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Unfolded Protein Response and A Possible Treatment for CFS

DeGenesis

Senior Member
Messages
172
References:

Cell Death Dis. 2014 Jul 17;5:e1332. doi: 10.1038/cddis.2014.301.
Fluvoxamine alleviates ER stress via induction of Sigma-1 receptor.
Omi T1, Tanimukai H2, Kanayama D2, Sakagami Y3, Tagami S2, Okochi M2, Morihara T2, Sato M2, Yanagida K2, Kitasyoji A4, Hara H4, Imaizumi K5, Maurice T6, Chevallier N6, Marchal S6, Takeda M2, Kudo T7.
Author information
Abstract

We recently demonstrated that endoplasmic reticulum (ER) stress induces sigma-1 receptor (Sig-1R) expression through the PERK pathway, which is one of the cell's responses to ER stress. In addition, it has been demonstrated that induction of Sig-1R can repress cell death signaling. Fluvoxamine (Flv) is a selective serotonin reuptake inhibitor (SSRI) with a high affinity for Sig-1R. In the present study, we show that treatment of neuroblastoma cells with Flv induces Sig-1R expression by increasing ATF4 translation directly, through its own activation, without involvement of the PERK pathway. The Flv-mediated induction of Sig-1R prevents neuronal cell death resulting from ER stress. Moreover, Flv-induced ER stress resistance reduces the infarct area in mice after focal cerebral ischemia. Thus, Flv, which is used frequently in clinical practice, can alleviate ER stress. This suggests that Flv could be a feasible therapy for cerebral diseases caused by ER stress.

Life Sci. 2014 Jan 30;95(2):89-100. doi: 10.1016/j.lfs.2013.12.019. Epub 2013 Dec 25.
Fluvoxamine rescues mitochondrial Ca2+ transport and ATP production through σ(1)-receptor in hypertrophic cardiomyocytes.
Tagashira H1, Bhuiyan MS2, Shioda N1, Fukunaga K3.
Author information
Abstract

AIMS:
We previously reported that fluvoxamine, a selective serotonin reuptake inhibitor with high affinity for the σ1-receptor (σ1R), ameliorates cardiac hypertrophy and dysfunction via σ1R stimulation. Although σ1R on non-cardiomyocytes interacts with the IP3 receptor (IP3R) to promote mitochondrial Ca(2+) transport, little is known about its physiological and pathological relevance in cardiomyocytes.

MAIN METHODS:
Here we performed Ca(2+) imaging and measured ATP production to define the role of σ1Rs in regulating sarcoplasmic reticulum (SR)-mitochondrial Ca(2+) transport in neonatal rat ventricular cardiomyocytes treated with angiotensin II to promote hypertrophy.

KEY FINDING:
These cardiomyocytes exhibited imbalances in expression levels of σ1R and IP3R and impairments in both phenylephrine-induced mitochondrial Ca(2+) mobilization from the SR and ATP production. Interestingly, σ1R stimulation with fluvoxamine rescued impaired mitochondrial Ca(2+) mobilization and ATP production, an effect abolished by treatment of cells with the σ1R antagonist, NE-100. Under physiological conditions, fluvoxamine stimulation of σ1Rs suppressed intracellular Ca(2+) mobilization through IP3Rs and ryanodine receptors (RyRs). In vivo, chronic administration of fluvoxamine to TAC mice also rescued impaired ATP production.

SIGNIFICANCE:
These results suggest that σ1R stimulation with fluvoxamine promotes SR-mitochondrial Ca(2+) transport and mitochondrial ATP production, whereas σ1R stimulation suppresses intracellular Ca(2+) overload through IP3Rs and RyRs. These mechanisms likely underlie in part the anti-hypertrophic and cardioprotective action of the σ1R agonists including fluvoxamine.

Biol Psychiatry. 2007 Oct 15;62(8):878-83. Epub 2007 Jul 30.
High occupancy of sigma-1 receptors in the human brain after single oral administration of fluvoxamine: a positron emission tomography study using [11C]SA4503.
Ishikawa M1, Ishiwata K, Ishii K, Kimura Y, Sakata M, Naganawa M, Oda K, Miyatake R, Fujisaki M, Shimizu E, Shirayama Y, Iyo M, Hashimoto K.
Author information
Abstract

BACKGROUND:
Sigma-1 receptors might be implicated in the pathophysiology of psychiatric diseases, as well as in the mechanisms of action of some selective serotonin reuptake inhibitors (SSRIs). Among the several SSRIs, fluvoxamine has the highest affinity for sigma-1 receptors (Ki = 36 nM), whereas paroxetine shows low affinity (Ki = 1893 nM). The present study was undertaken to examine whether fluvoxamine binds to sigma-1 receptors in living human brain.

