Itaconate Shunt (now called INFa-Itaconate shunt) Part 2!

[datadragon]

quinolinic acid, a metabolite of kynurenine is an endogenous excitotoxin that could cause selective loss of orexin neurons as compared to MCH neurons by activating glutamate NMDA receptors. In addition, quinolinic acid-induced decrease of orexin neurons was prevented by an inhibitor of poly(ADP-ribose) polymerases. These results provide the first evidence concerning cytotoxic consequences onto orexin neurons, and indicate that NMDA receptor-mediated injury may contribute to the selective loss of these neurons in the hypothalamus, a prominent neuropathological feature found in narcolepsy patients. https://pubmed.ncbi.nlm.nih.gov/14751771/

Interesting a bit up I mentioned that monoamine neurotransmitters such as dopamine, noradrenaline, and serotonin (5-HT) hyperpolarize and inhibit orexin neurons via alpha 2-adrenergic and 5-HT1A receptors as well so it seems any dysregulation in the kynurenine pathway and the kyn/trp ratio is but one factor so far of several that seems to have a lowering effect either way on orexin neurons.

This study that came out in 2019 mirrors the idea that IFN-a induced persistent fatigue which does not abate post-treatment, that is, once there is no longer immune activation from IFN-α. It mentions that in a study of chronic-activated Epstein-barr virus (CAEBV), higher fever was significantly associated with a higher kynurenine/tryptophan (Kyn/TRP) ratio and lower Tryptophan, while there were trends towards associations between a higher KYN/TRP ratio and severe tiredness and night sweats (Bellmann-Weiler et al., 2008). This suggests that inflammation-induced activation of IDO may be relevant for the persistence of symptoms, including fatigue, following an immune trigger and differs with the lower tryptophan and increased kynurenine. Levels of the KYN/TRP ratio and 3-HK were lower in this study in CFS patients than controls, while the tryptophan levels were similar to controls. This lower KYN/TRP ratio in CFS (and the lack of association with PF) is somewhat in opposition to a study of somatization which observed higher levels of the KYN/TRP ratio. Again differences among some studies which didnt make sense initially. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350004/
other kynurenine metabolites, quinolinic, and picolinic acids, can also enhance IFN-γ-dependent iNOS expression https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808205/

 

[Murph]

quinolinic acid, a metabolite of kynurenine is an endogenous excitotoxin that could cause selective loss of orexin neurons as compared to MCH neurons by activating glutamate NMDA receptors. In addition, quinolinic acid-induced decrease of orexin neurons was prevented by an inhibitor of poly(ADP-ribose) polymerases. These results provide the first evidence concerning cytotoxic consequences onto orexin neurons, and indicate that NMDA receptor-mediated injury may contribute to the selective loss of these neurons in the hypothalamus, a prominent neuropathological feature found in narcolepsy patients.

Can I please request a few more subheadings and signposting to make it easier for us to look at these. It's not clear to me if you're using these posts as a sort of filing system for your notes or if you're expecting to get some discourse out of them. A sentence about why you're posting each paragraph would be welcome, noting what it relates to, what you expect people to find interesting. Thanks!

 

[datadragon]

Can I please request a few more subheadings and signposting to make it easier for us to look at these. It's not clear to me if you're using these posts as a sort of filing system for your notes or if you're expecting to get some discourse out of them. A sentence about why you're posting each paragraph would be welcome, noting what it relates to, what you expect people to find interesting. Thanks!

@Murph Not sure yet. Just looking over what pathways might be involved with ME/CFS, I noticed that orexin-A plasma levels were higher in patients with insomnia and correlated with their severity of insomnia. Deficiency of orexins on the other hand leads to narcolepsy type 1, a disease manifesting in increased daytime somnolence, involuntary naps, disorganized sleep architecture, increased presence and shortened latency of REM sleep, and cataplexy, a sudden loss of muscle tone. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061179/ https://www.sleepfoundation.org/sleep-aids/orexins

Hypothalamic orexin neurons are responsible for the control of food intake and energy expenditure, motivation, circadian rhythm of sleep and wake, memory, cognitive functions, sexual function, and the cardiovascular system. Multiple studies show that orexinergic stimulation results in increased blood pressure and heart rate and that this effect may be efficiently attenuated by orexinergic antagonism. Increased activity of orexinergic neurons is also observed in animal models of hypertension. So thats why I became curious when many of the mentioned pathways in different posts I found interact with orexin pathways. They also seem to be involved in depression, anxiety, and drug addiction. I was taking some notes to see the interrelationships. I might add some extra info as requested, for example the last post I said any dysregulation in the kynurenine pathway and the kyn/trp ratio is but one factor so far of several that seems to have a lowering effect either direction on orexin neurons. D-lactate might have a lowering effect on L-lactate which increases orexin as another etc. Adenosine inhibits activity of hypocretin/orexin neurons by the A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect. leptin robustly inhibits orexin neurons, causing hyperpolarization and decreasing the firing rate. Ghrelin activates isolated orexin neurons inducing their depolarization and an increase in firing frequency. Orexin neurons are activated by fasting and low sugar levels etc. Hope that helps you with some of my thought process...

