The miRNA hsa-miR-6515-3p potentially contributes to lncRNA H19-mediated-lung cancer metastasis

Aberrant expression of long noncoding RNAs (lncRNAs) contributes to all phenotypes of cancer including metastasis, which is a major cause of death in many advanced malignancies. One particular lncRNA, H19, is found to be a crucial player in cancer progression by modulating multiple microRNAs (miRNAs). In this study, we screened miRNAs possibly associated with H19 using lung carcinoma cell lines and patient with lung cancer tissues, and selected one possible hit, hsa-miR-6515-3p, to perform in vitro functional assays. Its inhibition leads to decreased proliferation and migration of SPC-A1 lung cancer cells and is in good correlation with H19-knockdown groups. These results indicate that H19 may be an epigenetic regulator of miR-6515-3p, and its dysregulation may contribute to lung cancer progression and metastasis.     

Hyper-inflammatory responses in COVID-19 and anti-inflammatory therapeutic approaches

The coronavirus disease 2019 (COVID-19) is an ongoing global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with severe COVID-19 exhibit hyper-inflammatory responses characterized by excessive activation of myeloid cells, including monocytes, macrophages, and neutrophils, and a plethora of pro-inflammatory cytokines and chemokines. Accumulating evidence also indicates that hyper-inflammation is a driving factor for severe progression of the disease, which has prompted the development of anti-inflammatory therapies for the treatment of patients with COVID-19. Corticosteroids, IL-6R inhibitors, and JAK inhibitors have demonstrated promising results in treating patients with severe disease. In addition, diverse forms of exosomes that exert anti-inflammatory functions have been tested experimentally for the treatment of COVID-19. Here, we briefly describe the immunological mechanisms of the hyper-inflammatory responses in patients with severe COVID-19. We also summarize current anti-inflammatory therapies for the treatment of severe COVID-19 and novel exosome-based therapeutics that are in experimental stages.     

microRNA‐19b‐3p‐containing extracellular vesicles derived from macrophages promote the development of atherosclerosis by targeting JAZF1

Atherosclerosis has been regarded as a major contributor to cardiovascular disease. The role of extracellular vesicles (EVs) in the treatment of atherosclerosis has been increasingly reported. In this study, we set out to investigate the effect of macrophages‐derived EVs (M‐EVs) containing miR‐19b‐3p in the progression of atherosclerosis, with the involvement of JAZF1. Following isolation of EVs from macrophages, the M‐EVs were induced with ox‐low density lipoprotein (LDL) (ox‐LDL‐M‐EVs), and co‐cultured with vascular smooth muscle cells (VSMCs). RT‐qPCR and western blot assay were performed to determine the expression of miR‐19b‐3p and JAZF1 in M‐EVs and in VSMCs. Lentiviral infection was used to overexpress or knock down miR‐19b‐3p. EdU staining and scratch test were conducted to examine VSMC proliferation and migration. Dual‐luciferase gene reporter assay was performed to examine the relationship between miR‐19b‐3p and JAZF1. In order to explore the role of ox‐LDL‐M‐EVs carrying miR‐19b‐3p in atherosclerotic lesions in vivo, a mouse model of atherosclerosis was established through high‐fat diet induction. M‐EVs were internalized by VSMCs. VSMC migration and proliferation were promoted by ox‐LDL‐M‐EVs. miR‐19b‐3p displayed upregulation in ox‐LDL‐M‐EVs. miR‐19b‐3p was transferred by M‐EVs into VSMCs, thereby promoting VSMC migration and proliferation. mir‐19b‐3p targeted JAZF1 to decrease its expression in VSMCs. Atherosclerosis lesions were aggravated by ox‐LDL‐M‐EVs carrying miR‐19b‐3p in ApoE^−/− mice. Collectively, this study demonstrates that M‐EVs containing miR‐19b‐3p accelerate migration and promotion of VSMCs through targeting JAZF1, which promotes the development of atherosclerosis.     

Is the mechanism of COVID-19 coagulopathy still a rabbit’s hole?

The pathophysiology of COVID-19 is an enigma with its severity often determined by the extent of coagulopathy. Several regulatory pathways targeted by the SARS-CoV-2 include the renin-angiotensin system, von Willebrand Factor, and most importantly, the complement pathway. This article discusses these pathways to help design potential future therapies.     

