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Zinc deficiency alters purinergic signaling

pattismith

Senior Member
Messages
3,926
@nandixon

In some ME/CFS studies, alterations in the purine metabolism were found.

Low adenosine in the Naviaux (and high eATP)
Low IMP and cAMP in the Hanson


These changes are very close to what was found in Zinc deficiency, and many symptoms in ME/CFS patients overlap with Zinc deficiency .


"Zinc deficiency causes delayed ATP clearance and adenosine generation in rats and cell culture models
  • (2018)

Abstract
Zinc deficiency causes myriad pathophysiological symptoms, but why distinct phenotypes are generated by zinc deficiency remains unclear.

Considering that several ectoenzymes involved in purinergic signaling through extracellular adenine-nucleotide hydrolysis possess zinc ions in their active sites, and disorders in purinergic signaling result in diverse diseases that are frequently similar to those caused by zinc deficiency, herein we examine whether zinc deficiency affects extracellular adenine-nucleotide metabolism. Zinc deficiency severely impairs the activities of major ectoenzymes (ENPP1, ENPP3, NT5E/CD73, and TNAP), and also strongly suppresses adenine-nucleotide hydrolysis in cell-membrane preparations or rat plasma, thereby increasing ATP and ADP levels and decreasing adenosine levels.

Thus, zinc deficiency delays both extracellular ATP clearance and adenosine generation, and zinc modulates extracellular adenine-nucleotide metabolism.

Since the finely tuned balance between extracellular adenine nucleotides and adenosine is critical for purinergic signaling, these findings provide a novel insight into why zinc deficiency results in diverse symptoms."


Note:

They didn't study intracellular purine metabolism, but ADA and AMPA are two important zinc-dependent enzymes in purine metabolism that produce Inosine and IMP by deamination, so low Inosine and IMP would be relevant in Zinc deficiency as well.

Note bis:

Interestingly Zinc is also a P2X7 receptor antagonist (whereas eATP is activator),
here a recent study about this potency:

"Modulation of P2X7 purinergic receptor activity by extracellular Zn2+ in cultured mouse hippocampal astroglia.

Kovacs 2018

Abstract
The P2X7R protein, a P2 type purinergic receptor functioning as a non-selective cation channel, is expressed in different cell types of the central nervous system in several regions of the brain. The activation of the P2X7R protein by ATP modulates excitatory neurotransmission and contributes to microglial activation, apoptosis and neuron-glia communication. Zinc is an essential micronutrient that is highly concentrated in the synaptic vesicles of glutamatergic hippocampal neurons where free zinc ions released into the synaptic cleft alter glutamatergic signal transmission. Changes in both P2X7R-mediated signaling and brain zinc homeostasis have been implicated in the pathogenesis of mood disorders. Here, we tested the hypothesis that extracellular zinc regulates P2X7R activity in the hippocampus.

We observed that P2X7R is expressed in both neurons and glial cells in primary mouse hippocampal neuron-glia culture.

Propidium iodide (PI) uptake through large pores formed by pannexins and P2X7R was dose-dependently inhibited by extracellular zinc ions.

Calcium influx mediated by P2X7R in glial cells was also reduced by free zinc ions.
Interestingly, no calcium influx was detected in response to ATP or 3'-O-(4-Benzoyl) benzoyl ATP (BzATP) in neurons despite the expression of P2X7R at the plasma membrane.

Our results show that free zinc ions can modulate hippocampal glial purinergic signaling, and changes in the activity of P2X7R may contribute to the development of depression-like behaviors associated with zinc deficiency."


In some other studies, zinc deficiency was found to decrease Deiodinase type I activity. (convert T4 to T3 in Liver, Kidney and muscle). Deiodinase type I hypoactivity is involved in Low T3 syndrome, which was found in a subset of ME/CFS patients in the Nederland study.
 

jesse's mom

Senior Member
Messages
6,795
Location
Alabama USA
Are there any recommendations as to when and how to supplement with Zinc. As in: should it be taken in an empty stomach, or in the morning or night?
 

hixxy

Senior Member
Messages
1,229
Location
Australia
This is very interesting!

My serum and plasma zinc levels consistently show in the normal range (although lower end of normal) but 24hr urinary excretion usually shows very low. "Alternative" doctors say this is diagnostic of deficiency but then conventional doctors dismiss it as meaningless and won't consider anything besides a blood test result. I tend to believe the "alternative" doctors more but at the end of the day I can't tolerate zinc supplementation anyway, makes me feel horribly sick (not gut like most people, but full body sick). I also got a controversial very strong positive test result for pyroluria many years ago which is linked to zinc deficiency but also can't tolerate B6 supplementation (any form).
 
