Here are some notes I started putting together on both that might be helpful, still a lot to go through.
Itaconate Shunt video
https://forums.phoenixrising.me/threads/rob-phair-youtube-video.88163/#post-2405847 In absence of CoA, a B6 deficiency may then also further impede alternative ability to produce energy. Glutamic-oxaloacetic transaminase is a pyridoxal 5 phosphate-dependent (b6) enzyme which exists in cytoplasmic and mitochondrial forms, GOT1 and GOT2, respectively. GOT plays a role in amino acid metabolism and the urea and tricarboxylic acid cycles. See further below on B6.
https://www.genecards.org/cgi-bin/carddisp.pl?gene=GOT1
Glutamate decarboxylase 1 gene. Glutamate decarboxylase or glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the decarboxylation of glutamate to GABA and CO2. GAD uses PLP (active B6) as a cofactor
We evaluated the impact of excess fructose on hepatocyte mitochondrial enzymes; citrate synthase (CS), aconitase and glutamate-oxaloacetate transaminase (GOT). Fructose decreased the activities of aconitase and GOT by 35% and 47% respectively
https://www.oatext.com/fructose-imp...nzyme-glutamate-oxaloacetate-transaminase.php
A big one. Supplementation with high concentrations of the pyridoxine form of Vitamin B6 competitively inhibits the active Pyridoxal 5' phosphate (P5P) form which actually leads to decreased vitamin B6 function rather than enhancing it.
https://www.sciencedirect.com/science/article/abs/pii/S0887233317301959?via=ihub
Zinc, Magnesium, and Vitamin B2 (flavin mononucleotide (FMN); also known as riboflavin-5’-phosphate) are normally needed for the B6 conversion to the active P5P form. Its possible to see high levels of unconverted B6 in tests.
During inflammation or infection, zinc uptake levels are also lowered by also lowering levels of Shank3. we have reported expression of SHANK3 in human enterocytes, where SHANK3 was functionally linked to zinc (Zn) transporter levels mediating Zinc absorption. We detected decreased expression of Zn uptake transporters ZIP2 and ZIP4 on mRNA and protein level correlating with SHANK3 expression levels, and found reduced levels of ZIP4 protein co-localizing with SHANK3 at the plasma membrane. We demonstrated that especially ZIP4 exists in a complex with SHANK3. Zip2 and Zip4 proteins act as key players of zinc absorption in enterocytes. Low enterocytic SHANK3 levels result in diminished Zn transporter levels that could eventually explain reduced Zn concentrations in tissues and organs
https://www.ncbi.nlm.nih.gov/pubmed/28345660/
Robert Phair’s IDO metabolic trap hypothesis related notes I started taking.
The IDO1 and IDO2 genes each encode for enzymes that transform an essential amino acid (tryptophan) into an important regulator of the immune system (kynurenine). The main difference is that when tryptophan is at high levels in a cell, the IDO2 enzyme increases its production of kynurenine while, surprisingly, the IDO1 enzyme decreases its production of kynurenine. If you have a problem with IDO2 (mutations in the gene) then you must rely solely on IDO1 to produce kynurenine from tryptophan. If for any reason the tryptophan levels in a cell rise too high, then IDO1 will stop making kynurenine and tryptophan levels will remain high. This is the IDO metabolic trap. the predisposing factors are the damaging mutations in IDO2, the triggering factor is an elevation in tryptophan and the maintaining mechanism is that the IDO1 enzyme can’t convert tryptophan to kynurenine when tryptophan is high, therefore maintaining a high level of tryptophan and the low level of kynurenine in the cell. Dr. Robert Phair Video:
https://forums.phoenixrising.me/thr...cfs-research-update-by-dr-robert-phair.76012/ Paper:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787624/
The kynurenine pathway, which is often systemically up-regulated when the immune response is activated. IFN-y, which is induced by intense exercise, strongly induces IDO1 expression TRP breakdown was significantly induced by intense exercise as indicated by a decline in TRP levels by 12% (p<0.001) and an increase of KYN levels by 6% (p<0.02), accompanied by an elevation of KYN/TRP by 20% IFN-y is the most important stimulus of indoleamine 2,3-dioxygenase-1 (IDO1) activity although other mainly pro-inflammatory stimuli can do the same. IFN-γ is able to induce both the gene expression and enzymatic activity of IDO-1
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849644/figure/pone.0153617.g002/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849644/
The 24 hr delay for PEM correlates with IFN-y levels that are known to rise ~24 hrs after exertion.
