Prevymis (Letermovir) for CMV - FDA approved!

Hip

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And what about taking Valcyte & Letermovir simultaneously? That would be an interesting experiment for sure.
That could be very effective, as both drugs work by different mechanisms, and so likely would not interfere with each other's efficacy. Thus their individual antiviral effects would be additive.



But with the cessation of the production of infectious viral particles, I would think the immune response would be less severe. So you would still have ME/CFS symptoms, just greatly reduced.
This is the great mystery of ME/CFS: why is it that after an initial acute flu-like or gastrointestinal illness (that many patients have at the beginning of their ME/CFS), when the immune system clears all the virus from the blood, do symptoms still persist?

When you have the first acute infection, and there are high levels of virus in the blood, of course you would expect to have symptoms. But after a week or so, when the initial acute infection is brought under control, ME/CFS patients no longer have virus in the blood, yet symptoms persist.

This is why many researchers and clinicians don't believe in the viral infection theory of ME/CFS, because you generally don't find much virus in the blood in ME/CFS. So some believe it may be a malfunction of the immune system that causes the disease. Dr Robert Naviaux's cell danger response theory of ME/CFS goes along these lines.

But if you look at the enterovirus research on ME/CFS, you realize that the virus has not gone away, it's just hiding inside cells, and if you take perform a muscle or stomach tissue biopsy on ME/CFS patients, you can detect this ongoing enteroviral infection in the tissues. If you look at the last image at the bottom of this post, you can see this infection in the stomach tissues (the brown stain is the infection).

Have you been tested for enterovirus, by the way, using the ARUP Lab tests recommended by Dr Chia? Enteroviruses and herpesviruses are the main types of virus linked to ME/CFS.
 
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But if you look at the enterovirus research on ME/CFS, you realize that the virus has not gone away, it's just hiding inside cells,
Correct, same thing applies to herpesviruses. And this can be measured based on the high level of IgG antibodies for the virus.


Have you been tested for enterovirus, by the way, using the ARUP Lab tests recommended by Dr Chia? Enteroviruses and herpesviruses are the main types of virus linked to ME/CFS.
I've been tested for everything under the sun. I saw Dr. Lerner 3 times in his office back in 2011 & 2012. God rest his soul. Selfless man, worked his ass off literally until the day he died. God bless him. Saved my damn life.

I have a whole thread discussing my experience here. My CMV IgG is sky high and has been since Day 1. All other viruses are negative. That's why Letermovir is such a big deal for me.
 

Hip

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Correct, same thing applies to herpesviruses. And this can be measured based on the high level of IgG antibodies for the virus.
Unfortunately we have no direct incontrovertible evidence of an ongoing herpesvirus infection in ME/CFS; there are high titers, and the ME/CFS doctors interpret that as evidence for an ongoing infection; but other doctors and researchers just think the high titers are due to immune dysfunction.

Antibody titers do not detect the virus directly, like PCR does, but only detects the immune response to the virus.

That's why it would be great to get direct evidence of a chronic herpesvirus infection in the tissues, as this would convince more researchers that ongoing herpesvirus infection is involved in ME/CFS (assuming it is involved). Then we might find the drug companies start getting interested in developing drugs that target these herpesvirus infections in ME/CFS.



All other viruses are negative.
Some ME/CFS doctors don't use the right tests for enterovirus, and if the wrong test was used, even if you have high enterovirus titers, the test may not detect it. Enterovirus ME/CFS has some treatments, including oxymatrine and Epivir, so it's worth testing for.
 
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pibee

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To be exact, it costs about $434,000 for a 90 day supply. But with good health insurance, it is definitely affordable. For me, it would cost $120 for 90 day supply.

WOW. this made me want to log out of PR for good and never come back... until I scrolled down and saw you miscalculated.
Because it'd be ultimate selfishness to take the drug that costs that much.. without much proof it's needed.
 
