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Extracellular Vesicles

It was quite interesting to see more from the work of Maureen Hanson , Professor at University of Cornell [1]. In her Webpage -at the moment of Writing- Extracellular Vesicles (EVs) are being mentioned as one of her Current Research projects. More specifically it is stated that :

"Another project aims to identify differences in gene expression and cargo of extracellular vesicles at baseline and following exercise in healthy and in subjects diagnosed with ME/CFS"

I will visit EVs later in the post.

 A paper of great interest by Professor Hanson is [2]. In this paper we read the following :

"Primary bile acids such as sulfoglycolithocholate (13) are synthesized in the liver and the major bile salts result from its conjugation with taurine (28) and glycine, forming taurochenodeoxycholate and glycochenodeoxycholate (21), respectively, which are all numbered metabolites found to be significantly reduced in ME/CFS patients. Reduction in these compounds is suggestive of damage to the liver. A study from the FDA National Center for Toxicological Research (NCTR) was able to identify liver injury biomarkers as the result of drug-induced hepatotoxicity in rats. Strikingly, several other metabolites identical to our findings were also identified in their report, namely 5-guanidino-2-oxopentanoic acid (12, also named 2-oxoarginine), sebacic acid (60), along with energy metabolites from the glyoxylate and dicarboxylate metabolism. These biomarkers could be used to define a serum metabolic signature by creating a panel for hepatotoxicity prediction"

In other words this paper confirms several Topics discussed in this Blog, namely Bile Acids, Fat Metabolism and -potential- Liver-related issues.

Coming now back to EVs. In [3] we find a descritpion :

"Cells release into the extracellular environment diverse types of membrane vesicles of endosomal and plasma membrane origin called exosomes and microvesicles, respectively. These extracellular vesicles (EVs) represent an important mode of intercellular communication by serving as vehicles for transfer between cells of membrane and cytosolic proteins, lipids, and RNA"

Interestingly, many Topics identified by Machine Learning and Network Analysis seem to co-exist in Papers discussing EVs.

Some examples can be seen below. For convenience i add the Topics being discussed in this Blog in parentheses :

In [4]  we find : (ROCK1, Actin, Myosin, N-Linked Glycans, Liver Fibrosis)

"Phagocytosis of HepG2-derived ABs by hepatic stellate cells (HSC) activates JAK1/STAT3 and, to a lesser extent, PI3K/Akt/NF-kB survival pathways, upregulating Mcl-1 and A1 anti-apoptotic proteins, which leads to HSC survival and propagation of liver fibrosis"

"Exosomes also have polysaccharide and glycan signatures on their outer surface, predominantly comprising of mannose, α-2,3- and α-2,6-sialic acids, complex N-linked glycans, and polylactosamine"


"Actin polymerization results in the formation of restriction rings where bleb enucleation and formation occur [114,115]. This is achieved through caspase-3-mediated activation of gelsolin, which cleaves actin filaments in a calcium-independent manner [116]. After bleb enucleation, bleb expansion occurs through ROCK1-induced phosphorylation of the myosin light chain"

In [5] : (DOCK1, GAS6, Protein-S, Stabilin-2, MERTK, PPARGs,ABCA1, CD91)

In the same paper we find a detailed description of engulfement Signals and Phagocytosis (Phagocytosis has been described in previous posts). The paper contains also extensive coverage of EVs. 

Also of interest are the following excerpts :

"The clearance of apoptotic cells is an essential process for tissue homeostasis. To this end, cells undergoing apoptosis must display engulfment signals, such as ‘find-me' and ‘eat-me' signals. Engulfment signals are recognized by multiple types of phagocytic machinery in phagocytes, leading to prompt clearance of apoptotic cells. In addition, apoptotic cells and phagocytes release tolerogenic signals to reduce immune responses against apoptotic cell-derived self-antigens. Here we discuss recent advances in our knowledge of engulfment signals, the phagocytic machinery and the signal transduction pathways for apoptotic cell engulfment"

"The 12/15-lipoxygenase in resident peritoneal macrophages causes the cell surface exposure of oxidized phosphatidylethanolamine, which sequesters the MFG-E8 required for the clearance of apoptotic cells in inflammatory monocytes, suggesting that oxidized phosphatidylethanolamine on resident macrophages may be a signal to reduce immune responses"

Note : It is proposed that MFGE8, C1QA and Calreticulin are potential Research targets in the Syndromes discussed in this blog.

In [6] : (ER Stress, DAMPs)

In this paper we find several mentions of EVs along with ER Stress and DAMPs :

"In conclusion, our results suggest that severe ER stress-mediated release of EV-associated DAMPs may possibly contribute to the heightened systemic maternal inflammatory response and endothelial cell permeability characteristic of pre-eclampsia. These results may also be pertinent to other chronic inflammatory diseases which show elevated ER stress. Multiple mechanisms have been demonstrated by which ER stress can promote inflammation in these conditions, including delivery of danger signals to antigen presenting cells following ER stress-induced apoptosis [49]. Therefore it is conceivable that these effects may, in part, be mediated through the release of EV-associated DAMPs "

I would like now to provide a figure taken from [7] which shows several topics that have been previously discussed in this Blog :

In Red Boxes we see the Topics being mentioned in this Blog previously and in the Blue box are the new Targets suggested.

Interestingly, Inflammation and Auitoimmunity are mentioned in the bottom of the Figure



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As discussed in the previous post, Vitamin K appears to be one of the important topics according to the Network Analysis that has been performed. I wanted to see whether this would be the case using Classification Algorithms.

Below is a sample run with several algorithms being applied using Scikit-Learn (some topics found are not disclosed).

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See below Dr Ron Davis, discussing latest findings of  Research done at Stanford regarding Chronic Fatigue Syndrome. He mentions TCA Cycle :

From wikipedia, regarding TCA Cycle we read :

The citric acid cycle is a key metabolic pathway that connects carbohydr…