Unfolded Protein Response and A Possible Treatment for CFS

mariovitali

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FYI @Gondwanaland

Oxalate consumption leads to increased Uric Acid. Regarding Uric acid :



Uric acid induces fat accumulation via generation of endoplasmic reticulum stress and SREBP-1c activation in hepatocytes.
Choi YJ1, Shin HS1, Choi HS1, Park JW2, Jo I3, Oh ES4, Lee KY5, Lee BH5, Johnson RJ6, Kang DH1.
Author information

Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently one of the most common types of chronic liver injury. Elevated serum uric acid is a strong predictor of the development of fatty liver as well as metabolic syndrome. Here we demonstrate that uric acid induces triglyceride accumulation by SREBP-1c activation via induction of endoplasmic reticulum (ER) stress in hepatocytes. Uric acid-induced ER stress resulted in an increase of glucose-regulated protein (GRP78/94), splicing of the X-box-binding protein-1 (XBP-1), the phosphorylation of protein kinase RNA-like ER kinase (PERK), and eukaryotic translation initiation factor-2α (eIF-2α) in cultured hepatocytes. Uric acid promoted hepatic lipogenesis through overexpression of the lipogenic enzyme, acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD1) via activation of SREBP-1c, which was blocked by probenecid, an organic anion transport blocker in HepG2 cells and primary hepatocytes. A blocker of ER stress, tauroursodeoxycholic acid (TUDCA), and an inhibitor of SREBP-1c, metformin, blocked hepatic fat accumulation, suggesting that uric acidpromoted fat synthesis in hepatocytes via ER stress-induced activation of SREBP-1c. Uric acid-induced activation of NADPH oxidase preceded ER stress, which further induced mitochondrial ROS production in hepatocytes. These studies provide new insights into the mechanisms by which uricacid stimulates fat accumulation in the liver.
 

mariovitali

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So i finished another round of analysis. Here are the most frequently matched PubMed Topics :


Screen Shot 2015-09-08 at 9.08.06.png



NAC is a new entry which appears towards the top of list. Notice also redox_homeostasis. So i ran a special analysis to identify the elements that match along with the redox_homeostasis Topic :



Screen Shot 2015-09-08 at 9.07.32.png


Look how fads1, fads2, omega3, thioredoxin reductase, riboflavin and iron_deficiency are part of the matchings.

PBMC = Peripheral Blood Mononuclear Cell
SSHL = Sensorineural Hearing Loss

from Wikipedia :


A peripheral blood mononuclear cell (PBMC) is any blood cell having a round nucleus (as opposed to a lobed nucleus).[1] For example: a lymphocyte, a monocyte or a macrophage. These blood cells are a critical component in the immune system to fight infection and adapt to intruders. The lymphocyte population consists of T cells (CD4 and CD8 positive ~75%), B cells and NK cells (~25% combined).

These cells can be extracted from whole blood using ficoll, a hydrophilic polysaccharide that separates layers of blood, and gradient centrifugation,[2] which will separate the blood into a top layer of plasma, followed by a layer of PBMCs and a bottom fraction of polymorphonuclear cells (such as neutrophils and eosinophils) and erythrocytes. The polymorphonuclear cells can be further isolated by lysing the red blood cells. Basophils are sometimes found in both the denser and the PBMC fractions.[2]

PBMCs are widely used in research and clinical applications.
 

Ema

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I drank a lot of Kangen water a few years ago. It didn't have any effect on me personally. I'm not sure alkaline water can do all the magical things they advertise.
 

DeGenesis

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Fluvoxamine is very effective at inhibiting ER stress. It does so by strongly activating the sigma-1 receptor, which is completely independent of its activity as an SRI.

I will link some studies when I am over my current bout of eyestrain.
 

Violeta

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I am very interested on this subject. Is it high serotonin? Low serotonin? High amines?Low amines? Ammonia? H2O2? Definetly ROS...
Here's something from the list of side effects of fluvoxamine. It might be a side effect.
  • Some people may be at risk for eye problems from fluvoxamine. Your doctor may want you to have an eye exam to see if you are at risk for these eye problems. Call your doctor right away if you have eye pain, vision changes, or swelling or redness in or around the eye.
 