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Some ME/CFS doctors don't use the right tests for enterovirus, and if the wrong test was used, even if you have high enterovirus titers, the test may not detect it. Enterovirus ME/CFS has some treatments, including oxymatrine and Epivir, so it's worth testing for.
I know that it's only CMV causing my CFS/ME because A) Dr Lerner said so and B) I recovered on Valcyte alone. And Valcyte alone is the only drug that has ever worked for me. I'm switching to Letermovir because it's non-toxic. That's like 80% of the reason why I want to switch. I'm doing OK on Valcyte. My CFS/ME symptoms are barely noticeable on Valcyte. But the (long term) toxicity risk is quite frightening. So I wanna switch ASAP.
 

Hip

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I'm doing OK on Valcyte. My CFS/ME symptoms are barely noticeable on Valcyte.
Do you find that you need to keep taking Valcyte in order to keep your ME/CFS symptoms at bay? I know that some patients took Valcyte for a few years, improved, and then when they stopped, the improvements remained. But others found they got worse again after stopping.


Just out of interest, what kind of gains did you make on Valcyte, in terms of your before and after treatment position on the ME/CFS scale of Very Severe – Severe – Moderate – Mild – Remission?

And did you fall into the typical timescale on which improvements appear: I think Dr Lerner says the first signs of improvement appear after 3.5 months on antiviral therapy, and when I looked at his studies on Valcyte and Valtrex treatment, it seems that patients take around 2 years to obtain the full benefits (I put some details of Dr Lerner's studies in this post).

I am planning to try Valcyte myself this year for an active cytomegalovirus infection, so that's why I am interested; but I also have an active coxsackievirus B4 infection, which unfortunately did not respond to oxymatrine or Epivir, and Lerner's studies showed that patients with (bacterial) coinfections do not respond as well as to Valcyte/Valtrex as patients with pure herpesvirus infections.

Though one thing I might try is a combined Valcyte + oxymatrine protocol, to see if tackling both of my viruses together might yield results.


Are you still using the original Lerner dosing protocol, by the way, which I believe was Valcyte 900 mg in the morning and another 450 mg twelve hours later? Because I think some doctors find that lower doses will suffice.

In my case, as I am in the UK, I will likely have to pay for the Valcyte myself, and the cheapest Indian generic I can find costs around $7 per 450 mg tablet.
 
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Hip:

Yes, I have to keep taking Valcyte. I tried stopping a couple times, with symptoms returning withing a few months. After the 2nd attempt, I said never again.

As for gains, I would probably say I went from Moderate to Remission.

First signs of improvement was at about 5 months, and peaked at around 13 months.

You should definitely combine Valcyte & oxymatrine. Lerner said you have to tackle all viruses simultaneously to get any real benefit.

My Valcyte dosage is 900mg every night after dinner. I supplement with Bile acid, milk thistle and Artemisinin.

You should move to the US and get insurance here!
 

Hip

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As for gains, I would probably say I went from Moderate to Remission.
Wow, that is a pretty good improvement. It just shows how effective Valcyte can be, at least in patients with no other infections.



Yes, I have to keep taking Valcyte. I tried stopping a couple times, with symptoms returning withing a few months. After the 2nd attempt, I said never again.
When you stopped Valcyte and the symptoms started to return, and you then went back on Valcyte, did it also take another 13 months to get back to full health, or was the improvement quicker second time around? Or maybe you did not let your health slide too much, and restarted Valcyte as soon as the first signs of ME/CFS symptoms reappeared?



You should move to the US and get insurance here!
I know! In general I think Britain (and Europe) is back in the Dark Ages when it comes to ME/CFS treatment. Drugs like Valcyte should be free on the NHS for ME/CFS patients, but the NHS has no interest in this disease, apart from offering up these nonsense psychological therapies like CBT for ME/CFS.

In one way it's nice to have the NHS free socialized medical care system; but the disadvantage is that because nearly all doctors in the UK work for the NHS, the bureaucracy, the lack of clinical freedom, and the lack of business incentive tends to put the dampers on any motivation for these doctors to individually develop their own effective ME/CFS treatments, as several ME/CFS doctors in the US have done.



By the way, have you looked at Valtrex or Famvir as an alternative way of treating cytomegalovirus? I did not think these two antivirals worked for cytomegalovirus, and indeed the Merck Manual states that acyclovir and its prodrug valacyclovir have "minimal activity against CMV".