https://forums.phoenixrising.me/threads/the-rbc-nox-hypothesis.77228/#post-2222401
Exercise appears to have different effects on NLRP3 inflammasome (inflammation). In the case of chronic exercise with high intensity such as what occurs in many athletics/sports, a significant INCREASE in expression of gene, NLRP3 and serum levels of IL-1β, IL-18 cytokines were observed. Chronic exercise with light to moderate intensity such as walking however significantly reduced the expression of NLRP3 gene and subsequent serum levels of IL-1β, IL-18 cytokines. So there are differences in intensive vs light exercise with intensive pouring additional fuel on the fire of inflammation.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524053/
Increased synthesis of 5-HT was reported regarding fatigue after exercise. In addition, there is evidence demonstrating that during the development of exercise, levels of TRP hydroxylase and 5-HT elevates
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552521/
Tryptophan is the precursor for the neurotransmitter 5-hydroxytryptamine (5-HT), which is involved in fatigue and sleep. An increase in plasma free tryptophan leads to an increased rate of entry of tryptophan into the brain. This should lead to a higher level of 5-HT which may cause central fatigue. The plasma concentrations of these amino acids were measured in chronic fatigue syndrome patients (CFS) before and after exercise (Castell et al., 1998), and in patients undergoing major surgery (Yamamoto et al., 1997). In the CFS patients, the pre-exercise concentration of plasma free tryptophan was higher than in controls (p < 0.05) but did not change during or after exercise. This might indicate an abnormally high level of brain 5-HT in CFS patients leading to persistent fatigue. In the control group, plasma free tryptophan was increased after maximal exercise (p < 0.001), returning towards baseline levels 60 min later. The apparent failure of the CFS patients to change the plasma free tryptophan concentration or the free tryptophan/BCAA ratio during exercise may indicate increased sensitivity of brain 5-HT receptors, as has been demonstrated in other studies (Cleare et al., 1995).
https://pubmed.ncbi.nlm.nih.gov/10721121/
TRPV1 sensitization was maintained by 5-HT/5-HT3A.
https://pubmed.ncbi.nlm.nih.gov/31708101/
TNF-α could sensitize TRPV1 by promoting its expression, inhibition of TNF-α synthesis with thalidomide in vivo reversed TRPV1 protein expression
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840530/
Propofol is the most commonly used intravenous anesthetic for the induction and maintenance of general anesthesia and sedation. propofol causes direct activation of TRPV1 in both capsaicin-sensitive DRG neurons and in CHO-TRPV1 cells. While propofol’s response appears to be partially mediated by its stimulation of PKC, experimental activation of PKC significantly potentiates propofol’s effects on TRPV1. These effects of propofol appear similar to capsaicin-induced activation of TRPV1.
http://www.asaabstracts.com/strands/asaabstracts/abstract.htm?year=2004&index=12&absnum=1436
the kynurenine pathway of tryptophan degradation is activated by stress as well as directly by inflammatory factors (Gibney et al., 2013, Liu et al., 2013). Proinflammatory cytokines, including interleukin-1 (IL-1), IL-2, IL-6, interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), have been found to reduce the production of 5-HT by activation of the tryptophan (TRP)-metabolizing enzyme indoleamine-2,3-dioxygenase (IDO) and a less efficient inducer is IFN-α
https://www.sciencedirect.com/science/article/pii/S0889159112004965 https://www.sciencedirect.com/science/article/pii/S0166432812008315 https://www.ncbi.nlm.nih.gov/pubmed/3107562 anti-inflammatory cytokines (interleukin [IL]-4, IL-10, and transforming growth factor β) inhibit IDO induction by IFN-γ. The proinflammatory IL-1β and tumor necrosis factor α potentiate this induction and IL-2 acts via IFN-γ. Thus, the IDO status can be assumed to be determined by the balance between proinflammatory and anti-inflammatory cytokines. Interestingly, IFN-γ induction of IDO is potentiated by the synthetic glucocorticoid dexamethasone, which exerts no effect by itself. Nitric oxide (NO) may play an important role in the control of IDO activity. It inhibits the human enzyme.95 Activity of the recombinant human IDO is reversibly inhibited by NO by binding to heme, with the inactivated enzyme complex being the Fe2+-NO-Trp adduct.96 This inhibition may represent an important mechanism of regulating the immune function of IDO
https://journals.sagepub.com/doi/full/10.1177/1178646917691938
Butyrate, a short chain fatty acid produced when dietary fiber is fermented in the colon down regulates Indolamine 2,3-Dioxygenase 1 (IDO-1) Expression. the short chain fatty acid (SCFA) butyrate was the main metabolite controlling IDO-1 expression in human primary IECs and IEC cell-lines.