 

[datadragon]

TNF-α is involved in the regulation of hypocretin (orexin) expression, sleep and cognition. https://pubmed.ncbi.nlm.nih.gov/31386303/ Inflammation can increase IDO and kynurenine metabolites potentially killing orexin neurons which might be the more severe cases. 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

Orexins are activated by high protein diets. The top three amino acids that activate orexins are glycine, aspartate and cysteine. BCAA (Branched Chain Amino Acids) leucine, isoleucine, and valine also seem helpful, as they can restore orexin levels after brain injury.​

Fats, specifically triglycerides stimulate orexins as well. Nicotine patch, zinc, forskolin and berberine may all increase. https://drvanta.com/how-to-treat-orexin-deficiency-naturally/​

Angiotensin II reduces food intake by altering orexigenic (orexin) neuropeptide expression in the mouse hypothalamus​

Systemic Ang II (1 μg/kg · min) infusion in FVB mice rapidly reduced hypothalamic expression of neuropeptide Y (Npy) and orexin and decreased food intake at 6 h compared with sham-infused controls but did not change peripheral leptin, ghrelin, adiponectin, glucagon-like peptide, peptide YY, or cholecystokinin levels. These effects were completely blocked by the Ang II type I receptor antagonist candesartan or deletion of Ang II type 1a receptor. Thus, Ang II type 1a receptor-dependent Ang II signaling reduces food intake by suppressing the hypothalamic expression of Npy and orexin, likely via AMPK dephosphorylation. These findings have major implications for understanding mechanisms of cachexia in chronic disease states such as congestive heart failure and end-stage renal disease, in which the renin-angiotensin system is activated.
https://pubmed.ncbi.nlm.nih.gov/22234465/

Certain autoantibodies are specific for these receptors and can regulate their function, thus being known as functional autoantibodies. The function of these antibodies is similar to that of natural ligands, and it involves not only vasoconstriction, but also the secretion of proinflammatory cytokines (such as interleukin-6 (IL6), IL8 and TNF-α), collagen production by fibroblasts, and reactive oxygen species (ROS) release by fibroblasts and neutrophils. AT1R-AAs promoted inflammation through the expression of interleukin-6 (IL6), vascular cell adhesion molecule-1 (VCAM-1), and improved levels of NF-kB, a transcription factor that regulates many genes involved in inflammation. These effects were blocked by valsartan. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8778295/

@Murph

 

[hapl808]

Berberine seems to make my muscular problems (which feel more like demyelination) worse, but I'm not sure why. Testosterone did the same thing.

 

[datadragon]

IFN-a lowers orexin​

Cerebrospinal fluid-orexin decreases during intraventricular α-interferon therapy of the patients with subacute sclerosing panencephalitis​

We determined the orexin concentration in cerebrospinal fluid (CSF-OX) in two patients with subacute sclerosing panencephalitis who underwent intracerebroventricular (ICV) α-interferon (IFN-α) therapy. In these patients, CSF-OX were in the normal range before ICV administration of IFN-α, and it decreased to undetectable levels after the initiation of IFN-α therapy. It was reported that the production of prepro-OX, which is a precursor of OX, was prevented when IFN-α was given to the gene promoter region of prepro-OX. These results suggest that the production of OX may be suppressed by inhibition of promotor activity when IFN-α is given to the cerebral ventricle in humans.

https://link.springer.com/article/10.1046/j.1446-9235.2003.00026.x

 

[Rufous McKinney]

Berberine seems to make my muscular problems

my chinese herbalist warned me NOT to take berberine....(extracted from a Chinese herb and isolated).

It should be taken with a mix of other herbs (but don't ask me what those are at the moment)

 

[datadragon]

Is this related to PEM? IFN-y treatment continuously increased TNF-a levels released to the supernatant from 8 to 24 hours building up to higher levels...