Ema

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I would make sure you aren't one of the 2/3rds of MECFS patients with antibodies to serotonin before taking an SSRI...is there anything else that activates that receptor without so many side effects and a withdrawal syndrome?
 

mariovitali

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@all

I feel that this is very important. It blends redox homeostasis and chaperones :


The redox switch that regulates molecular chaperones.
Conway ME, Lee C.
Abstract
Modification of reactive cysteine residues plays an integral role in redox-regulated reactions. Oxidation of thiolate anions to sulphenic acid can result in disulphide bond formation, or overoxidation to sulphonic acid, representing reversible and irreversible endpoints of cysteine oxidation, respectively. The antioxidant systems of the cell, including the thioredoxin and glutaredoxin systems, aim to prevent these higher and irreversible oxidation states. This is important as these redox transitions have numerous roles in regulating the structure/function relationship of proteins. Proteins with redox-active switches as described for peroxiredoxin (Prx) and protein disulphide isomerase (PDI) can undergo dynamic structural rearrangement resulting in a gain of function. For Prx, transition from cysteine sulphenic acid to sulphinic acid is described as an adaptive response during increased cellular stress causing Prx to form higher molecular weight aggregates, switching its role from antioxidant to molecular chaperone. Evidence in support of PDI as a redox-regulated chaperone is also gaining impetus, where oxidation of the redox-active CXXC regions causes a structural change, exposing its hydrophobic region, facilitating polypeptide folding. In this review, we will focus on these two chaperones that are directly regulated through thiol-disulphide exchange and detail how these redox-induced switches allow for dual activity. Moreover, we will introduce a new role for a metabolic protein, the branched-chain aminotransferase, and discuss how it shares common mechanistic features with these well-documented chaperones. Together, the physiological importance of the redox regulation of these proteins under pathological conditions such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis will be discussed to illustrate the impact and importance of correct folding and chaperone-mediated activity.
 

DeGenesis

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I would make sure you aren't one of the 2/3rds of MECFS patients with antibodies to serotonin before taking an SSRI...is there anything else that activates that receptor without so many side effects and a withdrawal syndrome?
I'm not advocating anyone take an SSRI or SRI, but having said that, fluvoxamine (an SRI, it is not selective) is active at sigma-1 receptors before it significantly impacts the serotonin transporter.

Doses as low as 25 mg have been used to treat RLS, for example. An SSRI would make RLS worse, but at this dose it is only expected to be active at the sigma-1 receptor.

Yes, there is. Dextromethorphan is highly active at the sigma-1 receptor. That is the basis of the brand-name combination dextromethorphan/quinidine combination called Nuedexta, which is used to treat pseudobulbar affect. Quinidine inhibits the transformation of DXM into its active metabolite dextrophan, which is a potent NMDA antagonist and probably accounts for most of DXM's dissociative effect.

The sigma-1 receptor is also involved in laughing, coughing, sneezing and respiration.
 

DeGenesis

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Here's something from the list of side effects of fluvoxamine. It might be a side effect.
  • Some people may be at risk for eye problems from fluvoxamine. Your doctor may want you to have an eye exam to see if you are at risk for these eye problems. Call your doctor right away if you have eye pain, vision changes, or swelling or redness in or around the eye.
Drugs like fluvoxamine that inhibit the serotonin transporter or are agonists at the 5-HT2a receptor cause the pupil to dilate, which could raise intraocular pressure and worsen glaucoma. This is probably the basis for this warning.
 

DeGenesis

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I am very interested on this subject. Is it high serotonin? Low serotonin? High amines?Low amines? Ammonia? H2O2? Definetly ROS...
You are interested in the subject of eyestrain? I can only use a computer or read for a few minutes before I get eyestrain and have to stop. Bad headaches as well.

If this is about fluvoxamine, note to all that I don't take it..
 

Gondwanaland

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You are interested in the subject of eyestrain? I can only use a computer or read for a few minutes before I get eyestrain and have to stop. Bad headaches as well.
Electromagnetic Frequency caused me that when I was magnesium deficient. When I turned off the wi-fi on my computer I could then work longer on it. Also I had to replace all the cordless phones at home and workplace for older ones with cord.