Exercise, Reactive Oxygen Species, and Fatigue.

weyland

Well-Known Member
Then why did you say you haven't seen anything pointing to that in human studies?
I'm saying that I haven't seen anything demonstrating that in humans a riboflavin or other vitamin deficiency alone is enough to cause chronic pathogenic release of ROS.
 

RuthAnn

Well-Known Member
I'm saying that I haven't seen anything demonstrating that in humans a riboflavin or other vitamin deficiency alone is enough to cause chronic pathogenic release of ROS.
Then I will copy and paste from the Linus Pauling page that I linked before.
Although now you are adding in the words chronic and pathogenic!
"
xidation-reduction (redox) reactions

Living organisms derive most of their energy from redox reactions, which are processes that involve the transfer of electrons. Flavocoenzymes participate in redox reactions in numerous metabolic pathways (3). They are critical for the metabolism ofcarbohydrates, lipids, and proteins. FAD is part of the electron transport (respiratory) chain, which is central to energy production. In conjunction with cytochrome P-450, flavocoenzymes also participate in the metabolism of drugs and toxins (4).
mce-anchorAntioxidant functions

Glutathione reductase is an FAD-dependent enzyme that participates in the redox cycle of glutathione. The glutathione redox cycle plays a major role in protecting organisms from reactive oxygen species, such as hydroperoxides. Glutathione reductase (GR) requires FAD to regenerate two molecules of reduced glutathione from oxidized glutathione. Riboflavin deficiency has been associated with increased oxidative stress (4). Measurement of GR activity in red blood cells is commonly used to assess riboflavin nutritional status (5). The erythrocyte glutathione reductase activation coefficient (EGRac) assay assesses riboflavin status by measuring the activity of GR before and after in vitro reactivation with its prosthetic group FAD; EGRac is calculated as the ratio of FAD-stimulated to unstimulated enzyme activity and indicates the degree of tissue saturation with riboflavin. EGRac is thus a functional measure of riboflavin status and has shown to be effective in reflecting biomarker status from severe deficiency to normal status (6).
Glutathione peroxidases, selenium-containing enzymes, require two molecules of reduced glutathione to break down hydroperoxides. GPx are involved in the glutathione oxidation-reduction (redox) cycle (Figure 1)."

BTW, thanks for asking all these questions, it really does give me good ways to dig more deeply into oxidative stress. I have seen so many interesting things today.
Next, maybe we can look more deeply at ways to reduce oxidative stress!
Oops! Forgot to take my second dose of B2, excuse me for a minute.
PS: Who would like to start the thread for reducing oxidative stress?
 

IrisRV

Well-Known Member
But mice studies are useful and you dismiss it not to further our understanding, but only to try to appear intelligent.
This is a personal attack. That is against Health Rising rules.

It is also a statement telling another person why they are doing something. That is an unacceptable conversational technique and one many people objected to at PR. You do not live in someone else's head. You cannot (legitimately) make assertions about other people's intentions, thoughts, or beliefs.

I fail to understand how you do not see the connection.
That does seem to be a critical problem here. The fact that you fail to understand other viewpoints, research, conclusions, or opinions does not make those perspectives wrong and yours right. Your perspective is based on your interpretation of some of the data. Other people's understanding is based on their interpretation of some of the data. It is most likely that some perspectives will turn out to be more accurate in some ways, while other perspectives will be more accurate in other ways.

I think this conversation would go more smoothly if people stopped talking in absolutes. There are very few, if any, 100% certainties in ME or medicine in general.

All of the views and hypotheses about ROS, infections, or whatever are likely true to some extent in some people. None of them have come anywhere close to absolute truth regarding all patients. So how about if we stop talking about one thing or another as being THE explanation or THE cure or THE only treatment?

And while we're at it, a little less black and white thinking would help, too. For example, suggesting that ROS is not the complete picture for all patients does not mean the person is saying that ROS doesn't play any part at all. It doesn't have to be an all or nothing issue.
 

weyland

Well-Known Member
Although now you are adding in the words chronic and pathogenic!
Well, those are kind of the two qualifiers that would need to apply to ME, no? ROS is released daily by our bodies in response to diet, exercise, etc. In order to be debilitating to the level of ME, I assume it would need to be released continually in large amounts in specific tissues.

