Ulcerative Colitis / IBD

[HerrFisch]

Re: Mitochondrial problems.

https://link.springer.com/article/10.1007/s00210-014-0985-1

"Clinical trials indicated that in patients with UC, 4-week treatment with 5-ASA (2.4 g/day) plus N-acetyl-l-cysteine (0.8 g/day) not only improved clinical response but also correlated with decreased blood TNF-α, IL-6 and IL-8 concentration, as well as improved GSH content "


"Sulfasalazine is a potent cysteine transporter inhibitor composed of 5-aminosalicylic acid and sulfapyridine that has been routinely used in the clinical therapy of IBD "

@mattyb
Why does Sulfasalazine block the cysteine transporter but on the other hand NAC helps?


Thats what Im hoping for :
"It is likely that, in the near future, combination of currently used pharmaceutics with natural and synthetic potent anti-oxidative compounds, like lipoic acid or curcumine, will become a strategy of choice in IBD treatment."</r>

 

[mattyb]

Re: Mitochondrial problems.

<t>Sulfasalazine blocks the cystine-glutamate antiporter, which exchanges intracellular glutamate for extracellular cystine. Keep in mind, it's cystine (not cysteine), which is the oxidized dimer of cysteine - so it's a bit different. Cysteine is required for GSH synthesis, which is likely why inhibiting cystine importing doesn't affect GSH synthesis. My guess is that part of it's beneficial effect is that it inhibits the efflux of glutamate from cells, which is cytotoxic and inflammatory in high doses. It also sounds like, from the paper that you linked, that one of it's metabolites (Mesalazine) also directly inhibits formation of O2/H202, also acting as an antioxidant.<br/>
<br/>
The NAC helps for obvious reasons, because it's an anti-oxidant and reduces oxidative damage.<br/>
<br/>
In combo therapy, both of these would neutralize ROS, thereby relieving pressure on GSH, allowing GSH levels to restore to high resting levels.</t>

 

[HerrFisch]

Re: Mitochondrial problems.

<r><MENTION><s>[mention]</s>mattyb<e>[/mention]</e></MENTION> <br/>
Thank you !<br/>
<br/>
Do you have any good book suggestions for me ?<br/>
<br/>
And again one article about Butyrate. <br/>
<URL url="https://www.nature.com/articles/ncomms13419">https://www.nature.com/articles/ncomms13419</URL></r>

 

[HerrFisch]

Re: Mitochondrial problems.

<r>Im sick of my shitty problems.<br/>
<br/>
UC flare got better but is still there. <br/>
With help from cysteine all blood is gone. But still "fast" metabolism I guess. But slowly dissapearing flare. <br/>
<br/>
I actually like beeing in a flare more than being in remission. <br/>
And my old "urgency" problems starting to come back <E</E>. In flare those were gone and normal UC flare symptoms were present which are endurable though.<br/>
<br/>
I think while flaring, copper excretion did not work as well as I thought.<br/>
Maybe because bile is missing. Or it needs more time.<br/>
<br/>
Dont really know if its the best time now to start a fast.</r>

 

[HerrFisch]

Re: Mitochondrial problems.

<r><MENTION><s>[mention]</s>gbolduev<e>[/mention]</e></MENTION> Do you know if that high copper from my hair test could lead to my urgency symptoms?<br/>
<br/>
Maybe from bile+copper which leads to irritated gut?</r>

 

[mattyb]

Re: Mitochondrial problems.

<t>I imagine the urgency will stop once the fast is ongoing for a while. You can't have urgency if there is nothing to let go, right?</t>

 

[HerrFisch]

Re: Mitochondrial problems.

https://hackstasis.com/forums/-/list

"Since butyrate is a SCFA and an HDAC inhibitor, it could rescue the GF defects by acting either as an energy source or epigenetic factor. To distinguish between these two possible mechanisms, we repeated the butyrate rescue experiments but added a compound that blocks fatty-acid oxidation. This pharmacological inhibitor, etomoxir, prevents butyrate from increasing oxidative phosphorylation in mitotracker experiments. It also prevents butyrate from suppressing autophagy in GF colonocytes (Figure 5E).

