Unfolded Protein Response and A Possible Treatment for CFS

[mariovitali]

What makes you think rs10808739 (A,A) is pathogenic?

Ah, right i see what you mean.

The Bad version is ok (the second one listed in Promethease) whereas the first one rs10808739 has an homozygous mutation but it is NOT pathogenic.

To be honest i do not like the fact that it has such a low frequency, it isn't Pathogenic but unfortunately i do not know how confident we are that this is not a Pathogenic version. If by any chance you know this information please let me know.

 

[skwag]

To be honest i do not like the fact that it has such a low frequency, it isn't Pathogenic but unfortunately i do not know how confident we are that this is not a Pathogenic version. If by any chance you know this information please let me know.

We don't really know anything about it. There is only one study that mentions it in relation to HIV susceptibility ( which found a null result, I believe ).

I understand the worrisome nature of rare snps, but most snps don't affect function much, if at all. And it's likely that every single person on earth has more than a few rare snps.

In this case, it looks like other populations have a greater frequency of the (A,A) genotype, which might be a little reassuring. See the frequency chart here.

 

[mariovitali]

@skwag

So if this version exists at a much greater Frequency in other populations then it shouldn't be a problem. Makes sense.

The other thing that i was thinking is that if this version was a major problem then i would probably have known much earlier. But you see, i do not know how combinations of SNPs might work and what kind of outcomes they have when it comes to disease.

Anyway, Thank you for pointing this out.

 

[jump44]

Man its awesome you guys are researching this all and hopefully we are able to piece together a solid treatment, but damn this disease sucks with sooo many possibilities existing for whats wrong. And the liver seems extremely complex and I think unfortunately it is a huge player in this.

 

[mariovitali]

@jump44

I think we are very close. We just need more people to try the regimen.

Here is a Summary of the Thread :


-Hypothesis : CFS is caused by a vicious cycle of Oxidative and ER Stress. The same mechanism applies for Post-Finasteride Syndrome and Accutane Chronic Side Effects. The result of this condition is the disruption of several functions of the Human body which then leads to a multi-systemic-like disease.


-You have to adhere to a personalized regimen based on your DNA.


-The regimen aims in ameliorating Oxidative and Endoplasmic Reticulum Stress, bringing Redox homeostasis and -as a consequence- putting an end to the vicious cycle between Oxidative and ER Stress (Note : my Hypothesis).


-Key Targets : Methylation, Redox Homeostasis (through Cofactors and Vitamins),ER Stress amelioration, Choline Metabolism, BH4 Metabolism, Gluten Intolerance, Protein Oxidative Folding, Avoidance of selected CYP inhibitors.

-Redox Homeostasis Elements : Riboflavin,Molybdenum,Selenium, Manganese, Vitamin K, Vitamin C (among others)


-ER Stress amelioration Elements : TUDCA, Taurine, Resveratrol, Curcumin (possibly more)


-It is unclear if corrective actions should be aimed to both Oxidative and Endoplasmic Reticulum Stress. My hypothesis is that certain individuals may benefit only by achieving Redox homeostasis while others may need both strategies (especially if Liver function is impaired). It is unknown if ER Stress handling on its own may be of benefit.


-In the event that the regimen shows promising results : I have collected patterns based on personal observation that may shade light on several aspects of Oxidative Stress. These patterns were extracted using cutting-edge Data Mining Techniques. Needless to say, these should be evaluated on a larger scale.

 

[Violeta]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4524603/

Finasteride (FIN) suppresses neurosteroid synthesis via inhibition of 5α-reductase in astrocytic smooth endoplasmic reticulum [19]

"The smooth endoplasmic reticulum (abbreviated SER) has functions in several metabolic processes. It synthesizes lipids, phospholipids, and steroids. Cells which secrete these products, such as those in the testes, ovaries, and sebaceous glands have an abundance of smooth endoplasmic reticulum.[9] It also carries out the metabolism of carbohydrates, drug detoxification, attachment of receptors on cell membrane proteins, and steroid metabolism.[1"

"In liver cells the smooth ER contains enzymes for the detoxification of harmful drugs and metabolic by-products. In the reproductive organs, smooth ER in the cells produces the steroid hormones testosterone and estrogen."

 

[Violeta]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4524603/

Finasteride (FIN) suppresses neurosteroid synthesis via inhibition of 5α-reductase in astrocytic smooth endoplasmic reticulum [19]

"The smooth endoplasmic reticulum (abbreviated SER) has functions in several metabolic processes. It synthesizes lipids, phospholipids, and steroids. Cells which secrete these products, such as those in the testes, ovaries, and
sebaceous glands have an abundance of smooth endoplasmic reticulum.[9] It also carries out the metabolism of carbohydrates, drug detoxification, attachment of receptors on cell membrane proteins, and steroid metabolism.[1"

"In liver cells the smooth ER contains enzymes for the detoxification of harmful drugs and metabolic by-products. In the reproductive organs, smooth ER in the cells produces the steroid hormones testosterone and estrogen."

Does this make it seem as though the problems you are having from finasteride seem to be more located in the smooth ER(lipid metabolism) than in the rough ER(protein folding)?

I am looking for the link between smooth ER and rough ER. I see that smooth ER has a lot to do with fatty liver.