Riboflavin deficiency has been associated with increased oxidative stress (4).
So that's a reference to this paper, sadly I'm not able to gain access to the full text via sci-hub and the abstract offers nothing useful as it's a review article.

Next, maybe we can look more deeply at ways to reduce oxidative stress!
There is an existing thread on the subject.
 

Croatoan

Well-Known Member
Found it.

This study looks at the ROS produced by phagocytes, not total body ROS production. Why is this important? Because most of out body systems have feedback mechanisms. So when phagocytes start producing ROS they will get a signal from the environment that they are producing too much and another chemical signal will make them stop. So ROS produced outside the phagocytes sends a signal that tells the phagocyctes to stop making ROS! THIS is why stress makes people more prone to colds and flu, AND it is why people with autoimmune diseases get sick!

The redox-sensitive cation channel TRPM2 modulates phagocyte ROS production and inflammation
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3242890/
The NADPH oxidase activity of phagocytes and its generation of reactive oxygen species (ROS) is critical for host-defense, but ROS overproduction can also lead to inflammation and tissue injury. Here we report that TRPM2, a non-selective and redox-sensitive cation channel, inhibits ROS production in phagocytic cells and prevents endotoxin-induced lung inflammation in mice. TRPM2-deficient mice challenged with endotoxin (lipopolysaccharide) showed an increased inflammatory signature and decreased survival compared to controls. TRPM2 functions by dampening NADPH oxidase-mediated ROS production through depolarization of the plasma membrane in phagocytes. Since ROS also activates TRPM2, our findings establish a negative feedback mechanism inactivating ROS production through inhibition of the membrane potential-sensitive NADPH oxidase.
Phagocytes keep the ROS production local to the pathogen. This is why we get inflammation in the area of a cut or phlem when we have a cold. This is called respiratory burst.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2491708/
To combat infections, immune cells use NADPH oxidase to reduce O2 to oxygen free radical and then H2O2. Neutrophils and monocytes utilize myeloperoxidase to further combine H2O2 with Cl− to produce hypochlorite, which plays a role in destroying bacteria.
So we can see how a pollution, psychological stress, combined with a vitamin deficiency and/or gentics can trigger production of ROS outside of the phagocyte and tell that phagocyte to stop doing its job. This is the definition of an autoimmune disease.

The cofactors for NADPH oxidase are riboflavin and niacin.
http://www.uniprot.org/uniprot/Q9Y5S8

And for the grand finale....
Immune and hemorheological changes in Chronic Fatigue Syndrome
These results indicate immune dysfunction as potential contributors to the mechanism of CFS, as indicated by decreases in neutrophil respiratory burst, NK cell activity and NK phenotypes. Thus, immune cell function and phenotypes may be important diagnostic markers for CFS. The absence of rheological changes may indicate no abnormalities in erythrocytes of CFS patients.
And I quote this as well:
http://nutritionj.biomedcentral.com/articles/10.1186/1475-2891-7-29
Moreover, it has been demonstrated that a micronutrient deficiency can be the cause of suppression of immune function affecting both innate T-cell-mediated immune response and adaptive antibody response, thus altering the balanced host response. Therefore, an adequate intake of vitamins and antioxidant elements seems to be essential for an efficient function of the immune system.
I think that rests my case that ME is not caused by an infection, but rather caused by the bodies inability to fight infection because of exogenous ROS production and a genetic susceptibility to certain vitamin deficiencies.
 

RuthAnn

Well-Known Member
Good reading, thank you.

I have been reading at Lyme and coinfection groups for over a year now, and at one point was pointed to a vet's page about treating horses with Bartonella. www.equineshivers.com
That site is what made me realize that the idea of killing the pathogens was not only inadequate but actually damaging to the body. Now that I am aware of that I notice that many people taking antibiotics or herbal remedies are coming up with severe neurological issues. It's very difficult to get them to look for vitamin deficiencies because they have a hard time switching from the mode of thinking that you just have to keep killing the pathogen.

Especially for viruses, you don't actually kill them, you have to change the mitochondrial terrain so that they stop replicating.
 
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Veet

Well-Known Member
PS: Who would like to start the thread for reducing oxidative stress?
count me in.


I think that rests my case that ME is not caused by an infection, but rather caused by the bodies inability to fight infection because of exogenous ROS production and a genetic susceptibility to certain vitamin deficiencies
There are very likely multiple causes, which then find a common pathway in our collapse. It's fabulous that you've cured yourself. And I've benefited enormously from not only FMN form of B2, but have been returned to functionality from B12/folate. Unfortunately, many others have not gotten the same gains.

