Blockade of Exosome Generation with GW4869 Dampens the Sepsis-Induced Inflammation and Cardiac Dysfunction

[junkcrap50]

(Emphasis mine.)

Blockade of Exosome Generation with GW4869 Dampens the Sepsis-Induced Inflammation and Cardiac Dysfunction
Kobina Essandoh,1,* Liwang Yang,1,6,* Xiaohong Wang,1 Wei Huang,2 Dongze Qin,1,7 Jiukuan Hao,3 Yigang Wang,2 Basilia Zingarelli,4 Tianqing Peng,5 and Guo-Chang Fan1,*
Author information Copyright and License information Disclaimer

The publisher's final edited version of this article is available at Biochim Biophys Acta

Abstract
Sepsis is an infection-induced severe inflammatory disorder that leads to multiple organ failure. Amongst organs affected, myocardial depression is believed to be a major contributor to septic death. While it has been identified that large amounts of circulating pro-inflammatory cytokines are culprit for triggering cardiac dysfunction in sepsis, the underlying mechanisms remain obscure. Additionally, recent studies have shown that exosomes released from bacteria-infected macrophages are pro-inflammatory. Hence, we examined in this study whether blocking the generation of exosomes would be protective against sepsis-induced inflammatory response and cardiac dysfunction. To this end, we pre-treated RAW264.7 macrophages with GW4869, an inhibitor of exosome biogenesis/release, followed by endotoxin (LPS) challenge. In vivo, we injected wild-type (WT) mice with GW4869 for 1 h prior to endotoxin treatment or cecal ligation/puncture (CLP) surgery. We observed that pre-treatment with GW4869 significantly impaired release of both exosomes and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in RAW264.7 macrophages. At 12 h after LPS treatment or CLP surgery, WT mice pretreated with GW4869 displayed lower amounts of exosomes and pro-inflammatory cytokines in the serum than control PBS-injected mice. Accordingly, GW4869 treatment diminished the sepsis-induced cardiac inflammation, attenuated myocardial depression and prolonged survival. Together, our findings indicate that blockade of exosome generation in sepsis dampens the sepsis-triggered inflammatory response and thereby, improves cardiac function and survival.

Keywords: sepsis, exosomes, cardiac dysfunction, macrophages, inflammatory response

 

[junkcrap50]

From the introduction of the paper:

Currently, GW4869, a neutral sphingomyelinase inhibitor, is the most widely used pharmacological agent for blocking exosome generation [29–32]. GW4869 inhibits the ceramide-mediated inward budding of multivesicular bodies (MVBs) and release of mature exosomes from MVBs [30].

Seems like sphingomyelin is important in exosome release.

 

[Hip]

Looks like cannabidiol (CBD) is also an exosome and microvesicle inhibitor. Though I've not come across many stories of CBD oil generally helping ME/CFS, though a few patients report it helps with sleep.

 

[Peter Pain]

Looks like cannabidiol (CBD) is also an exosome and microvesicle inhibitor. Though I've not come across many stories of CBD oil generally helping ME/CFS, though a few patients report it helps with sleep.

the dose is probably too low. After all, people with epilepsy take hundreds of times the usual dose. the usual dose probably works only on placebo anyway.

 

[junkcrap50]

Also, ketotifen looks to be one also, interestingly: Inhibition of exosome release by ketotifen enhances sensitivity of cancer cells to doxorubici

 

[junkcrap50]

Looks like cannabidiol (CBD) is also an exosome and microvesicle inhibitor. Though I've not come across many stories of CBD oil generally helping ME/CFS, though a few patients report it helps with sleep.

From your link:

The secretion of exosomes is also affected via purinergic receptors such as P2X7 (Qu et al., 2007)...

 

[Peter Pain]

"But viruses, such as the HI viruses, use exosomes for transport and camouflage. Exosomes are currently being investigated as potential treatment options in the treatment of autoimmune diseases and cancer. The formation of exosomes can still be triggered by certain substances such as the antibiotic ciprofloxacin. [1]"

When does Davis finally look for RNA viruses?

@Janet Dafoe (Rose49)

 

[Jackb23]

From the introduction of the paper:

Seems like sphingomyelin is important in exosome release.

When I did a metabolomics study, they found that I had some sphingomyelin anomalies.

 

[Hip]

the dose is probably too low. After all, people with epilepsy take hundreds of times the usual dose. the usual dose probably works only on placebo anyway.

Possibly. In the in vitro tests in that study, they used CBD concentrations of 1 and 5 μM. To convert those to an oral dose, you can use the approximate equation detailed in this post.