But this study finds that valacyclovir (Valtrex) 2000 mg x 4 daily had similar anti-cytomegalovirus effects as valganciclovir (Valcyte) 900 mg x 2 daily. Although it was a small-scale study with some limitations.

So that study suggests that for cytomegalovirus, 2000 mg of Valtrex might be equivalent to 450 mg of Valcyte.

Valtrex or Famvir are much less toxic compared to Valcyte. However, it would obviously be risky for you to try these as an alternative to Valcyte, because I don't think they have ever been tried and tested by any ME/CFS doctor for cytomegalovirus, as far as I know. So if they did not work, and your ME/CFS came back, you would not be very happy.
 
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When you stopped Valcyte and the symptoms started to return, and you then went back on Valcyte, did it also take another 13 months to get back to full health, or was the improvement quicker second time around? Or maybe you did not let your health slide too much, and restarted Valcyte as soon as the first signs of ME/CFS symptoms reappeared?
It was much quicker the second time around. The first time I stopped, I waited about 9 months before I resumed Valcyte. It only took a few months to get back to full health instead of 13. 2nd time was even faster because I was off Valcyte for just a few months.

By the way, have you looked at Valtrex or Famvir as an alternative way of treating cytomegalovirus?
Yes, and tried both many times. Simple answer: They didn't work. Trust me, I've tried a couple dozen different medications and supplements over the years. Valcyte is the ONLY drug that consistently works for me. Hopefully Letermovir will change that fact.
 

Hip

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Yes, and tried both many times. Simple answer: They didn't work. Trust me, I've tried a couple dozen different medications and supplements over the years. Valcyte is the ONLY drug that consistently works for me. Hopefully Letermovir will change that fact.
That's very useful to know.


Regarding a trial of letermovir: it's possible substituting letermovir for Valcyte for might not do the job, if it is the immunomodulatory properties of Valcyte that result in the ME/CFS benefits.

As you may know, as well as being antiviral, Valcyte also has immunomodulatory effects. In Montoya's Valcyte studies, he states that he cannot be sure it is the antiviral action of Valcyte that led to improvements in ME/CFS, because Valcyte also have immunomodulatory properties. So Valcyte might also fight viruses by its immunomodulatory mechanism; or Valcyte's immunomodulation properties may help ME/CFS in way unconnected to viral infection, by altering immune function.

I guess the only way to know for sure if letermovir can substitute for Valcyte is by trying it.



The Supplement Genistein as Potent as Valcyte for Cytomegalovirus

By the way, I may have found a supplement, genistein, that in very high doses appears to have equal antiviral potency to Valcyte, at least by my calculations (as surprising as that may seem).

I spent several months doing some pharmacokinetic analysis of various compounds (supplements or off-label drugs) with in vitro antiviral effects, to see if I could find compounds with useful antiviral effects in vivo. Most supplements turned out to be very poor antivirals in vivo, even if they have good in vitro antiviral effects. But genistein was an exception, with potent in vivo effect.

I calculated that the genistein in very high doses of around 12 grams daily has about the same in vivo antiviral potency for cytomegalovirus as 900 mg of Valcyte. The downside is that 12 grams of the supplement genistein will cost you around $20, which is actually more expensive than Valcyte, at least the generic Indian version of Valcyte, which costs $7 for 450 mg.

It is possible high dose genistein may be less toxic than Valcyte, although this is debatable: one study gave 22 people around 12 grams of genistein daily for up to 24 months; over these two years there were several serious adverse events reported, as well as lots of less serious adverse events, which may or may not have been linked to the high dose genistein. You can read the full study on Sci Hub.

But of course you do not have to use such a very high 12 gram daily dose, you could try something lower like say 1 or 2 grams a day, and that should lessen the risk of adverse effects.



One advantage of genistein is that its antiviral mechanism for cytomegalovirus looks promising from the point of view of curtailing abortive cytomegalovirus infection: genistein appears to work by preventing early and late cytomegalovirus gene expression (see the study here), which means genistein will prevent CMV from making many of its proteins inside the cell, and this may be able to directly target any ongoing abortive cytomegalovirus infections in ME/CFS patients, reducing the viral proteins made by these abortive infections.

