ELV-N32 and RvD6 isomer decrease pro-inflammatory cytokines, senescence programming, ACE2 and SARS-CoV-2-spike protein RBD binding in injured cornea

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that causes coronavirus disease 2019 (COVID-19) has resulted in a pandemic affecting the most vulnerable in society, triggering a public health crisis and economic collapse around the world. Effective treatments to mitigate this viral infection are needed. Since the eye is a route of virus entrance, we use an in vivo rat model of corneal inflammation as well as human corneal epithelial cells (HCEC) in culture challenged with IFNγ as models of the eye surface to study this issue. We explore ways to block the receptor-binding domain (RBD) of SARS-CoV-2 Spike (S) protein to angiotensin-converting enzyme 2 (ACE2). We found that the lipid mediators, elovanoid (ELV)-N32 or Resolvin D6-isomer (RvD6i) decreased the expression of the ACE2 receptor, furin, and integrins in damaged corneas or IFNγ-stimulated HCEC. There was also a concomitant decrease in the binding of Spike RBD with the lipid treatments. Using RNA-seq analysis, we uncovered that the lipid mediators also attenuated the expression of pro-inflammatoy cytokines participating in hyper-inflammation and senescence programming. Thus, the bioactivity of these lipid mediators will contribute to open therapeutic avenues to counteract virus attachment and entrance to the body.

Resolution pharmacology and the treatment of infectious diseases

“…It is difficult to reconcile the data in these studies, but clearly a small sample size and differences in methodologies for lipid measurements may have contributed to the inconsistency between findings. A RvD6 isomer decreased the expression of ACE2 receptor and pro‐inflammatory cytokine levels in vitro (Pham et al, 2021) and treatment of macrophages with RvD1 and RvD2 upon SARS‐CoV‐2 infection reduced levels of TNF, IL‐6, IL‐8, CCL2 and CCL3 cytokines (Recchiuti et al, 2021). The latter set of data suggest that RvD administration may dampen the excessive inflammation observed in COVID‐19, but it is not possible to relate this consistently to any clinical findings in humans.…”

Specialized pro-resolving lipid mediators regulate inflammatory macrophages: A paradigm shift from antibiotics to immunotherapy for mitigating COVID-19 pandemic

“…Maresins 13S, 14S-epoxy-maresin intermediate generated during synthesis of Maresin (MaR1) is bioactive and stimulates the phenotype transition from M1 to M2 macrophages ( Serhan et al, 2022 ). RvD6 isomer and Elovanoid-N32 reduced expression of the ACE2 receptors and blocked the receptor binding domain of the virus spike protein thereby preventing receptor-virus interactions, reducing pro-inflammatory cytokine release ( Pham et al, 2021 ). The protectin (PD) family of mediators regulate viral propagation by inhibiting intracellular viral RNA transport mechanisms.…”

Statin Improves Early-Phase Obesity-Induced Renal Injury via Restoring Autophagy Failure Through Rho/Rho Kinase/mTOR Pathway Inhibition

“…The capillary-based western assay was performed using a Jess system (Protein Simple, San Jose, CA, USA) as previously described 40 . Brie y, renal cortices were homogenized in RIPA lysis buffer (Santa Cruz Biotechnology) and cell debris was removed by centrifugation at 16,000× g. Protein concentration was determined using Sample buffer (Jess/Wes Separation Module, Bio-Tech #SM-FL001), and 1 µg was used per reaction.…”