Rest periods and can CFS people get really well?

[Hip]

Hip, I am pretty sure that you have either not read, or not understood, my explanation of how ROS is involved these illnesses in the opening post of this thread, according to my hypothesis. It doesn't matter if your SOD works perfectly if you don't have enough NADPH to support glutathione reductase, because SOD makes H2O2 and without enough NADPH you won't have enough reduced glutathione, (and thioredoxin), in your mitochondria to get the H2O2 down to normal, and H2O2 damages iron-sulfur clusters. This is the heart of the vicious cycle causing these illnesses, according to my hypothesis.

OK, I have read this thread again, and I now follow your line of thinking better.

The hypothesis you are presenting appears to be the following (please correct if wrong):

You are pointing out that the energy produced in mitochondria can either be used to make ATP, the universal energy molecule, or to make the pro-antioxidant NADPH. NADPH is important to make because it protects certain delicate mitochondrial machinery (the iron-sulfur proteins) from being damaged by hydrogen peroxide.

Hydrogen peroxide is always being produced as a by-product of mitochondrial function: operating mitochondria generate the potent ROS superoxide, and this superoxide is then converted into the less potent ROS hydrogen peroxide by the enzyme SOD2 within the mitochondria. But if this hydrogen peroxide is not itself neutralized, it will cause damage.

NADPH facilitates the neutralization of hydrogen peroxide by ensuring that there is plenty of glutathione available in the mitochondria; it is glutathione which actually performs the job of neutralizing hydrogen peroxide. NADPH ensures glutathione is available by constantly regenerating the "spent" glutathione back into "fresh" glutathione again, ready to neutralize more hydrogen peroxide. Glutathione gets "spent" when it neutralizes hydrogen peroxide, being converted into glutathione persulfide (GSSH) during this neutralization process; but NADPH converts this "spent" glutathione, ie the GSSH, back into "fresh" glutathione.

You are hypothesizing that when ME/CFS patients engage in too much activity, most of the energy produced in the mitochondria is directed towards making ATP, in order to provide the energy needs of the body and brain; but this manufacture of ATP is done at the expense of NADPH manufacturing, which means that there will not be enough NADPH around to protect against the damage that hydrogen peroxide can inflict on the delicate iron-sulfur proteins found in the electron transport chain of the mitochondria.

This lack of NADPH then leads to further damage of the mitochondrial iron-sulfur proteins, resulting in even lower mitochondrial energy output, resulting in even less energy being spare to make the protective NADPH, and this is the basis of your proposed vicious circle of mitochondrial damage.

You are suggesting that if the ME/CFS patient only engages in short periods of energy expenditure, punctuated by periods of rest, then this will ensure that the levels of hydrogen peroxide will not rise too high, and will also allow breathing space for the mitochondria to direct their energy output to make the all-important protective NADPH.


I have to admit that on re-reading this thread, this hypothesis is intriguing. I guess a lot hinges on whether the damage inflicted by hydrogen peroxide on the iron-sulfur proteins in the mitochondria does actually lead to reduced mitochondrial energy output, as this is the basis of the vicious circle. And as with any mitochondrial theory of ME/CFS, it depends on whether reduced mitochondrial output and increased ROS can be shown to give rise to the symptoms observed in ME/CFS.


Incidentally, there is a theory by Dave Whitlock not dissimilar to yours, which hypothesizes ME/CFS is caused by low numbers of mitochondria. The average mitochondrion has a lifespan of around 1 month, after which it must be replaced. Whitlock thinks that in ME/CFS not enough new mitochondria are being made to replace the old ones. So ME/CFS patients are running on old, worn out mitochondria, which become leaky, thereby producing more reactive oxygen species and less energy output. More info here.

I have not been able to find antioxidants which deal with H2O2, and are not ultimately dependent on NADPH, and that can be taken in large enough amounts to deal with the ROS. As you can see in this diagram glutathione, vitamin C and vitamin E all depend on NADPH availability.

This study found that the nootropic supplement piracetam improves mitochondrial dysfunction following oxidative stress. I am not sure if this is useful for you. By my calculations, for a normal weight person, the piracetam concentrations of 100 microM and 1000 microM used in the study would work out to an oral dose of 570 mg and 5700 mg of piracetam respectively.

This catalase supplement by Invite Health may also be of interest. Coincidentally, in this thread @Mya Symons found that taking a catalase supplement improved his PEM, and he speculates that the mechanism is catalase's hydrogen peroxide scavenging ability.

There are some other drugs and supplements that support or stimulate the various mitochondrial complexes listed in the first post of this thread. I am not sure if these will be of any use from the perspective of your theory.

