![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 22 to 46 of 55. Go back in thread:
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
Posted by Larry Hoover on November 25, 2004, at 5:23:14
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on November 12, 2004, at 14:11:16
>
> > OK, you bum, you made me get out my textbooks.
>
> Sorry Lar :(Dude, I was teasing. I don't usually use my books.
> I see the oxidative stress as the root, and acidosis as the outcome.
>
> I can go with that!So, it still is oxidative stress that needs controlling, to avoid the acidotic response.
> > 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.Good tips, thanks.
> 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.I've been using inosine, and it certainly doesn't seem to have any adverse effects. It's totally inexpensive, and readily scavenges peroxynitrite. I'll leave the superoxide to my dismutase enzymes, which work best with lots of alphalipoic backing them up.
> 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.How?
> 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 dramaticallyMSM takes the load off of methionine for sulphation. How are you with methionine?
> > 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!
>
> RayYes, me too. In then end, it's what makes you feel better, not whether you can explain why it does so.
Lar
Posted by Larry Hoover on November 25, 2004, at 5:41:10
In reply to Re: dopamine oxidation .... to Ray...and » Larry Hoover, posted by tealady on November 14, 2004, at 4:04:46
> > 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??High urine output is polyuria, which is usually associated with dilute urine. Ascorbate increases the rate of uric acid clearance, which would mean lower blood concentrations.
> > > 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 thatThe acidotic response is also mediated by bicarbonate pumps, as there is always a ready supply of bicarbonate in the blood. Acid stress in a cell is almost a theoretical entity, in the sense that it never really gets very far. If it did, you'd be at the hospital right quickly.
> > 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??It would indicate that you might be in the initial stages of metabolic acidosis. What is your anion gap? Is creatine clearance normal? I'm thinking your kidneys might not be up to snuff.
> 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.
With a low bicarbonate, your buffer system is weaker than it ought to be. The bicarbonate ion serves as a "sponge", to decrease the pH change that comes from normal changes in metabolic rate. You're more likely to suffer from exercise exhaustion, for example. Your body tends towards being acid, with low bicarbonate.
Lar
Posted by raybakes on November 26, 2004, at 13:00:09
In reply to Re: dopamine oxidation » raybakes, posted by Larry Hoover on November 25, 2004, at 5:23:14
>
> > I see the oxidative stress as the root, and acidosis as the outcome.
> >
> > I can go with that!
>
> So, it still is oxidative stress that needs controlling, to avoid the acidotic response.I agree, but find 'oxidative stress' too vague and feel I need to know the specific pattern of oxidative stress for each condition, and what gets oxidised!
>
> I've been using inosine, and it certainly doesn't seem to have any adverse effects. It's totally inexpensive, and readily scavenges peroxynitrite. I'll leave the superoxide to my dismutase enzymes, which work best with lots of alphalipoic backing them up.Think I might try inosine to see how it feels - my only concern was if it raises adenosine, could it affect the adenosine receptor? Also does xanthine oxidase have any negative effects.
>
> > 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.> how?
'Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase.'"Recent evidence also indicates that iNOS-induced pathophysiological effects involve substrate deficiency. Thus, at low concentrations of L-arginine iNOS produces both NO and superoxide anions, which results in the increased synthesis of the highly reactive, detrimental oxidant peroxynitrite"
"Both endothelial NO synthase (eNOS) and inducible NO synthase (iNOS) isoforms are expressed in the atherothrombotic vasculature and, owing to a loss of substrate or reducing cofactors required for NO synthesis, undergo enzymatic "uncoupling" leading to both a loss of NO production and an increase in superoxide anion generation."
"Owing to the sizeable methylation stress created by supplemental L-arginine in these animals (creatine synthesis accounts for 70% of the total utilization of labile methyl groups in mammals under normal circumstances16), the remethylation of homocysteine to methionine would be limited. Thus, transsulfuration, which is localized principally to the liver, is likely to have been the principal metabolic mechanism for eliminating the increase in homocysteine"
http://atvb.ahajournals.org/cgi/content/full/23/1/3
> MSM takes the load off of methionine for sulphation. How are you with methionine?
