Aberrations in the Cross-Talks Among Redox, Nuclear Factor-κB, and Wnt/β-Catenin Pathway Signaling Underpin Myalgic Encephalomye... (Maes et al, 2022)

Consul

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Aberrations in the Cross-Talks Among Redox, Nuclear Factor-κB, and Wnt/β-Catenin Pathway Signaling Underpin Myalgic Encephalomyelitis and Chronic Fatigue Syndrome (Maes et al, 2022)

Authors
Michael Maes, Marta Kubera, Magdalena Kotańska

Abstract

There is evidence that chronic fatigue spectrum disorders (CFAS-Ds), including myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), and chronic fatigue with physiosomatic symptoms including when due to comorbid medical disease, are characterized by neuroimmune and neuro-oxidative biomarkers. This study was performed to delineate the protein–protein interaction (PPI) network of CFAS-D and to discover the pathways, molecular patterns, and domains enriched in their PPI network. We performed network, enrichment, and annotation analyses using differentially expressed proteins and metabolics, which were established in patients with CFAS-D. The PPI network analysis revealed that the backbone of the highly connective CFAS-D network comprises NFKB1, CTNNB1, ALB, peroxides, NOS2, tumor necrosis factor (TNF), and interleukin-6 (IL-6) and that the network comprises interconnected immune-oxidative-nitrosative and Wnt/β-catenin subnetworks. Multiomics enrichment analysis shows that the CFAS-D network is highly significantly associated with cellular (antioxidant) detoxification, hydrogen peroxide metabolic process, peroxidase and oxidoreductase activity, interleukin-10 (IL-10) anti-inflammatory signaling and neurodegenerative canonical Wnt, the β-catenin complex, cadherin domains, cell–cell junctions and TLR2/4 pathways, and the transcription factors nuclear factor kappa B (NF-κB) and RELA. The top 10 DOID annotations of the CFAS-D network include four intestinal, three immune system disorders, cancer, and infectious disease. The custom Gene Ontology (GO) term annotation analysis revealed that the CFAS-D network is associated with a response to a toxic substance, lipopolysaccharides, bacterium, or virus. In conclusion, CFAS-D may be triggered by a variety of stimuli and their effects are mediated by aberrations in the cross-talks between redox, NF-κB, and Wnt/β-catenin signaling pathways leading to dysfunctions in multicellular organismal homeostatic processes.

The study: https://www.frontiersin.org/articles/10.3389/fpsyt.2022.822382/full
 

Boba

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In conclusion, CFAS-D may be triggered by a variety of stimuli and their effects are mediated by aberrations in the cross-talks between redox, NF-κB, and Wnt/β-catenin signaling pathways leading to dysfunctions in multicellular organismal homeostatic processes
Can someone translate pls?
 

Boba

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This is interesting:


fpsyt-13-822382-g007.jpg



The new model of CFAS-D proposed here is shown in Figure 7. Disorders in the cross-talks among these three key pathways mediate the effects of a variety of trigger factors in the onset of CFAS-D. These findings also support the theory that once CFAS-D is present, the abovementioned pathways may increase morbidity and even mortality of IO&NS-associated medical disorders through the detrimental effects of disorders in redox, NF-κB, and Wnt axis (24, 26, 86–88). The model also explains that the acute phase of inflammatory conditions may lead to CFAS-D via disorders in this axis, oxidative damage and the neurotoxic effects of LPS, proinflammatory cytokines, and TRYCATs. Since the biomarkers included in this study were extracted from studies on ME/CFS and CF-like symptoms in comorbid disorders with duration > 6 months, we may conclude that after resolution of acute inflammation, CAFS-D symptoms are maintained by continued aberrations in the redox, NF-κB, and Wnt axis, increased IL-10 production, and increasing oxidative damage, including secondary autoimmune responses and nitrosylation.„
 

Wishful

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Can someone translate pls?
Not me. :D I think that's the most obscure abstract I've encountered.

The body is composed of all sorts of control loops (thousands? millions?) interacting with each other through various levels of connection, so of course there's going to be crosstalk. Figuring out which ones are involved in the core dysfunction of ME will be difficult, especially since some of them might be limited to small areas of the brain ... and may not yet even be known to medical science.
 

Boba

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Not me. :D I think that's the most obscure abstract I've encountered.

The body is composed of all sorts of control loops (thousands? millions?) interacting with each other through various levels of connection, so of course there's going to be crosstalk. Figuring out which ones are involved in the core dysfunction of ME will be difficult, especially since some of them might be limited to small areas of the brain ... and may not yet even be known to medical science.
I read the paper but didn’t understand the whole complexity. However they seem to propose that the initial trigger is gone and our bodies are in a loop of dysfunctional pathways which are very complex and hard to treat.
 