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pattismith

Senior Member
Messages
3,926
Are there any recommendations as to when and how to supplement with Zinc. As in: should it be taken in an empty stomach, or in the morning or night?

I have symptoms that may be related to low T3 (which I have), or low zinc (which I've never found in my old blood tests.

Some of these symptoms I experience occasionally or permanently are for example

moving feet when I am in my bed in the morning (permanent)
carotenemia (permanent, without eating carrots )
bad mood
burning mouth

So I am interested to see if a zinc trial could have any effect on them.

Zinc has anti-inflammatory properties, (it can reduce TNF alpha, oxidized LDL, and NADPH oxidase), and also increases metabolism of carotene to retinol (vitamine A).


So I started 15 mg zinc per day (this is the recommended daily intake) from Zinc gluconate, just a week ago.

I don't know when is the best time to take it. I tried it in the morning, but a few hours later, I happened to almost faint. I had tremors and nausea and could hardly stay on my feet. It happened one day and again another day.

I took sugar, calcium and magnesium and it slowly improved, but I have no idea of what happened.

Now I try to take it in the evening.
 
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pattismith

Senior Member
Messages
3,926
This is very interesting!

My serum and plasma zinc levels consistently show in the normal range (although lower end of normal) but 24hr urinary excretion usually shows very low. "Alternative" doctors say this is diagnostic of deficiency but then conventional doctors dismiss it as meaningless and won't consider anything besides a blood test result. I tend to believe the "alternative" doctors more but at the end of the day I can't tolerate zinc supplementation anyway, makes me feel horribly sick (not gut like most people, but full body sick). I also got a controversial very strong positive test result for pyroluria many years ago which is linked to zinc deficiency but also can't tolerate B6 supplementation (any form).

this is very interesting, did you experiment the same kind of sickness I noticed?

I wonder if it a sign that we need zinc, maybe we should take smaller dose to start?


I also found one study stating that zinc could improve blood fluidity:

https://link.springer.com/article/10.1385/BTER:113:2:139
 

andyguitar

Moderator
Messages
6,581
Location
South east England
I would'nt take to much notice of blood test results for zinc levels. Not accurate as it only tells you what is going on in your blood. Taking 15mg a day won't do any harm and if it causes a bad reaction then simply divide the dose in 2 or 4. It is one of the key minerals that is often overlooked and problems with absortion are not uncommon. Symptoms of deficiency are very varied and could easily be put down to something else. Hope you give a go people and good luck with it. One other thing is that if you correct a deficiency it will improve your sense of smell and taste.
 

andyguitar

Moderator
Messages
6,581
Location
South east England
Ah, and here is a problem all should be aware of. Because one of the symptoms of me/cfs is an over reaction to stimuli, how good your sense of smell/taste is will NOT be a reliable indication for zinc deficiency. But Zicatest can be usefull for those who do not have an over reaction to stimuli.
 

percyval577

nucleus caudatus et al
Messages
1,302
Location
Ik waak up
In the past I tried a couple of times zinc supplementation but didn´t notice any effect. (And I was and am sometimes very sensitive to stimuli, to my astonishment.) My blood zinc ever was in the normal range.

Only recently then zinc began to become an influence, and sometimes a very pleasant one. I assume that the reason is that I take other metals too. I began with nickel, than discovered chromium (you can google chromium and cfs), followed up by aluminium (from dishes only, ie in water, cold one), zinc, and finally silver (again from dishes but there are also supplements to buy, you can also google silver and cfs being led to this forum).

Interestingly a supplement with high amounts of zinc (10 or 15 mg) seems on the overall run not to be better than again very small amounts in water. It even seems to work worse. I need to investigate this further though.
I put a zinced nail in 0.2 l cold water, from this water a drop in again 0.2 l water, and again, and from this water I put a drop in my coffee or whatever. Sometimes I fear there might be dangerous? nanoparticles, I don´t care much though. A water solution could also be dangerous because the metal might get resorbed already in the mouth and would flow freely in the blood? I personally don´t care.
However, I use the metals not at the same time here, but one after another in different sequencies, not completly chaoticly (roughly silver, nickle, chromium, zinc, very carefully aluminium).

