Oxidative stress???

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Oxidative stress???

Postby koneall » Mon Oct 16, 2017 8:38 am

On my laptop this morning:

"Oxidative stress is the result of an imbalance in the body of free radicals. These free radicals damage proteins, lipids and nucleic acids, which in turn causes inflammation. The inflammation results in demyelination of the central nervous system and has a bearing on how severe a patient’s multiple sclerosis is.

MORE: Nanobionic clothing seen to clear body of free radicals associated with MS and other diseases

The levels of oxidative stress can be used as a biomarker for assessing the progression of multiple sclerosis in patients.

Researching oxidative stress and its effect on MS is enabling scientists to look at therapies where reducing the amount of oxidative stress may reduce the severity of a person’s MS symptoms, slow progression and hopefully reverse the effects of demyelination.
So far, researchers have discovered that oxidative inflammation increases the frequency of relapses in patients with relapse-remitting multiple sclerosis (RRMS) and that oxidative stress can be stopped by activating the Nrf2 pathway — which is a protein found in all of the body’s cells. The Nrf2 pathway regulates defensive antioxidants and can make remyelination occur and help to reverse the effects of multiple sclerosis."

In my veterinary practice I've used ozone for the past few years. The basic theory is ozone is an oxidant. Treatments with ozone stimulate production of antioxidant enzymes. Too much ozone given IV must be countered by injections of Vitamin C, a potent antioxidant. Again, the theory being that ozone as an oxidant can stimulate antioxidant enzymes but if overwhelmed by an IV dose, Vitamin C is needed to counter the effects.

Anyone have knowledge of "the Nrf2 pathway" and its effects on MS?

kaypeeoh
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Re: Oxidative stress???

Postby NHE » Mon Oct 16, 2017 9:37 am

koneall wrote:Anyone have knowledge of "the Nrf2 pathway" and its effects on MS?

Tecfidera was initially thought to activate Nrf2. I'm not sure if this is still the current paradigm on its efficacy. You might want to read the old posts in the Tecfidera forum. tecfidera-bg-12-dimethyl-fumarate-f52/

However, there are abundant molecules that nature has already provided that function as Nrf2 activators. See the following paper for some examples...

Nrf2 as a Master Redox Switch in Turning on the Cellular Signaling Involved in the Induction of Cytoprotective Genes by Some Chemopreventive Phytochemicals
https://www.thieme-connect.com/products ... 088302.pdf

    A wide array of dietary phytochemicals have been reported to induce the expression of enzymes involved in both cellular antioxidant defenses and elimination/inactivation of electrophilic carcinogens. Induction of such cytoprotective enzymes by edible phytochemicals largely accounts for their cancer chemopreventive and chemoprotective activities. Nuclear factor-erythroid-2-related factor 2 (Nrf2) plays a crucial role in the coordinated induction of those genes encoding many stress-responsive and cytoptotective enzymes and related proteins. These include NAD(P)H:quinone oxidoreductase-1, heme oxygenase-1, glutamate cysteine ligase, glutathione S-transferase, glutathione peroxidase, thioredoxin, etc. In resting cells, Nrf2 is sequestered in the cytoplasm as an inactive complex with the repressor Kelch-like ECH-associated protein 1 (Keap1). The release of Nrf2 from its repressor is most likely to be achieved by alterations in the structure of Keap1. Keap1 contains several reactive cysteine residues that function as sensors of cellular redox changes. Oxidation or covalent modification of some of these critical cysteine thiols would stabilize Nrf2, thereby facilitating nuclear accumulation of Nrf2. After translocation into nucleus, Nrf2 forms a heterodimer with other transcription factors, such as small Maf, which in turn binds to the 5'-upstream CIS-acting regulatory sequence, termed antioxidant response elements (ARE) or electrophile response elements (EpRE), located in the promoter region of genes encoding various antioxidant and phase 2 detoxifying enzymes. Certain dietary chemopreventive agents target Keap1 by oxidizing or chemically modifying one or more of its specific cysteine thiols, thereby stabilizing Nrf2. In addition, phosphorylation of specific serine or threonine residues present in Nrf2 by upstream kinases may also facilitate the nuclear localization of Nrf2. Multiple mechanisms of Nrf2 activation by signals mediated by one or more of the upstream kinases, such as mitogen-activated protein kinases, phosphatidylionositol-3-kinase/Akt, protein kinase C, and casein kinase-2 have recently been proposed. This review highlights the cytoprotective gene expression induced by some representative dietary chemopreventive phytochemicals with the Nrf2-Keap1 system as a prime molecular target.

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Re: Oxidative stress???