 

[Gondwanaland]

Just a couple of random thoughts:
Accutane can raise serum cholesterol (LDL/VLDL?)
Does Fin too?
Low thyroid raises LDL, would there be any connection with the impact on liver?

 

[mariovitali]

@Violeta

I do not know where the problem may be located. Perhaps in both smooth and rough ER


@Gondwanaland

I am not sure i am following you could you provide some additional thoughts?. All i can say is that i was hypothyroid and been taking T4 (75 mcg) for many years. I had no nodules but my endo was saying to me that my "Thyroid is lazy and we do not know why"

Now i know why (Just a Hypothesis). ER and Oxidative stress possibly dysregulates the HPA Axis, because i am not Hypothyroid any more.

 

[mariovitali]

For the Post-accutane sufferers reading this Thread... please see below :

Oral isotretinoin therapy of acne patients decreases serum paraoxonase-1 activity through increasing oxidative stress.
Ozkol HU1, Ozkol H, Karadag AS, Bilgili SG, Tuluce Y, Calka O.
Author information

Abstract
OBJECTIVES:
There are only a few earlier studies suggesting relationship between isotretinoin treatment and oxidative stress however, their results are conflicting. Therefore we aimed to concretize the influence of isotretinoin treatment on oxidant/antioxidant status together with paraoxonase-1 (PON1) activity for the first time.

METHODS:
The study was performed on serum samples obtained from 35 acne vulgaris patients before and after three months of isotretinointreatment. PON1 activity, total oxidant status (TOS), total antioxidant capacity (TAC), oxidative stress index (OSI) and some routine biochemical parameters were monitored.

RESULTS:
Dramatically decreased PON1 activity (p < 0.001), increased TOS level and OSI value (p < 0.001 and p < 0.001; respectively) as well as slightly diminished TAC level were noted in posttreatment stage. Moreover significant increases were observed in lactate dehydrogenase and gamma glutamyl transpeptidase activities and levels of total cholesterol, low density lipoprotein cholesterol, very low density lipoprotein cholesterol, triglycerides, low density lipoprotein cholesterol/high density lipoprotein cholesterol ratio respectively (p < 0.05, p < 0.001, p < 0.001, p < 0.001, p < 0.001, p < 0.001 and p < 0.001) while marked decrease was seen in high density lipoprotein cholesterol (p < 0.01).

CONCLUSION:
This study revealed that decreased PON1 activity and increased oxidative stress may have a crucial role in the pathogenesis ofisotretinoin's side effects. Further studies on a large number of patients are needed to verify these results.

and more (Note the role of Selenium)

Selenium ameliorates isotretinoin-induced liver injury and dyslipidemia via antioxidant effect in rats.
Saied NM1, Hamza AA.
Author information

Abstract
Isotretinoin (Iso) is a widely used retinoid for the treatment of dermatologic conditions. Although it has broad side effects, there is no well-designed study about preventive effects against its hepatic toxicity. This study was undertaken to evaluate the protective effect of selenium (Se) against Iso-induced hepatotoxicity in Wistar rats. Animals were divided into four groups. The first group served as control. The second, third and fourth groups received Se, Iso and Se & Iso, respectively, for 28 days. Se was administered daily orally at a dose of 50 µg / 100 g body weight. Iso was given daily orally at a dose of 0.75 mg/ 100 g /day in olive oil. Iso caused significant increases in serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, cholesterol, triglycerides, and high-density lipids content. Animals also showed significant rise in thiobarbituric acid reacting substance and nitric oxide content with concomitant decrease in reduced glutathione content and the antioxidant enzyme activities of superoxide dismutase and catalase in liver tissue after Iso exposure. Se administration produced a significant protection against the hepatotoxic effects of Iso and markedly alleviated alterations in these parameters. The results obtained herein clearly indicate that Iso causes induction of oxidative stress and the co-administration of Iso and Se provides protection against Iso-induced liver injury.

 

[Valentijn]

with a 2.7% Frequency

It's only a 2.7% frequency in a small sample of European-Americans from Utah. In other ethnic groups AA genotype frequency is up to and over 20%. There's also no research indicating that the AA genotype causes any abnormalities.

 

[jump44]

I guess the only thing I cant wrap my head around is this- Suppose a person having all these cfs type symptoms takes the gene test and it reveals for example they shouldnt be taking selenium.. However they are having sever oxidative stress/Er stress related symptoms and everytime they supplement with selenium(just using this as an example) they feel better. Does anyone see what Im getting at? Its a tricky dichotomy I think. Just look at all the people who experience bad side effects from methylation regimens whos gene tests say they definitively need it. I know for me the methylation treatment alone ended in disaster and these few supps we are talking about in this thread have helped me trend much more towards normal and I dont have any gene tests to analyze yet. Not saying they arent helpful certainly.

 

[Gondwanaland]

I am not sure i am following you could you provide some additional thoughts?. All i can say is that i was hypothyroid and been taking T4 (75 mcg) for many years. I had no nodules but my endo was saying to me that my "Thyroid is lazy and we do not know why"

Now i know why (Just a Hypothesis). ER and Oxidative stress possibly dysregulates the HPA Axis, because i am not Hypothyroid any more.

