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.

Treatment with M2000 in combination with conventional therapy showed a significantly superior efficacy along with a high safety profile compared to conventional-treated patients. Thereby, M2000 might be suggested as a suitable option in the treatment of RA.

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This study showed that drug M2000 as a novel NSAID with immunosuppressive property is able strongly to inhibit the activity of COX-1/COX-2 enzymes, with suppressing the gene expression of COX-2 specifically. Therefore, based on gene expression findings this drug might be categorized and introduced as a novel NSAID with selective COX-2 inhibitory effect.

The positive impacts of β‐d‐mannuronic acid (M2000) on the gene expression of miR‐155, its target molecules (SOCS1 and SHIP1), and NF‐κB transcription factor were demonstrated in a study using the HEK293‐TLR2 cell line. This new drug has been approved as a safe and effective medication by a randomized, multinational, phase III clinical trial on RA patients. The present study aimed to evaluate the oral administration effect of M2000 on the expression levels of the mentioned genes in RA patients. This research was conducted on 12 RA patients and 12 healthy individuals. After extraction of total RNA from PBMCs of patients and synthesis of cDNA, the expression levels of miR‐155, SOCS1, SHIP1, and NF‐κB genes were measured through quantitative Real‐time PCR at baseline and after 12 weeks of M2000 therapy. Our findings showed that the miR‐155 gene expression level significantly decreased in the M2000‐treated patients compared with the baseline (0.76‐fold, with p < .05). The expression levels of SOCS1 and SHIP1 genes significantly increased in the patients treated with M2000 compared with the before treatment (1.46‐, 1.54‐fold, with p < .01, p < .05, respectively). In addition, it was found that the gene expression level of the NF‐κB transcription factor significantly reduced in M2000‐treated patients compared with the baseline (0.81‐fold, with p < .05). This study showed that the oral administration of M2000 was able to reduce the expression of the miR‐155, increase the expression of SOCS1 and SHIP1, and decrease the NF‐κB gene expression (Trial Registration Number: IRCT2017100213739N10).

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