Xinyi Yang

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease with limited therapeutic options. To investigate the roles of the pulmonary microbiota and metabolism in fibrosis, we established a bleomycin (BLM)-induced mouse model at 14- and 28-day timepoints and performed integrated 16S rRNA gene amplicon sequencing and untargeted metabolomic analyses. Histological and Western blot analyses confirmed significant fibrotic changes and the upregulation of fibrotic markers. Microbiome profiling revealed marked dysbiosis after BLM exposure, characterized by reduced microbial diversity and enrichment of Klebsiella. LC-MS–based metabolomic analysis identified substantial perturbations in the lung tissue metabolome, particularly in lipid metabolism, amino acid metabolism, and energy pathways. Correlation analysis indicated a strong positive association between the abundance of Klebsiella and the levels of specific dipeptides, including Ala-Hyp-Gly, Asp-His, and Asp-Asn. The accumulation of these dipeptides may reflect increased collagen degradation and turnover in fibrotic lungs. Collectively, our findings demonstrate that BLM-induced pulmonary fibrosis is accompanied by coordinated alterations in the lung microbiome and metabolome. Notably, microbial dysbiosis, particularly the expansion of Klebsiella, may be associated with alterations in amino acid metabolism and fibrotic progression.

Chiral subcomponent self‐assembly is used to access optically pure, metallo‐helical species based on Zn and Fe(II) and incorporating three transazobenzene units. UV–vis, circular dichroism, and NMR spectroscopies, alongside X‐ray crystallographic and DFT computational studies are used to unambiguously characterize a highly reversible stepwise photochemical transformation to an all‐ cis state in which structural integrity and optical purity have been retained. Although the all‐ trans state of the water‐soluble enantiomers exhibited low or moderate activity against Gram‐positive strains, irradiation at 365 nm led to up to eight‐fold reduction in MIC. Electron microscopy and a cell permeability assay indicate a membrane disruption mechanism; the higher activity of the photochemically‐generated all‐ cis state is consistent with its more compact supramolecular fold.

Chiral subcomponent self‐assembly is used to access optically pure, metallo‐helical species based on Zn and Fe(II) and incorporating three transazobenzene units. UV–vis, circular dichroism, and NMR spectroscopies, alongside X‐ray crystallographic and DFT computational studies are used to unambiguously characterize a highly reversible stepwise photochemical transformation to an all‐ cis state in which structural integrity and optical purity have been retained. Although the all‐ trans state of the water‐soluble enantiomers exhibited low or moderate activity against Gram‐positive strains, irradiation at 365 nm led to up to eight‐fold reduction in MIC. Electron microscopy and a cell permeability assay indicate a membrane disruption mechanism; the higher activity of the photochemically‐generated all‐ cis state is consistent with its more compact supramolecular fold.

Azvudine (FNC) is a novel cytidine analogue that is widely used in the treatment of infectious diseases such as AIDS and COVID-19. Previous studies have demonstrated its anticancer activity in various cancer cell lines, including non-Hodgkin’s lymphomas and lung adenocarcinoma cell lines. However, its effects on hepatocellular carcinoma (HCC) and the underlying mechanisms remain unclear. This study aimed to investigate the anti-epithelial–mesenchymal transition (anti-EMT) activity of FNC and evaluate its potential application in HCC treatment. We found that FNC significantly inhibits the migration of the liver cancer cell line Huh7 by downregulating key EMT markers, such as matrix metalloproteinases (MMPs) and N-cadherin, at both the transcriptional and protein expression levels. Notably, we found that FNC inhibits HEY proteins, particularly HEY1, a transcriptional regulator of the Notch signalling pathway that is overexpressed in approximately 50% of HCC patients. To identify the primary target of FNC, microscale thermophoresis (MST) and molecular dynamics (MD) simulations were performed, revealing that FNC directly binds to Jagged1. This study provides valuable insights into the therapeutic potential of FNC in HCC treatment and elucidates its underlying mechanisms.

