![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 11 to 35 of 55. Go back in thread:
Posted by raybakes on October 31, 2004, at 3:45:56
In reply to Re: dopamine oxidation » raybakes, posted by TeeJay on October 29, 2004, at 21:03:25
> Ray
>
> am I right in remembering you are an englishman? If so, where roughly in the country are you from? (i'm from the west midlands)
>
> Also, where do you get your tests done?
>
> CheersHi TJ, yes I live in Surrey. Got the gene tests done by great smokies via a british agent, called diagnostic sevices. Say hello to the black country - was in wolverhampton last month to watch some speedway - the wolves lost :(
Ray
Posted by raybakes on October 31, 2004, at 3:57:54
In reply to Re: dopamine oxidation » raybakes, posted by Larry Hoover on October 30, 2004, at 8:27:39
> > Genetically i have high interleukin 1 and low glutathione (null gene), so I'm predisposed to autoimmune disease -
>
> Ray, I'm very sorry. I didn't know that. I couldn't sleep last night, thinking about this. Please accept my apology. If you mentioned this before, I didn't see it, or don't recall it. All my opinions have been expressed under the assumptions that generally hold true. I didn't know you were the exception. How did you find out about the glutathione problem? And isn't IL-1 a response to oxidative stressors?That's OK Larry! The gene tests were from great smokies - I do have a couple of glutathione genes but have one that is a null gene.
Yes oxidative stress is a major factor in Il-1 release and as you say, PLA2 is a big problem - I do take max DHA by Jarrow, but some research says that pure EPA is a better inhibitor of PLA2.
I'm interested in the caspases, that are releasing enzymes for the interleukins, and how mitochondrial damage can set neuronal apoptosis into action - interestingly, glutathione and creatine, inhibit caspases.
Got to go to work now, so will reply more in full later - thanks for your concern!! hope you didn't lose too much sleep!!!
Ray
Posted by TeeJay on October 31, 2004, at 6:33:29
In reply to Re: dopamine oxidation » TeeJay, posted by raybakes on October 31, 2004, at 3:45:56
Thanks for the reply Ray,
When I was younger my dad used to take me every week to watch the Birmingham Brummies. They used to beat wolves refularly too ;-)))
Posted by raybakes on October 31, 2004, at 14:11:02
In reply to Re: dopamine oxidation » raybakes, posted by Larry Hoover on October 30, 2004, at 8:27:39
> I'm immediately thinking of alphalipoic acid, and the polyphenolic antioxidants seen in e.g. pine bark or grape seed or berries. It would be lovely if someone ever put out a Venn diagram of the overlap between substrate activity of the different antioxidant systems. It would make this whole topic so very much easier to understand and to find appropriate interventions. I would need to look around a bit before I could come up with ideas not based on my intellectual intuition.
I do take a lipoic acid and thiamine combination - i feel awful if I take them individually - wonder whether it's due to a balance in the pyruvate dehyrogenase complex? Sometimes take 'proanthanol' from allergy research, but doing really well on jarrow's pomegranate concentrate at the moment - adore organic raspberries too!
>
> The other route would be immune modulation, as by omega-3 supplementation. Membrane disturbance induces degradation of phospholipids at the second position by phospholipase A2. You want an omega-3 fatty acid there, as much as is possible, to prevent inflammatory induction via cyclization of arachinodate to PGE-2.Interleukin 1 stimulates PLA2 unfortunately! Grrr! Take phospatidyl choline every now and then as well as omega 3s - and I think all the methyl factors I take probably assist phospholipid synthesis.
.
>
> What antioxidants are you presently using?thiodox and thorne's extra nutrient complex are the one's I use most - can only get on with small amounts of ascorbate - think high doses might use up too much glutathione? The get the most relief from the methyl factors though - as long as I avoid molybdenum - don't think activation of oxidase enzymes agrees with me!
Ray
Posted by joebob on November 2, 2004, at 9:24:27
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on October 31, 2004, at 14:11:02
the extra cost?
there's a lot of talk about it at the moment
Posted by Larry Hoover on November 2, 2004, at 9:28:34
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on October 31, 2004, at 3:57:54
> > > Genetically i have high interleukin 1 and low glutathione (null gene), so I'm predisposed to autoimmune disease -
> >
> >How did you find out about the glutathione problem? And isn't IL-1 a response to oxidative stressors?
>
> That's OK Larry! The gene tests were from great smokies - I do have a couple of glutathione genes but have one that is a null gene.That redundancy is probably keeping you safe.