METHODS:
A dynamic positron emission tomography (PET) data acquisition using the selective sigma-1 receptor ligand [(11)C]SA4503 was performed with arterial blood sampling to evaluate quantitatively the binding of [(11)C]SA4503 to sigma-1 receptors in 15 healthy male volunteers. Each subject had two PET scans before and after randomly receiving a single dose of either fluvoxamine (50, 100, 150, or 200 mg) or paroxetine (20 mg). The binding potential of [(11)C]SA4503 in 9 regions of the brain was calculated by a 2-tissue 3-compartment model. In addition, we examined the effects of functional polymorphisms of the sigma-1 receptor (SIGMAR1) gene on the binding potential of [(11)C]SA4503.

RESULTS:
Fluvoxamine bound to sigma-1 receptors in all brain regions in a dose-dependent manner, whereas paroxetine did not bind to sigma-1 receptors. However, there was no association between the SIGMAR1 gene polymorphism GC-241-240TT and binding potential.

CONCLUSIONS:
The study demonstrated that fluvoxamine bound to sigma-1 receptors in living human brain at therapeutic doses. These findings suggest that sigma-1 receptors may play an important role in the mechanism of action of fluvoxamine.
 

DeGenesis

Senior Member
Messages
172
Hmmm...Wikipedia says it's an SSRI.

https://en.m.wikipedia.org/wiki/Fluvoxamine

Not sure it really matters if it's not being used that way though anyway...

Yes, everyone refers to it as an SSRI because it was originally classed that way. With recent knowledge that it does not selectively inhibit the serotonin transporter, it is my own personal opinion that it is inappropriate to label it as an SSRI.

Edit: I shouldn't say originally classed that way because it is still classed that way. This is just my personal opinion.
 

DeGenesis

Senior Member
Messages
172
But back to ER stress. I agree with you about SSRIs and withdrawal syndrome. I think this goes beyond just SSRIs though. I think that any drug that uses a brute force approach, such as being a strong agonist or antagonist at a receptor will produce tolerance and a withdrawal syndrome. This at least has been my experience. Originally opioids and benzos got the brunt of the attention about withdrawal, but I think so many more drugs are getting attention now. Beta-blockers, histamine antagonists, Lyrica, these are all drugs that act strongly at one or more receptor and produce a withdrawal syndrome.
 

Ema

Senior Member
Messages
4,729
Location
Midwest USA
It probably would be a good idea to try to find the same information through a different author as he uses the word "inversely" too frequently.
So I got the original source (Flohe) and it's no help. It doesn't talk about cortisol at all - only how copper enzymes catalyse SOD.

Whatever editor allowed inverse shutdown/inversely permit to stand as written in a book, needs to be fired immediately.

So my search to better understand how cortisol affects this process continues...
 

Ema

Senior Member
Messages
4,729
Location
Midwest USA
NO, IT DOES NOT (always).



Flohe L, Beckman R, Giertz H, Loschen G (1985). "Oxygen Centered Free Radicals as Mediators of Inflammation". In Sies H. Oxidative stress. London: Orlando. p. 405. ISBN0-12-642760-7
On page 413, it says

"For unknown reasons, however, superoxide formation...also appears diminished under the influence of corticosteroids." (Nelson and Ruhmann-Wennhold, 1978).

So cortisol decreases ROS. But maybe or maybe not by stimulating SOD?

ETA: this article suggests that SOD is increased by corticosteroids. If you are a rat lung anyway...

http://m.pediatrics.aappublications.org/content/75/3/569.short
 
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mariovitali

Senior Member
Messages
1,214
@Valentijn

I managed to create a mechanism that uses NLP (Natural Language Processing) to *automatically* identify much better than before Topics of Interest.

For example we may create a query for locating mentions of HSP-70 Induction in PubMed entries :



Screen Shot 2015-09-12 at 13.14.13.png


Note that one entry is erroneously there but the amount of accuracy is between 90%-93% at the moment.