Methicillin-resistant Staphylococcus aureus (MRSA) infection is a serious clinical threat, and D-Serine (D-Ser) showed significant sensitization effects on β-lactams against MRSA in our previous study. Quantitative PCR analysis found the elevated expression of the dlt operon with D-Ser combination, which is responsible for wall teichoic acid (WTA) modification involving D-Alanine (D-Ala). This study aims to verify the effect of D-Ser on WTA modification through the dlt pathway and explore the related effects on bacteria. The DltA and DltC were recombined, and enzyme kinetic evaluations with different D-amino acids were then conducted; it was found that D-Ser is the second-best substrate for DltA (just after D-Ala), no matter whether DltC is present or not. D-Ser treatment also lowered WTA generation as demonstrated by WTA phosphate quantification and native-PAGE electrophoresis, increased the susceptibility of S. aureus to polymyxins, and elevated the mouse survival rate in the MRSA intraperitoneal infection model without affecting the bacterial loads in the main organs, indicating possible effects of D-Ser on MRSA virulence through WTA modification. In conclusion, the current study provided evidence for D-Ser modification of WTA via the dlt pathway, and its possible involvement in D-Ser sensitization deserves further investigation.

Idiopathic pulmonary fibrosis (IPF) is a progressive and chronic interstitial lung disease with unclear underlying pathogenic mechanisms. Dysbiosis of the lung microbiota is believed to be associated with the development of fibrosis; however, the roles of the microbiome in the respiratory functions of hosts with IPF remain poorly understood. To investigate the relationship between the lung microbiome and the pathological processes of idiopathic pulmonary fibrosis under laboratory conditions, C57BL/6 J mice were exposed to bleomycin and observed at 7, 14, 21, and 28 days post-exposure. 16S rDNA analysis revealed that the lung microbial community exhibited dysbiosis in the bleomycin-induced pulmonary fibrosis model, characterized by an abnormally high proportion of Klebsiella quasipneumoniae (K. quasipneumoniae), as confirmed by RNA fluorescence in situ hybridization. Throughout the progression of experimental pulmonary fibrosis, Tax4Fun analysis indicated that the abundance of K. quasipneumoniae differed significantly between model mice and control mice, correlating with the sustained activation of reactive oxygen species (ROS) pathways. Importantly, the dysbiosis of K. quasipneumoniae may serve as a critical factor triggering increased ROS levels, accompanied by macrophage mitophagy, ultimately leading to the overexpression of TGF-β1, a key player in the pathogenesis of pulmonary fibrosis. These findings suggest that lung microbiota dysbiosis exacerbates the progression of bleomycin-induced pulmonary fibrosis related to macrophage mitophagy.

Azvudine (FNC) is a novel cytidine analogue widely used in the treatment of AIDS and COVID-19 infectious disease. Previous studies have demonstrated its anticancer activity in various cancer cell lines, including non-Hodgkin’s lymphomas and lung adenocarcinoma cell lines. However, its effects on hepatocellular carcinoma (HCC) and the underlying mechanisms remain unclear. This study aimed to investigate the anti-epithelial-mesenchymal transition (anti-EMT) activity of FNC and evaluate its potential application in HCC treatment. We found that FNC significantly inhibits the migration of the liver cancer cell line Huh7 by downregulating key EMT markers, such as matrix metalloproteinases (MMPs) and E-cadherin, at both transcriptional and protein expression levels. Notably, we found that FNC inhibits HEY proteins, particularly HEY1, a transcriptional regulator of the Notch signalling pathway that is overexpressed in approximately 50% of HCC patients. To identify the primary target of FNC, microscale thermophoresis (MST) and molecular dynamics (MD) simulations were performed, revealing that FNC directly binds to Jagged1. This study provides valuable insights into the therapeutic potential of FNC in HCC treatment and elucidates its underlying mechanisms.