> Yes oxidative stress is a major factor in Il-1 release and as you say, PLA2 is a big problem - I do take max DHA by Jarrow, but some research says that pure EPA is a better inhibitor of PLA2.
Yes, but. The 2 in PLA2 is a positional specificity of the phospholipid hydrolysis. Whatever fatty acid is hanging there gets freed, and it is most likely to get cyclized. The eicosanoids arising from EPA do have that specific inhibitory effect, but as I understand it, the release of DHA from that position goes on to modulate gene expression. EPA has an acute suppressive effect, whereas DHA has a chronic down-regulatory effect.
http://www.pubmedcentral.gov/articlerender.fcgi?artid=122397Look at Table 5.
http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=208755
http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139963
http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149905
> I'm interested in the caspases, that are releasing enzymes for the interleukins, and how mitochondrial damage can set neuronal apoptosis into action - interestingly, glutathione and creatine, inhibit caspases.
>
> Got to go to work now, so will reply more in full later - thanks for your concern!! hope you didn't lose too much sleep!!!
>
> RayBrain hum, Ray. I get involved....no, INVOLVED.
Lar
Posted by Larry Hoover on November 2, 2004, at 9:30:51
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on October 31, 2004, at 14:11:02
> thiodox and thorne's extra nutrient complex are the one's I use most - can only get on with small amounts of ascorbate - think high doses might use up too much glutathione? The get the most relief from the methyl factors though - as long as I avoid molybdenum - don't think activation of oxidase enzymes agrees with me!
>
> RayAm I wrong to think that high glutathione burden due to ascorbate might indicate that you are consuming the ascorbate, i.e. you need it?
Lar
Posted by raybakes on November 3, 2004, at 14:15:25
In reply to Re: dopamine oxidation » raybakes, posted by Larry Hoover on November 2, 2004, at 9:30:51
>
> Am I wrong to think that high glutathione burden due to ascorbate might indicate that you are consuming the ascorbate, i.e. you need it?
>
Thanks Lar for the EPA/DHA abstracts...and thanks being involved!!My thoughts were that severe brian fogging I get with high dose ascorbate might be using up too much glutathione for me and causing excess production of the ascorbyl radical? This article suggests it might be possible.
"For example, after vitamin C donates an electron to a free radical, it becomes what is known as the ascorbyl radical. The antioxidant known as reduced glutathione can restore ascorbyl radical to the antioxidant form of vitamin C."
Ray
Posted by tealady on November 3, 2004, at 21:49:24
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on November 3, 2004, at 14:15:25
I dn't do well on higher doses onf VitC either. Only use on rare occasions
I suspect I'm very low on glutathione too due to the foods I prefer.
Jan
Posted by Larry Hoover on November 4, 2004, at 11:02:03
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on November 3, 2004, at 14:15:25
>
> >
> > Am I wrong to think that high glutathione burden due to ascorbate might indicate that you are consuming the ascorbate, i.e. you need it?
> >
>
> Thanks Lar for the EPA/DHA abstracts...and thanks being involved!!You're welcome. In case you didn't realize, PMC is only full-text articles. Sometimes, if you're lucky, there will be hotlinks in the references that get you "inside" fee-based journals without having to pay. If that happens, don't save the link. It won't work later. Instead, email the article to yourself.
> My thoughts were that severe brian fogging I get with high dose ascorbate might be using up too much glutathione for me and causing excess production of the ascorbyl radical? This article suggests it might be possible.
>
> "For example, after vitamin C donates an electron to a free radical, it becomes what is known as the ascorbyl radical. The antioxidant known as reduced glutathione can restore ascorbyl radical to the antioxidant form of vitamin C."
>
> RayThe key term in the above exchange is that vitamin C donates an electron to a free radical. What that does is it stabilizes that free radical, so it can no longer participate in chain reactions. (As an aside, the ozone depletion in the atmosphere is caused by free radical chain reactions.)
The ascorbyl radical can then participate in chain reactions, but it is less reactive than the originating free radical. Glutathione quenches the ascorbyl radical, but is itself now a radical. There are a few processes by which glutathione is regenerated, and one of those is via alphalipoic acid.
There are lots of free radials running around in your body. Some of them are astoundingly dangerous, in a chemical sense, like superoxide. Antioxidants are sacrificial (they are used up), but in the process they become somewhat dangerous themselves. Just less dangerous. Antioxidants are best thought of as a network, because they interact and "rearrange" the reactivity.