IFN-y induces COX-2 and iNOS expression in macrophages. This induction was absolutely dependent of the endogenous production of TNF-a elicited by IFN-y treatment, because primary peritoneal macrophages from TNF-a deficient mice were unable to express COX-2 or iNOS by IFN-y stimulation. RAW 264.7 cells produced some TNF-a in absence of stimulation. However, IFN-y treatment continuously increased TNF-a levels released to the supernatant from 8 to 24 h (last time tested). TNF-a production elicited by IFN-y was lower than that produced by LPS stimulation for 16. When TNF-a mRNA expression was determined by quantitative RT-PCR, we found that TNF-a mRNA quickly increases upon IFN-y treatment, being significantly different from the untreated cells at 30 min of stimulation. TNF-a mRNA increased up to 4 h of stimulation, when mRNA levels begin to decrease and reach basal level of expression after 16 h of IFN-y treatment.

http://www.jimmunol.org/content/jimmunol/181/7/4461.full.pdf

This one metions neutralization of IL-1α inhibits the antiviral activity of IFN-γ by 90%, whereas no inhibition of type I IFN activity was observed. Indeed, the antiviral activity of IFN-γ depends largely on the basal level of NF-κB, which is maintained by constitutively expressed IL-1α. https://www.sciencedirect.com/science/article/pii/S1568997221000227#s0070

Keep in mind that IFN-y is also induced by intense exercise, (and also strongly induces IDO1). The 24 hr delay for PEM correlates with IFN-y levels that are known to rise ~24 hrs after exertion. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849644/ Also mentioned was that naïve CD4+ T cells of women produced higher levels of IFNγ and tended to proliferate more than male T cells https://www.pnas.org/doi/10.1073/pnas.1118458109



-David (DataDragon)

 

[MJ_86]

I have this experience too, with progesterone

Adding a third anecdotal experience here. My doctor and I noticed I felt much better during the progesterone dominant part of my cycle so she had me start the progesterone-only birth control pill. I've had a noticeable improvement since starting it and a little over 2 months in, I'm still slowly improving.

 

[datadragon]

TRPV1 channels and the progesterone receptor Sig-1R interact to regulate pain.​

Here we show that TRPV1 physically interacts with the Sigma 1 Receptor (Sig-1R), a chaperone that binds progesterone, an antagonist of Sig-1R and an important neurosteroid associated to the modulation of pain. Antagonism of Sig-1R by progesterone results in the down-regulation of TRPV1 expression in the plasma membrane of sensory neurons and, consequently, a decrease in capsaicin-induced nociceptive responses. This is observed both in males treated with a synthetic antagonist of Sig-1R and in pregnant females where progesterone levels are elevated. https://www.pnas.org/doi/10.1073/pnas.1715972115

Female reproductive steroids, estrogen and progesterone and its physiologically active metabolite, allopregnanolone, provide anti-inflammatory functions, reshape competence of immune cells, stimulate antibody production and promote respiratory epithelial cell repair. Estradiol, allopregnanolone, and progesterone all have important anti-inflammatory functions and are involved in resetting the immune system. Progesterone and allopregnanolone can block the incredible overreaction of the inflammatory system, repressing it and avoiding the over-expression of pro-inflammatory cytokines. https://www.sciencedaily.com/releases/2020/11/201124122919.htm

Progesterone or Allopregnanolone could reverse the impaired spatial learning and memory abilities induced by ketamine https://pubmed.ncbi.nlm.nih.gov/33767621/

The SARS-CoV-2-infected hamsters showed ~2000- to 60,000-fold increase of mRNA levels of IL-6, IL-10, TNF-α, and IFN-γ as being compared to those form mock group (Fig. 1e). However, these stormily increased mRNA levels of proinflammatory cytokines were significantly suppressed by the 5-dose progesterone treatment (Fig. 1e). In addition, progesterone showed a dose-response for controlling proinflammatory cytokines https://www.nature.com/articles/s41392-021-00860-5

By binding to receptors located in immune cells, including natural killer cells, macrophages, dendritic cells, and T cells, as well in non-immune cells, such as epithelial and endothelial cells, progesterone-based compounds alter cellular signaling and activity to affect the outcome of infections at diverse mucosal sites, including the genital, gastrointestinal, and respiratory tracts. Progesterone can also decrease inflammation by inhibiting the production of proinflammatory cytokines (e.g., TNF-α, IFN-γ, and IL-12) and increasing production of anti-inflammatory cytokines, including IL-10. Progesterone also alters the distribution and activity of T cells. Treatment of either murine or human T cells in vitro with P4 can skew naive T cells away from Th1 responses and toward a Th2 type response, with increased production of IL-4, IL-5, and IL-10, In human monocyte-derived DCs, treatment with P4 induces a Th2 environment with increased concentrations of IL-10, IL-13, and IL-27.In T-cell lines, the addition of P4 to the culture media induces a Th2 environment, with greater secretion of IL-4 and IL-5 as compared with non-P4-treated cultures. Murine T cells cultured to differentiate into either Th1 or Th2 cells in the presence of P4, show a strong bias toward Th2 with decreased IFN-γ production and enhanced production of IL-4 https://www.nature.com/articles/mi201735

