the same way: it ramps up Th1, which is the antiviral mode of the immune response.
It's this immunomodulatory effect of tenofovir that may explain why it can be helpful for enterovirus ME/CFS. Dr Chia says tenofovir work for some ME/CFS patients (but he said it is less than 1 in 3 that it works for).
Furthermore, tenofovir is antiviral for human endogenous retroviruses (HERVs), and there has been some research to indicate that HERVs may be reactivated in ME/CFS. HERVs are also reactivated in multiple sclerosis.
Interferon definitely works for RNA viruses, as interferon therapy is a standard treatment for chronic hepatitis C virus infection, which is an RNA virus.
Interestingly, in one study of interferon therapy for ME/CFS, it was only the enterovirus ME/CFS patients who benefited, but the herpesvirus ME/CFS patients did not. So interferon does not seem useful for herpesvirus ME/CFS.
Here is the list of pathogens I might re-evaluate, based on the survey of Herbein et Wendling [1]. Their work is outdated, so I have to reevaluate potential new associations between HDACs and the listed pathogens
HBV
HCMV
HSV-1
EBV
HPV
HCV
HIV
RSV
I will cross-link it with the following list of HDAC inhibitors. During my research, I noticed that some of the activities are minor or even inconsistent. I'd like to classify them accordingly in order to identify the inhibitors that have strong activity. I will not go into class III HDACs though, since they are for NAD+-dependant SIRTs.
Butyrates
This includes BHB (e.g. from supplements or a ketogenic diet), sodium butyrate, potassium butyrate, and butyric acid (e.g. from microbiota). All the findings are consistent in that these butyrates share mild class I HDAC (i.e., 1, 2, 3, 8) inhibitory activity [2, 3, 4, 5]. The findings for class IIa HDACs (i.e., 4, 5, 7, 9) and class IIb HDACs (i.e., 6, 10) are inconsistent [2, 3, 5].
Some sources state that butyrates are inhibitory against all class IIa but not any class IIb [2, 3]. A new study contradicts this in that they find an inverse activity for these HDACs, namely a mild upregulation of HDAC4 and HDAC9, a moderate upregulation of HDAC5, and a mild downregulation of HDAC6 [5]. Strangely, there wasn't any obvious dose-dependent correlation. Their findings on TSA (as a positive control) don't match either [6]. I think the reason for this might be an indirect regulation of class II HDACs by class I HDACs via sirtuins and this adds bias to the result. From a physiological evolvement perspective, I don't see why butyrates would upregulate HDAC class II since HDAC class II activate FOXO1-mediated gluconeogenesis [7]. Overall, butyrates have direct or indirect mild to moderate effects on class II HDACs, but it's unclear in which direction.
γ-Aminobutyric acid (GABA)
GABA might play a role in the pathophysiology of CFS/ME but in a phase-dependant manner. During glutamatergic hyperexcitation, one might consider oral GABA though. GABA is thought not to be able to cross the blood-brain barrier (BBB) in significant amounts, but indirect effects from oral GABA supplementation on GABAergic activation seem to happen [8]. One possible indirect mechanism is the GABA-mediated HDAC inhibition that prevents pathological GABAaR α1 and γ2 subunit or GluR2 downregulation [9, 10, 11]. Accordingly, GABA is a potent HDAC class I inhibitor [4, 9]. I could not find any studies of GABA activity on other HDAC classes.
By the way, when pathogens upregulate HDAC, as evidenced by the pathological findings of CFS/ME patients [12, 13], the inverse situation is the case. This means that GABA receptors might become susceptible to downregulation by HDAC activity, thereby exacerbating the CAC-mediated phase-dependant glutamatergic excitotoxicity. HDAC inhibitors might be candidates to suppress at least the mid-term dysregulation of the GABA system.
Caffeic acid and Chlorogenic acid
I mention these two together because they are both most prevalent in coffee and some studies only evaluate coffee consumption in general. A receptor binding simulation identified these two acids as very potent among various HDAC8 inhibitors, with chlorogenic acid (CGA) even surpassing TSA [4]. Consequently, the dose-dependency was confirmed in vitro [4]. Another source [14] mentions caffeic acid's class I and II inhibitory potentials based on two studies on coffee but the referenced studies [15, 16] do not contain any evidence regarding HDACs or even mention them. The authors only speculate about an HDAC-MAPK mechanism due to their overlapping in vivo downstream measures.