One of the most common free radicals in the body is molecular oxygen. Although it's often represented as double-bonded, i.e. O=O, it doesn't stay like that. It resonates to the diradical form, represented as ·O-O· The dots represent unpaired electrons, called radicals. Molecular oxygen is so reactive that it can turn solid iron to powder (rust). Our bodies have evolved haemoglobin molecules to bind free molecular oxygen to iron atoms without oxidizing it permanently. This safely carries oxygen through the body without allowing its free radical character access to sensitive molecules. Oxygen is wicked dangerous, from a chemical perspective. Superoxide (O2-) cannot form a stable resonance structure, so it remains an oxygen free radical until it finds something to react with. It's all about stabilizing oxygen.....that's what life is all about.
Lar
Posted by raybakes on November 7, 2004, at 5:06:24
In reply to Re: dopamine oxidation » raybakes, posted by Larry Hoover on November 4, 2004, at 11:02:03
> The ascorbyl radical can then participate in chain reactions, but it is less reactive than the originating free radical. Glutathione quenches the ascorbyl radical, but is itself now a radical. There are a few processes by which glutathione is regenerated, and one of those is via alphalipoic acid.
>
>
Hi Lar,I can only tell you what if feels like - I think high dose ascorbate would be fine with someone with normal health. I know if I take over 1 gramme of magensium ascorbate, I feel incredibly ill, mentally.
I understand the outline that you give about how all the antioxidant systems working in concert produce radicals or become radicals in the process of dealing with a free radical, but matching how I feel to what you say, there must be something else going on. I feel my antioxidant system is extremely fragile, and can probably only work at a certain rate - It probably has a few weak links in the chain - enzymes that when pushed too hard, run out of co-factors (NADPH to reduce glutathione is a suspect, particularly because it requires energy, something my brain lacks!).
So ascorbate could produce more ascorbyl radicals than glutathione could mop up before I started running low on NADPH. With NADPH running low, hydrogen ions build up in the cell, the pH drops, all enzymes fail, and I end up with millions more free radicals that I started with!
Just a theory, but that's how it sort of feels!
Ray
Posted by Larry Hoover on November 7, 2004, at 11:07:11
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on November 7, 2004, at 5:06:24
>
> > The ascorbyl radical can then participate in chain reactions, but it is less reactive than the originating free radical. Glutathione quenches the ascorbyl radical, but is itself now a radical. There are a few processes by which glutathione is regenerated, and one of those is via alphalipoic acid.
> >
> >
> Hi Lar,
>
> I can only tell you what if feels like - I think high dose ascorbate would be fine with someone with normal health. I know if I take over 1 gramme of magensium ascorbate, I feel incredibly ill, mentally.Maybe that's the magnesium "talking"?
> I understand the outline that you give about how all the antioxidant systems working in concert produce radicals or become radicals in the process of dealing with a free radical, but matching how I feel to what you say, there must be something else going on.
I looked at the toxicity of vitamin C, and two possible mechanisms come to mind. One involves iron toxicity, exacerbated by the activation by ascorbate. Those with hemochromatosis are particularly vulnerable to this effect. The other mechanism involves enhanced excretion of uric acid. That might leave one vulnerable to peroxynitrite, as uric acid is an excellent peroxynitrite scavenger.
> I feel my antioxidant system is extremely fragile, and can probably only work at a certain rate - It probably has a few weak links in the chain - enzymes that when pushed too hard, run out of co-factors (NADPH to reduce glutathione is a suspect, particularly because it requires energy, something my brain lacks!).
You're the expert on how things make you feel, Ray. All I can do is offer you knew thoughts to try on for size.
> So ascorbate could produce more ascorbyl radicals than glutathione could mop up before I started running low on NADPH. With NADPH running low, hydrogen ions build up in the cell, the pH drops, all enzymes fail, and I end up with millions more free radicals that I started with!
I really doubt there's a pH mechanism at play. There are many many ways for cells to adjust pH. There are substantial buffer systems in place, just for that purpose. Do you understand the chemistry of buffer systems?
> Just a theory, but that's how it sort of feels!
>
> RayTry a different source of ascorbate, would be my suggestion.
Lar
Posted by raybakes on November 8, 2004, at 3:16:07
In reply to Re: dopamine oxidation » raybakes, posted by Larry Hoover on November 7, 2004, at 11:07:11
> > I can only tell you what if feels like - I think high dose ascorbate would be fine with someone with normal health. I know if I take over 1 gramme of magensium ascorbate, I feel incredibly ill, mentally.
>
> Maybe that's the magnesium "talking"?Don't think so, feel great on magnesium malate/citrate.
