Role of non-coding RNAs in tuberculosis and their potential for clinical applications.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of mortality due to infectious diseases, only surpassed in 2020 by COVID-19. Despite the development in diagnostics, therapeutics, and evaluation of new vaccines for TB, this infectious disease remains uncontrollable due to the emergence of multidrug-resistant (MDR) and extremely drug-resistant (XDR) TB, among other factors. The development in transcriptomics (RNomics) has enabled the study of gene expression in TB. It is considered that non-coding RNAs (ncRNAs) from host [microRNAs (miRNAs)] and Mtb [small RNAs (sRNAs)] are important elements in TB pathogenesis, immune resistance, and susceptibility. Many studies have shown the importance of host miRNAs in regulating immune response against Mtb via in vitro and in vivo mice models. The bacterial sRNAs play a major role in survival, adaptation, and virulence. Here, we review the characterization and function of host and bacteria ncRNAs in TB and their potential use in clinical applications as diagnostic, prognostic, and therapeutic biomarkers.

Promising use of immune cell-derived exosomes in the treatment of SARS-CoV-2 infections.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is persistently threatening the lives of thousands of individuals globally. It triggers pulmonary oedema, driving to dyspnoea and lung failure. Viral infectivity of coronavirus disease 2019 (COVID-19) is a genuine challenge due to the mutagenic genome and mysterious immune-pathophysiology. Early reports highlighted that extracellular vesicles (exosomes, Exos) work to enhance COVID-19 progression by mediating viral transmission, replication and mutations. Furthermore, recent studies revealed that Exos derived from immune cells play an essential role in the promotion of immune cell exhaustion by transferring regulatory lncRNAs and miRNAs from exhausted cells to the active cells. Fortunately, there are great chances to modulate the immune functions of Exos towards a sustained repression of COVID-19. Engineered Exos hold promising immunotherapeutic opportunities for remodelling cytotoxic T cells' function. Immune cell-derived Exos may trigger a stable epigenetic repression of viral infectivity, restore functional cytokine-producing T cells and rebalance immune response in severe infections by inducing functional T regulatory cells (Tregs). This review introduces a view on the current outcomes of immunopathology, and immunotherapeutic applications of immune cell-derived Exos in COVID-19, besides new perspectives to develop novel patterns of engineered Exos triggering novel anti-SARS-CoV-2 immune responses.

MicroRNAs in the development of potential therapeutic targets against COVID-19: A narrative review.

BACKGROUND: As the therapeutic regimens against the COVID-19 remain scarce, the microRNAs (miRNAs) can be exploited to generate efficient therapeutic targets. The miRNAs have been found to play pivotal roles in the several regulatory functions influencing the prognosis of viral infection. The miRNAs have a prospective role in the up and down regulation of the ACE2 receptors. This review examines the clinical applications, as well as the possible threats associated with the use of miRNAs to combat the deleterious consequences of SARS-CoV-2 infection. METHODOLOGY: This article was compiled to evaluate how the miRNAs are involved in the SARS-CoV-2 pathogenesis and infection, and their potential functions which could help in the development of therapeutic targets against the COVID-19. The sources of the collected information include the several journals, databases and scientific search engines such as the Google scholar, Pubmed, Science direct, official website of WHO, among the other sites. The investigations on the online platform were conducted using the keywords miRNA biogenesis, miRNA and ACE2 interaction, therapeutic role of miRNAs against SARS-CoV-2 and miRNA therapy side effects. RESULTS: This review has highlighted that the miRNAs can be exploited to generate potential therapeutic targets against the COVID-19. Changes in the miRNA levels following viral replication are an essential component of the host response to infection. The collection and modification of miRNA modulates may help to minimize the deleterious consequences of SARS-CoV-2 infection, such as by controlling or inhibiting the generation of cytokines and chemokines. The degradation of viral RNA by the cellular miRNAs, along with the reduced expression of ACE2 receptors, can substantially reduce the viral load. Specific miRNAs have been found to have an antiviral influence, allowing the immune system to combat the infection or forcing the virus into a latency stage. CONCLUSION: This review summarizes several studies revealing the involvement of miRNAs in diverse and complex processes during the infection process of SARS-CoV-2. The miRNAs can substantially reduce the viral load by degradation of viral RNA and reduced expression of ACE2 receptors, besides mitigating the deleterious consequences of the exaggerated secretion of cytokines. Extensive investigations need to be done by the scientific community to utilize the miRNA based strategies for the development of effective therapeutic targets against the COVID-19.

RNA Therapeutics: the Next Generation of Drugs for Cardiovascular Diseases.