The data presented above demonstrate that butyrate maintains energy homeostasis and prevents autophagy by acting as an energy source rather than as an HDAC inhibitor. To provide additional support for this mechanism, we performed mitotracker experiments with three molecules with defined actions similar to butyrate. Propionate is a SCFA that enters the TCA cycle through succinyl-CoA to function as an energy source and an HDAC inhibitor.
In contrast, palmitate is a long-chain fatty acid (LCFA) that enters the TCA cycle as acetyl-CoA and only functions as an energy source, whereas trichostatin A (TSA) only functions as an HDAC inhibitor. Consistent with the data presented above, propionate and palmitate stimulate mitochondrial respiration while TSA has no effect."

I think I slowly understand why palmitiate helped me. And I think researching some more towards Butyrate could get interesting.
<

https://hackstasis.com/forums/-/list

https://hackstasis.com/forums/-/list
https://hackstasis.com/forums/-/list

 

[HerrFisch]

Re: Mitochondrial problems.

<r><QUOTE author="mattyb" post_id="2444" time="1508766813" user_id="95"><s>

</s>
Hey sorry, forgot to reply to your earlier post. <br/>
<br/>
But yes, excessive mitochondrial fission can be caused by mitochondrial defects. I think that is the case more often in degenerative diseases of aging like Parkinson's and Alzheimer's. As we age defects are much more likely to pop up in the respiratory chain.<br/>
<br/>
I think in the case of autoimmune conditions developed in younger years, it's much more likely that certain stressors (radiation, metals, etc.) stimulates mitochondria to create excess ATP and ROS, and this sets off a signalling cascade that enhances mitochondrial fission, which further enhances ROS generation, and eventually causes mitochondrial defects (I also think the nutrient demand raises at this point, and a lack of nutrients could lead to defects as well). Then this further enhances ROS, and you have this vicious cycle going on and on indefinitely.<br/>
<br/>
I have started mapping some pathways for how things like ionizing radiation can directly stimulate mitochondrial fission. I think ionizing radiation can alter disulfide bond formation in protein structure and this may be a signal to the mitochondria to begin fission. We know that ionizing radiation can create disulfide radicals and break disulfide bonds, and disulfide bonds are extremely common in the inner mitochondrial membrane. The primary mitochondrial transport protein's (TIM23) function is reliant on a disulfide bond. The endoplasmic reticulum, which also controls mitochondrial fission, is literally lined with mostly oxidized thiol groups and it's primary function is in disulfide bond function - and we know the ER stress response is activated in response to things like ionizing radiation. I don't think the exact mechanism has been figured out by anyone yet, so I am trying to figure it out.<br/>
<br/>
I do think excess copper could definitely make things worse, along with many other heavy metals. Things like lead, iron, copper, tin, aluminum, etc. are all reactive and can enhance ROS function. I think if toxicity is quite high and chronic it could possibly be an inciting event, especially when coupled with environmental radiation exposure (solar flares, x-rays, etc.).
<e>

</e></QUOTE>

My big question right now is, what keeps ulcererative colitis from disappearing with getting in remission?</r>

 

[mattyb]

Re: Mitochondrial problems.

<r><QUOTE author="HerrFisch" post_id="3747" time="1510159490" user_id="114"><s>

</s>
<br/>
My big question right now is, what keeps ulcererative colitis from disappearing after getting in remission?
<e>

</e></QUOTE>

On-going damage, upregulating metabolic rate before things are healed, etc. It's why people go in and out of remission fairly quickly. You rarely hear stories about someone being in remission for 20 years and then getting a flare up out of nowhere. <br/>
<br/>
It's mostly because the tissue hasn't had enough time to heal and restore itself before the next insult comes, healing takes a long time. And remember, the insults can be nearly invisible. Things like geomagnetic storms can cause it - you would never be able to detect that on a somatic level.</r>

 

[HerrFisch]

Re: Mitochondrial problems.

