Aberrations in the Cross-Talks Among Redox, Nuclear Factor-κB and Wnt/Catenin Pathway Signaling Underpin ME and chronic fatigue, 2021, Maes et al

Hoopoe

Hoopoe

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

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.

https://www.preprints.org/manuscript/202109.0201/v1

Posting mainly because one of the genetic mutations I have affects a cadherin that normally forms a complex with beta-catenin so it seems like it could be relevant to the process being described here.
 
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That's a big claim in the title, hopefully the research lives up to it. Many of those components have appeared in me/cfs research over the years - IL-10 is one of the few cytokines that sticks out frequently enough to be a little curious about.
 
That is a complicated and jargon-heavy paper. It's using machine learning to pinpoint the hotspots relating to ME and the related disorders. The authors use the term "chronic fatigue spectrum disorders (CFAS-Ds)", in which they include myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), and chronic fatigue (CF). I haven't worked out where the 'A' comes in - maybe 'associated'.

They also appear to define a new term "physiosomatic symptoms" as a pushback against "psychosomatic symptoms", which they argue are not psychogenic. Before reading their complicated findings and discussion, it's probably worth quoting their opening position statements, particularly given that this paper is in a psychiatry journal (my highlights).

These different approaches, sometimes even competing, comprise folk psychology (the culprit of CFAS-D is a psychological problem) and the medical approach (the culprit is one specific virus or different viruses or bacteria). The dominant view, especially in Europe, is that of the cognitive-behavioral and the biopsychosocial schools. This view entails that CFAS-Ds, even when due to medical disease (e.g., cancer), are the consequence of psychosocial and biological factors and negative cognitions.
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The Wessely model, for example, conceptualizes that the effects of a trigger factor, which may be a virus, are mediated by boom and bust activity and bed rest and the Vercoulen model considers that CFAS-D symptoms are aggravated by causal attributions and reduced physical activity. Nevertheless, it appears that the label “biopsychosocial” is more window dressing than the actual approach because, in fact, folk psychology statements abound in their publications, as, for example, “it is in the mind,” “they think themselves ill,” and “it is a disorder of perception, whereby patients think those symptoms are the consequence of a virus”. Nevertheless, this folk psychology approach is embraced by the National Health Service (NHS), the Lancet, and national healthcare system all over Europe.
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CFAS-D symptoms are reflective manifestation of the symptomatome of, for example, coronavirus disease 2019 (COVID-19), chronic kidney disease with hemodialysis, schizophrenia, and rheumatoid arthritis, suggesting that CFAS-D symptoms are part of the core of these medical disorders and not the result of some “it is in the mind” process, if there would exist such a process.
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They do then get a bit self-referential.

It was not until 2010–2013, when Maes et al. launched a new biomedical model that more targeted medical research into CFAS-D began. These biomedical models of Maes et al. conceptualized CFAS-D as medical conditions whereby trigger factors such as immune activation, bacterial and viral infections, and a reduced protectome due to, for example, reduced antioxidant levels may cause multiple adverse outcome pathways (AOPs) leading to the phenome of CFAS-D.
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To quote a professor I worked with briefly: "NFkB is seen in everything". Also Wnt. He worked with inflammatory bowel disease and autoimmunity.

Off topic but I really enjoy we have a protein called "Frizzled" here :laugh:

Back on topic: I I do enjoy it when oxidative stress and problems with cell-cell junctions turn up. I don't think it's the whole story, but it's also seen in other chronic conditions. The junctions in the intestinal wall are in theory possible to manipulate through diet, but for the rest of the body it is more difficult (the compounds found in foods that could influence expression and/or localisation of cell junction proteins are not absorbed well, which is why concentration in the gut might become high enough to have an effect on gene expression/portein localisation, but for the rest of the body that just won't happen).
 
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