PURPOSE OF REVIEW: RNA therapeutics are a new and rapidly expanding class of drugs to prevent or treat a wide spectrum of diseases. We discuss the defining characteristics of the diverse family of molecules under the RNA therapeutics umbrella. RECENT FINDINGS: RNA therapeutics are designed to regulate gene expression in a transient manner. For example, depending upon the strategy employed, RNA therapies offer the versatility to replace, supplement, correct, suppress, or eliminate the expression of a targeted gene. RNA therapies include antisense nucleotides, microRNAs and small interfering RNAs, RNA aptamers, and messenger RNAs. Further, we discuss the mechanism(s) by which different RNA therapies either reduce or increase the expression of their targets. We review the RNA therapeutics approved (and those in trials) to treat cardiovascular indications. RNA-based therapeutics are a new, rapidly growing class of drugs that will offer new alternatives for an increasing array of cardiovascular conditions.

MiRNAs in Gestational Diabetes Mellitus: Potential Mechanisms and Clinical Applications.

Gestational diabetes mellitus (GDM) is a common pregnancy complication which is normally diagnosed in the second trimester of gestation. With an increasing incidence, GDM poses a significant threat to maternal and offspring health. Therefore, we need a deeper understanding of GDM pathophysiology and novel investigation on the diagnosis and treatment for GDM. MicroRNAs (miRNAs), a class of endogenic small noncoding RNAs with a length of approximately 19-24 nucleotides, have been reported to exert their function in gene expression by binding to proteins or being enclosed in membranous vesicles, such as exosomes. Studies have investigated the roles of miRNAs in the pathophysiological mechanism of GDM and their potential as noninvasive biological candidates for the management of GDM, including diagnosis and treatment. This review is aimed at summarizing the pathophysiological significance of miRNAs in GDM development and their potential function in GDM clinical diagnosis and therapeutic approach. In this review, we summarized an integrated expressional profile and the pathophysiological significance of placental exosomes and associated miRNAs, as well as other plasma miRNAs such as exo-AT. Furthermore, we also discussed the practical application of exosomes in GDM postpartum outcomes and the potential function of several miRNAs as therapeutic target in the GDM pathological pathway, thus providing a novel clinical insight of these biological signatures into GDM therapeutic approach.

Potential Therapeutic Effect of Micrornas in Extracellular Vesicles from Mesenchymal Stem Cells against SARS-CoV-2.

Extracellular vesicles (EVs) are cell-released, nanometer-scaled, membrane-bound materials and contain diverse contents including proteins, small peptides, and nucleic acids. Once released, EVs can alter the microenvironment and regulate a myriad of cellular physiology components, including cell-cell communication, proliferation, differentiation, and immune responses against viral infection. Among the cargoes in the vesicles, small non-coding micro-RNAs (miRNAs) have received attention in that they can regulate the expression of a variety of human genes as well as external viral genes via binding to the complementary mRNAs. In this study, we tested the potential of EVs as therapeutic agents for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. First, we found that the mesenchymal stem-cell-derived EVs (MSC-EVs) enabled the rescue of the cytopathic effect of SARS-CoV-2 virus and the suppression of proinflammatory responses in the infected cells by inhibiting the viral replication. We found that these anti-viral responses were mediated by 17 miRNAs matching the rarely mutated, conserved 3'-untranslated regions (UTR) of the viral genome. The top five miRNAs highly expressed in the MSC-EVs, miR-92a-3p, miR-26a-5p, miR-23a-3p, miR-103a-3p, and miR-181a-5p, were tested. They were bound to the complemented sequence which led to the recovery of the cytopathic effects. These findings suggest that the MSC-EVs are a potential candidate for multiple variants of anti-SARS-CoV-2.

miRNAs; a novel strategy for the treatment of COVID-19.

Coronavirus disease 2019 (COVID-19) is the seventh member of the bat severe acute respiratory syndrome family. COVID-19 can fuse their envelopes with the host cell membranes and deliver their genetic material. COVID-19 attacks the respiratory system and stimulates the host inflammatory responses, enhances the recruitment of immune cells, and promotes angiotensin-converting enzyme 2 activities. Patients with confirmed COVID-19 may have experienced fever, dry cough, headache, dyspnea, acute kidney injury, acute respiratory distress syndrome, and acute heart injury. Several strategies such as oxygen therapy, ventilation, antibiotic or antiviral therapy, and renal replacement therapy are commonly used to decrease COVID-19-associated mortality. However, these approaches may not be good treatment options. Therefore, the search for an alternative-novel therapy is urgently important to prevent the disease progression. Recently, microRNAs (miRNAs) have emerged as a promising strategy for COVID-19. The design of oligonucleotide against the genetic material of COVID-19 might suppress virus RNA translation. Several previous studies have shown that host miRNAs play an antiviral role and improve the treatment of patients with COVID-19. miRNAs by binding to the 3'-untranslated region (UTR) or 5'-UTR of viral RNA play an important role in COVID-19-host interplay and viral replication. miRNAs interact with multiple pathways and reduce inflammatory biomarkers, thrombi formation, and tissue damage to accelerate the patient outcome. The information in this review provides a summary of the current clinical application of miRNAs for the treatments of patients with COVID-19.