@Valentijn did you have a chance to look at the link i discussed in this post? : http://forums.phoenixrising.me/inde...e-treatment-for-cfs.37244/page-36#post-637799

Your input could be really helpful....


@all

I am waiting for the ultimate test for me which will be the change of season. Each and every year (7 of them) before i would have tinnitus episodes and various symptoms especially at the beginning of each Autumn.

If i do not get any symptoms then my recovery (or remission of symptoms) is 100% certain and i will have not even a 1% doubt (which i have now) that all is well.


@Ema

I will have to research about Alpha ketoglutarate,however i am a bit overwhelmed from the amount of work that i have to deliver at the moment :-(
 
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mariovitali

Senior Member
Messages
1,214
@Ema

This is a run for Cortisol from my software, FWIW

*********Topic : cortisol ***************
cortisol_levels.csv : 86.66 %
cortisol.csv : 63.80 %
hpa_axis.csv : 41.04 %
adrenal_hyperplasia.csv : 14.72 %
steroidogenesis_human.csv : 14.44 %
adrenal_insufficiency.csv : 14.24 %
hydroxysteroid_dehydrogenase.csv : 14.15 %
pregnenolone.csv : 8.03 %
p450scc.csv : 7.67 %
star.csv : 6.90 %
3betahsd.csv : 6.21 %
testosterone_production.csv : 6.21 %
triiodothyronine_levels.csv : 6.14 %
norepinephrine.csv : 5.62 %
hgh.csv : 5.42 %
dihydroprogesterone.csv : 4.77 %
freet3.csv : 3.71 %
allopregnanolone.csv : 3.52 %
serotonin_levels.csv : 3.20 %
cfs.csv : 2.70 %
dht.csv : 2.49 %
creatine_supplementation.csv : 2.44 %
5alphareductase.csv : 2.05 %
panic_disorder.csv : 1.83 %
cyp3a4.csv : 1.81 %
l_tryptophan.csv : 1.63 %
insulin_resistance.csv : 1.60 %
subclinicalhypo.csv : 1.49 %
social_anxiety.csv : 1.46 %
5-htp.csv : 1.43 %
p450oxidoreductase.csv : 1.22 %
angiotensin_human.csv : 1.13 %
anhedonia.csv : 1.12 %
limbic_system.csv : 0.92 %
caloric_restriction.csv : 0.92 %
insomnia.csv : 0.84 %
nad.csv : 0.73 %
dopamine.csv : 0.71 %
immune_response.csv : 0.67 %
finasteride.csv : 0.66 %
gaba_human.csv : 0.65 %
irritable_bowel.csv : 0.60 %
pyruvate_carboxylase.csv : 0.60 %
inflammatory_response.csv : 0.57 %
mucuna.csv : 0.55 %
il_10.csv : 0.55 %
adrenergic_receptor.csv : 0.50 %
cyp1a2.csv : 0.47 %
monoamine_oxidase.csv : 0.46 %
zinc_supplementation.csv : 0.45 %
cyp1a1.csv : 0.45 %
hsp70.csv : 0.44 %
oxidative_stress_markers.csv : 0.44 %
urea_cycle.csv : 0.43 %
l-dopa.csv : 0.43 %
uric_acid.csv : 0.42 %
pbmc.csv : 0.42 %
fmo3.csv : 0.40 %
steatohepatitis.csv : 0.40 %
pxr.csv : 0.38 %
dysautonomia.csv : 0.37 %
cyp2d6.csv : 0.37 %
acetylcholine.csv : 0.35 %
vitamin_d3.csv : 0.34 %
calcium_homeostasis.csv : 0.33 %
baroreceptor.csv : 0.33 %
cyp2e1.csv : 0.33 %
adhd.csv : 0.32 %
cimetidine.csv : 0.31 %
autism.csv : 0.31 %
orthostatic_intolerance.csv : 0.31 %
osmolytes.csv : 0.29 %
hmgcoa.csv : 0.28 %
bradycardia.csv : 0.26 %
phosphatidylcholine.csv : 0.26 %
udpgluc.csv : 0.26 %
ppp.csv : 0.26 %
acetyl_coa_carboxylase.csv : 0.25 %
l_tyrosine.csv : 0.25 %