 

[Kimsie]

@Kimsie I want to echo @sueami's post and ask you besides implementing the resting, what else are we supposed to do as part of your hypothesis? I don't understand any of the scientific diagrams (not b/c of you, they are just above my comprehension level.) But I was wondering on a practical level, what else do you advise besides resting?

I am interested in the Genova cysteine/sulphate test kit but how do you find a doctor familiar with this to test out a supplement protocol? Did you find a doctor in your son's case? You can always send me a PM if easier.

Thanks again!

Our ND is very open to exploring options with us, and so I just asked him if we could get the test done, and he was fine with it. I have been explaining my ideas to him as I have been coming up with them, so he knows where I am coming from on this. So many doctors, even ND's, are not open to this kind of collaboration, so we were very happy to find him.

I keep trying to find supplements, etc, that could help along with the rest periods, but I haven't found what I would like to find, which is a supplement that can be taken in large amounts that will lower the H2O2 levels in the cells without ultimately relying on the NADPH levels. Supplements that spare BH4 also spare NADPH because recycling BH4 uses NADPH so that is another possibility.

I think that Vitamin C is worth taking in amounts up to 15 grams a day in divided doses, or even nearly to bowel tolerance, but that can cause bloating and it doesn't last very long because it gets excreted so quickly. B12 in the form of hydroxocobalamin in very large amounts by IM or possibly by nasal spray might help. Glutathione IV's might help but that isn't very practical. NAC, glycine and glutamine help you to make your own glutathione. I think many people with ME/CFS have detox issues with glutathione, though, and it can only do just so much because it is dependent on NADPH.

The NAD recipe, or even taking niacinamide and D-ribose without the other ingredients, works to raise the pool of NADH and NADPH and pushes the electron transport chain, but there is no way for me to know whether a person is going to progress better with it or without it. However, it may be especially useful for people who have a tiny window or no window of activity, but only if they don't raise their activity levels when they feel more energy, which is a great temptation.

There is nothing I would like better than to figure out a way to make this easier, and the rest periods less needed, because I feel pretty sure that I am going to have only marginal cooperation from my son with schizophrenia on the rest periods. If you CFS people think it is hard to convince yourselves to rest when you don't feel tired, imagine how hard it is to convince someone who doesn't even have fatigue issues and has an illness that affects their ability to think!

If I succeed in finding anything that looks hopeful, you can be sure that I will report it here.

 

[Gingergrrl]

I have called Genova in the past to ask if there are any doctors near me who have ordered such kits. They kindly gave me names.

@Sushi This is a brilliant idea that I never would have thought of doing. Thank you!

Our ND is very open to exploring options with us, and so I just asked him if we could get the test done, and he was fine with it.

I am no longer seeing my former ND but would be open to finding another one who was more knowledgeable about ME/CFS and tests like these. Can I ask where you live and how you found yours? Also, even though he agreed to you doing the test kit, if he is not familiar with it, how does he know what supplements to recommend?

I keep trying to find supplements, etc, that could help along with the rest periods, but I haven't found what I would like to find, which is a supplement that can be taken in large amounts that will lower the H2O2 levels in the cells without ultimately relying on the NADPH levels.

Can you remind me what NADPH means? I keep googling all your different terms but am not retaining anything.

I think that Vitamin C is worth taking in amounts up to 15 grams a day in divided doses, or even nearly to bowel tolerance, but that can cause bloating and it doesn't last very long because it gets excreted so quickly. B12 in the form of hydroxocobalamin in very large amounts by IM or possibly by nasal spray might help. Glutathione IV's might help but that isn't very practical. NAC, glycine and glutamine help you to make your own glutathione. I think many people with ME/CFS have detox issues with glutathione, though, and it can only do just so much because it is dependent on NADPH.

I take 1000 mg of Liposomal Vitamin C per day and don't think my stomach would tolerate higher than that. I didn't tolerate the methylation supps either but have not tried hydroxy B-12. I also took liposomal glutathione for a long time but didn't notice anything (good or bad.)

There is nothing I would like better than to figure out a way to make this easier, and the rest periods less needed, because I feel pretty sure that I am going to have only marginal cooperation from my son with schizophrenia on the rest periods. If you CFS people think it is hard to convince yourselves to rest when you don't feel tired, imagine how hard it is to convince someone who doesn't even have fatigue issues and has an illness that affects their ability to think!

Please forgive me if you already explained this, but what led you to conclude that a treatment for schizophrenia would work for ME/CFS (or vice versa?)

If I succeed in finding anything that looks hopeful, you can be sure that I will report it here.

Thank you and please do!

 

[Kimsie]

OK, I have read this thread again, and I now follow your line of thinking better.