>
> I looked at the toxicity of vitamin C, and two possible mechanisms come to mind. One involves iron toxicity, exacerbated by the activation by ascorbate. Those with hemochromatosis are particularly vulnerable to this effect....cytochrome c seems to be invoved in moppping up peroxynitrite interestingly..
The other mechanism involves enhanced excretion of uric acid. That might leave one vulnerable to peroxynitrite, as uric acid is an excellent peroxynitrite scavenger.
I definitely think peroxynitrite is a problem and uric acid is interesting....
> You're the expert on how things make you feel, Ray. All I can do is offer you knew thoughts to try on for size.Thanks for your thoughts and ideas but I don't want to make my self sound too badly off - I'm feeling pretty good these days, in fact the best I've felt for 10 - 20 years!
>
> > So ascorbate could produce more ascorbyl radicals than glutathione could mop up before I started running low on NADPH. With NADPH running low, hydrogen ions build up in the cell, the pH drops, all enzymes fail, and I end up with millions more free radicals that I started with!
>
> I really doubt there's a pH mechanism at play. There are many many ways for cells to adjust pH. There are substantial buffer systems in place, just for that purpose. Do you understand the chemistry of buffer systems?I don't understand all the buffer systems but suspect the bicarbonate buffering to be underfunctioning. If I raise carbon dioxide by holding my breath, or drinking carbonated water, my brain becomes more clear. Might be something to do with the bohr effect too? Also I think it's common in autoimmune disease to have antibodies to carbonic anhydrase, vital for bicarbonate buffering and digestive function. Bicarbonate seems to have both positive and negative effects on peroxynitrite - some abstracts say it helps detoxify it, some say it hinders uric acid, ascorbate, GSH in it's detoxification.
Found this abstract on how carbonic anhydrase is invovled in helping produce the cerebrospinal fluid, and it thought to influence 'neuroexcitation'.'Carbonic anhydrase IV on brain capillary endothelial cells: a marker associated with the blood-brain barrier.'
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1495971&dopt=Abstract
Still think buffering is really important - especially as in fatigued cells, the mitochondria fail to get sufficient numbers of protons combining with oxygen to maintain an even pH.Ray
> Try a different source of ascorbate, would be my suggestion.
I've tried about 8 or 9 types of ascorbate - all work really well as long as I stay below a gramme.
>
Posted by Larry Hoover on November 8, 2004, at 11:09:03
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on November 8, 2004, at 3:16:07
> > > I can only tell you what if feels like - I think high dose ascorbate would be fine with someone with normal health. I know if I take over 1 gramme of magensium ascorbate, I feel incredibly ill, mentally.
> >
> > Maybe that's the magnesium "talking"?
>
> Don't think so, feel great on magnesium malate/citrate.Okay. <shrug>
> > I really doubt there's a pH mechanism at play. There are many many ways for cells to adjust pH. There are substantial buffer systems in place, just for that purpose. Do you understand the chemistry of buffer systems?
>
> I don't understand all the buffer systems but suspect the bicarbonate buffering to be underfunctioning.That would be quite a stretch. Every breath you take is part of a feedback loop to the partial pressure of carbon dioxide in the blood.
Here's a good overview.
http://www.cvm.okstate.edu/courses/vmed5412/14%20Acid-Base.docWithin cells, the bicarbonate buffer is replaced by protein/amino acid buffers, and phosphate buffering. The latter buffer is what makes those lime scale/iron stain removers powerful enough to remove deposits on e.g. bathroom fixtures, but moderate enough that you can get them on your hands without fear.
> If I raise carbon dioxide by holding my breath, or drinking carbonated water, my brain becomes more clear. Might be something to do with the bohr effect too?
Almost certainly it is the Bohr effect. Not much more than a parlor trick, though, as you will breath again and restore the normal chemistry.
> Also I think it's common in autoimmune disease to have antibodies to carbonic anhydrase, vital for bicarbonate buffering and digestive function.
It seems to have a vital role in the transfer of oxygen to and from hemoglobin, among other effects. Carbonic anhydrase, in the presence of CO2, will facilitate the "unloading" of O2 from hemoglobin, while simultaneously replacing the O2 with H+ and bicarbonate. Each of the latter will then interact with the aqueous component of blood.
> Bicarbonate seems to have both positive and negative effects on peroxynitrite - some abstracts say it helps detoxify it, some say it hinders uric acid, ascorbate, GSH in it's detoxification.
Yes, but....