Update: 2 Days of 30g Inulin stopped my flare to 0. WTF

I researched lots about Butyrate, gut microbiome, bifidobacteria, hydrogen peroxide ...<br/>
<br/>
In UC Butyrate production is 80% reduced. And Hydrogene peroxide production is way to high. <br/>
Hydrogen peroxide destroys bacteria cells.(desinfectant) Therefore lowering the homeostasis in gut bacteria /butyrate production.<br/>
<br/>
Hydrogen peroxide gets produced as a defensive mechanism of mitochondria within phagocytes. (ROS) <br/>

What if:

Start: Metabolism gets higher therefore more ROS produced. Body is not able to handle ROS. Hydrogen Peroxide destroys butyrate producing bacteria. Without butyrates for energy, colon cells undergo autophagy. Mitochondrial fission increases. More ROS is produced. -> back to start

Facts on Butyrate and Butyrate producing bacteria:
-Butyrate is a major metabolite in colonic lumen arising from bacterial fermentation of dietary fiber and has been shown to be a critical mediator of the colonic inflammatory response.<br/>
-produce vitamins, antioxidants, polyphenols, and conjugated linoleic acids
-preservation of gut barrier functions
-protection against pathogens by producing bacteriocins
-resistance to oxidative stress
-inhibition of nuclear factor κB
-regulating IL-1b, TNF-α, IL-2, IL-6, IL-8, IL-12, iNOS, COX-2 (Basically everything UC medications trying to block)

In order to test whether the thiolase enzyme could have been modified by reactive oxygen species, the biopsy homogenates were treated with 0.3 mM β‐mercaptoethanol, a reductant. This resulted in full recovery of mitochondrial acetoacetyl CoA thiolase to levels seen in control biopsies . In contrast, β‐mercaptoethanol had no significant effect on mitochondrial acetoacetyl CoA thiolase activity in mucosal homogenates from control patients. This suggests that the reduced mitochondrial acetoacetyl CoA thiolase activity in ulcerative colitis involves reversible oxidative modification of critical sulphydryl residues on the protein."

-> ROS decrease butyrate

Ulcerative colitis is characterised by evidence of oxidant injury to the colonic mucosa as well as a depletion of mucosal antioxidant defences.H2O2 is an oxidant that is continuously produced in cells, and 90% of this is produced by mitochondria as a toxic by‐product of electron transport chain activity. Our studies showed that low concentrations of exogenously added H2O2 were able to modulate mitochondrial acetoacetyl CoA thiolase activity. As expected, there was an increase in H2O2 formation in both inflamed and non‐inflamed biopsy specimens from patients with ulcerative colitis. We speculate that increased generation of reactive oxygen species may occur in the mitochondria of colonic epithelial cells in ulcerative colitis and lead to oxidative modification of several cysteine residues at or near the active site of the enzyme, which is located in the mitochondria in very close proximity to the electron transport chain. This explanation would imply that an increased generation of oxygen free radicals (possibly H2O2) in mitochondria occurs in ulcerative colitis epithelial cells even in quiescent disease and that it also occurs in the apparently normal mucosa of left‐sided ulcerative colitis patients.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2095666/

Limited evidence from pre-clinical studies shows that oxidative stress in the colonic mucosa can be modulated by butyrate. Oxidative stress is involved in both inflammation and the process of initiation and progression of carcinogenesis. During oxidative stress there is an imbalance between the generation of reactive oxygen species (ROS) and the antioxidant defense mechanisms, leading to a cascade of reactions in which lipids, proteins, and/or DNA may get damaged. In healthy humans, it has been demonstrated that locally administered butyrate in physiological concentrations increased the antioxidant GSH and possibly decreased ROS production, as indicated by a decreased uric acid production. As the human colon is continuously exposed to a variety of toxic stimuli, enhanced butyrate production in the colon could result in an enhanced resistance against toxic stimuli, thus improving the barrier function.

https://hackstasis.com/forums/-/list

I think Butyrate and butyrate producing bacteria are the missing factor in UC to heal the colon after a flare up. And I think that Butyrate keeps people from getting rid of UC.

