Jul 23, 2022¡edited Jul 23, 2022Liked by Moriarty
Due to the GP120 & GAG inserts I thought I would do a cross reference. Bingo!
I already considered NAD but not your kynurenine pathway, I will now need to add this to my review.
Note the doom loop you also referred to and the need to break the cycle with therapeutics.
Clinical Relevance of Kynurenine Pathway in HIV/AIDS: An Immune Checkpoint at the Crossroads of Metabolism and Inflammation
Jean-Pierre Routy et al. AIDS Rev. 2015 Apr-Jun.
Abstract
Tryptophan degradation along the kynurenine pathway is associated with a wide variety of pathophysiological processes, of which tumor tolerance and immune dysfunction in several chronic viral infections including HIV are well known. The kynurenine pathway is at the crossroads of metabolism and immunity and plays an important role in inflammation while also playing an opposing role in the control of acute and chronic infections. In this review we have summarized findings from recent studies reporting modulation of tryptophan degrading the kynurenine pathway in the context of HIV infection. This immuno-metabolic pathway is modulated by three distinct inducible enzymes: indoleamine 2,3-dioxygenase 1 and 2 and tryptophan 2,3-dioxygenase. Increased expression of these enzymes by antigen-presenting cells leads to local or systemic tryptophan depletion, resulting in a mechanism of defense against certain microorganisms. Conversely, it can also lead to immunosuppression by antigen-specific T-cell exhaustion and recruitment of T regulatory cells. Recently, among these enzymes, indoleamine 2,3-dioxygenase 1 has been recognized to be an immune response checkpoint that plays an important role in HIV immune dysfunction, even in the context of antiretroviral therapy. In addition to the activation of the kynurenine pathway by HIV proteins Tat and Nef, the tryptophan-degrading bacteria present in the intestinal flora have been associated with dysfunction of gut mucosal CD4 Th17/Th22 cells, leading to microbial translocation and creating a systemic kynurenine pathway activation cycle. This self-sustaining feedback loop has deleterious effects on disease progression and on neurocognitive impairment in HIV-infected patients. Therapy designed to break the vicious cycle of induced tryptophan degradation is warranted to revert immune exhaustion in HIV-infected persons.
Great articles highlighting and exploring this. Interesting that ME/CFS has a lot of overlap with long covid, yet some studies show reduced kynurenine to tryptophan ratio. I always try to ask if a pathway is an innocent bystander or the actual evil cause.. Maybe ME/CFS patients have absolute deficiency of kynurenine metabolites whereas in covid there's a relative deficiency leading to similar symptom pictures...ie the pathway is activated but it just can't meet demands because the NAD+/NADH ratio is so screwed in covid. Potentially, the immune suppression may be a protective mechanism and IDO also has some direct actions against viruses and bacteria. Or it may just be that the pathway was never meant to be chronically activated in the presence of long lasting or reoccuring spike. Or then again, it could be that viruses have learnt to amplify our own immune tolerance to cause suppression so they have an easier ride. IDO activation may also deplete melatonin.
The ME/CFS metabolic trap theory suggests that mutations in the IDO2 gene keep tryptophan levels high which deactivate IDO1 after a tryptophan-raising event leading to lower kynurene levels after the stressor has passed.
PLP works as antioxidant molecule by quenching oxygen reactive species (ROS) and counteracting the formation of Advanced Glycation End products (AGEs), genotoxic compounds associated with senescence and diabetes
Pyridoxal 5â˛-phosphate (PLP), the active form of vitamin B6, works as cofactor in numerous enzymatic reactions and it behaves as antioxidant molecule. PLP deficiency has been associated to many human pathologies including cancer and diabetes and the mechanism behind this connection is now becoming clearer.
Interesting hypothesis, I think this can actually be tested in a causal analysis (Mendelian randomisation), - there there are genetic instruments for IDO. Similar to here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560130/
There will be even higher powered studies available now and probably other members of the pathway.
Stupid question here but my family had covid last yr and recently I found out that I had two kidney stones which is not rare but my 23 yr old son also had kidney stone same time and while I was in er the lady in the next room also had kidney stone. Could this be related? We live in a very small town so I found it odd. Can covid damage kidneys?
So Iâm not imagining that the smell of my pee has changed since I had covid!! Long Covid sufferer here, it totally sucks. Zyrtec and nattokinase got me back on track but I relapsed when I tried interval training. Iâm like back at square one, brain fog and all.
This ties very very VERY closely to the following posts.
https://hiddencomplexity.substack.com/p/omicron-evasion-sars-cov2-and-the
https://hiddencomplexity.substack.com/p/sars-cov-2-the-brain-and-the-sugar
https://hiddencomplexity.substack.com/p/sars-cov-2-the-brain-and-amyloid
Due to the GP120 & GAG inserts I thought I would do a cross reference. Bingo!
I already considered NAD but not your kynurenine pathway, I will now need to add this to my review.
Note the doom loop you also referred to and the need to break the cycle with therapeutics.
