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DILI, Viruses and ER Stress

One of the most important papers i've read lately is quite possibly "Drug Induced Liver Injury : Interactions between drug properties and host factors" [1]. This paper is full of information that -in my opinion- deserves a closer look from Medical experts researching syndromes such as Chronic Fatigue, Fibromyalgia, Post-Accutane and others mentioned in this blog.


From Wikipedia we read the following about Drug-Induced Liver Injury (DILI) :


The human body identifies almost all drugs as foreign substances (i.e. xenobiotics) and subjects them to various chemical processes (i.e. metabolism) to make them suitable for elimination. This involves chemical transformations to (a) reduce fat solubility and (b) to change biological activity. Although almost all tissues in the body have some ability to metabolize chemicals, smooth endoplasmic reticulum in the liver is the principal "metabolic clearing house" for both endogenous chemicals (e.g., cholesterol, steroid hormones, fatty acids, proteins) and exogenous substances (e.g., drugs, alcohol). The central role played by liver in the clearance and transformation of chemicals makes it susceptible to drug-induced injury.

Drug metabolism may create Reactive Metabolites and Oxidative Stress [1]. The paper also states that :

Oxidative damage in the liver could be a consequence of cytosolic oxidant stress after drug metabolism or could arise from oxidant stress directly generated in mitochondria and the subsequent inflammatory cell response by injured hepatocytes.

Injured hepatocytes release ‘‘danger signals’’, such as the damage associated molecular patterns molecules (DAMPs) which favour the release of pro-inflammatory cytokines to induce a T/B- cell response against hepatocytes.

Of importance here is the induction of T Cell or B Cell response.


Continuing, we read :

Drugs initiate cellular damage through diverse mechanisms: reactive metabolite formation, which leads to covalent binding to cellular proteins, oxidative stress, endoplasmic reticulum stress, mitochondrial injury, DNA damage, epigenetic modifications, and/or inhibition of bile acid excretion 

and :

Gender and sex hormones are well-known to influence inflammation and immune response. An immune-mediated DILI model showed gender bias in immune response and inflammation; more severe hepatitis, more antibody production, and a higher level of pro-inflammatory hepatic cytokines in females vs. males


Interestingly, CFS appears to be more prevalent in Females vs Males [4]. Of interest also is the mention about Endoplasmic Reticulum (ER) Stress . 

A lot of cases of Chronic Fatigue, appear after -as an example- an EBV (Epstein-Bar virus) infection.

According to [2] :

In this review, we present a comprehensive summary of recent research in this field, which revealed that about 36 viruses trigger ER stress and differentially activate ER stress-related signaling pathways. We also highlight the strategies evolved by viruses to modulate ER stress-related signaling networks including immune responses in order to ensure their survival and pathogenesis.

In other words, apart from certain Medications (and for certain individuals), viruses also generate ER Stress which in turn may lead to the Unfolded Protein Response (UPR).

In [3] we also find connections between the UPR, Inflammation and Immunity (B Cells and T Cells are mentioned). As a concluding remark we read :

Much has been learned about the functions of the UPR beyond being simply a means to manage ER stress. The UPR has also now been recognized for its role in immune cell differentiation and function, and in regulating immune and inflammatory responses, including those associated with infections, tumours and autoimmune responses

So the UPR plays a central role in Inflammatory responses and autoimmune responses.

Interestingly on the latest video posted by Stanford where a symposium on CFS/ME took place, the main takeaways are T Cell activation (mentioned in the talk of Mark Davis) and also Inflammatory markers. No mentions however for ER Stress and UPR.

The algorithms used for this Research select both UPR and ER Stress as being important. Perhaps then, we may hypothesize that two mechanisms behind the syndromes discussed is the disruption of normal ER Stress and UPR functioning / activation.

References :

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