The hypothesis you are presenting appears to be the following (please correct if wrong):

You are pointing out that the energy produced in mitochondria can either be used to make ATP, the universal energy molecule, or to make the pro-antioxidant NADPH. NADPH is important to make because it protects certain delicate mitochondrial machinery (the iron-sulfur proteins) from being damaged by hydrogen peroxide.

Hydrogen peroxide is always being produced as a by-product of mitochondrial function: operating mitochondria generate the potent ROS superoxide, and this superoxide is then converted into the less potent ROS hydrogen peroxide by the enzyme SOD2 within the mitochondria. But if this hydrogen peroxide is not itself neutralized, it will cause damage.

NADPH facilitates the neutralization of hydrogen peroxide by ensuring that there is plenty of glutathione available in the mitochondria; it is glutathione which actually performs the job of neutralizing hydrogen peroxide. NADPH ensures glutathione is available by constantly regenerating the "spent" glutathione back into "fresh" glutathione again, ready to neutralize more hydrogen peroxide. Glutathione gets "spent" when it neutralizes hydrogen peroxide, being converted into glutathione persulfide (GSSH) during this neutralization process; but NADPH converts this "spent" glutathione, ie the GSSH, back into "fresh" glutathione.

You are hypothesizing that when ME/CFS patients engage in too much activity, most of the energy produced in the mitochondria is directed towards making ATP, in order to provide the energy needs of the body and brain; but this manufacture of ATP is done at the expense of NADPH manufacturing, which means that there will not be enough NADPH around to protect against the damage that hydrogen peroxide can inflict on the delicate iron-sulfur proteins found in the electron transport chain of the mitochondria.

This lack of NADPH then leads to further damage of the mitochondrial iron-sulfur proteins, resulting in even lower mitochondrial energy output, resulting in even less energy being spare to make the protective NADPH, and this is the basis of your proposed vicious circle of mitochondrial damage.

You are suggesting that if the ME/CFS patient only engages in short periods of energy expenditure, punctuated by periods of rest, then this will ensure that the levels of hydrogen peroxide will not rise too high, and will also allow breathing space for the mitochondria to direct their energy output to make the all-important protective NADPH.

Yes, now you understand. A nice, clear explanation, too. There are more ins and outs about the folate cycle and other things and how the variety of symptoms, not only symptoms of ME/CFS but of some mental and neurological illnesses and also fibro and RA, which I believe also have the same underlying cause, can be caused by this sort of mitochondrial problem, but what you have stated here so clearly is the basic vicious cycle as I have it in my hypothesis.

Except that I would like to add that at each level of activity and supplementation a person reaches a state of balance, or homeostasis, where they stay at the same level until they change something or something in their environment (such as exposure to a virus, for instance) changes. If all variables remain the same, their condition stays at the same level of homeostasis, they don't just keep getting worse forever.

This is why making an improvement, such as breaking up the activity times with rest periods to keep the ROS lower, can make an improvement in the state of the person. And on the other hand making a negative change, such as adding exercise when the person's ETC complexes are damaged, which raises ROS, causes a decrease in the person's wellness.

I have to admit that on re-reading this thread, this hypothesis is intriguing. I guess a lot hinges on whether the damage inflicted by hydrogen peroxide on the iron-sulfur proteins in the mitochondria does actually lead to reduced mitochondrial energy output, as this is the basis of the vicious circle. And as with any mitochondrial theory of ME/CFS, it depends on whether reduced mitochondrial output and increased ROS can be shown to give rise to the symptoms observed in ME/CFS.

Incidentally, there is a theory by Dave Whitlock not dissimilar to yours, which hypothesizes ME/CFS is caused by low numbers of mitochondria. The average mitochondrion has a lifespan of around 1 month, after which it must be replaced. Whitlock thinks that in ME/CFS not enough new mitochondria are being made to replace the old ones. So ME/CFS patients are running on old, worn out mitochondria, which become leaky, thereby producing more reactive oxygen species and less energy output. More info here.

I have to spend more time looking at this one before I can reply. There could very well be a connection with NO because BH4 is used in the synthesis of NO and BH4 depends on NADPH for synthesis and recycling.

I have some ideas about how various symptoms could be caused by this. For one thing, the use of the folate cycle for ATP production drains B6, and B6 us used in a myriad of aminotransferases that supply the correct amino acids for neurotransmitters and other functions in the body. For another thing, the synthesis of heme and catalase are affected, and that in turn affects the synthesis of norepinephrine, which can cause other problems. High sulfite levels and low sulfate can cause another large set of problems with enzymes. The list can go on and on but that's a sampling.