>
I'm fine with methionine as long as I take methyl factors - otherwise, I'm awful! Do even better with it if I take a little lysine too - think carnitine is very important for me. Interesting that homocysteine is linked with apoptosis.
> Yes, me too. In then end, it's what makes you feel better, not whether you can explain why it does so.
Yes, I tend to try things first - if it feels good, I try to find out why - but frequently the first few attempts to understand can be misguided!
Ray
Posted by tealady on December 2, 2004, at 18:27:43
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on November 26, 2004, at 13:00:09
http://www.alternativementalhealth.com/articles/walshMP.htm#Met
maybe already mentioned
Jan
Posted by Larry Hoover on December 10, 2004, at 8:39:40
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on November 26, 2004, at 13:00:09
> >
> > > I see the oxidative stress as the root, and acidosis as the outcome.
> > >
> > > I can go with that!
> >
> > So, it still is oxidative stress that needs controlling, to avoid the acidotic response.
>
> I agree, but find 'oxidative stress' too vague and feel I need to know the specific pattern of oxidative stress for each condition, and what gets oxidised!I'm a little confused by your confusion. The oxidative stress is always the same critters: superoxide anion, peroxynitrite, NO, molecular oxygen, peroxides....
What gets oxidized is either one of: antioxidant molecules like superoxide dismutase, reduced glutathione, tocopherol, ascorbate, etc. OR any other darn thing that gets in the way. Most susceptible are B vitamins followed by polyunsaturated fatty acids, thiols and sulphur bridges (sulphur moieties) and so on.
> >
> > I've been using inosine, and it certainly doesn't seem to have any adverse effects. It's totally inexpensive, and readily scavenges peroxynitrite. I'll leave the superoxide to my dismutase enzymes, which work best with lots of alphalipoic backing them up.
>
> Think I might try inosine to see how it feels - my only concern was if it raises adenosine, could it affect the adenosine receptor? Also does xanthine oxidase have any negative effects.I'm far more interested in ensuring adequate peroxynitrite scavenging than I am about anything else that might occur. It may be that my inherent belief (formed over many years) that I require a high protein diet, is directly related to the high inosine production that it promotes.
I need to do a "clean" inosine trial, all by its lonesome, but my current intake of other stuff won't really allow it.
> >
> > > 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.http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=324552
If you look at figure 1 (the link is hard to find, but it's right after reference 8 in the text), you'll see that superoxide itself oxidizes biopterin, so the relationship is complex. You're quite right about arginine depletion.
> > how?
>
> 'Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase.'
>
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12692136Reading this, I see the critical utility of ascorbate in restoring biopterin radical. What you have is a free radical chain of superoxide (+ NO) --> peroxynitrite --> BH3· --> ascorbate·
The latter is unreactive.Ascorbic acid also directly compete with NO for superoxide anion, so it has multiple quenching effects in this chain.
> "Recent evidence also indicates that iNOS-induced pathophysiological effects involve substrate deficiency. Thus, at low concentrations of L-arginine iNOS produces both NO and superoxide anions, which results in the increased synthesis of the highly reactive, detrimental oxidant peroxynitrite"
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12967769The apparent cause here is regulatory, in that arginase is increased, and uptake reduced. The cell is deprived of arginine, but it is not necessarily true that the organism is. Interesting though, as the obvious solution would seem to be more arginine.
> "Both endothelial NO synthase (eNOS) and inducible NO synthase (iNOS) isoforms are expressed in the atherothrombotic vasculature and, owing to a loss of substrate or reducing cofactors required for NO synthesis, undergo enzymatic "uncoupling" leading to both a loss of NO production and an increase in superoxide anion generation."