I have not put this pharmacokinetic info on the forum yet, as I am still double checking my figures. I have no background in biology, medicine or pharmacokinetics, so my calculations could easily be wrong, or my methods could be wrong, especially because it is hard to do maths when you have brain fog.

But I am going to be trying genistein myself, perhaps at 1 or 2 grams a day (2 grams of genistein will cost around $3 per day).

Just to give you some figures that I calculated for the in vivo potency:
  • Valcyte 900 mg daily for CMV: Antiviral Potency Factor = 4,410
  • Genistein 12,000 mg daily for CMV: Antiviral Potency Factor = 4,575
  • Genistein 4,000 mg daily for CMV: Antiviral Potency Factor = 1,525
  • Genistein 2,000 mg daily for CMV: Antiviral Potency Factor = 763

Note that even at a dose of 1 or 2 grams daily, given that genistein may more directly target abortive cytomegalovirus infections, even such lower doses might be effective for targeting the infections in ME/CFS.

In other words, even though 2 grams of genistein only has an antiviral Potency Factor of 763, compared to 4,500 for 900 mg of Valcyte, if genistein can directly target the abortive infections, that direct attack may well make up for its weaker antiviral effect at 2 grams.
 
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Regarding a trial of letermovir: it's possible substituting letermovir for Valcyte for might not do the job, if it is the immunomodulatory properties of Valcyte that result in the ME/CFS benefits.
Well you can't rule out the possibility that Letermovir also has immunomodulatory properties. I'm not sure if this has been studied or not. But you're right, there's only one way to find out for sure.

By the way, I may have found a supplement, genistein, that in very high doses appears to have equal antiviral potency to Valcyte, at least by my calculations (as surprising as that may seem).
The trouble with using this supplement is that the positive effects cannot be sustained at low doses. And it's not practical to consume genistein in such high doses. 12 grams a day, that would be insane! That would produce some seriously negative effects on the liver and probably other organs as well. Not to mention the financial expense. In addition, the half-life is much shorter than Valcyte's half-life. So you would have to consume it multiple times a day to have a sustained, round the clock effect. Valcyte has an intracellular half life of 18 hours. Genistein's half life is approx 4 hours.

I actually take a supplement similar to that of genistein called Baicalein. It is a chinese herb also known as Skullcap root. I've been drinking it in tea form for years. I drink about 1 gram a day. I discuss this in my old thread as well. Baicalein is actually more potent than Genistein. It blocks HCMV at cell entry as opposed to early or Immediate-early gene expression. Baicalein's half life is approx 10 hours. Longer than Genistein but shorter than Valcyte.

Read this Abstract for reference : Genistein vs Baicalein
 

Hip

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And it's not practical to consume genistein in such high doses. 12 grams a day, that would be insane!
Yes, such extremely high doses would be a concern, as there were serious side effects noted in the study where patients took 12 grams a day. I am thinking of trying 1 gram or so a day of genistein a day, but even at that dose, there may be a risk.

Swanson sell a genistein supplement with 125 mg x 60 capsules for $12. So eight of those capsules a day would be 1 gram.



Genistein's half life is approx 4 hours.
The pharmacokinetic data for genistein is a weird one, because there are lots of contradictory studies. I think genistein has some unusual properties, creating these contradictory results.

One study found a plasma half-life of 8.2 hours. And one study found that three different oral formulations, each containing the same amount of genistein, produced quite different figures for the plasma T1/2 half-life: 8.3 hours, 18 hours and 20.9 hours (see Table 2).

There is also some confusion because the half-life of different genistein metabolites varies a lot, so the half life depends which metabolites you are measuring.



I actually take a supplement similar to that of genistein called Baicalein. It is a chinese herb also known as Skullcap root. I've been drinking it in tea form for years. I drink about 1 gram a day. I discuss this in my old thread as well. Baicalein is actually more potent than Genistein. It blocks HCMV at cell entry as opposed to early or Immediate-early gene expression. Baicalein's half life is approx 10 hours. Longer than Genistein but shorter than Valcyte.
The in vitro antiviral genistein study (full paper here) I mentioned earlier, which is the same one that you cited above, found that baicalein is indeed a little more potent that genistein in vitro.