Chris Kresser ( ... ) The LDL receptor is what LDL particles bind to, and it removes LDL from the circulation and takes LDL cholesterol and everything else that the LDL particle carries and removes that from the circulation and puts it into the cell. So if someone has low levels of free T3, then they may have poorly functioning LDL receptors, and that can lead to high cholesterol and high LDL particle number.

That explains why studies have shown that patients even with TSH levels between 2.5 and 4.5, which, remember, would be considered normal in the conventional paradigm, show improvements in cardiovascular disease risk factors, including lipid profiles, endothelial cell function, which is better functioning of the blood vessels, and decreased thickness of the blood vessels, when their thyroid function improves. So the cardiovascular connection with thyroid hormone and the function of the thyroid system is really important to understand.

Dr. Amy Nett: Yeah, and there was actually another really recent study—it was actually just published last month—that looked at another potential, we’ll say, association between low thyroid function and cardiovascular disease risk. Specifically, this study noted that there is an association between subclinical hypothyroidism and atherosclerosis, but they looked a little bit further and specifically looked at the role of oxidation. Oxidation of LDL plays a pretty important role in the development of atherosclerosis or arterial plaques. So this study, again, it looked at oxidative stress in patients with subclinical hypothyroidism, and we just said that oxidation of LDL can make it a more atherogenic form that contributes to the development of those atherosclerotic lesions, and one of the major pathways of LDL oxidation is what’s called the lipoxygenase pathway. This pathway creates certain fatty acid oxidation products known to increase plaques, and they’re considered reliable biomarkers for oxidative stress. So this study looked at lipid peroxidation as measured by concentrations of these specific fatty acids, looked at the association between lipid oxidation, TSH levels, and then the carotid intima-media thickness, and you’ve talked about the IMT before, which is a biomarker of subclinical atherosclerosis. And this study did find that with subclinical hypothyroidism, especially when the TSH got even higher, up to about 10, there was a higher risk of atherosclerosis, and it seemed to be associated with that lipid peroxidation. So another interesting mechanism in terms of how the subclinical hypothyroidism or low thyroid function is contributing to atherosclerosis.

More interesting bits here

Mario, for a long time now I have suspected the liver is the underlying cause for my thyroid problems.

I guess the only thing I cant wrap my head around is this- Suppose a person having all these cfs type symptoms takes the gene test and it reveals for example they shouldnt be taking selenium.. However they are having sever oxidative stress/Er stress related symptoms and everytime they supplement with selenium(just using this as an example) they feel better. Does anyone see what Im getting at? Its a tricky dichotomy I think. Just look at all the people who experience bad side effects from methylation regimens whos gene tests say they definitively need it. I know for me the methylation treatment alone ended in disaster and these few supps we are talking about in this thread have helped me trend much more towards normal and I dont have any gene tests to analyze yet. Not saying they arent helpful certainly.

Well, I think the life history plays a huge part in it. Suppose you had a twin that never took Fin

 

[mariovitali]

Just finished a new round of Analysis. We have two new Topics that appear on the top places, namely :

-NAD(P)H Dehydrogenase (quinone) 1 - (NQO1)
-Antioxidant Response Element (ARE)

See more


https://en.wikipedia.org/wiki/NAD(P)H_dehydrogenase_(quinone_1)


Here are the PubMed Topics under consideration :

