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The Nutrigenomics of Selenium

ppodhajski

Senior Member
Messages
243
Location
Chapel Hill, NC
Ha, yeah, it's a big one.

Basically, check these genes out in promethease:

SEPP1
SEPHS1 - I have a rare SNP here
GPX1
GPX2
GPX3 - I have rare SNPs here
GPX4 - I have one rare SNP here
TXNRD1
TXNRD2 - I have a very rare SNP here
TXNRD3
SEP15

I take selenium and eat brazil nuts. It makes me feel better. I also take FMN (B2) since FAD is a cofactor for TXNRD2. FMN changed my life.
 
Messages
10
Thank you for the link re selenium.

Could you provide details re FMN (B2) ie brand; FAD as a cofactor for TXNRD2 (what is it?); and in particular how it has changed your life/health.

Many thanks,

A Canadian from Toronto
 

ppodhajski

Senior Member
Messages
243
Location
Chapel Hill, NC
I take Source Naturals Coenzymated B2 (FMN)
http://www.iherb.com/Source-Natural...&lc=en-US&w=coenzymated b2&rc=52&sr=null&ic=3

Here is a good chart of how riboflavin is transported and metabolized into FMN and FAD (both are cofactors and reduced forms of riboflavin)

F5.large.jpg


Here is a good brief explanation of FAD and FMN;
http://sandwalk.blogspot.com/2007/04/riboflavin-vitamin-b2-fmn-and-fad.html

If you are interested in the MTHFR gene you should look into riboflavin as well;
http://www.ncbi.nlm.nih.gov/books/NBK6145/

TXNRD2 is a thioredoxin Reducatse and helps with antioxidation in the mitocondria by recycling Thioredoixin. Thioredoixin is like glutathione.

363_metabolism_10.gif


When I first took FMN I had an immediate clarity and calmness that was so unusual it is indescribable. Now I notice it was a key to ending my IBS-D, fatigue, pain related to cartilage inflammation (costrocondritis). It also stops my heart palpitations 5 minutes after taking it. However, it is only part of my treatment. I found that taking FMN interacts with P5P, Zinc, and selenium.

Also, I found that since taking FMN I cannot take (nor do I need to) magnesium. When I do now, instead of it making me calm it makes me very up and anxious and keeps me awake instead of helping me drift off to sleep.
 

minkeygirl

But I Look So Good.
Messages
4,678
Location
Left Coast
@ppodhajski i was just looking at this for adrenal support and for some other oddball symptoms I have.

how does it react to the other things you mentioned, zinc and selenium?
 

ppodhajski

Senior Member
Messages
243
Location
Chapel Hill, NC
@minkeygirl I would not say react, more like they are interdependant.

First, riboflavin kinase (RFK) uses Riboflavin, ATP, Zinc, and Magnesium to turn riboflavin into FMN.
http://www.uniprot.org/uniprot/Q969G6

Also, for example, since Glutathione Perioxidase (GPX) is a selenium based enzyme when you take Selenium GPX activity will increase. That oxidizes the glutathione getting rid of H2O2. But now we have oxidized glutathione that we need to recycle and that is done by Glutathione Reductase which uses FAD as a cofactor and that will use up more FAD and therefor more B2 and FMN. So by taking selenium we could cause a greater riboflavin deficiency. Note it will also increase need for NADH, a reduced form of niacin.

riboflavin_figure1_v3.png


As for zinc and magnesium, I will point you to this pathway of B6 metabolism:

B6 Pathway.png
 

ppodhajski

Senior Member
Messages
243
Location
Chapel Hill, NC
@ppodhajski i was just looking at this for adrenal support and for some other oddball symptoms I have.

how does it react to the other things you mentioned, zinc and selenium?

Also, if you are looking at the adrenals, COMT is more highly expressed there than MAOA or MAOB, which points to magnesium and increasing SAMe production as well. (I also have slow COMT SNPs)

http://www.proteinatlas.org/ENSG00000093010-COMT/tissue
http://www.proteinatlas.org/ENSG00000069535-MAOA/tissue
http://www.proteinatlas.org/ENSG00000069535-MAOB/tissue
 

ppodhajski

Senior Member
Messages
243
Location
Chapel Hill, NC
First I search and sort for the gene in Promethease based on frequency:

gpx3.png


Then I look to see what the distribution of the SNPs look like in SNPedia

snpedia.png

CT is at 18% and we can see a homozygous SNP there is nearly on average 2%. That to me is important evolutionarily since it seems the C allele is not favorable and is not passed on frequently. the alleles which are more evenly spread seem less important to me.