MicroRNA Mimics or Inhibitors as Antiviral Therapeutic Approaches Against COVID-19.

Coronaviruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the coronavirus disease 2019 (COVID-19) pandemic, present a significant threat to human health by inflicting a wide variety of health complications and even death. While conventional therapeutics often involve administering small molecules to fight viral infections, small non-coding RNA sequences, known as microRNAs (miRNAs/miR-), may present a novel antiviral strategy. We can take advantage of their ability to modulate host-virus interactions through mediating RNA degradation or translational inhibition. Investigations into miRNA and SARS-CoV-2 interactions can reveal novel therapeutic approaches against this virus. The viral genomes of SARS-CoV-2, severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV) were searched using the Nucleotide Basic Local Alignment Search Tool (BLASTn) for highly similar sequences, to identify potential binding sites for miRNAs hypothesized to play a role in SARS-CoV-2 infection. miRNAs that target angiotensin-converting enzyme 2 (ACE2), the receptor used by SARS-CoV-2 and SARS-CoV for host cell entry, were also predicted. Several relevant miRNAs were identified, and their potential roles in regulating SARS-CoV-2 infections were further assessed. Current treatment options for SARS-CoV-2 are limited and have not generated sufficient evidence on safety and efficacy for treating COVID-19. Therefore, by investigating the interactions between miRNAs and SARS-CoV-2, miRNA-based antiviral therapies, including miRNA mimics and inhibitors, may be developed as an alternative strategy to fight COVID-19.

Regenerative Medicine Approaches in COVID-19 Pneumonia.

Regenerative medicine (RM) is an interdisciplinary field that uses different approaches to accelerate the repair and regeneration or replace damaged or diseased human cells or tissues to achieve normal tissue function. These approaches include the stimulation of the body's own repair processes, transplantation of progenitor cells, stem cells, or tissues, as well as the use of cells and exosomes as delivery-vehicles for cytokines, genes, or other therapeutic agents. COVID-19 pneumonia is a specific disease consistent with diffuse alveolar damage resulting in severe hypoxemia. Therefore, the most serious cause of death from COVID-19 is lung dysfunction. Here, we consider RM approaches to cure COVID-19 pneumonia based on what RM has so far used to treat lung diseases, injuries, or pneumonia induced by other pathogens. These approaches include stem and progenitor cell transplantation, stem cell-derived exosomes, and microRNAs therapy.

Tackling the COVID-19 "cytokine storm" with microRNA mimics directly targeting the 3'UTR of pro-inflammatory mRNAs.

COVID-19 is characterized by two major clinical phases, the SARS-CoV-2 infection of target cells and tissues, and a deep inflammatory state, known as "cytokine storm", caused by activation of pro-inflammatory genes, such as NF-kB, STAT-3, IL-6, IL-8, IL-1ß. Among possible anti-inflammatory agents, the "microRNA targeting" should be carefully considered, since it is well known that microRNAs are deeply involved in the expression of cytokines, chemokines and growth factors. The working general hypothesis is that targeting the microRNA network might be important for the development of therapeutic approaches to counteract the COVID-19 induction of inflammatory response. This hypothesis is based on several publications demonstrating the use of miRNA mimics for inhibitory effects on the production of proteins characterizing the COVID-19 "cytokine storm".

Genetics and genomics of SARS-CoV-2: A review of the literature with the special focus on genetic diversity and SARS-CoV-2 genome detection.

The outbreak of 2019-novel coronavirus disease (COVID-19), caused by SARS-CoV-2, started in late 2019; in a short time, it has spread rapidly all over the world. Although some possible antiviral and anti-inflammatory medications are available, thousands of people are dying daily. Well-understanding of the SARS-CoV-2 genome is not only essential for the development of new treatments/vaccines, but it also can be used for improving the sensitivity and specificity of current approaches for virus detection. Accordingly, we reviewed the most critical findings related to the genetics of the SARS-CoV-2, with a specific focus on genetic diversity and reported mutations, molecular-based diagnosis assays, using interfering RNA technology for the treatment of patients, and genetic-related vaccination strategies. Additionally, considering the unanswered questions or uncertainties in these regards, different topics were discussed.

A new approach for COVID-19 treatment by micro-RNA.