Postby koneall » Tue Oct 17, 2017 7:21 am

Thanks, a neurologist sent me this article. Abstract: Oxidative stress plays a crucial role in many neurodegenerative conditions such as Alzheimer’s disease, amyotrophic lateral sclerosis and Parkinson’s as well as Huntington’s disease. Inflammation and oxidative stress are also thought to promote tissue damage in multiple sclerosis (MS). Recent data point at an important role of anti-oxidative pathways for tissue protection in chronic-progressive MS, particularly involving the transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2). Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for MS treatment. Here, fumaric acid esters (FAE) are a new, orally available treatment option which had already been tested in phase II/III MS trials demonstrating beneficial effects on relapse rates and magnetic resonance imaging markers. In vitro, application of dimethylfumarate (DMF) leads to stabilization of Nrf2, activation of Nrf2-dependent transcriptional activity and abundant synthesis of detoxifying proteins. Furthermore, application of FAE involves direct modification of the inhibitor of Nrf2, Kelch-like ECH-associated protein 1. On cellular levels, the application of FAE enhances neuronal survival and protects astrocytes against oxidative stress. Increased levels of Nrf2 are detected in the central nervous system of DMF treated mice suffering from experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In EAE, DMF ameliorates the disease course and improves preservation of myelin, axons and neurons. Finally, Nrf2 is also up-regulated in the spinal cord of autopsy specimens from untreated patients with
MS, probably as part of a naturally occurring anti-oxidative response. In summary, oxidative stress and anti-oxidative pathways are important players in MS pathophysiology and constitute a promising target for future MS therapies like FAE.
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Re: Oxidative stress???

Postby Scott1 » Tue Oct 17, 2017 12:36 pm

Hi,

What he is talking about is either Tecfidera or an alternative similar product. This is the FDA note on it- https://www.accessdata.fda.gov/drugsatf ... 063lbl.pdf

It is not completely harmless and PML has been added to the list of problems it can cause - https://www.fda.gov/Drugs/DrugSafety/ucm424625.htm

Oxidative stress refers to the breakdown of oxygen molecules as they combine with other molecules in the body. These products contain unpaired electrons which are called free radicals. They, in turn collide with our cellular mechanisms doing damage and distract our immune system from its normal response to toxins . Over time metabolic waste accumulates in the body leading to disease. Hence antioxidants like vitamins C or E, minerals like selenium or zinc can cancel out that free radical activity by offering their own electrons to pair with, and neutralise, the free radical and thus protect our cells and DNA.

I've tried Tecfidera and didn't enjoy it all. By comparison, CoQ10 has that antioxidant property and if combined with Vitamin E can "recycle oxidised Vitamin E so that it can again be available to mop up more free radicals. If you google CoQ10 and Vitamin E you will see many references to them as successful partners.

Tecfidera might be like throwing a life preserver to a drowning man and then running over him with your boat.

Fumarate is both a substrate and product in the Krebs cycle. That cycle uses carbohydrates, fats and proteins to make carbon dioxide and chemical energy as ATP. It's a 10 step cycle and to isolate fumarate as the bit that needs to be fixed is simply not proven.

There are a lot of ways to influence oxidative stress.

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Re: Oxidative stress???

Postby 1eye » Wed Oct 18, 2017 4:36 pm

Tecfidera might be like throwing a life preserver to a drowning man and then running over him with your boat.


:-) I feel like they looked back and saw my ams still moving, so they came back to run me over a few more times.
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Re: Oxidative stress???

Postby NHE » Wed Oct 18, 2017 11:26 pm

Scott1 wrote:Fumarate is both a substrate and product in the Krebs cycle. That cycle uses carbohydrates, fats and proteins to make carbon dioxide and chemical energy as ATP. It's a 10 step cycle and to isolate fumarate as the bit that needs to be fixed is simply not proven.

The fumeric acid in the Krebs cycle and the dimethyl fumerate in Tecfidera are two different chemical entities with distinct molecular structures.

Because dimethyl fumerate is the methyl ester of fumeric acid it functions as a potent oxidant against thiol groups whereas fumeric acid does not.

http://www.thisisms.com/forum/drug-pipeline-f13/topic21253.html#p201134
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Re: Oxidative stress???

Postby Scott1 » Wed Oct 18, 2017 11:47 pm

Hi

Dimethyl fumarate metabolises to monomethyl fumarate https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4623310/

Monomethyl fumarate "is metabolized through the tricarboxylic acid (TCA) (Krebs)cycle to fumarate, glucose, and CO2, with exhalation of CO2 being the primary route of elimination" https://www.medscape.com/viewarticle/821109

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