http://www.biomedcentral.com/1755-8794/3/57
"However, disease-associated alleles were more likely to be low frequency derived alleles relative to null expectations. "

Then I research to if that SNP is associated with increased or decrease enzyme activity.
http://www.arcmedres.com/article/S0188-4409(14)00076-9/abstract
http://www.arcmedres.com/article/S0188-4409(14)00076-9/abstract

So this is me hypothesizing...
It looks like it is an increase in gene activity, and therefor I will use up more selenium and recycle glutithione very well. Which makes me think I have a heightened immune response, which would be true since I have several autoimmune issues. If I am exposed to mercury this could be a problem since mercury binds to selenium as well. So I am more sensitive to mercury exposure and a lab test would show that I have higher than average mercury levels then the general population.

Just based on intuition I feel that any SNP under 20% will show some difference from the general population, either increased or decreased activity which would make us outliers.
 
Messages
15,786
CT is at 18% and we can see a homozygous SNP there is nearly on average 2%. That to me is important evolutionarily since it seems the C allele is not favorable and is not passed on frequently. the alleles which are more evenly spread seem less important to me.
You can't assume a SNP is relevant just because it is rare. Everyone has hundreds or thousands of rare SNPs, yet this does not mean they are all walking around with a ton of "unfavorable" variations. The vast majority of those rare variations have no appreciable impact, and we can't guess that they are problematic simply based upon rarity.

And even if we could assume that rare SNPs have an impact (we can't), it's impossible to guess what that impact would be. But since rs8177404 and rs8177406 aren't even on GPX3, it's even more unlikely that they are capable of having an impact GPX3. They're actually located on uncharacterized LOC105378228.
 

ppodhajski

Senior Member
Messages
243
Location
Chapel Hill, NC
You can't assume a SNP is relevant just because it is rare. Everyone has hundreds or thousands of rare SNPs, yet this does not mean they are all walking around with a ton of "unfavorable" variations. The vast majority of those rare variations have no appreciable impact, and we can't guess that they are problematic simply based upon rarity.

I am not assuming it is relevant only because it is rare. I would never! That would be foolish! I also look at the research and I also look at it's function in relation to metabolism of nutrients and the creation of neurotransmitters and antioxidants. I am not looking at the whole geneome for rare SNPs, just the subset that have to do with nutrigenomics.

And hey, what can I say, it works. I am a 100% different man than I was a year ago. Would love you to help me figure out why it works.

And even if we could assume that rare SNPs have an impact (we can't), it's impossible to guess what that impact would be. But since rs8177404 and rs8177406 aren't even on GPX3, it's even more unlikely that they are capable of having an impact GPX3. They're actually located on uncharacterized LOC105378228.

First, if you could post references I would appreciate it, because I do not understand what you are saying here. When I look up in 23andme, promethease and in the research for rs8177404 and rs8177406 they are clearly SNPs in GPX3. The only thing I found for LOC105378228 was an RNA gene. Am I missing something?

rs8177404 at chr5:150399584 in GPX3
https://www.pharmgkb.org/rsid/rs8177404

rs8177406 at chr5:150399634 in GPX3
https://www.pharmgkb.org/rsid/rs8177406
 
Messages
15,786
I am not assuming it is relevant only because it is rare. I would never! That would be foolish! I also look at the research and I also look at it's function in relation to metabolism of nutrients and the creation of neurotransmitters and antioxidants.
http://www.ncbi.nlm.nih.gov/pubmed/24819036 says that they have no impact regarding metabolic syndrome. I don't see any other research regarding those SNPs. Being "polymorphic" simply means that they each have more than one observed allele, which is quite common - every SNP tested by 23andMe is polymorphic, with two possible alleles. And "tight linkage disequilibrium" means that the SNPs discussed (including rs8177404 and rs8177406) are almost always inherited together, which each one taking the same form (homozygous for the major allele, heterozygous, or homozygous for the minor allele).
First, if you could post references I would appreciate it, because I do not understand what you are saying here. When I look up in 23andme, promethease and in the research for rs8177404 and rs8177406 they are clearly SNPs in GPX3. The only thing I found for LOC105378228 was an RNA gene. Am I missing something?
Yes, http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs= is a better source if you want to see exactly where the SNP is. It's the most up to date. 23andMe data, such as SNP location on a chromosome or a gene, can be years out of date.
 
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ppodhajski

Senior Member
Messages
243
Location
Chapel Hill, NC
Yes, http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs= is a better source if you want to see exactly where the SNP is. It's the most up to date. 23andMe data, such as SNP location on a chromosome or a gene, can be years out of date.

