Synthesis and anti-HSV-1 activity of new 1,2,3-triazole derivatives

AbstractIn this work, a new series of arysulfonylhydrazine-1H-1,2,3-triazole derivatives were synthesized, and their ability to inhibit the in vitro replication of HSV-1 was evaluated. Among the 1,2,3-triazole derivatives, 1-[(5″-methyl-1″-(4‴-fluorophenylamino)-1H-1,2,3-triazol-4″-yl)carbonyl]-2-(4′-methylphenylsulfonyl)hydrazine and 1-[(5′-methyl-1′-(2″,5″-dichlorophenylamino)-1H-1,2,3-triazol-4′-yl)carbonyl]-2-(phenylsulfonyl)hydrazine, with IC50 values of 1.30 and 1.26μM, respectively, displayed potent activity against HSV-1. Because these compounds have low cytotoxicity, their selectivity indices are high. Under the assay conditions, they have better performance than does the reference compound acyclovir. The structures of all of the compounds were confirmed by one- and two-dimensional NMR techniques (1H, 13C-APT, COSY-1H×1H and HETCOR 1JCH) and by elemental analysis

Gut microbiota disturbances in hospitalized older adults with malnutrition and clinical outcomes.

OBJECTIVE Malnutrition is one of the most threatening conditions in geriatric populations. The gut microbiota has an important role in the host's metabolic and muscular health, however, its interplay with disease-related malnutrition is less well understood. We aimed to identify the association of malnutrition with the gut microbiota and predict clinical outcomes in hospitalized acutely ill older adults. METHODS We performed a secondary longitudinal analysis in 108 geriatric patients from a prospective cohort evaluated at admission and 72 hours of hospitalization. We collected clinical, demographic, nutritional, and 16S rRNA gene-sequenced gut microbiota data. Microbiota diversity, overall composition, and differential abundance were calculated and compared between patients with and without malnutrition. Microbiota features associated with malnutrition were used to predict clinical outcomes. RESULTS Patients with malnutrition (51%) had a different microbiota composition compared to well-nourished during hospitalization (ANOSIM R=0.079, P=0.003). Patients with severe malnutrition showed poorer α-diversity at admission (Shannon P=0.012, Simpson P=0.018) and follow-up (Shannon P=0.023, Chao1 P=0.008). Differential abundance of Lachnospiraceae NK4A136 group, Subdoligranulum, and Faecalibacterium prausnitzii were significantly lower and inversely associated with malnutrition, while Corynebacterium, Ruminococcaceae Incertae Sedis, and Fusobacterium were significantly increased and positively associated with malnutrition. Corynebacterium, Ruminococcaceae Incertae Sedis, and the overall composition were important predictors of critical care in patients with malnutrition during hospitalization. CONCLUSION Older adults with malnutrition, especially in a severe stage, may be subject to substantial gut microbial disturbances during hospitalization. The gut microbiota profile of patients with malnutrition might be able to predict worse clinical outcomes

Inhibition of SARS-CoV-2 infection in human iPSC-derived cardiomyocytes by targeting the Sigma-1 receptor disrupts cytoarchitecture and beating

SARS-CoV-2 infects cardiac cells and causes heart dysfunction. Conditions such as myocarditis and arrhythmia have been reported in COVID-19 patients. The Sigma-1 receptor (S1R) is a ubiquitously expressed chaperone that plays a central role in cardiomyocyte function. S1R has been proposed as a therapeutic target because it may affect SARS-CoV-2 replication; however, the impact of the inhibition of S1R in human cardiomyocytes remains to be described. In this study, we investigated the consequences of S1R inhibition in iPSC-derived human cardiomyocytes (hiPSC-CM). SARS-CoV-2 infection in hiPSC-CM was productive and reduced cell survival. S1R inhibition decreased both the number of infected cells and viral particles after 48 hours. S1R inhibition also prevented the release of pro-inflammatory cytokines and cell death. Although the S1R antagonist NE-100 triggered those protective effects, it compromised cytoskeleton integrity by downregulating the expression of structural-related genes and reducing beating frequency. Our findings suggest that the detrimental effects of S1R inhibition in human cardiomyocytes’ integrity may abrogate its therapeutic potential against COVID and should be carefully considered