>
> "Owing to the sizeable methylation stress created by supplemental L-arginine in these animals (creatine synthesis accounts for 70% of the total utilization of labile methyl groups in mammals under normal circumstances16), the remethylation of homocysteine to methionine would be limited. Thus, transsulfuration, which is localized principally to the liver, is likely to have been the principal metabolic mechanism for eliminating the increase in homocysteine"
>
> http://atvb.ahajournals.org/cgi/content/full/23/1/3Nice paper. I'm comforted by this quote:"Similarly, one might predict that dietary creatine supplementation would reduce de novo creatine synthesis by suppressing L-arginine:glycine amidinotransferase expression, thereby attenuating methylation stress and homocysteine production."
You helped me to grasp the significance of creatine vis a vis methylation stress. Hyperhomocysteinemia is a common finding in chronic depression, CFS, fibromyalgia, PTSD and related disorders. I've always advocated heavy supplementation of methyl donors, and this is another reason why.
> > MSM takes the load off of methionine for sulphation. How are you with methionine?
> >
>
> I'm fine with methionine as long as I take methyl factors - otherwise, I'm awful! Do even better with it if I take a little lysine too - think carnitine is very important for me. Interesting that homocysteine is linked with apoptosis.Homocysteine is also a part of atherosclerosis, being one of the precipitating factors for inflammation in the first place.
> > Yes, me too. In then end, it's what makes you feel better, not whether you can explain why it does so.
>
>
> Yes, I tend to try things first - if it feels good, I try to find out why - but frequently the first few attempts to understand can be misguided!
>
> RayMore, anon.
Lar
Posted by tealady on December 10, 2004, at 15:47:54
In reply to Re: dopamine oxidation » raybakes, posted by Larry Hoover on December 10, 2004, at 8:39:40
> > I agree, but find 'oxidative stress' too vague and feel I need to know the specific pattern of oxidative stress for each condition, and what gets oxidised!
>
> I'm a little confused by your confusion. The oxidative stress is always the same critters: superoxide anion, peroxynitrite, NO, molecular oxygen, peroxides....
>I'm confused too...but that's pretty much the norm:-) Some of these are good as well as perhpas bad ..like oxygen is like good,and peroxides as well I guess...
and I think peroxynitrite is always bad?
well you can see the confusion
> What gets oxidized is either one of: antioxidant molecules like superoxide dismutase, reduced glutathione, tocopherol, ascorbate, etc. OR any other darn thing that gets in the way. Most susceptible are B vitamins followed by polyunsaturated fatty acids, thiols and sulphur bridges (sulphur moieties) and so on.
>
>
> > >
> > > I've been using inosine, and it certainly doesn't seem to have any adverse effects. It's totally inexpensive, and readily scavenges peroxynitrite. I'll leave the superoxide to my dismutase enzymes, which work best with lots of alphalipoic backing them up.
> >
> > Think I might try inosine to see how it feels - my only concern was if it raises adenosine, could it affect the adenosine receptor? Also does xanthine oxidase have any negative effects.
>
> I'm far more interested in ensuring adequate peroxynitrite scavenging than I am about anything else that might occur. It may be that my inherent belief (formed over many years) that I require a high protein diet, is directly related to the high inosine production that it promotes.
>How about trying to stop the peroxidase from occuring in the first place? Is this a possibility?
Here's a bit of background
I've usually got lowish ferritin. I'd like it to be over 50. To low ferritin levels makes it difficult to tolerate adequte thyroid hormones, leading to anxiety and other symptoms, result is a lower BMR than is probably desirable...and lowish iron/ferritin causes depression in me too.
Before supplementation with iron ferritin was 15 , three years ago.
With a series of 3 injections I got it up to 55(after first injection I felt happier than believable..singing on train even!..and sno situation change at all), but it soon fell down to 20's (I think). With iron supps over many months I got it up to 37 in 2002.
I took iron supps, liquid and tablet on and off...more on than off!
I was feeling depressed after an endo visit (6th October) and got the chemist to make me up some strong ferrous gluconate (500mg/5ml), which worked in getting me out of depression. Started 6th October.
But after a few weeks I felt like I want to lash out but I was not sure at what or why.