Inhibition of butyrate oxidation in experimental animals resulted in mucosal inflammation similar to ulcerative colitis."LOL

 

[mattyb]

Re: Mitochondrial problems.

<t>I think all of that makes really good sense. This is why during the post-fast refeed (when the flare up is gone) it is important to reintroduce full fat dairy (provides butyrate on it's own) and a diverse set of vegetables that provide a wide range of digestible fibers. The latter will provide nutrients to establish a diverse population of gut bacteria.</t>

 

[HerrFisch]

Re: Mitochondrial problems.

<r><MENTION><s>[mention]</s>mattyb<e>[/mention]</e></MENTION> <br/>
<br/>
Where do you see similaritys or differences between UC and Crohns? <br/>
<br/>
How would you describe Crohns with Mitochondrial fission etc ?</r>

 

[mattyb]

Re: Mitochondrial problems.

<r><QUOTE author="HerrFisch" post_id="4022" time="1510440404" user_id="114"><s>

</s>
@mattyb <br/>
<br/>
Where do you see similaritys or differences between UC and Crohns? <br/>
<br/>
How would you describe Crohns with Mitochondrial fission etc ?
<e>

</e></QUOTE>

Crohn's is just more systemic, more severe. UC is much more specific to the lining of the colon. At a deep cellular mechanistic level I think they are very similar.</r>

 

[HerrFisch]

Re: Mitochondrial problems.

<r><QUOTE author="gbolduev" post_id="4158" time="1510655134" user_id="90"><s>

</s>
Magnesium will increase cortisol by putting potassium in the cell. It is the opposite of what Morley Robbins claims.And this actually will cause grey hair since this will put too much pressure on Iron.<br/>
<br/>
Look at Morley Robbins, Rick Malter. They all look the same. Very grey hair.And definetely not fast metabolism. Fat with big stomachs. their catalase enzyme does not work properly. Since iron won't work without its cofactors. And ceruloplasmin is just one of them. Another one is PH dependant ALDH, and AO. which is b2 and molybdenum , plus NAD dependant. this enzyme is highly PH dependant. And it is the main problem. <br/>
<br/>
Zinc converts ethanol to acetaldehyde which is broken down by these enzymes. thus zinc sometimes can cause lower iron bioavailability. And thus body is losing zinc to protect these enzymes in case of acetaldehyde overload. This creates low zinc environment and causes cancer. Zinc is needed to raise ceruloplasmin. But it only does that with b2 and molybdenum present.<br/>
Thus all these people could not get rid of their grey hair and actually created more oxidative stress to their bodies/<br/>
<br/>
Putting more copper in the cell, by artificially raising ceruloplasmin will increase SOD enzyme. this will increase hypoxia for once and also this will increase SOD enzyme which has hydrogen peroxide as a end product. To neutralize this peroxide you need catalase.( iron based enzyme)<br/>
<br/>
If anyone claims that they balanced their oxidation. always look at their hair. If grey. just forget anything that they are saying. Since their oxidation is def not balanced.
<e>

</e></QUOTE>

In ulcerative colitis there is way to much hydrogen peroxide in the colon. Does that mean, that the body increases copper in the cell to increase SOD / ceruloplasmin to fight the hydrogen peroxide? Could that be the cause for extreme excess copper in my hair test?</r>

 

[Nighteyes]

Re: Ulcerative Colitis / IBD (formerly mitocondrial problems)