['3betahsd.csv', '3methylcrotonyl_coa_carboxylase.csv', '5-htp.csv', '5alphareductase.csv', '5mthf.csv', 'acetyl-coa.csv', 'acetyl_coa_carboxylase.csv', 'acetylcholine.csv', 'adhd.csv', 'adrenal_hyperplasia.csv', 'adrenal_insufficiency.csv', 'adrenergic_receptor.csv', 'advanced_glycation_end.csv', 'akr1d1.csv', 'allopregnanolone.csv', 'ampa.csv', 'amyloid.csv', 'amyloidosis.csv', 'angiotensin_human.csv', 'anhedonia.csv', 'are.csv', 'asymmetric_dimethylarginine.csv', 'atf4.csv', 'atf6.csv', 'atrial_fibrillation.csv', 'autism.csv', 'baroreceptor.csv', 'benfotiamine.csv', 'beta-alanine.csv', 'biotin.csv', 'bradycardia.csv', 'butyrate.csv', 'calcium_homeostasis.csv', 'caloric_restriction.csv', 'car.csv', 'caspase_human.csv', 'catalase.csv', 'cerebrovascular_amyloidosis.csv', 'cfs.csv', 'chaperones.csv', 'cholestasis.csv', 'choline_deficiency.csv', 'chop.csv', 'cimetidine.csv', 'ckd.csv', 'coenzymeq10.csv', 'cofactor.csv', 'constipation.csv', 'cortisol.csv', 'cortisol_levels.csv', 'cox-2.csv', 'creatine_supplementation.csv', 'crohns_disease.csv', 'curcumin.csv', 'cyp1a1.csv', 'cyp1a2.csv', 'cyp1b1.csv', 'cyp27a1.csv', 'cyp2d6.csv', 'cyp2e1.csv', 'cyp3a4.csv', 'cyp7b1.csv', 'd-limonene.csv', 'd_aminoacid_oxidase.csv', 'd_serine.csv', 'dht.csv', 'dihydroprogesterone.csv', 'disulfide_bonds.csv', 'dolichol.csv', 'dopamine.csv', 'dpagt1.csv', 'dysautonomia.csv', 'ebv.csv', 'endothelial_nos.csv', 'er_stress.csv', 'erad.csv', 'ero1.csv', 'esr1.csv', 'excitotoxicity.csv', 'fad.csv', 'fads1.csv', 'fads2.csv', 'finasteride.csv', 'flavoprotein.csv', 'floaters.csv', 'fmn.csv', 'fmo3.csv', 'freet3.csv', 'gaba_human.csv', 'ginkgo.csv', 'glutamate.csv', 'glutaredoxin.csv', 'gluten.csv', 'glycerylphosphorylcholine.csv', 'glycoproteins.csv', 'glycosylation.csv', 'gnmt.csv', 'gpr78.csv', 'gtp_cyclohydrolase.csv', 'h2o2.csv', 'heat_shock_protein.csv', 'hepatocytes.csv', 'hepatotoxicity.csv', 'hexosamine.csv', 'hgh.csv', 'histone_deacetylase.csv', 'hmgb1.csv', 'hmgcoa.csv', 'hpa_axis.csv', 'hsc.csv', 'hsp70.csv', 'human_proteinuria.csv', 'human_semen.csv', 'hydrogen_sulfide.csv', 'hydroxysteroid_dehydrogenase.csv', 'hypobaric_hypoxia.csv', 'il_10.csv', 'immune_response.csv', 'inducible_nos.csv', 'inflammatory_response.csv', 'inositol.csv', 'insomnia.csv', 'insp3.csv', 'insulin_resistance.csv', 'intestinal_motility.csv', 'ire1.csv', 'iron_deficiency.csv', 'irritable_bowel.csv', 'isotretinoin.csv', 'kainate.csv', 'l-arginine.csv', 'l-dopa.csv', 'l_carnitine.csv', 'l_tryptophan.csv', 'l_tyrosine.csv', 'limbic_system.csv', 'lipoic_acid.csv', 'magnesium_deficiency.csv', 'mast_cell_activation.csv', 'mastocytosis.csv', 'mcp-1.csv', 'microbiome_humans.csv', 'microglia.csv', 'misfolded_proteins.csv', 'mitochondrial_dysfunction.csv', 'molybdenum.csv', 'monoamine_oxidase.csv', 'monosodium_glutamate.csv', 'mthfr.csv', 'mucuna.csv', 'n-acetylglucosamine.csv', 'nac.csv', 'nachr.csv', 'nad.csv', 'nadh_dehydrogenase.csv', 'nadph.csv', 'nafld.csv', 'neurite_outgrowth.csv', 'neuronal_nos.csv', 'ngf.csv', 'niacin.csv', 'nlinkedglycosylation.csv', 'nmda.csv', 'norepinephrine.csv', 'nox4.csv', 'nqo1.csv', 'nrf2.csv', 'o-glcnac.csv', 'o-glcnacylation.csv', 'omega3.csv', 'orthostatic_intolerance.csv', 'osmolytes.csv', 'oxalates.csv', 'oxidative_protein_folding.csv', 'oxidative_stress_markers.csv', 'oxidative_stress_protection.csv', 'p450oxidoreductase.csv', 'p450scc.csv', 'p53.csv', 'p5p.csv', 'panic_disorder.csv', 'pbmc.csv', 'pdi.csv', 'peristalsis.csv', 'perk.csv', 'peroxiredoxin.csv', 'peroxynitrite.csv', 'pgc1.csv', 'phenylketonuria.csv', 'phosphatidylcholine.csv', 'phosphatidylserine.csv', 'phospholamban.csv', 'phospholipid_human.csv', 'potassium_levels.csv', 'ppp.csv', 'pqq.csv', 'pregnenolone.csv', 'probiotics.csv', 'propionyl_coa_carboxylase.csv', 'protease_inhibitor.csv', 'ptp1b.csv', 'pxr.csv', 'pyruvate_carboxylase.csv', 'rar.csv', 'redox_cofactor.csv', 'redox_homeostasis.csv', 'redox_potential.csv', 'redox_regulation.csv', 'reduced_glutathione.csv', 'resistant_starch.csv', 'resveratrol.csv', 'riboflavin.csv', 'rituximab.csv', 'rls.csv', 'ros.csv', 'rxr.csv', 'scfa.csv', 'selenium.csv', 'selenium_deficiency.csv', 'serca.csv', 'serotonin_levels.csv', 'sinusitis.csv', 'sirt1.csv', 'sirt2.csv', 'sirt3.csv', 'social_anxiety.csv', 'sod1.csv', 'sod2.csv', 'sod3.csv', 'srd5a3.csv', 'sshl.csv', 'star.csv', 'stat1.csv', 'steatohepatitis.csv', 'steroidogenesis_human.csv', 'subclinicalhypo.csv', 'sulfite_oxidase.csv', 'sulforaphane.csv', 'systemic_amyloidosis.csv', 'tau.csv', 'taurine.csv', 'testosterone_production.csv', 'tetrahydrobiopterin.csv', 'thioredoxin.csv', 'tinnitus.csv', 'tmao.csv', 'tocotrienol.csv', 'triiodothyronine_levels.csv', 'trpv.csv', 'tudca.csv', 'udpglcnac.csv', 'udpgluc.csv', 'upr.csv', 'urea_cycle.csv', 'uric_acid.csv', 'vcam-1.csv', 'vitamin_b6.csv', 'vitamin_d3.csv', 'vitamin_k.csv', 'xanthine_oxidase.csv', 'xbp1.csv', 'zinc_supplementation.csv']