So I still do not understand. From that web site you gave me it still says they are both GPX3 SNPs. Can you point out to me exactly what you are talking about? Plus, I am pulling the data from promethease, which is very up to date and run by geneticists.

Screenshot.png


Screenshot-1.png
 
Messages
15,786
So I still do not understand. From that web site you gave me it still says they are both GPX3 SNPs. Can you point out to me exactly what you are talking about?
Hover over the gene on the map view (thick horizontal bar), or zoom out until you can see the gene labels. They aren't on GPX3.

And what research into those SNPs makes you think they're relevant?
 

ppodhajski

Senior Member
Messages
243
Location
Chapel Hill, NC
Hover over the gene on the map view (thick horizontal bar), or zoom out until you can see the gene labels. They aren't on GPX3.

And what research into those SNPs makes you think they're relevant?

Look at the images I pasted above, it clearly says "Gene: GPX3". How can you say they are not in the GPX3 gene? You are wrong.

I am not going to get into proving to you that any single SNP is significant. I have told you before that I use several gene SNPs and any evidence I show you just seem to say it is not good enough. I will let the several people who benefited from my ideas, like how FMN helps those with MAOA and MAOB SNPs, speak to what I see. If you want to help you can help me find out why I am better.

To everyone else: I am not responding to Valentijn's posts anymore. Do not let my silence let you think that what she says is correct to me, that is the only reason I responded to her in the past. I know what I am saying is mostly theory and speculative, but I am better and that is all the proof I need. No more anxiety, OCD, IBS, CFS, depression, paresthesia, inflammatory skin issues, costrocondritis, high blood pressure...that is my proof.
 
Messages
15,786
Look at the images I pasted above, it clearly says "Gene: GPX3". How can you say they are not in the GPX3 gene? You are wrong.
In those images, two genes are listed for each. SNPs are rarely on two genes at the same time, so it's a good indication that you need to look closer. And in this case, the SNPs are at best "near GPX3". Even dbSNP will say "GPX3" in one field and later clarify "nearGene" elsewhere. But currently the best evidence is that rs8177404 and rs8177406 are on an uncharacterized locus (suspected gene) close to GPX3.

The most recent assembly used by dbSNP shows that GPX3 is on chromosome 5 from positions 151,020,438 to 151,028,993. On that same assembly, rs8177404 is at position 151,020,023 on chromosome 5, and rs8177406 is on position 151,020,073 on chromosome 5. Thus rs8177404 is 415 SNPs away from being on the GPX3 gene, and rs8177406 is 365 SNPs away from GPX3.

Here's the dbSNP screen shot from http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=rs8177406 . The blue-purple horizontal bar is the locus on which rs8177404 and rs8177406 are located. The green horizontal bar on the right side is GPX3. The thin green vertical line is the the exact location of rs8177406, with rs8177404 being 50 SNPs to the left of it, even further away from GPX3. Also note "nearGene-5" in the "Function" field of the "Gene Models" section directly above the map view.
rs8177406.jpg


They are obviously not on GPX3. They are near it. And they are located with a different group of SNPs which is suspected of being an entirely different gene.

I am not going to get into proving to you that any single SNP is significant. I have told you before that I use several gene SNPs and any evidence I show you just seem to say it is not good enough.
Your method seems to be assuming that any rare-ish SNP on an interesting gene must be having a specific impact which you are arbitrarily assigning to it. But the vast majority of rare SNPs do not have an impact, and in the absence of research into those specific SNPs it is irrational to decide that they must be misbehaving. And it is even more irrational to randomly decide that the hypothetical misbehavior is in the form of an upregulation versus a downregulation, or vice versa.

There are billions of SNPs. We could spend many life times randomly picking ones that we label as doing this or that. That is not science. That is divining, right up there with astrology and tarot cards.
 
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mariovitali

Senior Member
Messages
1,214
Just to give my two cents :


Selenium is important for Endoplasmic Reticulum stress control :


Selenium inhibits adipogenesis through suppression of ER-stress and induction of selenoprotein S
Choon Young Kim, Julie L. Wiacek, Gyo-Nam Kim and Kee-Hong Kim
Department of Food Science, Purdue University, West Lafayette, IN