https://www.frontiersin.org/articles/10.3389/fimmu.2018.02838/full Butyrate aids in reducing the expression of many pro-inflammatory cytokines, as well as inflammation-inducing enzymes. This would explain how viral outbreaks, inflammation and exercise could have an effect on IDO-1 expression. Exercise enhances butyrate-producing fecal bacteria and increases butyrate production
https://www.ncbi.nlm.nih.gov/pubmed/31454784
Regulatory and functional aspects of the kynurenine (K) pathway (KP) of tryptophan (Trp) degradation are reviewed. The KP exists mainly in the liver, which contains all the enzymes necessary for NAD+ synthesis from Trp and is responsible for ~90% of overall Trp degradation under normal physiologic conditions. The KP also exists extrahepatically, but its contribution to Trp degradation is normally minimal (5%-10%) but becomes quantitatively more significant under conditions of immune activation. The KP is rate-limited by its first enzyme, Trp 2,3-dioxygenase (TDO), in liver and indoleamine 2,3-dioxygenase (IDO) elsewhere. Of important relevance to functional differences is that IDO activity, unlike that of TDO, can be substrate inhibited by high [Trp], with a Ki of ⩾200 µM. TDO is regulated by glucocorticoid induction, substrate activation and stabilization by Trp, cofactor activation by heme, and end-product inhibition by reduced nicotinamide adenine dinucleotide (phosphate). IDO is regulated by IFN-γ and other cytokines and by nitric oxide. The KP disposes of excess Trp, controls hepatic heme synthesis and Trp availability for cerebral serotonin synthesis, and produces immunoregulatory and neuroactive metabolites, the B3 “vitamin” nicotinic acid, and oxidized nicotinamide adenine dinucleotide.
https://journals.sagepub.com/doi/full/10.1177/1178646917691938
In relation to CNS function, an inverse relationship exists between TDO activity and brain [Trp] and 5-HT synthesis
https://academic.oup.com/alcalc/article-abstract/18/4/369/127471?redirectedFrom=fulltext&login=false
TDO is controlled by TRP levels and can be also induced by steroid hormones like cortisol
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195227/ as Trp inhibits IDO activity at concentrations greater than 50 µM,91 it is unlikely that IDO will be able to process any excess Trp.
https://www.ncbi.nlm.nih.gov/pubmed/3488060 TDO is found predominantly in mammalian liver and can be induced by a number of factors including fasting, glucocorticoids, hydrocortisone, L-tryptophan and nicotinic acid. The l-Trp-specific TDO and mainly liver-specific TDO use O2 as cosubstrate and heme as cofactor. Unlike TDO, IDO does not contain an activating site for tryptophan analogues and is induced primarily by the proinflammatory cytokine IFN-γ. IDO also uses the reactive oxygen intermediate (ROI) superoxide as opposed to molecular oxygen as a cofactor
https://pubmed.ncbi.nlm.nih.gov/2300969 https://pubmed.ncbi.nlm.nih.gov/6967714
Indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO, also known as TDO2) are two main enzymes involving in the first step of the Kyn pathway. IDO was extensively demonstrated in various organs throughout the body to catabolize most Trp, while TDO is mainly expressed in the liver . Most Trp is catabolized by IDO, which is expressed diffusely in the human body and can be induced by interferon gamma (IFN-γ). For example, IFN-γ activation of mononuclear phagocytes significantly increases IDO1 and flux through the Kyn pathway IDO1 can be induced during infection, where it displays antimicrobial activity and immune regulation. Moreover, some inflammatory cytokines, such as interleukin (IL) 6 and tumor necrosis factor-α (TNF-α), can highly induce IDO1. IDO1 is a 45-kDa monomeric enzyme that contains heme. The Fe2+ form can activate IDO1. TDO can be activated by cortisol and it was also revealed that TDO can be activated by Trp-induced reactive oxygen species. IDO2 is responsible for inflammatory autoimmunity.