MicroRNAs (miRNAs) naturally occur in plants and all living organisms. They play an important role in gene regulation through binding toa specific region in open reading frames (ORFs) and/or untranslated regions (UTRs) to block the translation processes through either degrading or blocking mRNA resulting in knocking down or suppression of targeted genes. Plants and many organisms protect themselves from viruses through the production of miRNAs, which are complementary to 3UTR of viruses resulting in degrading the viral mRNA or block the translation on ribosomes. As pandemic, COVID-19, and its consequences on the global economy, we hypothesized a new approach for the treatment of COVID-19 paints. This approach includes designing a mix of miRNAs targeting several regions on COVID-19 open reading frame (ORF) and 3 UTR and suitable delivery system targeting respiratory system tissues. These synthesized miRNAs may be delivered to humansinnon-viral delivery systems such as liposomes like exosome (extracellular vesicle), polymer-based carriers, or inorganic nanoparticles, which are considered to be more suitable for human use.

RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges.

RNA-based therapies, including RNA molecules as drugs and RNA-targeted small molecules, offer unique opportunities to expand the range of therapeutic targets. Various forms of RNAs may be used to selectively act on proteins, transcripts, and genes that cannot be targeted by conventional small molecules or proteins. Although development of RNA drugs faces unparalleled challenges, many strategies have been developed to improve RNA metabolic stability and intracellular delivery. A number of RNA drugs have been approved for medical use, including aptamers (e.g., pegaptanib) that mechanistically act on protein target and small interfering RNAs (e.g., patisiran and givosiran) and antisense oligonucleotides (e.g., inotersen and golodirsen) that directly interfere with RNA targets. Furthermore, guide RNAs are essential components of novel gene editing modalities, and mRNA therapeutics are under development for protein replacement therapy or vaccination, including those against unprecedented severe acute respiratory syndrome coronavirus pandemic. Moreover, functional RNAs or RNA motifs are highly structured to form binding pockets or clefts that are accessible by small molecules. Many natural, semisynthetic, or synthetic antibiotics (e.g., aminoglycosides, tetracyclines, macrolides, oxazolidinones, and phenicols) can directly bind to ribosomal RNAs to achieve the inhibition of bacterial infections. Therefore, there is growing interest in developing RNA-targeted small-molecule drugs amenable to oral administration, and some (e.g., risdiplam and branaplam) have entered clinical trials. Here, we review the pharmacology of novel RNA drugs and RNA-targeted small-molecule medications, with a focus on recent progresses and strategies. Challenges in the development of novel druggable RNA entities and identification of viable RNA targets and selective small-molecule binders are discussed. SIGNIFICANCE STATEMENT: With the understanding of RNA functions and critical roles in diseases, as well as the development of RNA-related technologies, there is growing interest in developing novel RNA-based therapeutics. This comprehensive review presents pharmacology of both RNA drugs and RNA-targeted small-molecule medications, focusing on novel mechanisms of action, the most recent progress, and existing challenges.

Hsa-miR-217 Inhibits the Proliferation, Migration, and Invasion in Non-small Cell Lung Cancer Cells Via Targeting SIRT1 and P53/KAI1 Signaling

Background: Brain metastasis is a major cause of cancer death in patients with lung cancer. Sirtuin 1 and hsa-miR-217 have been identified to mediate the development of non-small cell lung cancer. Aims: To investigate the roles of hsa-miR-217, its target sirtuin 1, and the P53/KAI1 axis in the brain metastasis from non-small cell lung cancer. Study Design: Cell culture study. Methods: Human pulmonary adenocarcinoma brain metastasis cell line PC-14/B were incubated and treated with constructed lentiviral plasmids expressing miR-217 and/or sirtuin 1. BEAS-2B cell line was used as a control. The targeted regulation of miR-217 to sirtuin 1was examined using a dual-luciferase reporter assay. Cell proliferation, migration, invasion, and related protein expression were detected to examine the effect of the miR-217/sirtuin 1 expression on metastasis. Results: PC-14/B cells expressed higher sirtuin 1 and lower P53 and KAI1 compared with BEAS-2B control cells (p<0.05). Sirtuin 1 was a direct target of miR-217. MiR-217 expression suppressed PC-14/B cell invasion (p=0.004), migration (p=0.001), and proliferation (p<0.05), whereas sirtuin 1 overexpression reversed all processes. sirtuin 1 expression inhibited P53, KAI1/CD82, matrix metalloproteinase-9, and ß-catenin but upregulated E-cadherin protein. MiR-217 overexpression induced reverse changes. Conclusion: Hsa-miR-217 and its target sirtuin 1 acted as metastasis suppressor and promoter gene in non-small cell lung cancer, respectively. The hsa-miR-217/sirtuin 1/P53/KAI1 metastasis regulatory pathway showed novel and crucial roles in brain metastasis from non-small cell lung cancer. This axis might be a potential target for the treatment of brain metastasis of lung cancer.