A Systematic Review of the Role of Purinergic Signalling Pathway in the Treatment of COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global health concern. Three years since its origin, despite the approval of vaccines and specific treatments against this new coronavirus, there are still high rates of infection, hospitalization, and mortality in some countries. COVID-19 is characterised by a high inflammatory state and coagulation disturbances that may be linked to purinergic signalling molecules such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine (ADO), and purinergic receptors (P1 and P2). These nucleotides/nucleosides play important roles in cellular processes, such as immunomodulation, blood clot formation, and vasodilation, which are affected during SARS-CoV-2 infection. Therefore, drugs targeting this purinergic pathway, currently used for other pathologies, are being evaluated in preclinical and clinical trials for COVID-19. In this review, we focus on the potential of these drugs to control the release, degradation, and reuptake of these extracellular nucleotides and nucleosides to treat COVID-19. Drugs targeting the P1 receptors could have therapeutic efficacy due to their capacity to modulate the cytokine storm and the immune response. Those acting in P2X7, which is linked to NLRP3 inflammasome activation, are also valuable candidates as they can reduce the release of pro-inflammatory cytokines. However, according to the available preclinical and clinical data, the most promising medications to be used for COVID-19 treatment are those that modulate platelets behaviour and blood coagulation factors, mainly through the P2Y12 receptor.

Mesenchymal Stem Cell-Derived Extracellular Vesicles Carrying miRNA as a Potential Multi Target Therapy to COVID-19: an In Silico Analysis.

In the end of 2019 COVID-19 emerged as a new threat worldwide and this disease present impaired immune system, exacerbated production of inflammatory cytokines, and coagulation disturbs. Mesenchymal stem cell (MSC) derived extracellular vesicles (EVs) have emerged as a therapeutic option due to its intrinsic properties to alleviate inflammatory responses, capable to promote the restoring of injured tissue. EVs contain heterogeneous cargo, including active microRNAs, small noncoding sequences involved in post-transcriptional gene repression or degradation and can attach in multiple targets. This study investigated whether the MSC-EVs miRNA cargo has the capacity to modulate the exacerbated cytokines, cell death and coagulation disturbs present in severe COVID-19. Through bioinformatics analysis, four datasets of miRNA, using different stem cell tissue sources (bone marrow, umbilical cord and adipose tissue), and one dataset of mRNA (bone marrow) were analyzed. 58 miRNAs overlap in the four miRNA datasets analyzed. Sequentially, those miRNAs present in at least two datasets, were analyzed using miRWalk for the 3'UTR binding target mRNA. The result predicted 258 miRNAs for exacerbated cytokines and chemokines, 266 miRNAs for cell death genes and 148 miRNAs for coagulation cascades. Some miRNAs may simultaneously attenuate inflammatory agents, inhibit cell death genes and key factors of coagulation cascade, consequently preventing tissue damage and coagulation disturbs. Therefore, the MSC-derived EVs due to their heterogeneous cargo are a potential multitarget approach able to improve the survival rates of severe COVID-19 patients.