The Adenosine - Phosphatidic Acid Hypothesis

Iritu1021

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Sadly, I have to inform you that I've found a critical flaw in this hypothesis. There are still many pieces to it which I would consider valuable ideas, but the whole no longer works together.

I have stated that "after activating the A1 receptors, a significant portion of this adenosine is actually brought into the cell by CNT2 transporters, and proceeds to activate AMPK. The exact mechanism by which it accomplishes that is not known, but my speculation is that it’s a different mechanism from the one AMP uses, and therefore serves as a fallback activation route in muscle exertion." - this is not fully correct. The andenosine is transported into the cells, and does activate AMPK, but the mechanism is not unknown. The adenosine turns into AMP, which activates AMPK in the usual manner. Meaning, this cannot be an alternetive, fallback activation route for AMPK in contracting skeletal muscle. Unfortunately, this is one of the very few places where an error like this means the whole hypothesis falls apart. The two halves of this hypothesis - the systemic part with the anti-beta2 antibodies, and the intracellular part, with the phospatidic acid - no longer fit together, as they were tied by this idea of adenosine constituting a fallback activation route.

This is fully my mistake, I missed an important part in one of my sources. I apologize terribly for wasting your time. The irony of working on this for half a year only to discover a critical flaw days after going public, would be funny to me if I wasn't so embarassed by this.

The above will be edited in at the beginning of the text of the hypothesis itself, and the untrue statement marked red.
Hey, no worries and no need to be embarrassed. This is what we are all here for - to brainstorm ideas off each other and to get the discussion going. Many of us here (and in science world) have invested a lot of time and effort and feelings into theories that didn't hold out in the end - but that's all part of the process. I'm sure that all the knowledge you've gained and all the connections you've made in your brain will come in handy at some point later.
Keep it up! As Thomas Edison put it: "I failed my way to success".:)
 
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EDIT 17/09/2018
Sadly, I have to inform you that I've found a critical flaw in this hypothesis.
Kudos for your intellectual approach and total transparency!

I will admit I didnt understand how the whole fitted together so I'm not grieving this like you would be, but I think there's some salvageable pieces you've highlighted, not least the ideas about ASIC and about low levels of adenosine meaning we are unable to tamp down an immune reaction to exercise.
 

Diwi9

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@necessary8 - Do not be embarrassed. Your willingness to share ideas and your ability to compile research results is huge for this community. It's not about being right, but getting to the right solution...step-by-step. Thank you so much for your contribution, I should have thanked you earlier. I look forward to how your ideas continue to evolve with new research.
 

kelly8

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Are you talking about phosphatidylcholine as an oral supplement addition or iv? I used some oral phosphatidylcholine at one point which seemed to help a bit but I wasn't just adding that at the time.
 

debored13

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Also there are quite a few of us here who feel improved with caffeine which is adenosine receptor antagonist.
I was going to bring this up, but I wasn't sure that other people had the same experience. It's not just that it gives me "energy" in the sense of most stimulants--amphetamines or methylphenidate don't help me and make me worse since being sick. It helps with all symptoms, even helps with sleep. More of a "relief" than stimulation.

It seems that xanthines are mast cell stabilizers so maybe this is part of that, although coffee has a number of effects including acetylcholinesterase inhibition (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676818/) and mitochondrial uncoupling (https://www.ncbi.nlm.nih.gov/pubmed/22710994), so it might not help directly via adenosine antagonism.
 

Iritu1021

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I was going to bring this up, but I wasn't sure that other people had the same experience. It's not just that it gives me "energy" in the sense of most stimulants--amphetamines or methylphenidate don't help me and make me worse since being sick. It helps with all symptoms, even helps with sleep. More of a "relief" than stimulation.

It seems that xanthines are mast cell stabilizers so maybe this is part of that, although coffee has a number of effects including acetylcholinesterase inhibition (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676818/) and mitochondrial uncoupling (https://www.ncbi.nlm.nih.gov/pubmed/22710994), so it might not help directly via adenosine antagonism.
Or intracellular calcium release - as we've been discussing in the other thread about T3/caffeine/intracellular Ca. Or phosphodiesterase inhibition. That's the problem - everything has at least a hundred different effects.
 

debored13

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Or intracellular calcium release - as we've been discussing in the other thread about T3/caffeine/intracellular Ca. Or phosphodiesterase inhibition. That's the problem - everything has at least a hundred different effects.
Yeah. The interesting thing is that if we ascribe any kind of unifying theory of life in terms of structure and energy, maybe the fact that drugs are "dirty" and have too many different effects can be explained... e.g. by the whole than the parts. I'm getting a little speculative here but part of this comes from the difficulty of parsing biology piece by separate piece. I'm not suggesting vulgar vitalism, but something like Szent-gyorgyi describes as a relationship between structure and energy in the living state. Maybe the multiple effects/targets of something like coffee or chaga are in concert rather than discordant.
 

JaimeS

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JaimeS

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Important!


Sadly, I have to inform you that I've found a critical flaw in this hypothesis. There are still many pieces to it which I would consider valuable ideas, but the whole no longer works together.

I have stated that "after activating the A1 receptors, a significant portion of this adenosine is actually brought into the cell by CNT2 transporters, and proceeds to activate AMPK. The exact mechanism by which it accomplishes that is not known, but my speculation is that it’s a different mechanism from the one AMP uses, and therefore serves as a fallback activation route in muscle exertion." - this is not fully correct. The adenosine is transported into the cells, and does activate AMPK, but the mechanism is not unknown. The adenosine turns into AMP, which activates AMPK in the usual manner. Meaning, this cannot be an alternative, fallback activation route for AMPK in contracting skeletal muscle. Unfortunately, this is one of the very few places where an error like this means the whole hypothesis falls apart. The two halves of this hypothesis - the systemic part with the anti-beta2 antibodies, and the intracellular part, with the phosphatidic acid - no longer fit together, as they were tied by this idea of adenosine constituting a fallback activation route.

This is fully my mistake, I missed an important part in one of my sources. I apologize terribly for wasting your time. The irony of working on this for half a year only to discover a critical flaw days after going public, would be funny to me if I wasn't so embarrassed by this.

The above will be edited in at the beginning of the text of the hypothesis itself, and the untrue statements as well as my ideas directly stemming from this misunderstanding, will be marked red.
The honest correction is what's important.
 

Iritu1021

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Yeah. The interesting thing is that if we ascribe any kind of unifying theory of life in terms of structure and energy, maybe the fact that drugs are "dirty" and have too many different effects can be explained... e.g. by the whole than the parts. I'm getting a little speculative here but part of this comes from the difficulty of parsing biology piece by separate piece. I'm not suggesting vulgar vitalism, but something like Szent-gyorgyi describes as a relationship between structure and energy in the living state. Maybe the multiple effects/targets of something like coffee or chaga are in concert rather than discordant.
That seems to be the case with marijuana since the pharmaceutical industry has been trying to bottle the active ingredient but it doesn't seem to work the same way as the whole plant.
 

debored13

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That seems to be the case with marijuana since the pharmaceutical industry has been trying to bottle the active ingredient but it doesn't seem to work the same way as the whole plant.
Yeah. Well it's true for a lot of things and it comes back to this debate about if there is a telos in substance itself, some kind of striving toward organization.
Back when I was just a casual drug user who was into pharmacology and I wasn't sick at the time, I was mystified that coca was not cardiotoxic even in heavy chewers, but cocaine is insanely cardiotoxic even used a few times. And it's not just dose at all, i'm talking people that would chew an equivalent amount of coca to doing 50 mg bumps of cocaine once an hour.