This study found that the nootropic supplement piracetam improves mitochondrial dysfunction following oxidative stress. I am not sure if this is useful for you. By my calculations, for a normal weight person, the piracetam concentrations of 100 microM and 1000 microM used in the study would work out to an oral dose of 570 mg and 5700 mg of piracetam respectively..

It's impossible for me to tell if it would be useful because no one knows how it works or what it does. I have found some things that help, but only temporarily, because they don't really deal with the underlying problem.

This catalase supplement by Invite Health may also be of interest. Coincidentally, in this thread @Mya Symons found that taking a catalase supplement improved his PEM, and he speculates that the mechanism is catalase's hydrogen peroxide scavenging ability..

According to my hypothesis (a part of my hypothesis that I don't mention too often here at PR because it complicates my explanations), catalase synthesis is low in these illnesses. I believe that the depression of my son who has had fatigue and depression is caused by this low catalase.

If this supplement can really deliver functional catalase to the cells, and especially to the brain cells, it should be helpful. I will take a look into it.

There are some other drugs and supplements that support or stimulate the various mitochondrial complexes listed in the first post of this thread. I am not sure if these will be of any use from the perspective of your theory.

I have already thought about melatonin from an antioxidant perspective, but I discarded it, probably because it isn't likely to be good to take it in large enough amounts to make much difference, and you should only take it when you are going to sleep, just the time you need it the least.

In general, if my theory turns out to be correct, then I wouldn't expect these to help. Has anyone taken these for a month or so and found that they helped?

 

[Kimsie]

I am no longer seeing my former ND but would be open to finding another one who was more knowledgeable about ME/CFS and tests like these. Can I ask where you live and how you found yours? Also, even though he agreed to you doing the test kit, if he is not familiar with it, how does he know what supplements to recommend?

Well, some of the things on the test are pretty standard. As far as the cysteine/sulfate ratio goes, I am the one who is doing the research on that. I consider my relationship with the doctor as being collaborative.

Can you remind me what NADPH means? I keep googling all your different terms but am not retaining anything.

NADPH is something that your body makes that you need to recycle glutathione and get rid of H2O2.

Please forgive me if you already explained this, but what led you to conclude that a treatment for schizophrenia would work for ME/CFS (or vice versa?)

I have actually never really explained why, but I guess I can tell more about our story here, and maybe it will be of interest here.

Over 10 years ago our oldest son became ill with what turned out to be schizophrenia. He was 16 years old at the time. I went to an orthomolecular doctor pretty soon after we figured out he had schizophrenia because we were aware that medications do not give people with schizophrenia a normal life, and we were hoping that we could find supplements that would help. We tried a lot of things with this doctor but nothing helped except that I could see that very large doses of vitamin C actually made his negative symptoms a little better, so I knew that maybe supplements could help if you could just find the right ones.

I ran out of ideas to try and he was on medication for many years, but he couldn't hold any job for long and he was far from normal, but at least he wasn't delusional.

Then 3 and a half years ago our youngest son, who was just barely 15 at the time, started having extreme fatigue that never went away. After a couple of months he was tested and we found out that he had recently had mono so we thought that the fatigue would go away in time, but it did not. Our son with schizophrenia also had mono shortly before his symptoms started.

After almost a year and a half of extreme fatigue we found out about the MTHFR mutations and D, (for depression) was found to have one copy of the C677T mutation. S has the A1298T mutation. They both got them from me. D started on 5 mg of methylfolate a day and his fatigue melted like magic 3 hours after the first dose.

After a couple of months of the folate it became apparent that he was becoming gradually depressed, but we didn't link it to the folate at that time. I thought it must be from gut dysbiosis so we were trying various things along those lines, including the GAPS diet in which you eat a lot of sauerkraut. One day we were so busy that he didn't get his kraut, and the next day he felt a lot better. I realized that there was a connection between his depression and histamine. (You can see old posts here about it, but I was wrong about what the connection was at the time).

Anyway, I found that D was so responsive to supplements, often going from deep depression to feeling pretty good in half an hour (for instance from 15 grams of vitamin C given at once) that I was able to learn about and track the metabolic pathways that were affected. Plus we also had testing done which ruled out heavy metals and certain mineral deficiencies.

In the midst of this process, I realized that the underlying cause of D and S's problems must be the same, and that mono had set them both off, even though at the time I was mistaken about the pathways that were affected. Later as I was studying more and more it became apparent to me that other illnesses were caused by the same underlying cause, for instance, mitochondrial problems are suspected in both schizophrenia and Alzheimer's, so I started looking at Alzheimer's more and I realized it was one of the illnesses. I also became convinced that sulfite oxidase was affected, and for quite a while I thought that might be the heart of the vicious cycle but now I think it is not the heart, but that it interferes with a number of metabolic pathways and contributes to symptoms in these illnesses.

