Bio-Responsive Sliver Peroxide-Nanocarrier Serves as Broad-Spectrum Metallo-ß-lactamase Inhibitor for Combating Severe Pneumonia.

Metallo-ß-lactamases (MBLs) represent a prevalent resistance mechanism in Gram-negative bacteria, rendering last-line carbapenem-related antibiotics ineffective. Here, a bioresponsive sliver peroxide (Ag2 O2 )-based nanovesicle, named Ag2 O2 @BP-MT@MM, is developed as a broad-spectrum MBL inhibitor for combating MBL-producing bacterial pneumonia. Ag2 O2 nanoparticle is first orderly modified with bovine serum albumin and polydopamine to co-load meropenem (MER) and [5-(p-fluorophenyl)-2-ureido]-thiophene-3-carboxamide (TPCA-1) and then encapsulated with macrophage membrane (MM) aimed to target inflammatory lung tissue specifically. The resultant Ag2 O2 @BP-MT@MM effectively abrogates MBL activity by displacing the Zn2+ cofactor in MBLs with Ag+ and displays potent bactericidal and anti-inflammatory properties, specific targeting abilities, and great bioresponsive characteristics. After intravenous injection, the nanoparticles accumulate prominently at infection sites through MM-mediated targeting . Ag+ released from Ag2 O2 decomposition at the infection sites effectively inhibits MBL activity and overcomes the resistance of MBL-producing bacteria to MER, resulting in synergistic elimination of bacteria in conjunction with MER. In two murine infection models of NDM-1+ Klebsiella pneumoniae-induced severe pneumonia and NDM-1+ Escherichia coli-induced sepsis-related bacterial pneumonia, the nanoparticles significantly reduce bacterial loading, pro-inflammatory cytokine levels locally and systemically, and the recruitment and activation of neutrophils and macrophages. This innovative approach presents a promising new strategy for combating infections caused by MBL-producing carbapenem-resistant bacteria.

Hyperbaric oxygen improves depression-like behaviors in chronic stress model mice by remodeling gut microbiota and regulating host metabolism.

AIMS: There is growing evidence that the gut microbiota plays a significant part in the pathophysiology of chronic stress. The dysbiosis of the gut microbiota closely relates to dysregulation of microbiota-host cometabolism. Composition changes in the gut microbiota related to perturbations in metabolic profiles are vital risk factors for disease development. Hyperbaric oxygen therapy is commonly applied as an alternative or primary therapy for various diseases. Therefore, a metabolic and gut bacteria perspective is essential to uncover possible mechanisms of chronic stress and the therapeutic effect of hyperbaric oxygenation. We determined that there were significantly disturbed metabolites and disordered gut microbiota between control and chronic stress group. The study aims to offer further information on the interactions between host metabolism, gut microbiota, and chronic stress. METHODS: At present, chronic unpredictable mild stress is considered the most widespread method of modeling chronic stress in animals, so we used a chronic unpredictable mild stress mouse model to characterize changes in the metabolome and microbiome of depressed mice by combining 16S rRNA gene sequencing and UHPLC-MS/MS-based metabolomics. Pearson's correlation-based clustering analysis was performed with above metabolomics and fecal microbiome data to determine gut microbiota-associated metabolites. RESULTS: We found that 18 metabolites showed a significant correlation with campylobacterota. Campylobacterota associated metabolites were significantly enriched mainly in the d-glutamate and d-glutamine metabolism. Hyperoxia treatment may improve depression-like behaviors in chronic stress model mice through regulating the disrupted metabolites. CONCLUSIONS: Hyperbaric oxygen improves depression-like behaviors in chronic stress model mice by remodeling Campylobacterota associated metabolites.

Mouse Bone Marrow Mesenchymal Stem Cells Inhibit Sepsis-Induced Lung Injury in Mice via Exosomal SAA1.

Sepsis is a global disease burden, and approximately 40% of cases develop acute lung injury (ALI). Bone marrow mesenchymal stromal cells (BMSCs) and their exosomes are widely used in treating a variety of diseases including sepsis. As an acute phase protein, serum amyloid A1 (SAA1) regulates inflammation and immunity. However, the role of SAA1 in BMSCs-exosomes in septic lung injury remains to be elucidated. Exosomes derived from serum and BMSCs were isolated by ultracentrifugation. SAA1 was silenced or overexpressed in mouse BMSCs using lentiviral plasmids, containing either SAA1-targeting short interfering RNAs or SAA1 cDNA. Sepsis was induced by cecal ligation and puncture (CLP). LPS was used to induce ALI in mice. Mouse alveolar macrophages were isolated by flow cytometry. Levels of SAA1, endotoxin, TNF-α, and IL-6 were measured using commercial kits. LPS internalization was monitored by immunostaining. RT-qPCR or immunoblots were performed to test gene and protein expressions. Serum exosomes of patients with sepsis-induced lung injury had significantly higher levels of SAA1, endotoxin, TNF-α, and IL-6. Overexpression of SAA1 in BMSCs inhibited CLP- or LPS-induced lung injury and decreased CLP- or LPS-induced endotoxin, TNF-α, and IL-6 levels. Administration of the SAA1 blocking peptide was found to partially inhibit SAA1-induced LPS internalization by mouse alveolar macrophages and reverse the protective effect of SAA1. In conclusion, BMSCs inhibit sepsis-induced lung injury through exosomal SAA1. These results highlight the importance of BMSCs, exosomes, and SAA1, which may provide novel directions for the treatment of septic lung injury.

Gene expression profiling reveals candidate biomarkers and probable molecular mechanisms in chronic stress.

Chronic stress refers to nonspecific systemic reactions under the over-stimulation of different external and internal factors for a long time. Previous studies confirmed that chronic psychological stress had a negative effect on almost all tissues and organs. We intended to further identify potential gene targets related to the pathogenesis of chronic stress-induced consequences involved in different diseases. In our study, mice in the model group lived under the condition of chronic unpredictable mild stress (CUMS) until they expressed behaviors like depression which were supposed to undergo chronic stress. We applied high-throughput RNA sequencing to assess mRNA expression and obtained transcription profiles in lung tissue from CUMS mice and control mice for analysis. In view of the prediction of high-throughput RNA sequences and bioinformatics software, and mRNA regulatory network was constructed. First, we conducted differentially expressed genes (DEGs) and obtained 282 DEGs between CUMS (group A) and the control model (group B). Then, we conducted functional and pathway enrichment analyses. In general, the function of upregulated regulated DEGs is related to immune and inflammatory responses. PPI network identified several essential genes, of which ten hub genes were related to the T cell receptor signaling pathway. qRT-PCR results verified the regulatory network of mRNA. The expressions of CD28, CD3e, and CD247 increased in mice with CUMS compared with that in control. This illustrated immune pathways are related to the pathological molecular mechanism of chronic stress and may provide information for identifying potential biomarkers and early detection of chronic stress.