hepatocytes.csv : 0.25 %
heat_shock_protein.csv : 0.24 %
omega3.csv : 0.23 %
protease_inhibitor.csv : 0.23 %
endothelial_nos.csv : 0.22 %
asymmetric_dimethylarginine.csv : 0.22 %
cyp1b1.csv : 0.21 %
pgc1.csv : 0.21 %
mcp-1.csv : 0.21 %
taurine.csv : 0.21 %
beta-alanine.csv : 0.21 %
ginkgo.csv : 0.20 %
car.csv : 0.19 %
reduced_glutathione.csv : 0.19 %
selenium.csv : 0.19 %
human_semen.csv : 0.19 %
butyrate.csv : 0.19 %
nlinkedglycosylation.csv : 0.18 %
sirt3.csv : 0.18 %
sod2.csv : 0.18 %
tau.csv : 0.18 %
nafld.csv : 0.18 %
phospholipid_human.csv : 0.17 %
crohns_disease.csv : 0.17 %
inositol.csv : 0.17 %
glutamate.csv : 0.16 %
amyloid.csv : 0.16 %
mast_cell_activation.csv : 0.16 %
ngf.csv : 0.16 %
tetrahydrobiopterin.csv : 0.15 %
monosodium_glutamate.csv : 0.15 %
cholestasis.csv : 0.14 %
xbp1.csv : 0.14 %
l_carnitine.csv : 0.14 %
mitochondrial_dysfunction.csv : 0.14 %
chop.csv : 0.13 %
ckd.csv : 0.13 %
constipation.csv : 0.13 %
tinnitus.csv : 0.12 %
resveratrol.csv : 0.12 %
microbiome_humans.csv : 0.12 %
nmda.csv : 0.12 %
glycoproteins.csv : 0.12 %
probiotics.csv : 0.11 %
l-arginine.csv : 0.11 %
ire1.csv : 0.11 %
redox_homeostasis.csv : 0.11 %
oxidative_stress_protection.csv : 0.11 %
sinusitis.csv : 0.11 %
hepatotoxicity.csv : 0.11 %
isotretinoin.csv : 0.11 %
xanthine_oxidase.csv : 0.11 %
nadh_dehydrogenase.csv : 0.10 %
er_stress.csv : 0.10 %
glycosylation.csv : 0.10 %
mastocytosis.csv : 0.10 %
cox-2.csv : 0.09 %
magnesium_deficiency.csv : 0.09 %
vitamin_k2.csv : 0.09 %
hexosamine.csv : 0.09 %
human_proteinuria.csv : 0.09 %
ebv.csv : 0.09 %
chaperones.csv : 0.09 %
redox_regulation.csv : 0.09 %
iron_deficiency.csv : 0.09 %
acetyl-coa.csv : 0.09 %
biotin.csv : 0.09 %
nadph_oxidase.csv : 0.08 %
vitamin_b6.csv : 0.08 %
atf4.csv : 0.08 %
sirt1.csv : 0.08 %
gtp_cyclohydrolase.csv : 0.08 %
fad.csv : 0.08 %
stat1.csv : 0.08 %
systemic_amyloidosis.csv : 0.07 %
lipoic_acid.csv : 0.07 %
scfa.csv : 0.07 %
nrf2.csv : 0.07 %
trpv.csv : 0.07 %
perk.csv : 0.07 %
excitotoxicity.csv : 0.07 %
ros.csv : 0.07 %
glutaredoxin.csv : 0.07 %
microglia.csv : 0.07 %
gluten.csv : 0.06 %
inducible_nos.csv : 0.06 %
insp3.csv : 0.06 %
rxr.csv : 0.06 %
upr.csv : 0.06 %
vcam-1.csv : 0.06 %
curcumin.csv : 0.06 %
dolichol.csv : 0.06 %
peroxiredoxin.csv : 0.06 %
nac.csv : 0.06 %
p5p.csv : 0.05 %
thioredoxin.csv : 0.05 %
selenium_deficiency.csv : 0.05 %
oxalates.csv : 0.05 %
pdi.csv : 0.05 %
riboflavin.csv : 0.05 %
ampa.csv : 0.04 %
phenylketonuria.csv : 0.04 %
kainate.csv : 0.04 %
choline_deficiency.csv : 0.04 %
mthfr.csv : 0.04 %
redox_potential.csv : 0.04 %
caspase_human.csv : 0.04 %
coenzymeq10.csv : 0.04 %
histone_deacetylase.csv : 0.03 %
amyloidosis.csv : 0.03 %
advanced_glycation_end.csv : 0.03 %
fmn.csv : 0.03 %
sshl.csv : 0.03 %
hmgb1.csv : 0.03 %
p53.csv : 0.03 %
rar.csv : 0.03 %
n-acetylglucosamine.csv : 0.02 %
atrial_fibrillation.csv : 0.02 %
sod1.csv : 0.02 %
neurite_outgrowth.csv : 0.02 %
rituximab.csv : 0.02 %
misfolded_proteins.csv : 0.02 %
peroxynitrite.csv : 0.01 %
disulfide_bonds.csv : 0.01 %
 