 

[mariovitali]

@mariovitali

I will cease Tudca for a few days and see what happens. Also, after reading through your first post again I noticed you warned against testosterone induction/therapy as it can contribute to ER stress. I found this interesting because the few times Ive felt closer to "normal" during this shitshow(pardon the term haha) has been when I was on Testosterone replacement.. Dhea also causes some improvements.Now this couldve just been because my libido/sexual function improved somewhat and when this is working better other symptoms become much more tolerable(for me at least) because like the post fin guys for some reason this illness has really decimated my sex drive/function etc. Also I found a few(nothing definitive just correlations) things online that DHT itself may be protective against ER stress and even oxidative stress. Just curious if you had any thoughts on this. thanks.

Yes, well this completely makes sense, since DHEA possibly Induces several P450 CYPs :

Dehydroepiandrosterone Induces Human CYP2B6 through the Constitutive Androstane Receptor

Next Section
Abstract
Dehydroepiandrosterone (DHEA), the major precursor of androgens and estrogens, has several beneficial effects on the immune system, on memory function, and in modulating the effects of diabetes, obesity, and chemical carcinogenesis. Treatment of rats with DHEA influences expression of cytochrome P450 (P450) genes, including peroxisome proliferator-activated receptor α (PPARα)- and pregnane X receptor (PXR)-mediated induction ofCYP4As and CYP3A23, and suppression of CYP2C11. DHEA treatment elevated the expression and activities of CYP3A4, CYP2C9, CYP2C19, and CYP2B6 in primary cultures of human hepatocytes. Induction of CYP3A4 in human hepatocytes was consistent with studies in rats, but induction of CYP2Cs was unexpected

I bet my two cents that you will feel better if you take Dexamethasone (= a potent P450 Inducer).

NOTE : I AM NOT SUGGESTING THAT YOU OR ANYONE ELSE SHOULD TAKE DEXAMETHASONE

 

[mariovitali]

I am sure that by now you know that i like taking screenshots


So this is a screenshot of the Python program i use to find Topic Frequencies :

You see the list of PubMed Topics that are searched and the phrases/keywords. The first one is "bile acid"

I did not have this entry as a Topic so i downloaded all PubMed entries regarding Bile Acids.

The program matches an awful lot of Topics, among them resistant starch, human microbiome and intestinal motility :