Adipogenesis is a potential target to treat or prevent obesity. It is associated with an induction of cellular stress such as endoplasmic reticulum (ER) stress. Selenium, a micronutrient, elicits a variety of health benefits, mainly through its incorporation into selenoproteins. Among those, an ER resident Selenoprotein S (SEPS1) has been shown to attenuate ER stress and the unfolded protein response. The objective of this study was to determine the role of selenium supplementation in modulating adipogenesis and its related ER stress in vitro. Exposure of 3T3-L1 preadipocytes to selenate over a 6-day differentiation program dose-dependently inhibited adipogenesis without any cytotoxic effect. Consistent with this finding, adipogenic gene expressions, such as peroxisome proliferator-activated receptor-gamma and fatty acid synthase, were suppressed in the presence of selenate. The early stage of adipogenesis was found to be critical for selenate’s inhibitory action on differentiation. Furthermore, a 24 h selenate pretreatment suppressed adipogenesis. We found that the selenate-inhibited adipogenesis is associated with alteration of ER stress in 3T3-L1 cells. Selenate treatment suppressed X-box protein 1 mRNA expression and increased SEPS1 protein level during the early stages of differentiation. Furthermore, 3T3-L1 preadipocytes transducted with lentivirus containing SEPS1 shRNA significantly blunted selenate-inhibited adipogenesis, suggesting a requirement of SEPS1 in mediating anti-adipogenic role of selenate. Taken together, our results indicate that selenate plays both inhibitory and preventive function in adipogenesis and this is possibly through modulation of SEPS1-mediated ER stress.


also Selenium is very important for proper protein folding :


Is there a therapeutic role for selenium in alpha-1 antitrypsin deficiency?
Greene CM1, Chhabra R, McElvaney NG.
Author information

Abstract
Selenium is an essential trace mineral of fundamental importance to human health. Much of its beneficial influence is attributed to its presence within selenoproteins, a group of proteins containing the rare amino acid selenocysteine. There are 25 known human selenoproteins including glutathione peroxidases, thioredoxin reductases and selenoproteins. Selenoprotein S (SEPS1) is an endoplasmic reticulum (ER) resident selenoprotein involved in the removal of misfolded proteins from the ER. SEPS1 expression can be induced by ER stress, an event that is associated with conformational disorders and occurs due to accumulation of misfolded proteins within the ER. Alpha-1 antitrypsin (AAT) deficiency, also known as genetic emphysema, is a conformational disorder in which the roles of ER stress, SEPS1 and selenium have been investigated. SEPS1 can relieve ER stressin an in vitro model of AAT deficiency by reducing levels of active ATF6 and inhibiting grp78 promoter- and NFκB activity; some of these effects are enhanced in the presence of selenium supplementation. Other studies examining the molecular mechanisms by which selenium mediates its anti-inflammatory effects have identified a role for prostaglandin 15d-PGJ2 in targeting NFκB and PPARγ. Together these ER stress-relieving and anti-inflammatory properties suggest a therapeutic potential for selenium supplementation in genetic emphysema.


However too much of it should be avoided :


HIGH SELENIUM INTAKE IS ASSOCIATED WITH ENDOTHELIAL DYSFUNCTION: CRITICAL ROLE FOR ENDOPLASMIC RETICULUM STRESS
  1. M Zachariah,
  2. MP Rayman,
  3. A Agouni
+Author Affiliations

  1. School of Biosciences & Medicine, Faculty of Health and Medical Sciences, University of Surrey, UK
Abstract
Selenium, an essential trace element, is important to human health. Recently, supra-nutritional selenium intake was shown to be associated with an increased risk of type II diabetes and may therefore affect cardiovascular-disease risk, though the underpinning mechanisms are not clear. Some cancer studies reported that high selenium doses cause apoptosis through the induction of endoplasmic reticulum (ER) stress response. Because ER stress is also involved in the pathogenesis of insulin resistance and endothelial dysfunction (ED), which are implicated in the development of atherosclerosis, we hypothesised that supra-nutritional selenium intake could cause diabetes and ED through ER stress.

The Eahy.926 endothelial-cell line or human umbilical-vein endothelial cells (HUVECs) were treated with varying doses of selenite in the presence or absence of the chemical chaperone, 4-phenylbutryic acid (PBA), which inhibits ER stress. ER-stress activation was evaluated by qPCR. Apoptosis was assessed by flow cytometry, western blot and caspase 3/7 colorimetric assay. To assess endothelial function, we evaluated nitric-oxide (NO) release and eNOS activation.

In contrast to physiological concentrations of selenite, high doses enhanced mRNA expression of pro-apoptotic ER-stress markers e.g. activating transcription factor-4 and C/EBP homologous protein. High selenite doses also significantly decreased cell viability and increased apoptosis. Interestingly, these effects were significantly prevented in the presence of PBA, implicating ER-stress. Furthermore, we observed that ER stress induced by high selenite decreased NO production, indicating ED.

Overall, we show that supra-nutritional selenium doses activate ER-stress-mediated apoptosis in the endothelium, reducing the bioavailability of NO and causing ED, a hallmark of cardiovascular disease.