Clinical Relevance of Kynurenine Pathway in HIV/AIDS: An Immune Checkpoint at the Crossroads of Metabolism and Inflammation
Jean-Pierre Routy et al. AIDS Rev. 2015 Apr-Jun.
Abstract
Tryptophan degradation along the kynurenine pathway is associated with a wide variety of pathophysiological processes, of which tumor tolerance and immune dysfunction in several chronic viral infections including HIV are well known. The kynurenine pathway is at the crossroads of metabolism and immunity and plays an important role in inflammation while also playing an opposing role in the control of acute and chronic infections. In this review we have summarized findings from recent studies reporting modulation of tryptophan degrading the kynurenine pathway in the context of HIV infection. This immuno-metabolic pathway is modulated by three distinct inducible enzymes: indoleamine 2,3-dioxygenase 1 and 2 and tryptophan 2,3-dioxygenase. Increased expression of these enzymes by antigen-presenting cells leads to local or systemic tryptophan depletion, resulting in a mechanism of defense against certain microorganisms. Conversely, it can also lead to immunosuppression by antigen-specific T-cell exhaustion and recruitment of T regulatory cells. Recently, among these enzymes, indoleamine 2,3-dioxygenase 1 has been recognized to be an immune response checkpoint that plays an important role in HIV immune dysfunction, even in the context of antiretroviral therapy. In addition to the activation of the kynurenine pathway by HIV proteins Tat and Nef, the tryptophan-degrading bacteria present in the intestinal flora have been associated with dysfunction of gut mucosal CD4 Th17/Th22 cells, leading to microbial translocation and creating a systemic kynurenine pathway activation cycle. This self-sustaining feedback loop has deleterious effects on disease progression and on neurocognitive impairment in HIV-infected patients. Therapy designed to break the vicious cycle of induced tryptophan degradation is warranted to revert immune exhaustion in HIV-infected persons.
https://pubmed.ncbi.nlm.nih.gov/26035167/#:~:text=The%20kynurenine%20pathway%20is%20at,of%20acute%20and%20chronic%20infections.
https://doorlesscarp953.substack.com/p/pathophysiology-of-spike-protein
No doubt Biden's cognitive capacity will significantly benefit from this kynurenine pathway activation.
Ketogenic?
Great articles highlighting and exploring this. Interesting that ME/CFS has a lot of overlap with long covid, yet some studies show reduced kynurenine to tryptophan ratio. I always try to ask if a pathway is an innocent bystander or the actual evil cause.. Maybe ME/CFS patients have absolute deficiency of kynurenine metabolites whereas in covid there's a relative deficiency leading to similar symptom pictures...ie the pathway is activated but it just can't meet demands because the NAD+/NADH ratio is so screwed in covid. Potentially, the immune suppression may be a protective mechanism and IDO also has some direct actions against viruses and bacteria. Or it may just be that the pathway was never meant to be chronically activated in the presence of long lasting or reoccuring spike. Or then again, it could be that viruses have learnt to amplify our own immune tolerance to cause suppression so they have an easier ride. IDO activation may also deplete melatonin.
The ME/CFS metabolic trap theory suggests that mutations in the IDO2 gene keep tryptophan levels high which deactivate IDO1 after a tryptophan-raising event leading to lower kynurene levels after the stressor has passed.
"Could the kynurenine pathway be the key missing piece of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) complex puzzle?"
Of note: Section titled "Treatments under investigation"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9276562/
Hi John,
Would love if you can do a deep dive on these weird protein clots being reported.
https://www.naturalnews.com/2022-07-22-vaccine-clot-biostructures-harvest-conductive-metals-from-blood.html
You are welcome.
I got this info from a Chat GPT query
â Some of the metabolites generated in the
Kynurenine Pathway have been linked to various physiological and pathological processes, including inflammation, neurodegenerative disordersâ
Is it just obesity that can cause this negative effect of the KP or are other factors involved?
PLP works as antioxidant molecule by quenching oxygen reactive species (ROS) and counteracting the formation of Advanced Glycation End products (AGEs), genotoxic compounds associated with senescence and diabetes
Pyridoxal 5â˛-phosphate (PLP), the active form of vitamin B6, works as cofactor in numerous enzymatic reactions and it behaves as antioxidant molecule. PLP deficiency has been associated to many human pathologies including cancer and diabetes and the mechanism behind this connection is now becoming clearer.
You mean the insect diet fix it right!? /s
Interesting hypothesis, I think this can actually be tested in a causal analysis (Mendelian randomisation), - there there are genetic instruments for IDO. Similar to here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560130/
There will be even higher powered studies available now and probably other members of the pathway.
Stupid question here but my family had covid last yr and recently I found out that I had two kidney stones which is not rare but my 23 yr old son also had kidney stone same time and while I was in er the lady in the next room also had kidney stone. Could this be related? We live in a very small town so I found it odd. Can covid damage kidneys?
So Iâm not imagining that the smell of my pee has changed since I had covid!! Long Covid sufferer here, it totally sucks. Zyrtec and nattokinase got me back on track but I relapsed when I tried interval training. Iâm like back at square one, brain fog and all.
So is this where NMN supplements come in post-infection?