<r>Very interesting thread this one! I am still a little confused about lactic acidosis and respiratory alkalosis. I know you will probably explain these concepts in greater detail in your new thread about acids and bases <MENTION><s>[mention]</s>mattyb<e>[/mention]</e></MENTION> but maybe you can still help me with this: Why would running and exercise help lower lactate overall since you would be ventilating faster (hyperventilating). This faster breathing would further increase respiratory alkalosis right? I have the same high copper on my hair results and also high lactate so quite curious about ways to lower lactic acidosis. This would not help minerals (such as copper) become better available in the blood right? <E></E></r>

 

[mattyb]

Re: Ulcerative Colitis / IBD (formerly mitocondrial problems)

<r><QUOTE author="Nighteyes" post_id="4267" time="1510783055" user_id="93"><s>

</s>
Very interesting thread this one! I am still a little confused about lactic acidosis and respiratory alkalosis. I know you will probably explain these concepts in greater detail in your new thread about acids and bases @mattyb but maybe you can still help me with this: Why would running and exercise help lower lactate overall since you would be ventilating faster (hyperventilating). This faster breathing would further increase respiratory alkalosis right? I have the same high copper on my hair results and also high lactate so quite curious about ways to lower lactic acidosis. This would not help minerals (such as copper) become better available in the blood right? <E></E>
<e>

</e></QUOTE>

Exercise entrains the body to better metabolize lactate. One major site of lactate clearance is the heart, so with enhanced cardiac function you can improve lactate metabolism. <br/>
<br/>
Consistent training also decreases lactate concentrations because the body becomes much more efficient at metabolizing oxygen, decreasing the need for lactate altogether. Without pressure from lactic acidosis, there is no need for persistent respiratory compensation (alkalosis). Yes, acutely during exercise there is an increase in ventilation, but that's only because the body becomes very acidic from the increased CO2 and lactate load.<br/>
<br/>
The more in shape you are, the less likely you are to even produce lactate in the first place. Anaerobic threshold is always delayed in well trained people. They simply don't produce as much lactate.<br/>
<br/>
The adaptations from the activity are much more important than the acute and temporary effects. Notice how out of shape people are sucking wind after jogging for 5 minutes, but some athletes can run for hours with a consistent breathing rate? Those athletes get really efficient with oxygen.</r>

 

[dante]

"With help from cysteine all blood is gone"
It's also very interesting that sulfur containing compounds/amino acids are good copper binding/chelating agents too. For example, zinc induced metallothionein is a very good copper binding agent(as well as cadmium too) and can act as an reservoir in case of deficiency. Similarly, penicillamine , a known copper chelator , has sulfur in it and it binds copper with sulfhydryl groups and this complex is subsequently removed from the organism via the urine.

 

[Helen]

This is what you get when you eat Ray Peat, I had so many people with this high copper on ray peat. People have problems with glutathione . You eat copper you increase SOD. you increase antioxidants in hypoxia. Sod's end product is hydrogen peroxide. Copper will cause SIBO. This is not good. as a slow oxidizer you need to exercise. And improve your methylation and redox.

If you this toxic in copper, you might need to take zinc carnosine for a little bit. Or zinc manganese with plenty of b2.

Slow oxidizers are low on B2. This causes high lactate. If ventilation is increased they are lucky. Some have already failed sympathetic nervous system and not able to increase the ventilation. And this causes complete potassium waste from the cell and CFS

I would take magnesium potassium ,b2, b1 zinc carnosine. manganese. and molybdenum. And may be add some methylation with thorne extra and taurine. if you are a woman could add some iron

Also do liver flushes.

 

[HerrFisch]

Im taking 50mg of zinc gluconate with 15mg manganese gluconate right now. My Hair (HTA) said 150mg of zinc daily + 75mg manganese. But I thought its a bit over the top.

 

[Helen]

Im taking 50mg of zinc gluconate with 15mg manganese gluconate right now. My Hair (HTA) said 150mg of zinc daily + 75mg manganese. But I thought its a bit over the top.

zinc CARNOSINE much faster will take care of free copper.much faster

You can just add l- carnosine.. Carnosine will chelate brain and liver copper very fast.