Cosmic kidney disease: an integrated pan-omic, physiological and morphological study into spaceflight-induced renal dysfunction

Missions into Deep Space are planned this decade. Yet the health consequences of exposure to microgravity and galactic cosmic radiation (GCR) over years-long missions on indispensable visceral organs such as the kidney are largely unexplored. We performed biomolecular (epigenomic, transcriptomic, proteomic, epiproteomic, metabolomic, metagenomic), clinical chemistry (electrolytes, endocrinology, biochemistry) and morphometry (histology, 3D imaging, miRNA-ISH, tissue weights) analyses using samples and datasets available from 11 spaceflight-exposed mouse and 5 human, 1 simulated microgravity rat and 4 simulated GCR-exposed mouse missions. We found that spaceflight induces: 1) renal transporter dephosphorylation which may indicate astronauts' increased risk of nephrolithiasis is in part a primary renal phenomenon rather than solely a secondary consequence of bone loss; 2) remodelling of the nephron that results in expansion of distal convoluted tubule size but loss of overall tubule density; 3) renal damage and dysfunction when exposed to a Mars roundtrip dose-equivalent of simulated GCR

Metabolomic Analysis and SARS-CoV-2 Antiviral Screening of Marine Cyanobacterial Library Identify Jobosnoic Acid, an Unreported Virus-selective Fatty Acid Inhibitor.

Current small molecule-based treatments for pre-exposure prophylaxis or active infection of SARS-CoV-2 remain poorly available worldwide and risk-inducing drug-induced viral resistance. Compounds that block multiple aspects of the SARS-CoV-2 replication cycle would be expected to pose a higher genetic barrier to drug resistance. Therefore, a marine algae extract library, and two distinct biochemical assays were used to screen for natural products that could inhibit two well-defined and validated COVID-19 drug targets, disruption of the Spike protein/ACE-2 interaction and the main protease (Mpro) of SARS-CoV-2. Upon initial screening of 86 crude extracts, we counter-screened and performed an untargeted metabolomic analysis of 16 cyanobacterial extracts. This orthogonal approach revealed three extracts with similar metabolomic and biological profiles, all from similar collection sites, leading to the isolation of an unusual saturated fatty acid, jobosnoic acid (1). We confirmed that 1 demonstrated dual inhibitory activity towards both viral targets while retaining activity against the Spike-RBD/ACE-2 interaction of the SARS-CoV-2 omicron variant. To initially explore its Structure Activity Relationship (SAR), we semi-synthetically accessed the methyl and benzyl ester derivatives of 1, both of which demonstrated acute loss of bioactivity in both SARS-CoV-2 biochemical assays. This effort has provided copious amounts of a fatty acid natural product that warrants further investigation in terms of SAR, determination of the absolute configuration of its C2 and C5 methyl substituents and understanding of its specific mechanisms of action and binding site to potentially describe new therapeutic avenues for SARS-CoV-2 drug development

CCR2 plays a protective role in Rocio virus–induced encephalitis by promoting macrophage infiltration into the brain

Rocio virus (ROCV) is a highly neuropathogenic mosquito-transmitted flavivirus responsible for an unprecedented outbreak of human encephalitis during 1975-1976 in Sao Paulo State, Brazil. Previous studies have shown an increased number of inflammatory macrophages into the central nervous system (CNS) of ROCV-infected mice, implying a role for macrophages in the pathogenesis of ROCV. Here, we showed that ROCV infection results in increased expression of C-C chemokine ligand 2 (CCL2) in the blood and in infiltration of macrophages into the brain. Moreover, we showed using C-C chemokine receptor 2 (CCR2) knockout mice that CCR2 expression was essential for macrophage infiltration in the brains during ROCV infection and that the lack of CCR2 resulted in increased disease severity and mortality. Thus, our findings show the protective role of CCR2-mediated infiltration of macrophages in the brain during ROCV infection