However, another wide-scale evaluation of 131 natural compounds identified caffeic acid as one among 18 HDAC inhibitors [17]. Unfortunately, caffeic acid only showed general activity against undifferentiated HDACs but not against any particular recombinant HDAC. This is inconsistent with the previous finding targeting HDAC8 [4]. One possible reason is the considerably high HDAC8 IC50 of 2.54 mmol/l which is about 4 orders of magnitudes greater than the attainable tissue concentration of 1 to 20 mcmol/l that I determined using different pharmacokinetic simulation models assuming the ingestion of 100g of black chokeberries. The hydrolysis of CQA to caffeic acid in the GIT wouldn't make any difference because the hydrolyzed caffeic acid would constitute only a fraction of the free caffeic acid (by ca. one order of magnitude) [22, 23].
One study analyzed in vitro activity of CGA against HDACs 1, 2, 3, 6, and 8 and potential downstream pathways [18]. CGA showed inhibitory potential against all of them, but predominantly HDAC6. The required concentration for an HDAC6 IC50 (i.e. 792 nmol/l) was not cytotoxic in NSCLC cells. The previously identified HDAC8 IC50 in HeLa cells was considerably high (i.e. 375 mcmol/l) [4]. Assuming this result is also translatable for the other class IIb HDAC10, this suggests a complementary function with butyrates in order to achieve pan-HDAC inhibition without expensive medication.
The HDAC6 IC50 from CGA still isn't achievable by drinking coffee from roasted beans (by a difference of ca. one order of magnitude) [20]. Green coffee beans contain much greater doses of CGA, but in total, we don't ingest as much in one capsule of 0.5g to 1g as is resolved in one portion of brewed coffee from 10g to 20g of roasted coffee beans. Even large doses wouldn't reach the HDAC8 levels regardless.
As a side note, due to their HDAC inhibition, caffeine acid and chlorogenic acid also have been evaluated for their potential as a therapeutic for spinal muscular atrophy [19]. I think this might be translatable for CFS/ME neuromuscular atrophies.
Nevertheless, there is a more potent carboxylic acid, namely curcumin, which is even more promising and without the negative side effects on the GIT that caffeine has. I intend to evaluate this and other compounds in the coming days.
Molecular modifications on carboxylic acid derivatives as potent histone deacetylase inhibitors: Activity and docking studies (2009) [10.1016/j.bmc.2009.05.042]
Human gut bacteria as potent class I histone deacetylase inhibitors in vitro through production of butyric acid and valeric acid (2018) [10.1371/journal.pone.0201073]
Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group (2013) [10.1038/nchembio.1223]
Improving Insulin Sensitivity With HDAC Inhibitor (2013) [10.2337/db12-1354]
Effects of Oral Gamma-Aminobutyric Acid (GABA) Administration on Stress and Sleep in Humans: A Systematic Review (2020) [10.3389/fnins.2020.00923]
As a Histone Deacetylase Inhibitor, γ-Aminobutyric Acid Upregulates GluR2 Expression: An In Vitro and In Vivo Study (2019) [10.1002/mnfr.201900001]
Histone deacetylases mediate GABAA receptor expression, physiology, and behavioral maladaptations in rat models of alcohol dependence (2018) [10.1038/s41386-018-0034-8]
Histone Deacetylase 2 Cell Autonomously Suppresses Excitatory and Enhances Inhibitory Synaptic Function in CA1 Pyramidal Neurons (2013) [10.1523/JNEUROSCI.3162-12.2013]
Epigenetic Components of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Uncover Potential Transposable Element Activation (2019) [10.1016/j.clinthera.2019.02.012]
Increased HDAC in association with decreased plasma cortisol in older adults with chronic fatigue syndrome (2011) [10.1016/j.bbi.2011.04.007]
Food Bioactive HDAC Inhibitors in the Epigenetic Regulation of Heart Failure (2018) [10.3390/nu10081120]
The impact of coffee consumption on blood pressure, cardiovascular disease and diabetes mellitus (2017) [10.1080/14779072.2017.1287563]
Coffee reduces the risk of death after acute myocardial infarction: a meta-analysis (2016) [10.1097/MCA.0000000000000397]
Targeting the epigenome: Screening bioactive compounds that regulate histone deacetylase activity (2018) [10.1002/mnfr.201600744]
Chlorogenic-induced inhibition of non-small cancer cells occurs through regulation of histone deacetylase 6 (2018) [10.14715/cmb/2018.64.10.22]
Carboxylic acid derivatives of histone deacetylase inhibitors induce full length SMN2 transcripts: a promising target for spinal muscular atrophy therapeutics (2011) [doi.org/10.5114/aoms.2011.22072]
Dose–response plasma appearance of coffee chlorogenic and phenolic acids in adults (2014) [10.1002/mnfr.201300349]
Bioavailability and metabolism of chlorogenic acids (acyl-quinic acids) in humans (2020) [10.1111/1541-4337.12518]
Aronia melanocarpa Fruits as a Rich Dietary Source of Chlorogenic Acids and Anthocyanins: 1H-NMR, HPLC-DAD, and Chemometric Studies (2020) [10.3390/molecules25143234]
Chlorogenic acid is absorbed in its intact form in the stomach of rats (2006) [10.1093/jn/136.5.1192]
Autophagy and apoptosis are part of the natural cell cycle. HDAC inhibitors just increase the selection pressure on cells so that senescent cells and unhealthy cells become susceptible to apoptosis. This ensures the survival of healthy cells which can then proliferate again while the ones with damaged function are sorted out and can not further proliferate. Infected cells would be affected by this cell cycle as well and immediately sorted out. This is why pathogens have acquired genomes that intervene with this natural intracellular cell cycle mechanism, which is also triggered by the innate immune system. This allows viral cells to survive longer despite the unhealthy behavior and evade apoptosis.