It doesn't benefit us to get into squabbling due to our communication styles. Or, maybe it's not about communication, and you truly believe that everyone will find the same way out of this illness. I don't share that belief. Please help make this a safe and friendly space. Personally, I tend to scan things, particularly scientific information. I skip over things that might be over-stated or otherwise provocative to some. But for those with science brains, words matter. We've all heard claims for *cures*. It's not helpful to imply that you have the only answer, when what we need is citizen science, compiling accounts of what works and what hurts, allowing us to gain a broader perspective.

Add: I notice you make it clear here that you're talking about yourself, not curing everyone. thanks
 

weyland

Well-Known Member
I see you're not replying to me Croatoan, but assuming you didn't put me on ignore, I thought you might find this interesting, a potential alternate explanation for your improvement on riboflavin:

Mitochondrial Myopathy in Follow-up of a Patient With Chronic Fatigue Syndrome.
Galán F1, de Lavera I2, Cotán D2, Sánchez-Alcázar JA2.
Author information


Abstract

Introduction. Symptoms of mitochondrial diseases and chronic fatigue syndrome (CFS) frequently overlap and can easily be mistaken. Methods. We report the case of a patient diagnosed with CFS and during follow-up was finally diagnosed with mitochondrial myopathy by histochemical study of muscle biopsy, spectrophotometric analysis of the complexes of the mitochondrial respiratory chain, and genetic studies. Results. The results revealed 3% fiber-ragged blue and a severe deficiency of complexes I and IV and several mtDNA variants. Mother, sisters, and nephews showed similar symptoms, which strongly suggests a possible maternal inheritance. The patient and his family responded to treatment with high doses of riboflavin and thiamine with a remarkable and sustained fatigue and muscle symptoms improvement. Conclusions. This case illustrates that initial symptoms of mitochondrial disease in adults can easily be mistaken with CFS, and in these patients a regular reassessment and monitoring of symptoms is recommended to reconfirm or change the diagnosis.
 

RuthAnn

Well-Known Member
I see you're not replying to me Croatoan, but assuming you didn't put me on ignore, I thought you might find this interesting, a potential alternate explanation for your improvement on riboflavin:
Back in the beginning of the thread Croatoan posted this:
"It is my belief that the fatigue ME patients have originates in a disruption the Electron Transport Chain:



When electrons are not "transported" to be used they attach to oxygen and lipids and produce free radicals as well as limit the amount of ATP created.

The electron transport chain takes place in the mitochondria. See the ovals with Roman Numerals in them? Those are the five complexes of the electron transport chain. So he was explaining that that is where the problem is.

So this could simply be a confirmation that riboflavin reduces oxidative stress, because:
"A major cause of muscular damage in the myopathies is Oxidative Stress. Many articles show the role played by oxidative stress"
 
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weyland

Well-Known Member
I think that rests my case that ME is not caused by an infection, but rather caused by the bodies inability to fight infection because of exogenous ROS production and a genetic susceptibility to certain vitamin deficiencies.
I agree it's likely that micronutrient deficiency can affect immune function, but it's not the only thing that can. Biology is not so black and white. Persistent viral infection can cause the same thing:
Persistent virus infections induce host derived immunosuppressive factors that attenuate the immune response and prevent control of infection. Although the mechanisms of T cell exhaustion are being defined, we know surprisingly little about the underlying mechanisms that induce the immunosuppressive state and the origin and functional programming of the cells that deliver these signals to the T cells. We recently demonstrated that type I interferon (IFN-I) signaling was responsible for many of the immune dysfunctions associated with persistent virus infection and in particular the induced expression of the suppressive factors IL-10 and PDL1 by dendritic cells (DCs).
Source
 

RuthAnn

Well-Known Member
I agree it's likely that micronutrient deficiency can affect immune function, but it's not the only thing that can. Biology is not so black and white. Persistent viral infection can cause the same thing:

Source
You make a good case with that study, @weyland, maybe we can split this off into a different thread and then those that want to follow this thought can follow on that thread and those that want to follow the thought that Croatoan is thinking can follow on this thread. What do you think? If Croatoan has a way of looking at things that don't fit with your ideas, and you have a strong leading in another direction, it would be helpful to have both ways of looking at things in different threads so that it will be easier to find the various ways of dealing with this one stickler of a group of symptoms.
 