Bicarbonate is everywhere in your circulation, so whether it tips this balance a certain way, and that one another, is moot.
>
> Found this abstract on how carbonic anhydrase is invovled in helping produce the cerebrospinal fluid, and it thought to influence 'neuroexcitation'.
>
> 'Carbonic anhydrase IV on brain capillary endothelial cells: a marker associated with the blood-brain barrier.'
>
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1495971&dopt=AbstractWhen I read that, I see that a specific form of carbonic anhydrase is responsible for facilitating gas transfer at the capillary wall in the brain, i.e. at the blood-brain barrier. Red blood cells can't get across, so the unloading occurs at this membrane surface. Diffusion probably takes the 02 to the mitochondria.
> Still think buffering is really important - especially as in fatigued cells, the mitochondria fail to get sufficient numbers of protons combining with oxygen to maintain an even pH.
>
> RayOnly in extreme circumstances. That's what buffers do....maintain supplies of H+ without changing pH dramatically.
http://www.sparknotes.com/chemistry/acidsbases/buffers/section1.html
Lar
Posted by raybakes on November 8, 2004, at 13:55:57
In reply to Re: dopamine oxidation » raybakes, posted by Larry Hoover on November 8, 2004, at 11:09:03
>
> Only in extreme circumstances. That's what buffers do....maintain supplies of H+ without changing pH dramatically.
>
Thanks Lar, but I do think chronic fatigue and nervous system disorders are extreme circumstances - In nervous system disorders, mitochondrial failure surely means an accumulation of protons in the cell, lowering pH. How can a buffer system keep up when the only energy production in the cell is anaerobic?Ray
Posted by Larry Hoover on November 9, 2004, at 15:35:57
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on November 8, 2004, at 13:55:57
> >
> > Only in extreme circumstances. That's what buffers do....maintain supplies of H+ without changing pH dramatically.
> >
>
> Thanks Lar, but I do think chronic fatigue and nervous system disorders are extreme circumstances - In nervous system disorders, mitochondrial failure surely means an accumulation of protons in the cell, lowering pH. How can a buffer system keep up when the only energy production in the cell is anaerobic?
>
> RayRay, I fear we're far apart on our theoretical underpinnings. Or perhaps I'm just not grasping the unique character of a particular form of dysfunction you're trying to address.
Here's a pretty good summary of what goes wrong, IMHO (before it slides into the promotion of particular propietary remedies). http://www.immunesupport.com/library/showarticle.cfm/ID/4535/
The key is electron transport defects. Protonation (the hydrogen ion) is tightly controlled because of the high amine content in proteins (amines love to mop up protons), and because of the phosphate buffer.
Mitochondrial failure is associated with ROS (reactive oxygen species) at levels which overwhelm antioxidant defenses. Despite the failure of the mitochondrial membranes, stimulatory signals are still received by the mitochondria, which churn out ROS unhindered.
Anaerobic metabolism is extra-mitochondrial. It occurs in cell cytoplasm, and is very inefficient. Large amounts of "partially spent" molecules accumulate, the gross debris of inefficiency. Those include lactic acid, which is responsible for pain and spasm in over-exerted muscle, for example. But that is not a chronic state. Well, if it is, you're in big trouble, and you're likely in the ICU already.
If I've not grasped something you're putting forth, I'd really appreciate it if you'd spend some time with it, and lay it out for me anew.
Thanks,
Lar
Posted by raybakes on November 11, 2004, at 5:06:01
In reply to Re: dopamine oxidation » raybakes, posted by Larry Hoover on November 9, 2004, at 15:35:57
Hi Larry,
I've been reading abstracts like this one recently, and maybe it's explains why we don't see things in a similar way? The article you attached, talks of the accumulation of lactic acid causing fatigue in a cell, whereas the articles I've been reading talk of lactic acid being produced to reduce cellular acidosis.
Biochemistry of exercise-induced metabolic acidosis.
'When the ATP demand of muscle contraction is met by mitochondrial respiration, there is no proton accumulation in the cell, as protons are used by the mitochondria for oxidative phosphorylation and to maintain the proton gradient in the intermembranous space'
My interest is regarding my own brain fog, because if I improve buffering and support my mitochondria, my symtoms dramatically improve.
Found this abstract on creatine as well..
http://physrev.physiology.org/cgi/content/short/80/3/1107
'Disturbances of the CK system have been observed in muscle, brain, cardiac, and renal diseases as well as in cancer. On the other hand, Cr and Cr analogs such as cyclocreatine were found to have antitumor, antiviral, and antidiabetic effects and to protect tissues from hypoxic, ischemic, neurodegenerative, or muscle damage'
Ray
Posted by Larry Hoover on November 11, 2004, at 10:56:35
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on November 11, 2004, at 5:06:01
> Hi Larry,
OK, you bum, you made me get out my textbooks.