*********Topic : bile acid ***************
bile_acid.csv : 98.17 %
akr1d1.csv : 56.76 %
tudca.csv : 41.78 %
cyp7b1.csv : 31.79 %
cyp27a1.csv : 27.07 %
taurine.csv : 14.26 %
pxr.csv : 12.58 %
car.csv : 10.20 %
cholestasis.csv : 6.98 %
hmgcoa.csv : 6.08 %
hydroxysteroid_dehydrogenase.csv : 4.19 %
resistant_starch.csv : 4.18 %
3betahsd.csv : 3.70 %
scfa.csv : 3.12 %
rxr.csv : 2.50 %
hepatocytes.csv : 2.16 %
niacin.csv : 1.99 %
udpgluc.csv : 1.88 %
hepatotoxicity.csv : 1.74 %
steatohepatitis.csv : 1.66 %
nafld.csv : 1.27 %
pgc1.csv : 1.26 %
intestinal_motility.csv : 1.13 %
microbiome_humans.csv : 1.11 %
phospholipid_human.csv : 0.99 %
probiotics.csv : 0.91 %
hsc.csv : 0.90 %
irritable_bowel.csv : 0.88 %
cyp3a4.csv : 0.78 %
star.csv : 0.75 %
pregnenolone.csv : 0.72 %
p450oxidoreductase.csv : 0.67 %
phosphatidylcholine.csv : 0.62 %
acetyl_coa_carboxylase.csv : 0.55 %
nrf2.csv : 0.55 %
rar.csv : 0.53 %
gluten.csv : 0.52 %
beta-alanine.csv : 0.50 %
tocotrienol.csv : 0.49 %
acetyl-coa.csv : 0.48 %
butyrate.csv : 0.47 %
atf6.csv : 0.45 %
crohns_disease.csv : 0.44 %
caloric_restriction.csv : 0.43 %
nad.csv : 0.42 %
constipation.csv : 0.41 %
nqo1.csv : 0.41 %
selenium.csv : 0.40 %
dihydroprogesterone.csv : 0.38 %
o-glcnacylation.csv : 0.37 %
cyp2e1.csv : 0.37 %
allopregnanolone.csv : 0.35 %
er_stress.csv : 0.35 %
choline_deficiency.csv : 0.35 %
omega3.csv : 0.34 %
dolichol.csv : 0.34 %
urea_cycle.csv : 0.33 %
atf4.csv : 0.33 %
cyp1a2.csv : 0.30 %
mitochondrial_dysfunction.csv : 0.29 %
tmao.csv : 0.29 %
steroidogenesis_human.csv : 0.28 %
nadph.csv : 0.28 %
cox-2.csv : 0.27 %
sirt1.csv : 0.27 %
peristalsis.csv : 0.27 %
n-acetylglucosamine.csv : 0.27 %
curcumin.csv : 0.27 %
fmo3.csv : 0.27 %
cimetidine.csv : 0.26 %
gnmt.csv : 0.25 %
nlinkedglycosylation.csv : 0.25 %
insp3.csv : 0.24 %
vitamin_d3.csv : 0.24 %
d_aminoacid_oxidase.csv : 0.24 %
monosodium_glutamate.csv : 0.23 %
vitamin_k.csv : 0.22 %
oxalates.csv : 0.22 %
l_carnitine.csv : 0.21 %
5alphareductase.csv : 0.21 %
o-glcnac.csv : 0.20 %
insulin_resistance.csv : 0.19 %
triiodothyronine_levels.csv : 0.19 %
gpr78.csv : 0.19 %
glycoproteins.csv : 0.19 %
resveratrol.csv : 0.19 %
reduced_glutathione.csv : 0.18 %
sirt3.csv : 0.18 %
caspase_human.csv : 0.18 %
coenzymeq10.csv : 0.18 %
upr.csv : 0.17 %
perk.csv : 0.17 %
calcium_homeostasis.csv : 0.17 %
zinc_supplementation.csv : 0.17 %
phosphatidylserine.csv : 0.17 %
fad.csv : 0.16 %
uric_acid.csv : 0.16 %
catalase.csv : 0.16 %
sulforaphane.csv : 0.16 %
l_tyrosine.csv : 0.15 %
fmn.csv : 0.15 %
cyp1a1.csv : 0.15 %
serca.csv : 0.15 %
cofactor.csv : 0.14 %
ros.csv : 0.14 %
hexosamine.csv : 0.13 %
esr1.csv : 0.13 %
flavoprotein.csv : 0.13 %
asymmetric_dimethylarginine.csv : 0.13 %
nac.csv : 0.13 %
oxidative_stress_markers.csv : 0.13 %
oxidative_stress_protection.csv : 0.13 %
selenium_deficiency.csv : 0.13 %
adrenal_insufficiency.csv : 0.13 %
dht.csv : 0.12 %
osmolytes.csv : 0.11 %
ppp.csv : 0.11 %
redox_cofactor.csv : 0.11 %
vcam-1.csv : 0.11 %
glutamate.csv : 0.11 %
chop.csv : 0.11 %
redox_potential.csv : 0.11 %
ire1.csv : 0.11 %
hydrogen_sulfide.csv : 0.11 %
cyp1b1.csv : 0.11 %
inducible_nos.csv : 0.10 %
chaperones.csv : 0.10 %
erad.csv : 0.10 %
inositol.csv : 0.10 %
are.csv : 0.10 %
l-arginine.csv : 0.10 %
udpglcnac.csv : 0.10 %
pdi.csv : 0.10 %
lipoic_acid.csv : 0.10 %
thioredoxin.csv : 0.10 %
inflammatory_response.csv : 0.09 %
acetylcholine.csv : 0.09 %
glycosylation.csv : 0.09 %
p450scc.csv : 0.09 %
hmgb1.csv : 0.09 %
vitamin_b6.csv : 0.08 %
histone_deacetylase.csv : 0.08 %
stat1.csv : 0.08 %
adrenal_hyperplasia.csv : 0.08 %
endothelial_nos.csv : 0.08 %
nox4.csv : 0.08 %
misfolded_proteins.csv : 0.08 %
protease_inhibitor.csv : 0.08 %
hgh.csv : 0.07 %
tau.csv : 0.07 %
p53.csv : 0.07 %
trpv.csv : 0.07 %
cyp2d6.csv : 0.07 %
xbp1.csv : 0.07 %
l_tryptophan.csv : 0.07 %
h2o2.csv : 0.07 %
riboflavin.csv : 0.06 %
mcp-1.csv : 0.06 %
freet3.csv : 0.06 %
creatine_supplementation.csv : 0.06 %
testosterone_production.csv : 0.06 %
xanthine_oxidase.csv : 0.06 %
nadh_dehydrogenase.csv : 0.06 %
il_10.csv : 0.06 %
sod2.csv : 0.06 %
serotonin_levels.csv : 0.06 %
ckd.csv : 0.06 %
disulfide_bonds.csv : 0.06 %
bradycardia.csv : 0.06 %
heat_shock_protein.csv : 0.06 %
cortisol_levels.csv : 0.06 %
redox_homeostasis.csv : 0.05 %
systemic_amyloidosis.csv : 0.05 %
immune_response.csv : 0.05 %
cortisol.csv : 0.05 %
amyloid.csv : 0.05 %
advanced_glycation_end.csv : 0.05 %
molybdenum.csv : 0.04 %
peroxynitrite.csv : 0.04 %
potassium_levels.csv : 0.04 %
phenylketonuria.csv : 0.04 %
amyloidosis.csv : 0.04 %
hsp70.csv : 0.03 %
cfs.csv : 0.03 %
ginkgo.csv : 0.03 %
gaba_human.csv : 0.03 %
peroxiredoxin.csv : 0.03 %
p5p.csv : 0.03 %
neuronal_nos.csv : 0.03 %
microglia.csv : 0.02 %
sod1.csv : 0.02 %
angiotensin_human.csv : 0.02 %
pbmc.csv : 0.02 %
adrenergic_receptor.csv : 0.02 %
excitotoxicity.csv : 0.02 %
iron_deficiency.csv : 0.02 %
sshl.csv : 0.02 %
human_proteinuria.csv : 0.02 %
norepinephrine.csv : 0.01 %
monoamine_oxidase.csv : 0.01 %
hpa_axis.csv : 0.01 %
dysautonomia.csv : 0.01 %
kainate.csv : 0.01 %
ngf.csv : 0.01 %
neurite_outgrowth.csv : 0.01 %
autism.csv : 0.01 %
nmda.csv : 0.01 %
dopamine.csv : 0.01 %
biotin.csv : 0.01 %
ebv.csv : 0.01 %
rituximab.csv : 0.01 %
insomnia.csv : 0.01 %
atrial_fibrillation.csv : 0.01 %
human_semen.csv : 0.01 %
adhd.csv : 0.00 %
phospholamban.csv : 0.00 %
5-htp.csv : 0.00 %
mastocytosis.csv : 0.00 %
limbic_system.csv : 0.00 %
5mthf.csv : 0.00 %
panic_disorder.csv : 0.00 %
ampa.csv : 0.00 %
dpagt1.csv : 0.00 %
gtp_cyclohydrolase.csv : 0.00 %
propionyl_coa_carboxylase.csv : 0.00 %
mast_cell_activation.csv : 0.00 %
orthostatic_intolerance.csv : 0.00 %
rls.csv : 0.00 %
cerebrovascular_amyloidosis.csv : 0.00 %
ero1.csv : 0.00 %
social_anxiety.csv : 0.00 %
finasteride.csv : 0.00 %
glutaredoxin.csv : 0.00 %
isotretinoin.csv : 0.00 %
glycerylphosphorylcholine.csv : 0.00 %
benfotiamine.csv : 0.00 %
anhedonia.csv : 0.00 %
redox_regulation.csv : 0.00 %
sulfite_oxidase.csv : 0.00 %
sod3.csv : 0.00 %
baroreceptor.csv : 0.00 %
fads2.csv : 0.00 %
sinusitis.csv : 0.00 %
pqq.csv : 0.00 %
mucuna.csv : 0.00 %
d_serine.csv : 0.00 %
fads1.csv : 0.00 %
oxidative_protein_folding.csv : 0.00 %
tetrahydrobiopterin.csv : 0.00 %
mthfr.csv : 0.00 %
pyruvate_carboxylase.csv : 0.00 %
ptp1b.csv : 0.00 %
nachr.csv : 0.00 %
3methylcrotonyl_coa_carboxylase.csv : 0.00 %
floaters.csv : 0.00 %
d-limonene.csv : 0.00 %
l-dopa.csv : 0.00 %
tinnitus.csv : 0.00 %
sirt2.csv : 0.00 %
magnesium_deficiency.csv : 0.00 %
subclinicalhypo.csv : 0.00 %
hypobaric_hypoxia.csv : 0.00 %
srd5a3.csv : 0.00 %