Genistein's in vitro viral titer reduction IC50 is 3.2 μM, whereas the baicalein's IC50 = 1.2 μM — the smaller the IC50, the more potent the antiviral. Figures from Table 1 of the study.

The IC50 is the concentration of the antiviral compound that leads to a 50% reduction of viral levels, in a cell line test in vitro.


However, if my pharmacokinetic calculations are right (and they may not be, especially given my constant brain fog, which never helps when doing maths), then in vivo, baicalein is around 300 times weaker than genistein, because of issues with poor oral absorption / bioavailability of baicalein. This poor bioavailability means you cannot get baicalein at high enough blood concentrations to achieve a good antiviral effect.

I can post my genistein and baicalein pharmacokinetic calculations here for you to inspect if you like. The maths is pretty basic and straightforward (but with my brain fog, I may still have made a mistake).
 
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Hey OnlyInDreams
Sorry if it's already been asked but how long were you sick for before trying valganciclovir? I have a feeling most people who recover or have big improvements with antivirals were only sick for a few years. Antivirals were tried in a clinic here in Italy but everyone stopped prescribing them because they weren't deemed effective, i suspect that's partly because all the patients have been sick for decades.
 

Hip

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Antivirals were tried in a clinic here in Italy but everyone stopped prescribing them because they weren't deemed effective,
A forum member from Italy commented that Valcyte was used to treated HHV-7 infections in ME/CFS patients in Italy, but this did not get results. Well Valcyte is potent for EBV, HHV-6 and cytomegalovirus, but from what I can work out, Valcyte does not work for HHV-7.

So if these ME/CFS patients in Italy had HHV-7, or had EBV, HHV-6 or CMV infections plus co-infection with HHV-7, then that could explain why Valcyte did not work for them. More info in this post.
 
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A forum member from Italy commented that Valcyte was used to treated HHV-7 infections in ME/CFS patients in Italy, but this did not get results. Well Valcyte is potent for EBV, HHV-6 and cytomegalovirus, but from what I can work out, Valcyte does not work for HHV-7.

So if these ME/CFS patients in Italy had HHV-7, or had EBV, HHV-6 or CMV infections plus co-infection with HHV-7, then that could explain why Valcyte did not work for them. More info in this post.
As far as i know they were tried on everyone, i could be wrong though
was that member Paolo?
 
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It was fablepd. You can see his post here.
Hmm, maybe he was referring to only some but that is definitely very interesting, i need to keep this in mind together with other things, maybe i can convince them to try an antiviral approach. Thanks!
 

debored13

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Yes, such extremely high doses would be a concern, as there were serious side effects noted in the study where patients took 12 grams a day. I am thinking of trying 1 gram or so a day of genistein a day, but even at that dose, there may be a risk.

Swanson sell a genistein supplement with 125 mg x 60 capsules for $12. So eight of those capsules a day would be 1 gram.





The pharmacokinetic data for genistein is a weird one, because there are lots of contradictory studies. I think genistein has some unusual properties, creating these contradictory results.

One study found a plasma half-life of 8.2 hours. And one study found that three different oral formulations, each containing the same amount of genistein, produced quite different figures for the plasma T1/2 half-life: 8.3 hours, 18 hours and 20.9 hours (see Table 2).

There is also some confusion because the half-life of different genistein metabolites varies a lot, so the half life depends which metabolites you are measuring.





The in vitro antiviral genistein study (full paper here) I mentioned earlier, which is the same one that you cited above, found that baicalein is indeed a little more potent that genistein in vitro.

Genistein's in vitro viral titer reduction IC50 is 3.2 μM, whereas the baicalein's IC50 = 1.2 μM — the smaller the IC50, the more potent the antiviral. Figures from Table 1 of the study.

The IC50 is the concentration of the antiviral compound that leads to a 50% reduction of viral levels, in a cell line test in vitro.