> I've been reading abstracts like this one recently, and maybe it's explains why we don't see things in a similar way? The article you attached, talks of the accumulation of lactic acid causing fatigue in a cell,
Right. Lactic acid causes muscle cells to register what we know as fatigue, by some unknown signalling method. Lactic acid accumulates to keep pyruvate from increasing to toxic levels from glycolysis. Glycolysis is anaerobic (doesn't require oxygen), consumes 2 ATP, produces 4 ATP, converts 2 NAD+ to NADH, releasing 2 protons, and 2 pyruvate. That is the source of the acid stress. 2 pyruvate can produce 2 lactate, but in the process, 2 NADH are changed back to NAD+, consuming 2 protons. Lactic acid accumulation is a measure of compensatory response to excess formation of pyruvate. Only if pyruvate is in excess is lactate produced. There is no net release of protons from lactate production. You end up with 2 ATP from each glucose molecule, but respiration dead ends at lactate. Lactate is readily exported from the cell, but it is really a marker for excess pyruvate. Circulating lactate is at least partially reconverted to glucose in the liver (at the expense of ATP, of course). Proton stress is proportional to pyruvate production via glycolysis.
> whereas the articles I've been reading talk of lactic acid being produced to reduce cellular acidosis.
>
> Biochemistry of exercise-induced metabolic acidosis.
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15308499
>
> 'When the ATP demand of muscle contraction is met by mitochondrial respiration, there is no proton accumulation in the cell, as protons are used by the mitochondria for oxidative phosphorylation and to maintain the proton gradient in the intermembranous space'It would also be just as true to say that there is also no pyruvate accumulation in the cell, under normal respiratory conditions. Under excess anaerobic ATP production via glycolysis, the net accumulation in the cytosol from one glucose is 2 pyruvate, 2 protons (H+), and 2NADH. Pyruvate is taken into the mitochondrion as the base substrate for oxidative formation of ATP. Cytosolic NADH reacts with mitochondrial NAD+ (in essence, they switch places), with the net effect of pumping protons *out* of the mitochondrion. That is really the source of the cytosolic proton excess....mitochondrial respiration. In the mitochondria, 2 NADH + 2 H+ + O2 --> 2 NAD+ + 2 H2O. The cytosolic proton excess, however, comes at the expense of cytosolic NAD+, so acidosis may be a sign of NAD+ deficiency. There are many ways of looking at the same animal.
To summarize, there is always an ongoing balancing act between glycolysis (cytosolic) and oxidative respiration (mitochondrial). Whenever the mitochondria fall behind demand for ATP, the pyruvate production is imbalanced, and compensatory lactate is formed. However, lactate formation regenerates NAD+, and mops up protons, at the expense of energy efficiency.
Now, where we seem to part ways is on what comes first. Mitochondrial dysfunction is a very real entity, and I'm sure that it applies to my poor body. The root of mitochondrial dysfunction/low functioning is oxidative destruction of the two-layer mitochondrial membrane that is responsible for maintaining the proton/NAD shuttle. I see the oxidative stress as the root, and acidosis as the outcome.
> My interest is regarding my own brain fog, because if I improve buffering and support my mitochondria, my symtoms dramatically improve.
What is it, explicitly, that you do to improve buffering capacity? And separately, what do you do to support your mitochondria?
> Found this abstract on creatine as well..
>One thing at a time, Ray. I must pace myself.
Lar
Posted by raybakes on November 12, 2004, at 14:11:16
In reply to Re: dopamine oxidation » raybakes, posted by Larry Hoover on November 11, 2004, at 10:56:35
> OK, you bum, you made me get out my textbooks.Sorry Lar :(
I see the oxidative stress as the root, and acidosis as the outcome.I can go with that!
> What is it, explicitly, that you do to improve buffering capacity? And separately, what do you do to support your mitochondria?
Carnosine (good for detoxing aldehydes from mitochondrial lipid peroxidation), carnitine and creatine all work well for both.Do better with precursors - arginine and methyl factors for creatine - lysine and methyl factors for carnitine.
CoQ10 also needs methylation, and tyrosine, biopterin and cholesterol.
Also looking at ways to reduce superoxide and peroxynitrite as they uncouple a lot of mitochondrial enzymes.