One of the mechanisms by which pathogens evade apoptosis and cell arrest is HDAC upregulation. This study gives an overview of just the EBV-related ones:
HDAC inhibitors at least suppress a part of the mechanism. Bcl-2 inhibitors would be nice as well because this is the primary target of many viruses to suppress mTor function. Ivermectin interacts with Bcl-2 any many of the EBV mechanisms though. It's just a dosing question. This is why I begin with Ivermectin in the combination treatment. The inhibition of HDAC just accelerates the whole process. Any apoptosis-inducing drug would, but I choose HDAC not because of its role in viral diseases but because I think it plays a central role in the functional CFS/ME disease.
Theoretically, this selection pressure from apoptosis-inducing drugs can also uncover sleeping cancer cells which then proliferate and cause cancer. But most of these cells are actually destroyed in the process, reduce the overall long-term risk of cancer. The cancer that really happens in such a case is a cancer that would have happened anyways eventually. It's the same with viruses. They are sleeping and waiting for their chance. HDAC inhibitors give them their chance but without tricks, and when you combine this with the right pathogen-specific drugs, all the different sleeper cells and pathogens just evaporate.
Autophagy and apoptosis are part of the natural cell cycle. HDAC inhibitors just increase the selection pressure on cells so that senescent cells and unhealthy cells become susceptible to apoptosis. This ensures the survival of healthy cells which can then proliferate again while the ones with damaged function are sorted out and can not further proliferate. Infected cells would be affected by this cell cycle as well and immediately sorted out. This is why pathogens have acquired genomes that intervene with this natural intracellular cell cycle mechanism, which is also triggered by the innate immune system. This allows viral cells to survive longer despite the unhealthy behavior and evade apoptosis.
One of the mechanisms by which pathogens evade apoptosis and cell arrest is HDAC upregulation. This study gives an overview of just the EBV-related ones:
HDAC inhibitors at least suppress a part of the mechanism. Bcl-2 inhibitors would be nice as well because this is the primary target of many viruses to suppress mTor function.
Theoretically, this selection pressure from apoptosis-inducing drugs can also uncover sleeping cancer cells which then proliferate and cause cancer. But most of these cells are actually destroyed in the process, reduce the overall long-term risk of cancer. The cancer that really happens in such a case is a cancer that would have happened anyways eventually. It's the same with viruses. They are sleeping and waiting for their chance. HDAC inhibitors give them their chance but without tricks, and when you combine this with the right pathogen-specific drugs, all the different sleeper cells and pathogens just evaporate.
Interesting even if your sentence “ The cancer that really happens in such a case is a cancer that would have happened anyways eventually” is a bit odd IMO because it makes a lot of a difference if I develop cancer at 30 or 80.
Another problem is that it would be a bit pricey for off-label use 😁 so we would have to wait for many years again.
But great ideas
Interesting even if your sentence “ The cancer that really happens in such a case is a cancer that would have happened anyways eventually” is a bit odd IMO because it makes a lot of a difference if I develop cancer at 30 or 80.
Another problem is that it would be a bit pricey for off-label use 😁 so we would have to wait for many years again.
But great ideas
Every cancer happens at some point and the longer the body doesn't undergo a "regeneration" process like the ketogenic diet, fasting period, Ramadan, etc. the more likely cancer happens. With 30, the chances of cancer therapy are far better than with 80. HDAC inhibitors are actually used for cancer therapy, e.g. in combination with chemotherapy.
I'm aware of the off-label and patent-price issue, so I'm trying to create a protocol that circumvents the need for drugs that can not be acquired easily. I can simulate the ingestion of multiple drugs/supplements/foods at the same time and their accumulative enzyme interactions. But there isn't always sufficient raw data to work with. The typical databases don't list all the parameters. So I need more simulations for the raw data, e.g. when there is no in vitro IC50 available. And for this, I need appropriate molecule models. Not all molecules are available in databases the way I need them, so I might need to remodel them. This is where I'm currently at the moment. I try to find appropriate free HDAC molecule structures and not complexes that need remodeling.