In other words : Bile Acids may be important (just a hypothesis), Will post more ASAP.

 

[mariovitali]

OK so perhaps another Hypothesis for Finasteride users and how they got into this mess. Note that AKR1D1 is involved in bile acid synthesis (recall how high it appeared on the previous post about bile acids :

Inhibition of human steroid 5beta-reductase (AKR1D1) by finasteride and structure of the enzyme-inhibitor complex.
Drury JE1, Di Costanzo L, Penning TM, Christianson DW.
Author information

Abstract
The Delta(4)-3-ketosteroid functionality is present in nearly all steroid hormones apart from estrogens. The first step in functionalization of the A-ring is mediated in humans by steroid 5alpha- or 5beta-reductase. Finasteride is a mechanism-based inactivator of 5alpha-reductase type 2 with subnanomolar affinity and is widely used as a therapeutic for the treatment of benign prostatic hyperplasia. It is also used for androgen deprivation in hormone-dependent prostate carcinoma, and it has been examined as a chemopreventive agent in prostate cancer. The effect of finasteride on steroid 5beta-reductase (AKR1D1) has not been previously reported. We show that finasteride competitively inhibits AKR1D1 with low micromolar affinity but does not act as a mechanism-based inactivator. The structure of the AKR1D1.NADP(+)*finasteride complex determined at 1.7 A resolution shows that it is not possible for NADPH to reduce the Delta(1-2)-ene of finasteride because the cofactor and steroid are not proximal to each other. The C3-ketone of finasteride accepts hydrogen bonds from the catalytic residues Tyr-58 and Glu-120 in the active site of AKR1D1, providing an explanation for the competitive inhibition observed. This is the first reported structure of finasteride bound to an enzyme involved in steroid hormone metabolism.