The balance of arginine/NOS/biopterin/methylation seems important. Low biopterin or low arginine can switch NOS to produce superoxide instead of nitric oxide. Arginine without methyl factors can increase homocysteine.
I'm being cautious with NAC at the moment because although I want to raise glutathione, I get the feeling that cysteine dioxygenase (interleukin 1, 6 and TNF alpha related I think) doesn't clear the excess of cysteine properly for me - my lungs burned when I last took NAC. Do badly with sulfites (triggers superoxide production from NADPH), taking molybdenum worsens my symptoms, but MSM improves them dramatically
> One thing at a time, Ray. I must pace myself.
Sorry, hope that's not too much - I think I like forests more than trees!Ray
Posted by raybakes on November 13, 2004, at 13:15:41
In reply to Re: dopamine oxidation » raybakes, posted by Larry Hoover on November 11, 2004, at 10:56:35
Mitochondrial creatine and creatine kinase looks interesting for brain energy..
"the highly regulated cellular expressions of creatine biosynthetic and metabolic enzymes suggest that the creatine/phosphocreatine shuttle system plays a role in brain energy homeostasis through a novel neuron-glial relationship"
"Octameric mitochondrial creatine kinase induces and stabilizes contact sites between the inner and outer membrane."
Ray
Posted by tealady on November 14, 2004, at 4:04:46
In reply to Re: dopamine oxidation » raybakes, posted by Larry Hoover on November 7, 2004, at 11:07:11
OK guys I'm back, exams over and feeling much better
> > > The ascorbyl radical can then participate in chain reactions, but it is less reactive than the originating free radical. Glutathione quenches the ascorbyl radical, but is itself now a radical. There are a few processes by which glutathione is regenerated, and one of those is via alphalipoic acid.
> > >
> > >
> > Hi Lar,
> >
> > I can only tell you what if feels like - I think high dose ascorbate would be fine with someone with normal health. I know if I take over 1 gramme of magensium ascorbate, I feel incredibly ill, mentally.Ray
Magnesium ascorbate is what I usually take too..and I do best with under 1 gram as well. I uually don't take it daily for this reason...just what is in my multi...and fruit
>
> Maybe that's the magnesium "talking"?
>
> > I understand the outline that you give about how all the antioxidant systems working in concert produce radicals or become radicals in the process of dealing with a free radical, but matching how I feel to what you say, there must be something else going on.
>With me too Ray. I agree.
> I looked at the toxicity of vitamin C, and two possible mechanisms come to mind. One involves iron toxicity, exacerbated by the activation by ascorbate. Those with hemochromatosis are particularly vulnerable to this effect. The other mechanism involves enhanced excretion of uric acid. That might leave one vulnerable to peroxynitrite, as uric acid is an excellent peroxynitrite scavenger.
>
I think I have a problem with peroxynitrate (amongst other things).
Lar,
In your opinion if one produce a lot of urine(say 6L a day) and it seemed to be produced faster than would be expected (I guess this happens as I always have problems with ultrasounds:) is that what you mean by enhanced excretion of uric acid??> > I feel my antioxidant system is extremely fragile, and can probably only work at a certain rate - It probably has a few weak links in the chain - enzymes that when pushed too hard, run out of co-factors (NADPH to reduce glutathione is a suspect, particularly because it requires energy, something my brain lacks!).
>
Yes I'm the same and gluthathione from reading your posts is something I think I lack too. Still trying to learn about.
BTW where did you get that list of glutahione foods..if you have a link easily located that is.>
> > So ascorbate could produce more ascorbyl radicals than glutathione could mop up before I started running low on NADPH.
Maybe that is what happens to me as well>With NADPH running low, hydrogen ions build up in the cell, the pH drops, all enzymes fail, and I end up with millions more free radicals that I started with!
Hmm I don't think it works like that, hydrogen ions are after NADH is made..in the chemiosmosis the next stage..and the NADH has its electrons passed along the mitochondrial membrane and H+ ions get pumped into the intermembrane space thru the proton pumps (NADH-ubiquinone oxidoreductase, then ubiquinone-cytochrome c oxidoreductase, then cytochrome c oxidase) .. and in the last one Oxygen is consumed and water formed...or something like that
I keep thiking its my dumb oxygen as I still run short on it..or feel like it sometimes..that's when I get real depressed , and sometimes my circulation in my extremities kinda shuts down, I go cold and hands turn blueish etc and numb
>
> I really doubt there's a pH mechanism at play. There are many many ways for cells to adjust pH. There are substantial buffer systems in place, just for that purpose. Do you understand the chemistry of buffer systems?