(is this a high iron, choline/acetylcholine thing?..can't find anything on, but that's another topic).That was on the 6th Nov,04. (so about a month on high liquid iron)..always taken with a meat meal, like steak and usually with a bit of VitC too...and usually with then the fish oil, VitE , CoQ10 etc.
I stopped the selenium ,iron, lecithin I was taking(and the fish oil, CoQ10, VitE as well) and had my iron tested on 24th Nov...so that's 18 days later
results were (after being off iron supps for 18 days)
Serun Iron 38 umol/L (10-30) ****HIGH*** 212.3 mcg/dL (US units)
Transferrin 42 umol/L (27-53) can't find a unit conversion to US
Transferrin Saturation 46% (12-45) **HIGH**Serum Ferritin 37 ug/L
So the ferritin hadn't gone up (OK , it may have dropped and then rose again)
I seem to be able to absorb iron into my bloodstream just fine....but for some reason I don't get that iron easily into ferritin..
I put this on the thyroid forumas there are a few there who have difficulty getting feritin up too..
Got a lot of help and it looks like its NO to blame again with me..which fits as my skin goes like supersensitive sometimes, and I get inflammation too.think I get hypoxia too, which is why long doses of Coq10 backfire with me..something to do with all this oxidisation...
Now I'm also wondering if serum ferritin measures the cytolsolic ferritin, all ferritin or just extracellular if that exists!..any idea?
Oh yes, one more that ties in that glutiathione I was craving for a while (over that intense craving as of this week)
http://www.ccia.org.au/page.php?id=102
It's just that all of this ties in with what is being discussed on here by Ray as well.One day I'll get back to replying Lar on the ADH, osmosis stuff...been occupied by this lately and still awaiting reults of 2nd ADH (arginine vasopressin) test done under water restriction and fasting etc conditions.( First test showed undetectable ADH.) One thing though with water restriction all my electroyltes and even albumin(back right mid normal was lowish) look great!..so that's been my problem there
Jan
> I need to do a "clean" inosine trial, all by its lonesome, but my current intake of other stuff won't really allow it.
>
> > >
> > > > 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.
>
> http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=324552
> If you look at figure 1 (the link is hard to find, but it's right after reference 8 in the text), you'll see that superoxide itself oxidizes biopterin, so the relationship is complex. You're quite right about arginine depletion.
>
> > > how?
> >
> > 'Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase.'
> >
> >
> > http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12692136
>
> Reading this, I see the critical utility of ascorbate in restoring biopterin radical. What you have is a free radical chain of superoxide (+ NO) --> peroxynitrite --> BH3· --> ascorbate·
> The latter is unreactive.
>
> Ascorbic acid also directly compete with NO for superoxide anion, so it has multiple quenching effects in this chain.
>
> > "Recent evidence also indicates that iNOS-induced pathophysiological effects involve substrate deficiency. Thus, at low concentrations of L-arginine iNOS produces both NO and superoxide anions, which results in the increased synthesis of the highly reactive, detrimental oxidant peroxynitrite"
> >
> > http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12967769
>
> The apparent cause here is regulatory, in that arginase is increased, and uptake reduced. The cell is deprived of arginine, but it is not necessarily true that the organism is. Interesting though, as the obvious solution would seem to be more arginine.
>
> > "Both endothelial NO synthase (eNOS) and inducible NO synthase (iNOS) isoforms are expressed in the atherothrombotic vasculature and, owing to a loss of substrate or reducing cofactors required for NO synthesis, undergo enzymatic "uncoupling" leading to both a loss of NO production and an increase in superoxide anion generation."
> >
> > "Owing to the sizeable methylation stress created by supplemental L-arginine in these animals (creatine synthesis accounts for 70% of the total utilization of labile methyl groups in mammals under normal circumstances16), the remethylation of homocysteine to methionine would be limited. Thus, transsulfuration, which is localized principally to the liver, is likely to have been the principal metabolic mechanism for eliminating the increase in homocysteine"
> >
> > http://atvb.ahajournals.org/cgi/content/full/23/1/3
>
> Nice paper. I'm comforted by this quote:"Similarly, one might predict that dietary creatine supplementation would reduce de novo creatine synthesis by suppressing L-arginine:glycine amidinotransferase expression, thereby attenuating methylation stress and homocysteine production."