The Emergence of the Spike Furin Cleavage Site in SARS-CoV-2

Compared with other SARS-related coronaviruses (SARSr-CoVs), SARS-CoV-2 possesses a unique furin cleavage site (FCS) in its spike. This has stimulated discussion pertaining to the origin of SARS-CoV-2 because the FCS has been observed to be under strong selective pressure in humans and confers the enhanced ability to infect some cell types and induce cell–cell fusion. Furthermore, scientists have demonstrated interest in studying novel cleavage sites by introducing them into SARSr-CoVs. We review what is known about the SARS-CoV-2 FCS in the context of its pathogenesis, origin, and how future wildlife coronavirus sampling may alter the interpretation of existing data.     

COVID-19 impact on the diagnosis of Inborn Errors of Metabolism: Data from a reference center in Brazil

The COVID-19 pandemic led to the reorganization of health care in several countries, including Brazil. Inborn Errors of Metabolism (IEM) are a group of rare and difficult to diagnose genetic diseases caused by pathogenic variants in genes that code for enzymes, cofactors, or structural proteins affecting different metabolic pathways. The aim of this study was to evaluate how COVID-19 affected the diagnosis of patients with IEM during the first year of the pandemic in Brazil comparing two distinct periods: from March 1^st, 2019 to February 29^th, 2020 (TIME A) and from March 1^st, 2020 to February 28^th, 2021 (TIME B), by the analysis of the number of tests and diagnoses performed in a Reference Center in South of Brazil. In the comparison TIME A with TIME B, we observe a reduction in the total number of tests performed (46%) and in the number of diagnoses (34%). In both periods analyzed, mucopolysaccharidoses (all subtypes combined) was the most frequent LD suspected and/or confirmed. Our data indicates a large reduction in the number of tests requested for the investigation of IEM and consequently a large reduction in the number of diagnoses caused by the COVID-19 pandemic leading to a significant underdiagnosis of IEM.     

Efficient incorporation and template-dependent polymerase inhibition are major determinants for the broad-spectrum antiviral activity of remdesivir

Remdesivir (RDV) is a direct-acting antiviral agent that is approved in several countries for the treatment of coronavirus disease 2019 caused by the severe acute respiratory syndrome coronavirus 2. RDV exhibits broad-spectrum antiviral activity against positive-sense RNA viruses, for example, severe acute respiratory syndrome coronavirus and hepatitis C virus, and nonsegmented negative-sense RNA viruses, for example, Nipah virus, whereas segmented negative-sense RNA viruses such as influenza virus or Crimean-Congo hemorrhagic fever virus are not sensitive to the drug. The reasons for this apparent efficacy pattern are unknown. Here, we expressed and purified representative RNA-dependent RNA polymerases and studied three biochemical parameters that have been associated with the inhibitory effects of RDV-triphosphate (TP): (i) selective incorporation of the nucleotide substrate RDV-TP, (ii) the effect of the incorporated RDV-monophosphate (MP) on primer extension, and (iii) the effect of RDV-MP in the template during incorporation of the complementary UTP. We found a strong correlation between antiviral effects and efficient incorporation of RDV-TP. Inhibition in primer extension reactions was heterogeneous and usually inefficient at higher NTP concentrations. In contrast, template-dependent inhibition of UTP incorporation opposite the embedded RDV-MP was seen with all polymerases. Molecular modeling suggests a steric conflict between the 1′-cyano group of the inhibitor and residues of the structurally conserved RNA-dependent RNA polymerase motif F. We conclude that future efforts in the development of nucleotide analogs with a broader spectrum of antiviral activities should focus on improving rates of incorporation while capitalizing on the inhibitory effects of a bulky 1′-modification.     

Human Organoids as a Promising Platform for Fighting COVID-19

The coronavirus disease 2019 (COVID-19) global pandemic evoked by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a major public health problem with significant morbidity and mortality. Understanding the pathogenesis and molecular mechanisms underlying this novel virus is crucial for both fundamental research and clinical trials in order to devise effective therapies and vaccination regimens. Basic research on SARS-CoV-2 largely depends on ex vivo models that allow viral invasion and replication. Organoid models are now emerging as a valuable tool to investigate viral biology and disease progression, serving as an efficient platform to investigate potential therapies for COVID-19. Here, we summarize various human stem cell-derived organoid types employed in SARS-CoV-2 studies. We highlight key findings from these models, including cell tropisms and molecular mechanisms in viral infection. We also describe their use in identifying potential therapeutic agents against SARS-CoV-2. As more and more advanced organoids emerge, they will facilitate the understanding of disease pathogenesis for drug development in this dreaded pandemic.