Aberrations in the Cross-Talks Among Redox, Nuclear Factor-κB and Wnt/Catenin Pathway Signaling Underpin ME and CFS: A Review and New Hypothesis

[nerd]

Aberrations in the Cross-Talks Among Redox, Nuclear Factor-κB and Wnt/Catenin Pathway Signaling Underpin Myalgic Encephalomyelitis andChronic Fatigue Syndrome: A Review and New Hypothesis Based on Results of Network, Enrichment and Annotation Analyses

This paper is a preprint and it has not been peer-reviewed yet.

Authors: Michael Maes, Marta Kubera, Magdalena Kotańska
doi: 10.20944/preprints202109.0201.v1

Abstract

There is evidence that chronic fatigue spectrum disorders (CFAS-D) 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. The present 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 analysis using differentially expressed proteins and metabolics, which we established in CFAS-D patients. PPI network analysis revealed that the backbone of the highly connective CFAS-D network comprises NFKB1, CTNNB1, ALB, peroxides, NOS2, TNF, and IL6, and that the network comprises interconnected immune-oxidative-nitrosative and Wnt/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, IL10 anti-inflammatory signaling, and neurodegenerative, canonical Wnt, the catenin complex, cadherin domains, cell-cell junctions and TLR2/4 pathways; and the transcription factors 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. Custom 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/catenin signaling pathways leading to dysfunctions in multicellular organismal homeostatic processes.

 

[nerd]

@mariovitali What's your take on this?

Overall, this review supports the hypotheses of viral, bacterial, and toxin etiopathogenesis all the same.

Our enrichment analysis shows that the pro-inflammatory TNF-related weak inducer of apoptosis (TWEAK) signaling pathway is another possible link between tissue injury and upregulation of NFKB1- associated DEPs/genes by activating the NF-κB pathways [41].

Hereby, they also provide an explanation for the trauma etiopathogenesis theory.

The results of our network and enrichment analyses show that NFKB1 was not only one of the most important hotspots in the CFAS-D network, but also that NF-κB (p50-p52 unit) and
RELA (NF-κB p65 unit or transcription factor p65) were the most important transcription factors controlling the network and that the NF-κB signaling pathway was one of the most important paths enriched in the network.

NF-κB is one of the biomarkers I previously suggested in the context of a viral etiopathogenesis because it's so prevalent in gamma-herpes signaling. I don't think it's the problem but merely a physiological response to the problem. Its suppression wouldn't serve as a biomarker that the pathogenesis is resolved. It's more useful as a confirmation of chronic infection and inflammation if it's elevated persistently, though it might have a range of other origins and not necessarily a viral one.

Our enrichment analysis also showed an association between the IO&NS subnetwork and the lactoferrin (LTF) danger signal response pathway.

I take lactoferrin regularly. If it was more bioavailable, it would not only upregulate NF-κB response but also balance cytokine receptor activation, prevent the adhesion of SARS-CoV-2 proteins to cells, and improve immunity overall. Unfortunately, its bioavailability is limited. There is an ongoing phase 2 trial with liposomal lactoferrin against COVID-19. My personal anecdotal experience with it was an improvement of rheumatic-like symptoms and GIT inflammation. Maybe it's worth trying to create my own liposomes from it. Though, it's unclear if an increase in NF-κB can really resolve a dormant viral or bacterial pathogenesis or if it might just enhance inflammation without any benefit.

Finally, our network and enrichment analyses showed that the TRYCAT pathway may be involved in CFAS-D, although it is not a key component but rather a spin-off of the IO&NS
response. Previously, it was reported that this pathway is highly strongly associated with somatization disorder, a psychiatric disease accompanied by physiosomatic symptoms but not necessarily by fatigue [46].

When there's evidence for a biomedical involvement in the ultimate psychiatric condition "without physiological underlying cause", you know how lost the old psychiatric community really is with their ideology. Yet, this is their way of discrediting our symptoms as non-relevant and non-existent. The authors also work for a psychiatric department, amusing enough.

Thus 3OHK, one of the metabolics in our MPI network, is one of the neurotoxic TRYCATS produced during activation of this pathway as a consequence of IO&NS activation. KYNU (kynurenine hydroxylase) is as IDO an oxygen-consuming enzyme which catabolizes kynurenine into 3OHK (STRING).

And here is the link between the somatization disorder and kynurenine hydroxylation. Similar to this previous paper, it doesn't support the IDO trap theory but it supports a dysregulation of the tryptophan metabolism.

An important spin-off is increased IL10 production, which may contribute to immunosuppression and recurrent or protracted infections, and also increased TRYCAT production may aggravate the neurotoxic effects of oxidative stress.

This reminds me of my EBV IL-10 homolog theory again.

Although not further discussed, they also identified an EPA subnetwork, indicating that EPA supplementation might help to compensate a fraction of the pathophysiology.

We found 5 subnetworks: one centered around hydroperoxides (46 nodes), another around EPA (6 nodes), 6 around 3OHK, 4 around NO, and 3 around DHEA (albeit some overlapping).

 

[mariovitali]

@nerd

Thank you for pointing this out, they touch some very interesting aspects i think but i must take a better look on how they actually came up with these concept nodes.

I will get back with some more comments.

 

[mariovitali]

@mariovitali What's your take on this?

I use a specialised information extraction system where i input concepts related to ME research and the system replies with a number of concepts that are of interest. From the paper i found the following concepts to be related to this work :

ACE,AGER,AGRN,ALBUMIN,CCL2,CCL4,CCL11,CD3D,CD8A,CD19,CD38, CD69, HLA-DR, creatine phosphokinase,cldn5,CSF2,CTNNB1, DKK1, ELANE, GPX1, HbA1,HMGB1, IL1A,IL1B,IL1RN (IL-1RA), IL6, IL10, LYZ, NFKB1,NOS2, OCLN,OPRK1,OPRM1,POMC,PTGS2,RSPO1,TLR4,TNFRSF1A,TNFRSF1B,lactosylceramide,xanthurenate,picolinic acid,3-OH-Lkynurenine,hydrogen peroxides,neopterin


So the above concepts were fed to the system. Unfortunately i cannot comment on the results but what is interesting is that most studies so far point to specific concepts and some of them have not been looked at before.

I have shared however many of these results with a few researchers, hoping that they will help them.

 

[Martin aka paused||M.E.]

CCL2,CCL4,CCL11

Interestingly CCL-5 is missing.

 

[mariovitali]

Interestingly CCL-5 is missing.

Yes Martin, you are right ! Actually there are other entries missing from the list i posted as well , i just haven't copied them here (e.g. zinc, copper, Coenzyme Q10 etc).

These methods are exactly what we should be doing. In other words we must try to identify how all the findings about ME we have connect and whether there are "super-nodes" or certain Points of failure.

This is what i tried to do, starting from 2017 but unfortunately, i never had any help (from medical professionals) in doing so. Please believe me, i tried very very hard to have researchers look at these methods and only recently something is changing.

 

[Martin aka paused||M.E.]

Please believe me, i tried very very hard to have researchers look at these methods and only recently something is changing.

Yes, I have trouble with direct contact to researchers too. Luckily I'm friends with one who also attended the OMF symposium. But its very hard to get insight bc researchers are not interested most of the time.

I think it's very hard to identify ONE pathomechanism especially when looking at cytokines. Studies are inconsistent and cytokines can be released for whatever reason.