Phoenix Rising was always a place I had learned a lot from the time I began to research about MTHFR, so I had read a lot of things from posts here and I thought that some things I had learned might help people here, but I didn't become convinced that the underlying cause was the same until relatively recently, when I realized that the mitochondria and energy production were at the heart of the problems that my sons have.

I hope this is fairly clear. I know I have been rambling. I think that schizophrenia and depression can be caused by other things in some people, so I don't think this treatment will work for everyone who has schizophrenia or depression, but in the case of my sons, I believe that their illnesses are caused by mitochondrial failure. I have found that I can completely take away my son's symptoms of schizophrenia with supplements (my combination of supplements is different from the original doctor's), but only for a couple of months and then I have to keep juggling the supplements around. I have figured out that this is because pushing the ETC leads to more ROS and damage unless he will do the rest periods along with the supplements. After a while the supplements don't work as well because the damage to the ETC is greater.

 

[adreno]

@Kimsie

I wonder if antioxidants which are already reduced (e.g., ubiquinol) are still dependent on NADPH?

 

[adreno]

This is interesting:

Scientists Reverse Autoimmune Disease Progression With Naturally Occurring Molecule

This new research conducted by Brigham and Women's Hospital (BWH) has identified NAD+ (Nicotinamide adenine dinucleotide), a naturally occurring molecule in living cells, plants, and food that has the potential to turn “destructive” cells that attack healthy tissues into “protective” cells. The molecule has also been found to reverse disease progression by restoring tissue damaged by the autoimmunity process.

I wonder if nicotinamide riboside is worth a try? Is it any better than regular nicotinamide?

ChromaDex developed its breakthrough patent-protected ingredient NIAGEN™ as the first and only commercially available brand of nicotinamide riboside (NR). NR, the active ingredient in NAD+ Cell Regenerator™, boosts levels of NAD+ in cells and tissue. Studies have demonstrated that increasing the levels of NAD+ can support healthy aging by stimulating mitochondrial energy production and activating sirtuin function.

http://www.prnewswire.com/news-rele...l-regenerator-featuring-niagen-277726701.html

 

[Gondwanaland]

@Kimsie I am most fascinated by your studies. I have only shallow knowledge on the subject and beg you to apologize my ignorance:

Alzheimer's boomed after the low-fat revolution during the 1980's - refined oils, low-fat this low-fat that, no-cholesterol fever. My question is: how do you think diet can influence the improvement of these conditions - apart from the fact that I don't think that diet can undo what mono did, that is.

 

[Hip]

@Kimsie
Regarding raising catalase, @adreno posted the following in another thread:

Turns out that reishi can raise all of these (SOD, glutathione and catalase):

http://www.ncbi.nlm.nih.gov/pubmed/20214017

 

[adreno]

@Kimsie
Regarding raising catalase, @adreno posted the following in another thread:

That was a rat study, btw. Might not work for humans.

 

[Kimsie]

@Kimsie

I wonder if antioxidants which are already reduced (e.g., ubiquinol) are still dependent on NADPH?

You have to understand that normally antioxidants are used and then recycled. It is the recycling of antioxidants such as GSH, vitamin C, vitamin E and TRX that is ultimately dependent on NADPH. Catalase is also dependent on NADPH to avoid being changed to an inactive form.

The same recycling idea goes for CoQ10, in all its forms, except that CoQ10 becomes recycled when it gives its electrons to Complex III, so it isn't dependent on NADPH. But Complex III is dependent on iron-sulfur clusters, so it is likely to be inhibited in these illnesses, which means that a certain percentage of Complex III's in the mitochondria are likely to be non-functional. So I think that the benefit of taking any form of CoQ10 is mainly that it increases the number of them that are able to accept electrons from (funtional)Complex I's and II's and find functional Complex III's to give them to so this helps overcome the inhibition until the Complex III's are maxed out.

If you can take some antioxidants in large enough quantities, such as vitamin C up to a point, or IV glutathione, then you might get enough to make a difference, even though most of it only gets used once before it is excreted, since there isn't enough NADPH to keep recycling it all. I think of this as suicidal antioxidants, where they are only used once and then excreted. (It is the antioxidant that is suicidal, not the person taking it!)

This is interesting:

Scientists Reverse Autoimmune Disease Progression With Naturally Occurring Molecule

I wonder if nicotinamide riboside is worth a try? Is it any better than regular nicotinamide?

http://www.prnewswire.com/news-rele...l-regenerator-featuring-niagen-277726701.html

NAD has been available for years as a supplement. NADH has been around for a while, too. It doesn't matter what form you take because the forms get changed so quickly in the body, anyway.

