Biomedical subjects

Yongle Du

Publications and source records attributed to Yongle Du.

3 recordsLinked to original sources

PubMed2026

Super enhancer-driven transcriptional reprogramming promotes abiraterone resistance via neuroendocrine transition and ferroptosis evasion in castration-resistant prostate cancer.

Abiraterone resistance represents a major clinical challenge in the management of castration-resistant prostate cancer (CRPC), yet the epigenetic mechanisms that sustain this resistance remain poorly understood. In particular, how super enhancers (SEs) reprogram transcriptional networks to promote this therapy resistance has not been fully elucidated. Here, by integrating chromatin immunoprecipitation sequencing and transcriptome profiling, we identified aberrantly activated oncogenic SEs that drive the transcriptional upregulation of the transcription factors ELF3 and JUNB in abiraterone-resistance CRPC cells. Importantly, SE-driven activation of the ELF3/JUNB axis promotes abiraterone resistance by inducing WNT11-mediated neuroendocrine transition. In parallel, this transdifferentiated state is closely associated with ferroptosis resistance, as evidenced by the upregulation of key ferroptosis-protective genes, including FTH1 and GPX4. In contrast, disruption of the ELF3/JUNB-WNT11 axis markedly restored abiraterone sensitivity and triggered ferroptotic cell death in CRPC cells both in vitro and in vivo. Collectively, our findings highlight targeting SE-driven transcriptional programs as a promising strategy for overcoming abiraterone resistance in CRPC.

Male↗

PubMed2025

Discovery of Isonitrile Lipopeptide Chalkophores from Pathogenic Mycobacteria.

The virulence-associated isonitrile lipopeptide (INLP) biosynthetic gene cluster is conserved across Mycobacterium tuberculosis and many nontuberculous mycobacteria (NTM) pathogens, yet the corresponding mycobacterial metabolites have not been fully characterized, and their biological functions are still debated. Here, we report a precursor neutral loss chromatography based mass spectrometry strategy that enables the targeted discovery of INLPs from Mycobacterium fortuitum, a fast-growing NTM pathogen. By monitoring a characteristic neutral loss of 27.1 Da corresponding to hydrogen cyanide, we identified a family of INLPs directly from bacterial culture extracts. Structural elucidation of a representative compound using NMR and high-resolution MS revealed a distinctive terminal methylated carboxyl group, contrasting with previously reported INLPs bearing linear alcohol, acetal, or cyclic motifs. Bioinformatic analysis and in vitro enzymatic assays identified a methyltransferase encoded within the INLP BGC responsible for methyl ester formation. Furthermore, metal-binding assays demonstrated selective chelation of Cu(I) and Cu(II) by the isolated INLP, but no detectable interaction with Zn(II), suggesting a role in copper homeostasis. These findings represent the first full structural characterization of an INLP from pathogenic mycobacteria, expand our understanding of the enzymes involved in INLP modification, and unequivocally support the copper-binding activity of INLPs from these pathogens.

Lipopeptides↗

PubMed2024

Engineered probiotic overcomes pathogen defences using signal interference and antibiotic production to treat infection in mice.

Probiotic supplements are suggested to promote human health by preventing pathogen colonization. However, the mechanistic bases for their efficacy in vivo are largely uncharacterized. Here using metabolomics and bacterial genetics, we show that the human oral probiotic Streptococcus salivarius K12 (SAL) produces salivabactin, an antibiotic that effectively inhibits pathogenic Streptococcus pyogenes (GAS) in vitro and in mice. However, prophylactic dosing with SAL enhanced GAS colonization in mice and ex vivo in human saliva. We showed that, on co-colonization, GAS responds to a SAL intercellular peptide signal that controls SAL salivabactin production. GAS produces a secreted protease, SpeB, that targets SAL-derived salivaricins and enhances GAS survival. Using this knowledge, we re-engineered probiotic SAL to prevent signal eavesdropping by GAS and potentiate SAL antimicrobials. This engineered probiotic demonstrated superior efficacy in preventing GAS colonization in vivo. Our findings show that knowledge of interspecies interactions can identify antibiotic- and probiotic-based strategies to combat infection.

Animals↗