Wishful

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However they seem to propose that the initial trigger is gone and our bodies are in a loop of dysfunctional pathways which are very complex and hard to treat.
That's how I see ME too: a positive feedback loop keeping us in this abnormal state. That feedback loop could involve dozens or hundreds or even more individual mechanisms, each only slightly off of 'normal' and thus hard to notice, yet altogether they result in one mechanism switching to a state that results in various symptoms downstream. I think it's unlikely that a researcher will do a blood test and identify a clear culprit. I think it's more likely that someone will stumble upon a treatment that works for many PWME, which in turn will lead to identifying what it's correcting.

I still believe that if I'd been able to go in for exhaustive testing when I had something that would reliably trigger temporary remission, we might have an effective treatment now. The medical research system just isn't set up to do that sort of thing. :grumpy:
 
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Too ill to contribute atm but perhaps others can build on this

@Wishful, doesn't cumin affect nf-kB? I think I remember reading that somewhere.. Maybe how it blocks PEM or part of the mechanism?

Lithium interacts with wnt/b-catenin, I wonder if we can play with the components a bit using cumin and lithium..? Can't remember the direct effect of lithium.

Just some raw thoughts to ponder.
 

Wishful

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For CuEO (cumin essential oil):

"Real-time PCR tests showed that CuEO significantly inhibited the mRNA expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), interleukin- (IL-) 1, and IL-6. Moreover, western blotting analysis revealed that CuEO blocked LPS-induced transcriptional activation of nuclear factor-kappa B (NF-κB) and inhibited the phosphorylation of extracellular signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). These results suggested that CuEO exerted anti-inflammatory effects in LPS-stimulated RAW 264.7 cells via inhibition of NF-κB and mitogen-activated protein kinases ERK and JNK signaling; the chemical could be used as a source of anti-inflammatory agents as well as dietary complement for health promotion."

So yes, cumin could work against PEM that way. I'm not sure how it could have made that effect permanent in me. Immune cell training?

Now I have this mental image of cumin molecules yelling at rows of immune cells. :D
 
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Just stumbled onto this

https://onlinelibrary.wiley.com/doi/full/10.1002/glia.24123

Lithium inhibits tryptophan catabolism via the inflammation-induced kynurenine pathway in human microglia

Abstract
Despite its decades' long therapeutic use in psychiatry, the biological mechanisms underlying lithium's mood-stabilizing effects have remained largely elusive. Here, we investigated the effect of lithium on tryptophan breakdown via the kynurenine pathway using immortalized human microglia cells, primary human microglia isolated from surgical specimens, and microglia-like cells differentiated from human induced pluripotent stem cells.

Interferon (IFN)-γ, but not lipopolysaccharide, was able to activate immortalized human microglia, inducing a robust increase in indoleamine-2,3-dioxygenase (IDO1) mRNA transcription, IDO1 protein expression, and activity. Further, chromatin immunoprecipitation verified enriched binding of both STAT1 and STAT3 to the IDO1 promoter. Lithium counteracted these effects, increasing inhibitory GSK3βS9 phosphorylation and reducing STAT1S727 and STAT3Y705 phosphorylation levels in IFN-γ treated cells. Studies in primary human microglia and hiPSC-derived microglia confirmed the anti-inflammatory effects of lithium, highlighting that IDO activity is reduced by GSK3 inhibitor SB-216763 and STAT inhibitor nifuroxazide via downregulation of P-STAT1S727 and P-STAT3Y705.

Primary human microglia differed from immortalized human microglia and hiPSC derived microglia-like cells in their strong sensitivity to LPS, resulting in robust upregulation of IDO1 and anti-inflammatory cytokine IL-10. While lithium again decreased IDO1 activity in primary cells, it further increased release of IL-10 in response to LPS. Taken together, our study demonstrates that lithium inhibits the inflammatory kynurenine pathway in the microglia compartment of the human brain.


Added a couple of spaces myself.
@Pyrrhus do you think this warrants it's own thread? I'm too tired to read it properly but it looked interesting at a glance. I think the IDO hypothesis involved IDO2 not 1 but not sure if it could be worth reading into regardless.

Edit:I think it is IDO1 after all but yeah
 
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Wishful

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I'm fairly convinced that my PEM involved IFN-g and IDO, with the result being excess toxic kynurenines. I never tried lithium. Since I no longer get PEM, I suppose lithium isn't likely to work now.