In our family we have found that the NAD recipe works just as well; even taking just niacinamide and D-ribose works pretty well, and adding any of the other ingredients makes it work even better. The problem is that you have to do the rest periods, too, for reasons I have already given.

The first article you linked to was about a study where they took healthy mice and gave them NAD and then gave them something to make them sick, and the NAD (but the NAD recipe would have worked, too, in my opinion) helped them resist the stuff they gave them to make them sick.

This is very different from giving NAD to someone who already has an inhibited ETC and who is already sick. Those mice didn't have trouble making NADPH, at least not at the start.

@Kimsie I am most fascinated by your studies. I have only shallow knowledge on the subject and beg you to apologize my ignorance:

Alzheimer's boomed after the low-fat revolution during the 1980's - refined oils, low-fat this low-fat that, no-cholesterol fever. My question is: how do you think diet can influence the improvement of these conditions - apart from the fact that I don't think that diet can undo what mono did, that is.

I think that the best thing a person can do is to avoid all vegetable oils, except for olive oil (and don't use that for cooking because it isn't stable at high heat) and to eat non processed foods as much as possible, and avoid sugar. Animal fats are fine as long as the animals haven't been raised on hormones and contaminated foods. Vegetable oils are all extracted with high heat and chemicals and you should consider them like poison. Most processed foods have vegetable oils in them. During the low fat craze all kinds of unnatural substances were used to make things be low fat but taste like they had fat.

Nut oils are fine for eating but probably not for cooking, and coconut oil is fine for cooking and everything. Coconut oil also helps supply the brain with ketones for energy production and to bypass the pyruvate dehydrogenase complex, which is likely to be inhibited to some degree in these illnesses, but be sure to get coconut oil that isn't artificially hydrogenated. There are several brands that carry safe coconut oil that doesn't smell or taste like coconut for those that don't want all their cooking to taste like coconut.

@Kimsie
Regarding raising catalase, @adreno posted the following in another thread:

This appears to be another case of healthy (but old) mice. The mice probably had reduced production of CAT and GSH, but didn't have problems with NADPH. Since CAT and GSH are both dependent on NADPH, I wouldn't expect this herb to make very much difference.

 

[Gondwanaland]

I benefit from a paleo diet myself, which is a big help against inflammation, but unfortunately it is not enough...

 

[Kimsie]

...
This catalase supplement by Invite Health may also be of interest. Coincidentally, in this thread @Mya Symons found that taking a catalase supplement improved his PEM, and he speculates that the mechanism is catalase's hydrogen peroxide scavenging ability.
.

I had checked out catalase supplements before, but I forgot last night that I had rejected them because catalase would not survive digestion.
Mya Symons was using several other things with the catalase, including baking soda which seems to help with PEM, so I am not convinced that it was the catalase that was helping in that case.

This morning I saw this study and it seems that catalase would have to be liposomal to be effective. I am going to do more research on this idea later today.

 

[Hip]

You have to understand that normally antioxidants are used and then recycled. It is the recycling of antioxidants such as GSH, vitamin C, vitamin E and TRX that is ultimately dependent on NADPH. Catalase is also dependent on NADPH to avoid being changed to an inactive form.

I had a look online for articles detailing the process of recycling antioxidants such as GSH, vitamin C, vitamin E by NADPH, but could not find much. Since NADPH is so crucial for recycling of these antioxidants, I would have thought it should be better known and documented.

However, I found A few interesting references to NADPH from Richard Van Konynenburg:

New biomarker test for ME/CFS: NADPH measurement at Riordan Clinic

Here's a press release about a newly patented diagnostic for ME/CFS:

http://www.marketwatch.com/story/ri...ents-with-chronic-fatigue-syndrome-2012-04-11

Note that low NADPH has a lot of ramifications: NADPH is normally used to convert folic acid to THF. It is also used to reduce oxidized glutathione. It also supports Phase I detox by the CYP450 enzymes. It does other good things, also.

I think that the reason it [NADPH] is low in ME/CFS is that the main source of it is the pentose phosphate shunt on the glycolysis pathway. When the mitochondria become dysfunctional in ME/CFS, the cells are forced to ramp up glycolysis to try to make up the shortfall in ATP production. This is done primarily by the enzyme phosphofructokinase, which is upregulated by low ATP and high AMP. When this occurs, more of the flow goes through the main glycolysis chain, and less is available to enter the pentose phosphate shunt, so less NADP+ gets reduced to NADPH, and therefore, NADPH goes down.

Bolding above is mine.