>
> You helped me to grasp the significance of creatine vis a vis methylation stress. Hyperhomocysteinemia is a common finding in chronic depression, CFS, fibromyalgia, PTSD and related disorders. I've always advocated heavy supplementation of methyl donors, and this is another reason why.
>
>
> > > MSM takes the load off of methionine for sulphation. How are you with methionine?
> > >
> >
> > I'm fine with methionine as long as I take methyl factors - otherwise, I'm awful! Do even better with it if I take a little lysine too - think carnitine is very important for me. Interesting that homocysteine is linked with apoptosis.
>
> Homocysteine is also a part of atherosclerosis, being one of the precipitating factors for inflammation in the first place.
>
> > > Yes, me too. In then end, it's what makes you feel better, not whether you can explain why it does so.
> >
> >
> > Yes, I tend to try things first - if it feels good, I try to find out why - but frequently the first few attempts to understand can be misguided!
> >
> > Ray
>
> More, anon.
>
> Lar
Posted by tealady on December 10, 2004, at 16:07:33
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on November 26, 2004, at 13:00:09
Posted by raybakes on December 11, 2004, at 5:26:50
In reply to Re: dopamine oxidation » Larry Hoover, posted by tealady on December 10, 2004, at 15:47:54
Hi Jan, when I looked up ferritin I kept coming up with insulin resistance leading to excess iron accumulation. So I was wondering what your insulin levels were like? - if your autoimmunity is affecting your pancreas, could you have low insulin?
This abstract talks a bit about relationship between insulin and ferritin...
Ray
Posted by tealady on December 11, 2004, at 15:35:36
In reply to ferritin » tealady, posted by raybakes on December 11, 2004, at 5:26:50
Hi Ray,
I know ferritin say over 100 or so is a factor in diabetes II. My Mum had high ferritin and high iron and developed diabetes II. I wrote something about before somewhere.
My ferritin is low and even taking iron it doesn't convert to ferritin...probably NO levels or peroxidation etc... and glutathione is in there too, as is glucose reducing the damage..hence the cravings I think.
Also both my glucose and glutathione cravings have stopped this week. Only difference is taking milk thistle..maybe coincidence, but also fits.Jan
Posted by raybakes on December 12, 2004, at 3:25:06
In reply to Re: ferritin » raybakes, posted by tealady on December 11, 2004, at 15:35:36
> Hi Ray,
>
> I know ferritin say over 100 or so is a factor in diabetes II. My Mum had high ferritin and high iron and developed diabetes II. I wrote something about before somewhere.
>
> My ferritin is low and even taking iron it doesn't convert to ferritin...probably NO levels or peroxidation etc... and glutathione is in there too, as is glucose reducing the damage..hence the cravings I think.
> Also both my glucose and glutathione cravings have stopped this week. Only difference is taking milk thistle..maybe coincidence, but also fits.
>
>Hi Jan,
My line of thinking was that if ferritin is high when insulin is high in type 2 diabetes - could low insulin in autoimmune disease lower ferritin? or doesn't it work that way?
Ray
Posted by raybakes on December 12, 2004, at 14:33:43
In reply to Re: ferritin » raybakes, posted by tealady on December 11, 2004, at 15:35:36
> do you think lactoferrin supplements would be of any use?
http://www.lfplus.com/s2/2214.html
this on interleukin 10 and hyperferritinemia..
http://www.jimmunol.org/cgi/content/abstract/169/4/2204
and also interleukin 10's effect on supressing nitric oxide..
"IL-10, TGF-b and IL-4 can suppress the inflammatory activation of macrophages, thereby inhibiting NO production."
Possibility that autoimmunity is triggering macrophages to release NO and disrupt ferritin? What do you think?
Ray
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