Icosapent ethyl (VASCEPA®) as treatment for post-acute sequelae of SARS CoV-2 (PASC) vaccine induced injury and infection.

OBJECTIVES: As the COVID-19 pandemic continues, a prolonged post-infectious syndrome or "long COVID" has been reported. This is a multi-organ post viral syndrome that persists well after infection. Currently, there is no available treatment. Emerging evidence credits this "long COVID" syndrome to ongoing inflammatory response following resolution of symptoms during infection. An omega-three fatty acid derivative used in the treatment of hypertriglyceridemia, Icosapent Ethyl (IPE, VASCEPA®/Epadel®), was previously shown to reduce cardiovascular risk, likely via immunomodulatory effects. This study aims to evaluate the effectiveness of Icosapent Ethyl. METHODS: Following previous publications in treatment of severe acute COVID-19, we analyze two case studies of adults treated with Icosapent Ethyl. RESULTS: After experiencing the symptoms of Long Covid, both individuals analyzed across two case studies experiences a resolution of symptoms after treatment with Icosapent Ethyl. CONCLUSION: After review and analysis we conclude that Icosapent Ethyl may have been a determining factor in Long COVID symptom resolution and should be studied further.

Isomerization of Keggin Al13 Ions Followed by Diffusion Rates.

The solution chemistry of aluminum has long interested scientists due to its relevance to materials chemistry and geochemistry. The dynamic behavior of large aluminum-oxo-hydroxo clusters, specifically [Al13 O4 (OH)24 (H2 O)12 ]7+ (Al13 ), is the focus of this paper. 27 Al NMR, 1 H NMR, and 1 H DOSY techniques were used to follow the isomerization of the ϵ-Al13 in the presence of glycine and Ca2+ at 90 °C. Although the conversion of ϵ-Al13 to new clusters and/or Baker-Figgis-Keggin isomers has been studied previously, new 1 H NMR and 1 H DOSY analyses provided information about the role of glycine, the ligated intermediates, and the mechanism of isomerization. New 1 H NMR data suggest that glycine plays a critical role in the isomerization. Surprisingly, glycine does not bind to Al30 clusters, which were previously proposed as an intermediate in the isomerization. Additionally, a highly symmetric tetrahedral signal (δ=72 ppm) appeared during the isomerization process, which evidence suggests corresponds to the long-sought α-Al13 isomer in solution.

Cutting edge: ABIN-1 protects against psoriasis by restricting MyD88 signals in dendritic cells.

Psoriasis is a chronic, inflammatory skin disease caused by a combination of environmental and genetic factors. The Tnip1 gene encodes A20 binding and inhibitor of NF-κB-1 (ABIN-1) protein and is strongly associated with susceptibility to psoriasis in humans. ABIN-1, a widely expressed ubiquitin-binding protein, restricts TNF- and TLR-induced signals. In this study, we report that mice lacking ABIN-1 specifically in dendritic cells (DCs), ABIN-1(fl) CD11c-Cre mice, exhibit perturbed immune homeostasis. ABIN-1-deficient DCs display exaggerated NF-κB and MAPK signaling and produce more IL-23 than do normal cells in response to TLR ligands. Challenge of ABIN-1(fl) CD11c-Cre mice with topical TLR7 ligand leads to greater numbers of Th17 and TCRγδ T cells and exacerbated development of psoriaform lesions. These phenotypes are reversed by DC-specific deletion of the TLR adaptor MyD88. These studies link ABIN-1 with IL-23 and IL-17, and they provide cellular and molecular mechanisms by which ABIN-1 regulates susceptibility to psoriasis.

ABIN-1 is a ubiquitin sensor that restricts cell death and sustains embryonic development.

Proteins that directly regulate tumour necrosis factor receptor (TNFR) signalling have critical roles in regulating cellular activation and survival. ABIN-1 (A20 binding and inhibitor of NF-kappaB) is a novel protein that is thought to inhibit NF-kappaB signalling. Here we show that mice deficient for ABIN-1 die during embryogenesis with fetal liver apoptosis, anaemia and hypoplasia. ABIN-1 deficient cells are hypersensitive to tumour necrosis factor (TNF)-induced programmed cell death, and TNF deficiency rescues ABIN-1 deficient embryos. ABIN-1 inhibits caspase 8 recruitment to FADD (Fas-associated death domain-containing protein) in TNF-induced signalling complexes, preventing caspase 8 cleavage and programmed cell death. Moreover, ABIN-1 directly binds polyubiquitin chains and this ubiquitin sensing activity is required for ABIN-1's anti-apoptotic activity. These studies provide insights into how ubiquitination and ubiquitin sensing proteins regulate cellular and organismal survival.

A kinase inhibitor activates the IRE1alpha RNase to confer cytoprotection against ER stress.

Unfolded proteins in the endoplasmic reticulum (ER) cause trans-autophosphorylation of the bifunctional transmembrane kinase IRE1alpha, inducing its RNase activity to splice XBP1 mRNA, in turn triggering a transcriptional program in the unfolded protein response (UPR). As we previously showed with the yeast IRE1 kinase ortholog, a single missense mutation in the ATP-binding pocket of murine IRE1alpha kinase sensitizes it to the ATP-competitive inhibitor 1NM-PP1, and subordinates RNase activity to the drug. This highly unusual mechanism of kinase signaling requiring kinase domain ligand occupancy-even through an inhibitor-to activate a nearby RNase has therefore been completely conserved through evolution. We also demonstrate that engagement of the drug-sensitized IRE1alpha kinase through this maneuver affords murine cells cytoprotection under ER stress. Thus kinase inhibitors of IRE1alpha are useful for altering the apoptotic outcome to ER stress, and could possibly be developed into drugs to treat ER stress-related diseases.

Selective glucocorticoid control of Rho kinase isoforms regulate cell-cell interactions.

The two Rho kinase isoforms ROCK1 and ROCK2 are downstream effectors of the small GTPase RhoA, although relatively little is known about potential isoform specific functions or the selective control of their cellular activities. Using Con8 rat mammary epithelial cells, we show that the synthetic glucocorticoid dexamethasone strongly stimulates the level of ROCK2 protein, which accounts for the increase in total cellular ROCK2 activity, whereas, steroid treatment down-regulated ROCK1 specific kinase activity without altering ROCK1 protein levels. In Con8 cells, the glucocorticoid induced formation of tight junctions requires the steroid-mediated down-regulation RhoA and function of the RhoA antagonist Rnd3. Treatment with the ROCK inhibitor Y-27632 ablated both the glucocorticoid-induced and Rnd3-mediated stimulation in tight junction sealing. Taken together, our results demonstrate that the expression and activity of ROCK1 and ROCK2 can be uncoupled in a signal-dependent manner, and further implicate a new function for ROCK2 in the steroid control of tight junction dynamics.