CD147 is involved with cancer and a tumor's malignant progression, invasiveness, and metastasis https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227170/ CD147 expression has been proposed to inversely correlate with estrogen and progesterone expression. A significant association was found between CD147/EMMPRIN overexpression and adverse tumor outcomes, such as overall survival, disease-specific survival, progression-free survival, metastasis-free survival or recurrence-free survival, irrespective of the model analysis. https://www.nature.com/articles/srep32804

Sounds like its helping in the inflammatory phase, where those in a high fatigue, high IL-10 state which does not ablate post-treatment, that is, once there is no longer immune activation and no longer in a high inflammatory state might want to look into restoring butyrate levels which is found low in those with ME/CFS. I. https://forums.phoenixrising.me/thr...ed-abnormalities-in-me-cfs.90173/post-2437768

 

[datadragon]

Dopamine also interacts with Orexin/hypocretin neurons.

Orexin/hypocretin neurons in the lateral hypothalamus and adjacent perifornical area (LH/PFA) innervate midbrain dopamine (DA) neurons that project to corticolimbic sites and subserve psychostimulant-induced locomotor activity. We examined the ability of dopamine agonists to activate orexin neurons in the rat, as reflected by induction of Fos. The mixed dopamine agonist apomorphine increased Fos expression in orexin cells, with a greater effect on orexin neurons located medial to the fornix. Both the selective D1-like agonist, A-77636, and the D2-like agonist, quinpirole, also induced Fos in orexin cells, suggesting that stimulation of either receptor subtype is sufficient to activate orexin neurons. https://pubmed.ncbi.nlm.nih.gov/15978010/

 

[Alvin2]

I guarantee you that Orexin deficiency has nothing to do with ME/CFS, lack of Orexin causes Narcolepsy and that is a very different condition than what we have.

We have no constant REM sleep proclivities or cataplexy.

The three drug cocktail thats commonly used for Narcolepsy does little for us, Stimulant, Antidepressant and Sleeping Pill.

 

[datadragon]

I guarantee you that Orexin deficiency has nothing to do with ME/CFS, lack of Orexin causes Narcolepsy and that is a very different condition than what we have.

We have no constant REM sleep proclivities or cataplexy.

The three drug cocktail thats commonly used for Narcolepsy does little for us, Stimulant, Antidepressant and Sleeping Pill.

The symptoms of narcolepsy-cataplexy have been shown to result from the death of a small group of brain cells that normally regulate the sleep-wake cycle by releasing chemicals called hypocretins (orexin).
Researchers theorized that the variants found in people with narcolepsy-cataplexy predispose them to an autoimmune reaction that destroys their hypocretin-producing cells. The researchers reported on May 3, 2009, in Nature Genetics that people with narcolepsy-cataplexy are more likely to have unique variants of the TCRA gene, which encodes a receptor protein on the surface of T cells. T cells are the mobile infantry of the immune system. TCRA encodes the major receptor that, in concert with HLA, enables T cells to recognize and attack foreign invaders, such as bacteria and viruses. Changes to this receptor may mistakenly lead the cells to direct their attack against the body. The researchers calculated that variants in HLA and TCRA together can cause up to a 20-fold increase in risk for narcolepsy-cataplexy. So we should also note that genes are also potentially involved with orexin balance. https://www.nih.gov/news-events/nih-research-matters/immune-system-tied-narcolepsy

There are similarities between the two conditions and human narcoleptic patients suffer from extreme episodes of daytime sleepiness. https://www.webmd.com/sleep-disorders/narcolepsy-vs-chronic-fatigue-syndrome In both humans and animals, narcolepsy is accompanied by higher BMI, increased prevalence of obesity, and reduced physical activity levels (Daniels, 1934; Hara et al., 2001; Kok et al., 2003; Heier et al., 2011) but you are correct that its not just having lower orexin only. Oxexins do have involvement with physical activity, food intake, depression and many others https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4219460/ I see so far that after an immune activation event orexin neuron balance is reduced initially even directly by the cytokines like INF-a and TNF-a increases over 8-24 hrs later which also has effect on orexin, but then there are additional effects due to the ongoing cytokines related to leaky gut, change in short chain fatty acids, potential lowering of B12 causing undermethylation, loss of energy production and TH1/TH2 balance around dendritic cells leading to high IL-10 levels and eventual continued fatigue even after resolution of the immune activation event/stressor/heavy exercise. So certainly there are differences beyond solely high vs low orexin to consider which have some info but needs further discussion.