To convert folic acid to methylfolate, four sequential reactions are required. The first two require NADPH, which is based on vitamin B3, and it requires some additional metabolism to form NADPH, including burning of glucose via the pentose phosphate shunt on the glycolysis chain. Magnesium is also needed. These two reactions convert folic acid to tetrahydrofolate (THF).

That's true. Dr. Cheney thinks the reason is that PWMEs are low in NADPH (which he has measured in his patients), and that is needed by glutathione reductase to recycle glutathione. So when glutathione is added, it gets oxidized,and that shifts the GSH to GSSG ratio down, worsening the redox environment in the cells.

I don't favor direct boosting of glutathione on its own. I tried that from 1999 through 2004, and the results were as you stated. The way to raise glutathione is to correct the partial methylation cycle block, which is upstream of glutathione synthesis. We have lab evidence from our clinical trial that this works.

I have suggested boosting glutathione as an add-on to the methylation treatment to counter the excitotoxicity that many people experience on this treatment, which I suspect is due to an initial further drop in glutathione. More recently, I've suggested trying L-cystine (not cysteine) to boost production of glutathione in the brain during this treatment. This should not be done if a high body burden of mercury is suspected.

Normally, oxidized glutathione in the cells is recycled back to reduced glutathione by glutathione reductase, an enzyme that requires vitamin B2 and NADPH. If this reaction is overwhelmed by oxidative stress, the cells export excess GSSG to the plasma. In some (but not all) PWCs, GSSG is elevated above the normal
range, and this represents oxidative stress. It is more common in CFS to see this level in the high-normal range. This value may increase slightly under initial treatment of a partial methylation cycle block.*

If you want to see the other things that Richard Van Konynenburg wrote on NADPH, search this forum under his username richvank.


By the way, is the supplement NADH of any benefit in all of this?

 

[Kimsie]

I had a look online for articles detailing the process of recycling antioxidants such as GSH, vitamin C, vitamin E by NADPH, but could not find much. Since NADPH is so crucial for recycling of these antioxidants, I would have thought it should be better known and documented.

However, I found A few interesting references to NADPH from Richard Van Konynenburg:

Bolding above is mine.

If you want to see the other things that Richard Van Konynenburg wrote on NADPH, search this forum under his username richvank.

By the way, is the supplement NADH of any benefit in all of this?

The fact that GSH needs NADPH to be recycled is so well known that it is the sort of thing you look for in text books and it wouldn't be talked about so much in articles, which focus on new discoveries. Vitamin C is recycled by GSH and E is recycled by C from what I can find.

That NADPH is needed to recycle GSH is well known, but since the Pentose Phosphate Pathway supposedly makes all the NADPH we needs it is ignored a lot.

I agree with Rich that there is something wrong in these illnesses that makes the PPP not function as well as it should. If it did there should not be a problem because it is a shunt that should be able to go around and around making NADPH, and at least one of the enzymes involved that makes NADPH from the PPP is found in the mitochondria and not just in the cytosol. My personal take is that the problem with the PPP has something to do with the sufite oxidase inhibition - perhaps one or more of the enzymes is being inhibited by sufite, either directly or indirectly. I think that if what Rich said about it was true that the problem could be overcome by providing more glucose.

At the time Rich died, the research about the folate pathway contribution to NADPH production in normal cells still had not been done, and it appears that he believed that the PPP was the main producer of NADPH, but now it is known that NNT is probably the main producer of NADPH in the mitochondria, because almost 50% less NADPH is made when the proton motive force is turned off during in vitro experiments.

Here is a quote from that article:
Small interfering RNA (siRNA) silencing of NNT in PC12 cells results in decreased cellular NADPH levels, altered redox status of the cell in terms of decreased GSH/GSSG ratios and increased H2O2 levels, thus leading to an increased redox potential (a more oxidized redox state).

I believe that when the electron transport chain is inhibited enough to create a high dependency on alternative pathways for ATP production it creates a situation very similar to silencing, or nearly silencing, the NNT, depending on how much ATP is being demanded by activity levels.

When ATP levels are low the folate pathway will be used more for ATP production and less NADPH will be produced through that pathway, so that source of NADPH is also affected. By the way, the idea that the folate pathway is used for ATP production is my own, I can't find anyone else saying this, although I can find studies that I feel support the idea, such as the rat heart study, even though the people doing the study didn't reach the same conclusion that I did. I also base this on the fact that my son had great fatigue until he started taking high dose folate. I know that this could be from increased purine synthesis, but he wasn't taking niacinamide at the time, so I don't really think that could be the only reason why the folate helped his fatigue so much. I suspect that he doesn't use the glycolysis pathway very well for ATP, and my other son doesn't either.