However, if my pharmacokinetic calculations are right (and they may not be, especially given my constant brain fog, which never helps when doing maths), then in vivo, baicalein is around 300 times weaker than genistein, because of issues with poor oral absorption / bioavailability of baicalein. This poor bioavailability means you cannot get baicalein at high enough blood concentrations to achieve a good antiviral effect.

I can post my genistein and baicalein pharmacokinetic calculations here for you to inspect if you like. The maths is pretty basic and straightforward (but with my brain fog, I may still have made a mistake).
baicalein might have more than just antiviral effects and might be very good for CFS for another reason, I will elaborate on different post
 

debored13

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baicalein might have more than just antiviral effects and might be very good for CFS for another reason, I will elaborate on different post
A user named Travis, on another forum, made this post in response to my questions about treating the issues with pyruvate dehydrogenase in ME/CFS directly. It's a tiny bit above my head, but I remember reading Szent-gyorgyi's work "cancer and the living state" and him talking about methylgloxal as possibly really important for the formation of life on earth, and having an important role in protein conductivity/the redox aspects of the living state. So now I want to go back and read that and refresh myself, anyway, here's the post:


"I can't think of anything besides thiamine, unless of course you'd find a way to increase the expression of the enzyme. Yet there could be a way to do this: Since pyruvate dehydrogenase is under negative regulation by hypoxia inducible factor-1—via transcribing-for pyruvate dehydrogenase kinase—then taking baicalein and/or lapachol should ultimately act to increase it. These phytochemicals are the two most powerful natural glyoxalase-1 inhibitors (Kᵢ ≈ 5–7 μM), acting to increase methylglyoxal by inhibiting its degradation to lactate. Methylglyoxal is very powerful because it selectively reacts with exposed arginyl side-chains on proteins, irreversibly converting them into hydroimidazolone rings. By reacting with 'hot spot' arginine residues is how methylglyoxal been shown to regulate transcription (Yao, 2007), and the transcription factor HIF-1 is also inactivated in this manner (Bento, 2010). Taking a glyoxalase inhibitor such as baicalein could be expected to: increase intracellular methylglyoxal, decrease intracellular lactate, inhibit 15-lipoxygenase (Deschamps, 2006), inactivate hypoxia inducible factor-1α (Bento, 2010) thereby increasing pyruvate dehydrogenase expression. Methylglyoxal had acquired a pathological reputation because it reacts with extracellular proteins in diabetes, yet this only occurs in states where glucose cannot get into the cell where it belongs. Methylglyoxal also forms inside the cell mainly from carbohydrates, and appears to be the biochemical signal for their metabolic rate. Intracellular methylglyoxal has also acquired reputation for powerfully inhibiting cancer, and very likely the reason why baicalein and lapachol have been so successful at treating it.



Kim, Jung-Whan. "HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia." Cell metabolism (2006)



'Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. Forced PDK1 expression in hypoxic HIF-1a null cells increases ATP levels, attenuates hypoxic ROS generation, and rescues these cells from hypoxia-induced apoptosis. These studies reveal a hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production.' ―Jung-Whan



Bento, C. F. "The chaperone-dependent ubiquitin ligase CHIP targets HIF-1α for degradation in the presence of methylglyoxal." PloS one (2010)



'Methylglyoxal has recently been shown to modify HIF-1α on arginine residues [22], probably leading to changes in protein conformation. Indeed, immunoprecipitation experiments showed that methylgloxal-modified lysine and arginine residues of HIF-1α, increasing its immunoreactivity against N-carboxymethyl-lysine and Nα-acetyl-Nδ(5-hydro-5-methyl)-4-imidazolone (MG-H1) antibodies, respectively. Thus, we hypothesized that modification by methylgloxal might stimulate proteasome-dependent degradation of HIF-1α, as a result of post-translational modifications.' ―Bento



Yao, Dachun. "High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A." Journal of Biological Chemistry (2007)



'Our studies demonstrate for the first time that methylglyoxal causes post-translational modification of a coregulator protein and that this modification affects gene expression. The extent of this modification reflects the net effect of a variety of intracellular processes, including metabolic flux and reactive oxygen formation, and may thus function as a new integrating signal to coordinately regulate distinct patterns of gene expression.' ―Yao"