IDO1 consumes Trp and produces Kyn metabolites to help attenuate inflammation and maintain tissue homeostasis. Ogiso et al. demonstrated that IDO1 blocked the functions of inflammatory cells and stimulated immunologic tolerance. Additionally, IDO1-expressing DCs, active Tregs and Trp catabolites cooperate to suppress infection in inflammation. Interestingly, IDO1 can downregulate IFN-γ and upregulate IL-6 at the early stage of tumorigenesis to transform the inflammatory environments to immunosuppressive environments Merlo et al. revealed that the activation of autoreactive T and B cells, pathogenic autoantibody production and rheumatoid arthritis development were induced by IDO2. Remarkably, IDO2 expressed in B cells can regulate the function of B cells via interacting with T cells. The role of IDO2 in inflammatory autoimmunity implies that IDO2 is, to some extent, the opposite of IDO1. IDO1 promotes angiogenesis to facilitate cancer growth via downregulating IFN-γ and upregulating IL-6. IDO1 suppresses the immune system to aggravate cancer cell growth, migration and invasion in three ways. A poor prognosis of various cancers has been shown to be related to high IDO1 expression
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584917/
Unlike IDO1-deficient mice, IDO2-deficient mice have reduced inflammatory cytokines IL-6, IFN-γ, and TNF-α, hematopoietic cytokines GM-CSF and G-CSF, and reduced MCP-1 relative to wt mice. These data again point to the pro-inflammatory function of IDO2 and identify IDO1 and IDO2 as nonredundant players in inflammatory responses. Accumulating evidence indicates that IDO2 acts as a pro-inflammatory mediator of autoimmunity, with a functional phenotype distinct from IDO1. IDO2 is expressed in antigen-presenting cells, including B cells and dendritic cells, but affects inflammatory responses in the autoimmune context specifically by acting in B cells to modulate T cell help in multiple model systems
https://journals.sagepub.com/doi/pdf/10.4137/CPath.S39930
kynureninase (kynase) is a Vitamin B6 PLP dependent enzyme that catalyses the cleavage of kynurenine (Kyn) into anthranilic acid (Ant). It can also act on 3-hydroxykynurenine (to produce 3-hydroxyanthranilate). This is part of the pathway for the catabolism of Trp and the biosynthesis of NAD cofactors from tryptophan (Trp). The other PLP-dependent enzyme of the KP, KAT, is also subject to inhibition in B6 deficiency.
Trp is not only catabolized by IDO and TDO. Two other important enzymes, TPH1 enzyme (Tryptophan hydroxylase 1 ) and TPH2 enzyme (Tryptophan hydroxylase 2), are involved in Trp catabolism via a pathway that ultimately leads to the synthesis of serotonin and dopamine, two important neurotransmitters.
https://bpsbioscience.com/ido-tdo-pathway
Tryptophan converts to 5-hydroxytryptophan with the enzyme Tryptophan Hydroxylase (Folate, Iron, B3, Calcium and Tetrahydrobiopterin (BH4). 5-hydroxytryptophan, also known as 5-HTP requires zinc, magnesium, vitamin b6 and copper to convert into serotonin via Dopa Decarboxylase enzyme.
https://ojrd.biomedcentral.com/articles/10.1186/s13023-020-01379-8 https://understand-andcure-anxietya...pression.com/images/MelatoninCopperBlocks.jpg