I think you can raise the NADH/NADPH pool very well with the NAD recipe, which should be cheaper than taking NADH. As I keep saying, whether raising the NAD and NADP pools helps or hurts depends on the rest periods, because pushing the electron transport chain increases ROS, because ROS is a byproduct of oxidative phosphorylation, or energy production through the electron transport chain. Mary found that taking NADH helped her not to crash for about 10 days and then it stopped working. She also increased her activity during those 10 days and I think that is why it stopped working. She should have stayed at the same level of activity for a month or so before increasing.

 

[nandixon]

This is interesting:

Scientists Reverse Autoimmune Disease Progression With Naturally Occurring Molecule

I wonder if nicotinamide riboside is worth a try? Is it any better than regular nicotinamide?

http://www.prnewswire.com/news-rele...l-regenerator-featuring-niagen-277726701.html

I didn't notice any effect from Niagen. I posted about it here and answered a couple questions, I think:
http://forums.phoenixrising.me/inde...ndrial-communication.27319/page-2#post-416787

 

[Hip]

At the time Rich died, the research about the folate pathway contribution to NADPH production in normal cells still had not been done, and it appears that he believed that the PPP was the main producer of NADPH, but now it is known that NNT is probably the main producer of NADPH in the mitochondria, because almost 50% less NADPH is made when the proton motive force is turned off during in vitro experiments.

That's very interesting, Kimsie.

 

[Kimsie]

Today I ran across something that may account for some of the symptoms in these illnesses, as relating to low NADPH, which is the heart of my hypothesis.

NADPH is required for most of the cytochrome P450 enzymes, of which humans have 57. They are involved in steroid synthesis such as cortisol and cortisone, the synthesis of cholesterol, the detoxification of various drugs and xenobiotics, the activation of vitamin D, and they affect the synthesis and metabolism various hormones, bile synthesis, and other pathways.

It seems possible that some of these enzymes could be affected by low NADPH levels. Some of these P450 enzymes are actually in the mitochondria. It's just a thought.

 

[adreno]

I wonder why nicotinamide is a SIRT1 inhibitor, when NAD+ is a SIRT1 activator? Feedback loop? We definitely want SIRT1 activation, not inhibition. But if both forms interconvert, I guess it doesn't matter.

It seems that substances such as resveratrol are dependent on SIRT1 to raise NAD+ and improve mito function. At the same time, SIRT1 is also dependent upon NAD+?

SIRT1 Is Required for AMPK Activation and the Beneficial Effects of Resveratrol on Mitochondrial Function

This study seems to confirm that a lack of NAD+ is bad news for neurons under duress:

Nicotinamide prevents NAD+ depletion and protects neurons against excitotoxicity and cerebral ischemia: NAD+ consumption by SIRT1 may endanger energetically compromised neurons.

Just thinking whether SIRT1 activators would be helpful or not. I guess that still depends on rest, if I understand correctly.

 

[Hanna]

I apologize in advance if my knowledge is very poor and I ask rather bad questions. But...

1. The mitochondry membrane is the only one - I read - that countains in its inner part cardiolipin (as 20% of total lipids there), and it was found in a study (*) that 95% of CFS patients have anti-cardiolipin antibodies.

(I belong to the group with elevated IGM anticardiolipin antibodies - and the number increased with the severity of the symptoms from 1998 to now).

2. From wikipedia :
Cardiolipin serves as proton trap for oxidative phosphorylation[edit]
During the oxidative phosphorylation process catalyzed by Complex IV, large quantities of protons are transferred from one side of the membrane to another side causing a large pH change. CL is suggested to function as a proton trap within the mitochondrial membranes, thereby strictly localizing the proton pool and minimizing the changes in pH in the mitochondrial intermembrane space.

This function is due to CL’s unique structure. As stated above, CL can trap a proton within the bicyclic structure while carrying a negative charge. Thus, this bicyclic structure can serve as an electron buffer pool to release or absorb protons to maintain the pH near the membranes.[7]

Other functions[edit]

• Cholesterol translocation from outer to the inner membrane of mitochondrial
• Activates mitochondrial cholesterol side-chain cleavage
• Import protein into mitochondrial matrix
• Anticoagulant function

==> so my question is :
Could this anticardiolipin antibodies - which are present in a lot of CFS/ME patients - impair the way our mitochondries work ?
If yes, what can be done about it?
Perhaps it is another point - beside the rest and the supplementation - that has to be examined in order to make ATP ?

I have no scientific background, so please, forgive me in advance if it is a silly question,
Thanks

(*) Hokama Y, Campora CE, Hara C, Kuribayashi T, Le Huynh D, Yabusaki K. Anticardiolipin antibodies in the sera of patients with diagnosed chronic fatigue syndrome. J Clin Lab Anal. 2009;23(4):210-2.