Messages
15,786
I managed to create a mechanism that uses NLP (Natural Language Processing) to *automatically* identify much better than before Topics of Interest.
It does seem like it could be a useful mechanism. But my (limited) perception is that it runs into much of the same problems as seen with gene maps: 1) everything is ultimately connected to everything else, and 2) there's an inherent bias in that some areas have been researched more and therefore will be weighted more heavily.

So that sort of networking makes for a relatively easy potential starting point, but then where do you go from there?

@Valentijn did you have a chance to look at the link i discussed in this post? : http://forums.phoenixrising.me/inde...e-treatment-for-cfs.37244/page-36#post-637799

Your input could be really helpful....
I skimmed over it, but it's a little too abstract for me. Where does it take us?
 

mariovitali

Senior Member
Messages
1,214
It does seem like it could be a useful mechanism. But my (limited) perception is that it runs into much of the same problems as seen with gene maps: 1) everything is ultimately connected to everything else, and 2) there's an inherent bias in that some areas have been researched more and therefore will be weighted more heavily.

So that sort of networking makes for a relatively easy potential starting point, but then where do you go from there?

There are tools that can find potentially interesting hypotheses and associations. Biograph is one of them, do you know it?



Screen Shot 2015-09-12 at 14.44.14.png



So this graph shows the potential relationship of HSPA4 (Gene) with Protein Folding (Function).


Here is the relationship between redox homeostasis and Glutathione metabolism pathway :



Screen Shot 2015-09-12 at 14.46.58.png



I skimmed over it, but it's a little too abstract for me. Where does it take us?


I think it may be useful to find out more about the interaction between ER Stress and Redox functions. It *may* be very important for us given the fact that i have a lot of hits about redox_homeostasis (after @ppodhajski suggestions) in my software (unlike other Topics). Does that prove anything? No it doesn't... but then again this doesn't mean that we shouldn't look at this area, (namely ER Stress - Redox homeostasis / signalling), right?
 
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JaimeS

Senior Member
Messages
3,408
Location
Silicon Valley, CA
I know that someone mentioned this at some point, but I admit I don't have the wherewithal to search the 39 pages of responses so far! Can anyone recommend a brand for TUDCA? All of the stuff I can find is from bodybuilding companies, and is not therefore from a brand I recognize as being of high quality, or have tried in the past.

-J
 

mariovitali

Senior Member
Messages
1,214
@JaimeS

I would recommend the following brands :

http://www.amazon.com/Premium-Powders-TUDCA-Tauroursodeoxycholic-Capsules/dp/B00CFOQAWQ/ref=sr_1_1?ie=UTF8&qid=1442066408&sr=8-1&keywords=tudca

http://www.amazon.com/Olympus-Labs-...?ie=UTF8&qid=1442066408&sr=8-2&keywords=tudca


-Premium Powders was the best i think. Olympus Labs (the TUDCA i am using now) is a BodyBuilding company but they seem to have on their product the Good Manufacturing Practice sign, if that says anything.


I am not so sure about a company named "Gunshow supplements" :

http://www.amazon.com/Clear-Professional-N-acetyl-Cysteine-Capsules/dp/B00GPONVD8
 

JaimeS

Senior Member
Messages
3,408
Location
Silicon Valley, CA

With the tagline, "Turning Men Into Demigods". :confused:

You can see why I was a little hesitant to pick a random brand! They all use uber-masculine packaging and marketing which makes me think of people who market steroid-like supplements promising the perfect body with no side effects. I am not kidding when I say that every brand I looked at had a pitch-black label with maybe a little matte, a little shiny bits to draw attention to its Manliness. All the advertisers are drawing from the same graphic design playbook methinks. :)

But if that brand works for you, then I guess they can use a sparkly pink unicorn or a monster truck; it really doesn't matter!

(Oh, and thanks, @mariovitali ! LOL)
 
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