>Umm Lar I have high Cl-(topmof range) and low bicarbonate ions(bottom of range)...so that would indicate what?? pH related??
Remember I once said I didn't get all this acid/base stuff..well I still don't really get it..the buffer sytems..but I'm beginning to grasp a little
> > Just a theory, but that's how it sort of feels!
yep..now that I understand!!
> >
> > Ray
Jan
Posted by tealady on November 14, 2004, at 4:10:48
In reply to Re: dopamine oxidation .... to Ray...and » Larry Hoover, posted by tealady on November 14, 2004, at 4:04:46
Meant to add I'm not sure where NADPH fits in(except in plants photosynthesis)..that was NADH.
I know its somewhere<g>
Jan
Posted by tealady on November 14, 2004, at 5:44:00
In reply to Re: dopamine oxidation » raybakes, posted by Larry Hoover on November 8, 2004, at 11:09:03
Just working my way thru this thread and just lost this post!
> > > > I can only tell you what if feels like - I think high dose ascorbate would be fine with someone with normal health. I know if I take over 1 gramme of magensium ascorbate, I feel incredibly ill, mentally.
> > >
> > > Maybe that's the magnesium "talking"?
> >
> > Don't think so, feel great on magnesium malate/citrate.I don't think so with me either. I'm fine on MgO and Mg Carbonate and Mg Citrate..
Lar, I see you answered with a link on buffering :)
It mentions anion gap.. back 3 years ago, before thyroid meds, my sodium, chloride and bicarbonate were low (below range)..and my anion gap was 20..also my lactate dehydrogenase was high ..345 (range 100-310). Also phosphate was 1.42 (just above range)Any ideas?
In last test lactate dehydrogenase was still dropping and had reached 141 which looks good..whatever it is? (No worries if noone has any ideas ..looks fine now anyway..I'm just trying to figure out what has been going on with me)Never tested anion gap since..but I did "fiddle" with salts intake/licorice(almost off) and managed to get sodium and potassium up..but Cl is now high, ..and phosphate is still high, but both in range.
> >
> > I don't understand all the buffer systems but suspect the bicarbonate buffering to be underfunctioning.
>Larrian(that doc I mention sometimes) used to say to take some sodium bicarbonate to help acidosis
Here's some of her replies..not much detail, but may give some ideas
http://forums.about.com/ab-thyroid/messages?msg=30095.1135
http://forums.about.com/ab-thyroid/messages?msg=16340.13
http://forums.about.com/ab-thyroid/messages?msg=27262.48
> That would be quite a stretch. Every breath you take is part of a feedback loop to the partial pressure of carbon dioxide in the blood.
>
> Here's a good overview.
> http://www.cvm.okstate.edu/courses/vmed5412/14%20Acid-Base.doc
>Thanks Lar, I'll try to decipher some of it..
too tired to go further.. Just wanted to say I haven't finished reading this thread as yet.
Jan
Posted by raybakes on November 14, 2004, at 16:25:13
In reply to Re: dopamine oxidation .... to Ray, posted by tealady on November 14, 2004, at 4:10:48
> Meant to add I'm not sure where NADPH fits in(except in plants photosynthesis)..that was NADH.
> I know its somewhere<g>
> Jan
I think NADH is involved in energy production and NADPH invovled in biosynthesis - they are subtley different to allow a tight control of energy production feedback mechanisms - I'm sure Lar has a more accurate explaination!Ray
Posted by raybakes on November 14, 2004, at 16:47:04
In reply to Re: dopamine oxidation .... to Ray...and » Larry Hoover, posted by tealady on November 14, 2004, at 4:04:46
Jan wanted to answer more of your reply, but will have to leave it til another day :( ...
This is the glutathione list off the web..I think whey protein is good for glutathione, I'm allergic to it though!
Several foods contain glutathione including: asparagus, watermelon (excellent source), grapefruit, potato, acorn squash, strawberries, oranges,tomato, cantaloupe, broccoli, okra, peaches, zucchini, and spinach.
Lar said this about acidosis...
"The root of mitochondrial dysfunction/low functioning is oxidative destruction of the two-layer mitochondrial membrane that is responsible for maintaining the proton/NAD shuttle. I see the oxidative stress as the root, and acidosis as the outcome."
Protecting our mitochondria is so important - when they fail they also send out signals for the immune system to destroy the cell (apoptosis), this mechanism seems to be behind a lot of brain disorders and excitotoxicity.
Ray
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