 

[datadragon]

ME/CFS?

Serotonin binds to the 5HT2 and 5HT1A receptors in the motoneuron system. 5HT2 receptors are excitatory and appear to be the receptor that allows serotonin to be involved with promoting locomotion. When serotonin levels reach very high levels, a spillover effect will be seen, and serotonin will begin binding to 5HT1A receptors (which are known to be inhibitory) and will prevent motoneuron firing. (and orexin). Overexpression of serotonin 5HT1A receptor in the orexin neurons enhanced serotonergic inhibition and resulted in severe fragmentation of wakefulness, specifically early in the dark (active) period. Normalization of 5HT1A expression in the orexin neurons in the presence of doxycycline (DOX) eliminated this fragmentation. These results suggest that serotonergic inhibition of orexin neurons may function as a negative feedback circuit early in the active period and could thereby contribute to the diurnal rhythms of sleep and wakefulness. Consistent with its likely role in promoting wakefulness, blockade of 5HT neuro-transmission through 5HT2A antagonists reduces wakefulness and enhances SWS. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738049/

Wei, Glaser, and Deng (2014), through indirect measures with humans, found that serotonin release increases in concentration as the force of muscular contraction increases in exercise (addition of the inhibitory axonal binding site). No studies on humans have directly measured serotonin concentrations in the brain; however, 5HT1A receptors are known to exist in humans, and D’Amico et al. (2015) showed that motoneuron excitability in humans can be reduced via 5HT1A agonist drugs administration. https://simplifaster.com/articles/central-fatigue-role-neurotransmitters-reduced-work-output

(Consider that under inflammation, many cytokines induce IDO1 and therefore will shunt tryptophan away from serotonin lowering 5ht2a) quinolinic acid, a metabolite of kynurenine is an endogenous excitotoxin that could cause selective loss of orexin neurons as compared to MCH neurons by activating glutamate NMDA receptors. In addition, quinolinic acid-induced decrease of orexin neurons was prevented by an inhibitor of poly(ADP-ribose) polymerases. These results provide the first evidence concerning cytotoxic consequences onto orexin neurons, and indicate that NMDA receptor-mediated injury may contribute to the selective loss of these neurons in the hypothalamus, a prominent neuropathological feature found in narcolepsy patients. https://pubmed.ncbi.nlm.nih.gov/14751771/

 

[datadragon]

TNF-α, as well as certain other cytokines, have been shown to influence both expression and transport activity of the serotonin transporter. In neuronally derived cells and choriocarcinoma cells, TNF-α, INF-γ, and IL1β increase function https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2790184/ pharmacological agonists of 5-hydroxytryptamine2A (5-HT2A) receptors can block the pro-inflammatory effects of Tumor Necrosis Factor (TNF) https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0075426 https://pubmed.ncbi.nlm.nih.gov/18708586/ TNF-a mentioned further above increases over 8-24 hrs after IFN-y. TNF-a and IFN-y (induced by IFN-a) not only increase the function of the serotonin transporter, but also are mentioned to inhibit orexin neurons posted earlier.

doxycycline inhibits LPS priming of NLRP3. doxycycline dose dependently inhibited the production of the cytokines IL-1β, IL-6, TNF-α, and IFN-γ and the chemokines MCP-1, MIP-1α, and MIP-1β by PBMC https://pubmed.ncbi.nlm.nih.gov/34577552/

 

[HTester]

I believe all nucleated cells are considered immune cells. See the immunologist, Prof Barker's Immunology lectures. Begin at min 15 if you don't want to listen to entire lecture.

See also: https://pubmed.ncbi.nlm.nih.gov/25988887/

Thanks for this. It was nice for a non-immunologist (me) to hear a lecture by an immunologist making the argument about all nucleated cells responding to IFNa. This point is critical for the itaconate shunt model and it is not made in the textbook (Abbas, 10th edition) from which I'm learning immunology.

I had stopped the Barker video to make note of the Altfield and Gale review, and only later realized that you had posted the PubMed link to it.

You are a careful listener and observer. I'm grateful that you took the time to include me in your learning process.