Entrez Gene Summary for AKR1D1 Gene

• The enzyme encoded by this gene is responsible for the catalysis of the 5-beta-reduction of bile acid intermediates and steroid hormones carrying a delta(4)-3-one structure. Deficiency of this enzyme may contribute to hepatic dysfunction. Three transcript variants encoding different isoforms have been found for this gene. Other variants may be present, but their full-length natures have not been determined yet. [provided by RefSeq, Jul 2010]

GeneCards Summary for AKR1D1 Gene
AKR1D1 (Aldo-Keto Reductase Family 1, Member D1) is a Protein Coding gene. Diseases associated with AKR1D1 include bile acid synthesis defect, congenital, 2 and congenital bile acid synthesis defect. Among its related pathways are Metabolism and Metabolism. GO annotations related to this gene include steroid binding and delta4-3-oxosteroid 5beta-reductase activity. An important paralog of this gene is AKR1B1.

UniProtKB/Swiss-Prot for AKR1D1 Gene

• AK1D1_HUMAN,P51857

• Efficiently catalyzes the reduction of progesterone, androstenedione, 17-alpha-hydroxyprogesterone and testosterone to 5-beta-reduced metabolites. The bile acid intermediates 7-alpha,12-alpha-dihydroxy-4-cholesten-3-one and 7-alpha-hydroxy-4-cholesten-3-one can also act as substrates.

Just a thought of course.

 

[Violeta]

Im getting better and better, however I do not strictly use mariovital protocoll but Vit C is a key component in my regime (which is not completed yet). It's still to early to give a detailed update.

However, I tend to a low blood pressure and im taking Grape Seed Extract. My think my blood pressure drops down after intake (106 / 65, 78) which increases light headedness. However, Grape Seed Extract contains many flavonoids and im wondering how I get these flavonoids (which I think, that they help me) by taking Resveratrol.

Any Idea?

The resveratrol might be making your blood pressure drop because it increases production of Nitric Oxide, which lowers blood pressure.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110487

Let me see if I can think of some antioxidants that don't cause increase in nitric oxide.

 

[Violeta]

OK so perhaps another Hypothesis for Finasteride users and how they got into this mess. Note that AKR1D1 is involved in bile acid synthesis (recall how high it appeared on the previous post about bile acids :

Inhibition of human steroid 5beta-reductase (AKR1D1) by finasteride and structure of the enzyme-inhibitor complex.
Drury JE1, Di Costanzo L, Penning TM, Christianson DW.
Author information

Abstract
The Delta(4)-3-ketosteroid functionality is present in nearly all steroid hormones apart from estrogens. The first step in functionalization of the A-ring is mediated in humans by steroid 5alpha- or 5beta-reductase. Finasteride is a mechanism-based inactivator of 5alpha-reductase type 2 with subnanomolar affinity and is widely used as a therapeutic for the treatment of benign prostatic hyperplasia. It is also used for androgen deprivation in hormone-dependent prostate carcinoma, and it has been examined as a chemopreventive agent in prostate cancer. The effect of finasteride on steroid 5beta-reductase (AKR1D1) has not been previously reported. We show that finasteride competitively inhibits AKR1D1 with low micromolar affinity but does not act as a mechanism-based inactivator. The structure of the AKR1D1.NADP(+)*finasteride complex determined at 1.7 A resolution shows that it is not possible for NADPH to reduce the Delta(1-2)-ene of finasteride because the cofactor and steroid are not proximal to each other. The C3-ketone of finasteride accepts hydrogen bonds from the catalytic residues Tyr-58 and Glu-120 in the active site of AKR1D1, providing an explanation for the competitive inhibition observed. This is the first reported structure of finasteride bound to an enzyme involved in steroid hormone metabolism.



Entrez Gene Summary for AKR1D1 Gene

• The enzyme encoded by this gene is responsible for the catalysis of the 5-beta-reduction of bile acid intermediates and steroid hormones carrying a delta(4)-3-one structure. Deficiency of this enzyme may contribute to hepatic dysfunction. Three transcript variants encoding different isoforms have been found for this gene. Other variants may be present, but their full-length natures have not been determined yet. [provided by RefSeq, Jul 2010]

GeneCards Summary for AKR1D1 Gene
AKR1D1 (Aldo-Keto Reductase Family 1, Member D1) is a Protein Coding gene. Diseases associated with AKR1D1 include bile acid synthesis defect, congenital, 2 and congenital bile acid synthesis defect. Among its related pathways are Metabolism and Metabolism. GO annotations related to this gene include steroid binding and delta4-3-oxosteroid 5beta-reductase activity. An important paralog of this gene is AKR1B1.

UniProtKB/Swiss-Prot for AKR1D1 Gene

• AK1D1_HUMAN,P51857

• Efficiently catalyzes the reduction of progesterone, androstenedione, 17-alpha-hydroxyprogesterone and testosterone to 5-beta-reduced metabolites. The bile acid intermediates 7-alpha,12-alpha-dihydroxy-4-cholesten-3-one and 7-alpha-hydroxy-4-cholesten-3-one can also act as substrates.

Just a thought of course.

You probably already realize this, but when you talk about steroid production and bile acids you are talking about the smooth endoplasmic reticulum.

 

[mariovitali]

@Violeta

Yes it is the smooth endoplasmic reticulum but why is this important? Does that mean that ER Stress is the main culprit?