Another method to get zinc (and nickel, chromium and aluminium) is chocolate. Here I find that it must not be too much of it, only up to ca. 35 gramm. And than maybe a coffee with silver (here I use again very small amounts, silver in hot water, say a spoon, a drop in 0.2 l, and only from this water I put a drop in my coffee).

My hypothesis on all this is that it would work in the basal ganglia and (zinc) thalamus, I have googled some matches. I will look at other results later (in the terms of metabolism it seems to be a bad idea in some cases).


I am sorry currently to to be able at all to relate my observations to your literature, pattismith, but maybe they could be helpful?



PS: I don´t know if this is of generel importance: I ever use an anticholinergic in each drink (a spoon from tomatoegreen tea, but not with pesticides) and for a second periode Ambroxol (thank you again pattismith, this is a great invention!!! I use only half a drop of it.).
 
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pattismith

Senior Member
Messages
3,926
My trial with zinc is such a game changer for me.

Within a few days, it totally changed my reaction to Inosine/caffeine.

Before zinc, I could take advantage of Inosine+caffeine at a given dose, but after zinc, although I still need Inosine + caffeine:
-I had to lower the dose
-My body started to be much warmer each time I take inos+caf, which never happened before zinc.


Zinc has so many function in cells, it is hard to say what is happening really.


It is also an intracellular messenger, and is associated in some protein in "zinc fingers" module.

I found in my gene a missense mutation in a zinc transporter which is located in the brain and nervous system, SLC39A12 (allele frequency 2%). Unfortunately it does not show up in studies.

It is a mysterious gene. One paper says that among the less known genes of the brain "Only two ignorome genes (SLC39A12, CMTM5) are expressed preferentially in astrocytes, Bergmann glia, and oligodendrocytes", so I am curious about it.
 

pattismith

Senior Member
Messages
3,926
@pattismith I was wondering if your still taking thyroid, or have stopped it in light of your new discoveries

I was taking 6.25 mcg T3 every morning for many months.
Then when I started Ambroxol, I was able to take T3 only every other day.
And when I started Inosine/caffeine/Inositol, I was able to stop totally T3, it was a month ago.

(Then when I started zinc, I stopped Inositol and lowered Inosine)

I had a thyroid panel done a month ago, my TSH and my T3 were very low.

I had another thyroid panel today, my T3 and TSH improved, back into the reference ranges, and back to the levels before I started to take T3.

I am curious to see if the levels will keep going up in the future!
 

S-VV

Senior Member
Messages
310
Thanks!!

It really seems that the body is trying hard to downregulate T3. Alternatively, the hypothalamus is going crazy.

I wish you the best with your experiments!!
 

pattismith

Senior Member
Messages
3,926
Thanks!!

It really seems that the body is trying hard to downregulate T3. Alternatively, the hypothalamus is going crazy.

I wish you the best with your experiments!!

Thank you,

I found this study that gives me hope that zinc supplementation may improve my fT3 level
and lower my rT3:


Zinc supplementation alters thyroid hormone metabolism in disabled patients with zinc deficiency.(1994)
Nishiyama S1, Futagoishi-Suginohara Y, Matsukura M, Nakamura T, Higashi A, Shinohara M, Matsuda I.


Abstract
OBJECTIVE:
We examined zinc (Zn) status in relation to thyroid function in disabled persons, because the association between Zn deficiency and thyroid function remains controversial.

METHODS:
After measuring serum free 3,5,3'-triiodothyronine (T3) and free thyroxine (T4) in 134 persons, TSH-releasing hormone (TRH) injection test and estimation of Zn status were conducted in persons with low free T3.

RESULTS:

Thirteen had low levels of serum free T3 and normal T4.

Patients with elevated levels of serum 3,3',5'-triiodothyronine (rT3) showed an enhanced reaction of serum thyrotropin (TSH) after TRH injection.

Nine of 13 patients had mild to moderate Zn deficiency evaluated by body Zn clearance and increased urinary Zn excretion.
After oral supplementation of Zn sulphate (4-10 mg/kg body weight) for 12 months, levels of serum free T3 and T3 normalized, serum rT3 decreased, and the TRH-induced TSH reaction normalized. Serum selenium concentration (Type 1 T4 deionidase contains selenium in the rat) was unchanged by Zn supplementation.

CONCLUSION:
Zn may play a role in thyroid hormone metabolism in low T3 patients and may in part contribute to conversion of T4 to T3 in humans.