weyland

Well-Known Member
When electrons are not "transported" to be used they attach to oxygen and lipids and produce free radicals as well as limit the amount of ATP created.
Right, but what I've been trying to explain is that this is exactly what is expected in the environment of pathogenic or toxic exposure:
Before a cell is broken or lysed, mitochondria in an infected eukaryotic cell sense the presence of an intruding microbe by detecting the diversion of electrons (as NADH and NADPH) and carbon to viral biogenesis centers for polymer synthesis to make viral RNA, protein, and DNA from building blocks in the host cell. This “electron steal” is sensed as a voltage drop, or decrease in electron flow available within the cell for oxidative phosphorylation in mitochondria. The metabolic consequences are nearly instantaneous. Mitochondria rapidly decrease their oxygen consumption, which is coupled to electron flow. The dissolved oxygen concentration in the cell begins to rise because mitochondria are the oxygen sink in every eukaryotic cell. This makes the cellular redox chemistry more oxidizing (Naviaux, 2012). Highly oxidizing environments strongly inhibit the assembly of monomeric building blocks into polymers, and rapidly decrease the efficiency of RNA, protein, and DNA synthesis by the infecting virus. Oxidizing conditions also result in the oxidation of sulfur in methionine, and thiols like cysteine, homocysteine, and glutathione, and the disassembly of iron–sulfur clusters in many enzyme systems, and decrease the availability of the thiol of coenzyme A that is essential for intermediary metabolism.

The ability of mitochondria to monitor electron flow and sulfur oxidation makes them ideally suited as generalized cell “danger alarms”. Their rapid metabolism makes mitochondria the “canaries in the coal mine” for the cell. Any trace or heavy metal that acts as an electrophile or sulfurophile in the cell will trigger a mitochondrial response that is similar to that of a viral infection, because metal electrophiles and replicating pathogens both divert and consume electrons. Likewise, a large number of molecules have been synthesized since the 1850s as dyes, pesticides, drugs, and industrial chemicals. Many are polyaromatic and halogenated. These modern chemicals with conjugated ring systems, multiple double bonds, and delocalized π orbital electron clouds are highly electrophilic and will produce an electron steal within the cell that can also activate the CDR. The CDR is a generic, but highly evolved response that often complicates more specific molecular effects that occur when a synthetic molecule binds to a receptor, or competes with and disrupts normal metabolic or hormone signaling. Mixtures of chemical and biological threats can have synergistic effects, and the total load of danger triggers can influence the magnitude and form of the CDR. When danger is detected, mitochondria alter cellular metabolism to help shield the cell from further injury. This is accomplished by stiffening cell membranes, activating the production of reactive oxygen species (ROS), and producing changes in many different pathways in intermediary metabolism that have the effect of limiting pathogen replication and limiting the spread of danger (Naviaux, 2012). These pathways are immature in newborns and growing children (Wood et al., 2010), leading to effects that are not limited to inflammation and innate immunity in peripheral tissues, but can also alter neurodevelopment (Landrigan et al., 2012) and increase the risk of other chronic childhood diseases.
It wasn't my intention to hijack this thread or have a large debate, I simply wanted to inject an interesting perspective that I had recently come across that shook my understanding quite a bit. I've been devoting so many posts trying to explain that but I don't seem to be doing a very good job so I will try to summarize it one last time and leave you folks to it.

The presence of ROS represents the smoke, not the fire. The body produces large amounts of ROS in response to a threat, the ROS itself isn't the threat. Finding and removing the threat should make the ROS production stop.
 

RuthAnn

Well-Known Member
Do you mean something like this?

"It is also well know that after stressful life events, high protein diet, high calorie diet, heat stress, exogenous toxins, and viral or bacterial infection and the inability to remove ROS.
These being the things that cause the ROS and one should work on to remove.

I believe that the ROS in genetically susceptible people (nature) becomes to much to handle after any combination of these environmental issues (nurture).
And then while you're doing that in order to remove symptoms try to help your body reduce the symptoms through various channels.

Your whole life should be focused on limiting the creation of, and reducing ROS if you want to feel better.
And if the symptoms don't stay away keep working at it so that you are as symptom free as you can be.

