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SARS-CoV-2, as the causative agent of COVID-19, is an enveloped positives-sense single-stranded RNA virus that belongs to the Beta-CoVs sub-family. A sophisticated hyper-inflammatory reaction named cytokine storm is occurred in patients with severe/critical COVID-19, following an imbalance in immune-inflammatory processes and inhibition of antiviral responses by SARS-CoV-2, which leads to pulmonary failure, ARDS, and death. The miRNAs are small non-coding RNAs with an average length of 22 nucleotides which play various roles as one of the main modulators of genes expression and maintenance of immune system homeostasis. Recent evidence has shown that Homo sapiens (hsa)-miRNAs have the potential to work in three pivotal areas including targeting the virus genome, regulating the inflammatory signaling pathways, and reinforcing the production/signaling of IFNs-I. However, it seems that several SARS-CoV-2-induced interfering agents such as viral (v)-miRNAs, cytokine content, competing endogenous RNAs (ceRNAs), etc. preclude efficient function of hsa-miRNAs in severe/critical COVID-19. This subsequently leads to increased virus replication, intense inflammatory processes, and secondary complications development. In this review article, we provide an overview of hsa-miRNAs roles in viral genome targeting, inflammatory pathways modulation, and IFNs responses amplification in severe/critical COVID-19 accompanied by probable interventional factors and their function. Identification and monitoring of these interventional elements can help us in designing the miRNAs-based therapy for the reduction of complications/mortality rate in patients with severe/critical forms of the disease.

Pernio or chilblains is characterized by erythema and swelling at acral sites (eg, toes and fingers), typically triggered by cold exposure. Clinical and histopathologic features of pernio are well described, but the pathogenesis is not entirely understood; vasospasm and a type I interferon (IFN-I) immune response are likely involved. During the coronavirus disease 2019 (COVID-19) pandemic, dermatologists have observed an increase in pernio-like acral eruptions. Direct causality of pernio due to COVID-19 has not been established in many cases because of inconsistent testing methods (often negative results) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a form of COVID-19‒associated pernio (also called COVID toes) is likely because of the increased occurrence, frequently in young patients with no cold exposure or prior history of pernio, and reports of skin biopsies with positive SARS-CoV-2 immunohistochemistry. PubMed was searched for 2020 publications using the following keywords: pernio, chilblain, and acral COVID-19. On the basis of our review of the published literature, we speculate that several unifying cutaneous and systemic mechanisms may explain COVID-19‒associated pernio: 1) SARS-CoV-2 cell infection occurs through the cellular receptor angiotensin-converting enzyme 2 (ACE2) mediated by transmembrane protease serine 2 (TMPRSS2), subsequently affecting the renin-angiotensin-aldosterone system (RAAS) with an increase in the vasoconstricting, proinflammatory, and prothrombotic angiotensin II pathway. 2) SARS-CoV-2 cell infection triggers an immune response with robust IFN-I release in patients predisposed to COVID-19‒associated pernio. 3) Age and sex discrepancies correlated with COVID-19 severity and manifestations, including pernio as a sign of mild disease, are likely explained by age-related immune and vascular differences influenced by sex hormones and genetics, which affect susceptibility to viral cellular infection, the RAAS balance, and the IFN-I response., Article Highlights • One of the most common cutaneous manifestations associated with COVID-19 is pernio or chilblains, which has previously been associated with vasospasm and an IFN-I response. • ACE2 is the cellular receptor for SARS-CoV-2, which is processed differently by the proteases TMPRSS2 (ACE2 cleavage facilitates viral cellular entry) and ADAM17 (cleaves cell-bound ACE2, releasing an active form into the circulation). TMPRSS2 is stimulated by androgens, while ADAM17 is stimulated by estrogens; expression of both proteases increases with aging and inflammation. • Age and sex affect the response to COVID-19 infection because of differences in sex hormone activity, endothelial function, and innate immunity. Adult males and the aged demonstrate more pathogenic activity of TMPRSS2, ANGII, and IL-6; females and the young demonstrate more protective activity of ANG1-7 and IFN-I. • The complete RAAS resides in the skin and includes ANGII, which is involved in the cutaneous thermoregulatory vasoconstriction response, and ACE2, expressed in cutaneous endothelial cells and eccrine epithelial cells, both of which may be involved in the pathogenesis of COVID-19‒associated pernio. • Through an understanding of the interconnected cutaneous and systemic mechanisms, the varying skin manifestations of COVID-19 provide important signs of disease severity and may assist in unifying the therapeutic algorithm.

The outbreak of mysterious pneumonia at the end of 2019 is associated with widespread research interest worldwide. The coronavirus disease-19 (COVID-19) targets multiple organs through inflammatory, immune, and redox mechanisms, and no effective drug for its prophylaxis or treatment has been identified until now. The use of dietary bioactive compounds, such as phenolic compounds (PC), has emerged as a putative nutritional or therapeutic adjunct approach for COVID-19. In the present study, scientific data on the mechanisms underlying the bioactivity of PC and their usefulness in COVID-19 mitigation are reviewed. In addition, antioxidant, antiviral, anti-inflammatory, and immunomodulatory effects of dietary PC are studied. Moreover, the implications of digestion on the putative benefits of dietary PC against COVID-19 are presented by addressing the bioavailability and biotransformation of PC by the gut microbiota. Lastly, safety issues and possible drug interactions of PC and their implications in COVID-19 therapeutics are discussed.