Antiviral activity of nitazoxanide against Morbillivirus infections.

The measles virus (MeV) and canine distemper virus (CDV) belong to the genus Morbillivirus of the Paramyxoviridae family. They are enveloped viruses harboring a non-segmented negative-sense RNA. Morbilliviruses are extremely contagious and transmitted through infectious aerosol droplets. Both MeV and CDV may cause respiratory infections and fatal encephalitis, although a high incidence of brain infections is unique to CDV. Despite the availability of a safe and effective vaccine against these viruses, in recent years we are witnessing a strong resurgence of Morbillivirus infection. Measles still kills more than 100,000 people each year, and CDV causes widespread outbreaks, especially among wild animals, including non-human primates. No drugs are currently approved for MeV and CDV. Therefore, the identification of effective antiviral agents represents an unmet medical need. Here, we have investigated the potential antiviral properties of nitazoxanide (NTZ) against MeV and CDV. Antiviral activity was explored with live virus and cell-based assays. NTZ is a thiazolide that is approved by the FDA as an antiprotozoal agent for the treatment of Giardia intestinalis and Cryptosporidium parvum. Further, nitazoxanide and its metabolite tizoxanide have recently emerged as broad-spectrum antiviral agents. We found that NTZ blocks the MeV and CDV replication, acting at the post-entry level. Moreover, we showed that NTZ affects the function of the viral fusion protein (F), impairing viral spread. Our results indicate that NTZ should be further explored as a therapeutic option in measles and canine distemper virus treatment.

Drugs for the prevention and treatment of COVID-19 and its complications: An update on what we learned in the past 2 years.

The COVID-19 Committee of the Lincei Academy has reviewed the scientific evidence supporting the efficacy and safety of existing and new drugs/biologics for the preventing and treating of COVID-19 and its complications. This position paper reports what we have learned in the field in the past 2 years. The focus was on, but not limited to, drugs and neutralizing monoclonal antibodies, anti-SARS-CoV-2 agents, anti-inflammatory and immunomodulatory drugs, complement inhibitors and anticoagulant agents. We also discuss the risks/benefit of using cell therapies on COVID-19 patients. The report summarizes the available evidence, which supports recommendations from health authorities and panels of experts regarding some drugs and biologics, and highlights drugs that are not recommended, or drugs for which there is insufficient evidence to recommend for or against their use. We also address the issue of the safety of drugs used to treat underlying concomitant conditions in COVID-19 patients. The investigators did an enormous amount of work very quickly to understand better the nature and pathophysiology of COVID-19. This expedited the development and repurposing of safe and effective therapeutic interventions, saving an impressive number of lives in the community as well as in hospitals.

Human inhalable antibody fragments neutralizing SARS-CoV-2 variants for COVID-19 therapy.

As of December 2021, coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global emergency, and novel therapeutics are urgently needed. Here we describe human single-chain variable fragment (scFv) antibodies (76clAbs) that block an epitope of the SARS-CoV-2 spike protein essential for ACE2-mediated entry into cells. 76clAbs neutralize the Delta variant and other variants being monitored (VBMs) and inhibit spike-mediated pulmonary cell-cell fusion, a critical feature of COVID-19 pathology. In two independent animal models, intranasal administration counteracted the infection. Because of their high efficiency, remarkable stability, resilience to nebulization, and low cost of production, 76clAbs may become a relevant tool for rapid, self-administrable early intervention in SARS-CoV-2-infected subjects independently of their immune status.

Human NF-κB repressing factor acts as a stress-regulated switch for ribosomal RNA processing and nucleolar homeostasis surveillance.

The nucleolus, a dynamic nuclear compartment long regarded as the cell ribosome factory, is emerging as an important player in the regulation of cell survival and recovery from stress. In larger eukaryotes, the stress-induced transcriptional response is mediated by a family of heat-shock transcription factors. Among these, HSF1, considered the master regulator of stress-induced transcriptional responses, controls the expression of cytoprotective heat shock proteins (HSPs), molecular chaperones/cochaperones constituting a major component of the cell protein quality control machinery essential to circumvent stress-induced degradation and aggregation of misfolded proteins. Herein we identify human NF-κB repressing factor (NKRF) as a nucleolar HSP essential for nucleolus homeostasis and cell survival under proteotoxic stress. NKRF acts as a thermosensor translocating from the nucleolus to the nucleoplasm during heat stress; nucleolar pools are replenished during recovery upon HSF1-mediated NKRF resynthesis. Silencing experiments demonstrate that NKRF is an unconventional HSP crucial for correct ribosomal RNA (rRNA) processing and preventing aberrant rRNA precursors and discarded fragment accumulation. These effects are mediated by NKRF interaction with the 5'-to-3' exoribonuclease XRN2, a key coordinator of multiple pre-rRNA cleavages, driving mature rRNA formation and discarded rRNA decay. Under stress conditions, NKRF directs XRN2 nucleolus/nucleoplasm trafficking, controlling 5'-to-3' exoribonuclease nucleolar levels and regulating rRNA processing. Our study reveals a different aspect of rRNA biogenesis control in human cells and sheds light on a sophisticated mechanism of nucleolar homeostasis surveillance during stress.

2-Cyclopenten-1-one and prostaglandin J2 reduce restenosis after balloon angioplasty in rats: role of NF-kappaB.

The aim of this study was to evaluate, using a rat model of balloon angioplasty, whether prostaglandin (PG) J(2) and 2-cyclopenten-1-one are able to reduce restenosis. We found that both PGJ(2) and 2-cyclopenten-1-one, administered by local application on carotid arteries, caused a dose-dependent inhibition of neointimal formation. Furthermore, both agents prevented vascular negative remodeling. The effect of these compounds on restenosis was correlated with an inhibition of nuclear factor-kappaB (NF-kappaB) activation as well as of intercellular adhesion molecule-1 (ICAM-1) protein expression in injured carotid arteries of control animals. Our results show that cyclopentenone PGs and their derivatives reduce restenosis and may have therapeutic relevance for the prevention of human restenosis.