Something like that?
 

Remy

Administrator
The presence of ROS represents the smoke, not the fire. The body produces large amounts of ROS in response to a threat, the ROS itself isn't the threat. Finding and removing the threat should make the ROS production stop.
Yes. This.
You make a good case with that study, @weyland, maybe we can split this off into a different thread and then those that want to follow this thought can follow on that thread and those that want to follow the thought that Croatoan is thinking can follow on this thread. What do you think?
I appreciate the sentiment but the problem with this is that it leaves a group of people potentially looking at a thread where everything is presented as a fact and no one around to put on the brakes and say, no, wait, this doesn't really line up with the science. It's only fair to allow a balanced perspective but so far all that gets us is personal attacks and general unpleasantness. We have to have polite discourse on this forum or it will die before it gets off the ground.

Surely there is some happy medium of moderation between anarchy and dictatorship?
 

RuthAnn

Well-Known Member
"It is also well know that after stressful life events, high protein diet, high calorie diet, heat stress, exogenous toxins, and viral or bacterial infection and the inability to remove ROS.
These being the things that cause the ROS and one should work on to remove.
The presence of ROS represents the smoke, not the fire. The body produces large amounts of ROS in response to a threat, the ROS itself isn't the threat. Finding and removing the threat should make the ROS production stop.
It doesn't seem as though weyland is presenting a conflicting theory, but that he has not seen since the first post in this thread that Croatoan said that it is good to get rid of the causes of ROS.
So what he thinks he is trying to prove to be wrong with Croatoan's proposition is actually not wrong with Croatoan's proposition.
Where they divide is that Croatoan gives methods for relieving oxidative stress, because actually (although you say oxidative stress does not line up with science, that may not be true) it's the oxidative stress that is causing the symptoms. Did you see the post above about the myopathy and reversing it with riboflavin? That's because the issues of myopathy were caused by oxidative stress in the mitochondria.
 

Croatoan

Well-Known Member
Right, but what I've been trying to explain is that this is exactly what is expected in the environment of pathogenic or toxic exposure:

It wasn't my intention to hijack this thread or have a large debate, I simply wanted to inject an interesting perspective that I had recently come across that shook my understanding quite a bit. I've been devoting so many posts trying to explain that but I don't seem to be doing a very good job so I will try to summarize it one last time and leave you folks to it.

The presence of ROS represents the smoke, not the fire. The body produces large amounts of ROS in response to a threat, the ROS itself isn't the threat. Finding and removing the threat should make the ROS production stop.
Only phagocytes produce ROS when there is a pathogen. ROS produced outside of the phagocyte will make the phagocyte stop releasing ROS and this makes them unable to kill the pathogen. I explained this in my earlier post.
 

Croatoan

Well-Known Member
I just ran across this new research today:

Impaired immune response as cause of rare autoimmune diseases
https://www.sciencedaily.com/releases/2016/02/160224070523.htm
"Although we were not able to support this hypothesis, the bacterial infestation did not produce significant differences between healthy and diseased test persons. However, it became apparent that the patients' immune response to the infection was impaired and continuously fuelled by a large number of white blood corpuscles. This causes constant infection processes in the body, which are decisively involved in the generation of these autoimmune diseases." This overt immune response was still active even after the infection had long been overcome."
 

weyland

Well-Known Member
It doesn't seem as though weyland is presenting a conflicting theory
It's essentially the hit and run theory (his) vs. the persistent infection theory (mine). Still a very active area of ME research.

He is saying that an initial trigger causes run away ROS production due to the inability to neutralize it. I'm saying that there is an ongoing stressor that is perpetually causing the ROS production as part of the immune response. Both theories seem to fit the observed clinical picture, we may someday learn that both are happening in various subsets of patients.

I was getting stuck on his insistence that vitamin deficiency alone causes ROS production, but after rereading most of the thread I don't think that he was intending to argue that, even though that's what he said at several points. I think he is asserting that it is always in combination with some stressor to trigger the ROS production in the first place.

it's the oxidative stress that is causing the symptoms
I agree that this is part of it but it's not the whole story. It's this, as well as production of various cytokines, eicosanoids such as prostaglandins, purines, etc. All of the various danger signals that are part of the immune response that tell the body and brain that something is wrong and induce the symptoms we experience. The question that science has to answer still is if this is happening appropriately or inappropriately.
 

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