Daily Ards Research Analysis

Corticosteroids decrease the duration of organ dysfunction in sepsis and a range of overlapping and complementary infectious critical illnesses, including septic shock, pneumonia and the acute respiratory distress syndrome (ARDS). The risk and benefit of corticosteroids are not fully defined using the construct of organ dysfunction duration. This retrospective multicenter, proof-of-concept study aimed to evaluate the association between usage of corticosteroids and mortality of patients with sepsis, pneumonia and ARDS by emulating a target trial framework stratified by predicted organ dysfunction trajectory. The study employed a two staged machine learning (ML) methodology to first subphenotype based on organ dysfunction trajectory then predict this defined trajectory. Once patients were classified by predicted trajectory we conducted a target trial emulation. Our analysis revealed that the association between corticosteroid use and 28-day mortality varied by predicted trajectory and between cohorts.Our findings suggest that matching treatment strategies to empirically observed pathobiology may offer a more nuanced understanding of corticosteroid utility.

The efficacy of clinical drugs for acute lung injury/acute respiratory distress syndrome (ALI/ARDS) remains suboptimal. Phillyrin (PHN), a compound derived from Forsythia, is believed to alleviate sepsis-related ALI/ARDS; however, its mechanisms are not fully elucidated. In this study, we screened 8331 target genes associated with ALI/ARDS from public databases and identified six hub genes relevant to PHN treatment: AKT1, GSK-3β, PPP2CA, PPP2CB, PPP2R1A, and AR. Receiver operating characteristic analysis and single-cell sequencing analysis revealed the expression of AKT1, GSK-3β, PPP2CA, PPP2CB, and PPP2R1A were markedly elevated. Molecular docking and dynamics simulations indicated that PHN forms a structurally stable complex with glycogen synthase kinase-3β (GSK-3β). Mendelian randomization analyses suggested that PHN, as a potent GSK-3β inhibitor, may promote M2 macrophage polarization and reduce neutrophil recruitment. We validated these findings through in vivo and in vitro experiments, demonstrating that PHN lowers iNOS levels and raises MMR levels by downregulating GSK-3β mRNA expression and protein activity during lipopolysaccharide (LPS)-induced macrophage inflammation. Additionally, PHN inhibited GSK-3β mRNA expression and protein activity, reducing NF-κB-p65 nuclear translocation in LPS-induced zebrafish inflammation and mice ALI. This inhibition decreased levels of TNF-α and IL-6, increased IL-10 levels, promoted M2 macrophage polarization, suppressed neutrophil recruitment, and ultimately ameliorated ALI/ARDS. In conclusion, our results indicate that PHN effectively alleviates LPS-induced ALI/ARDS by suppressing GSK-3β signaling.

Influenza presents a significant public health threat, as severe cases can lead to excessive inflammation and complications such as pneumonia or acute respiratory distress syndrome. Current antiviral agents targeting viral proteins may lead to the development of resistance, highlighting the need for new agents targeting host factors. Neurotransmitter receptors are vital for cellular signaling and cell cycle modulation, making them promising antiviral therapeutic targets. Recent research has demonstrated that screening libraries of compounds aimed at these receptors can help identify inhibitors that prevent the replication of various viruses, including filoviruses and SARS-CoV-2. We screened a neurotransmitter receptor modulator library in influenza-infected U937 cells and found that many adrenergic, histamine, dopamine, and serotonin receptor agonists and antagonists exhibit antiviral activity. We identified 20 candidate compounds with IC50 values below 20 μM, suggesting a critical role for these receptors in influenza replication. Three representative compounds (isoxsuprine, ciproxifan, and rotigotine) inhibited H1N1 replication in a dose-dependent manner in multiple cell lines, and were effective against H1N1, oseltamivir-resistant H1N1, H3N2, and influenza B strains. Mechanistic studies indicated that these compounds affect virus internalization during the early infection stages. In a mouse model of lethal influenza, isoxsuprine significantly decreased lung viral titers, mitigated pulmonary inflammation, and enhanced survival rates. These findings highlight neurotransmitter receptors as potential targets for developing novel anti-influenza agents, providing a foundation for further optimization of the identified compounds as potential therapeutic agents.