Cellular and Molecular Life Sciences最新文献

Age-related pulmonary diseases pose a significant health burden, yet the underlying mechanisms remain poorly understood. This study investigates the role of interleukin-21 (IL-21) in driving age-associated changes in lung function and immune responses. Using both murine models and human samples, we demonstrate that IL-21 induces a pro-inflammatory state in the lungs, characterized by increased levels of key inflammatory cytokines including TNF-α, IL-6, IL-33, CXCL-10, and IL-18. IL-21 exposure also promoted cellular senescence, evidenced by upregulation of senescence-associated genes and increased frequencies of KLRG1-positive T cells. Notably, IL-21 treatment led to significant alterations in lung macrophage phenotype and function. We observed increased lipid accumulation in macrophages, accompanied by upregulation of lipid uptake receptors TREM-2 and CD36. These changes were associated with elevated TGF-β secretion, suggesting a potential mechanism for IL-21-induced pulmonary fibrosis. Furthermore, IL-21 exposure resulted in impaired antiviral responses, characterized by reduced MHC-II expression on macrophages and diminished IFN-α production in response to viral challenges. Importantly, aged mice exhibited a lung phenotype strikingly similar to that induced by IL-21 treatment in young mice, including increased inflammation, cellular senescence, and altered macrophage lipid metabolism. Furthermore IL-21 expression was found to be elevated in the lungs of Idiopathic pulmonary fibrosis (IPF) patients compared to controls. These findings suggest that age-related elevation of IL-21 levels may be a key driver of pulmonary dysfunction in the elderly.

Pulmonary inflammatory response represents a predominant complication arising from influenza virus infections. This investigation elucidates the protective efficacy of Lactiplantibacillus plantarum GUANKE (GUANKE) supplementation against influenza A virus (IAV)-induced pulmonary damage in C57BL/6 murine models, with particular emphasis on its mechanistic underpinnings. The results showed that the use of GUANKE (5 × 10⁹ CFU/day) or exogenous linoleic acid (a metabolite of GUANKE) supplementation (40 mg/kg) significantly attenuated inflammatory cytokine secretion while counteracting virus-mediated downregulation of pulmonary barrier proteins. Mechanistic profiling revealed that GUANKE and GUANKE-derived linoleic acid modulates mitochondrial quality control through enhanced Parkin-dependent mitophagy coupled with restored mitochondrial oxidative phosphorylation (OXPHOS) capacity, thereby providing protection in IAV-infected mice.

Although androgen receptor (AR) inhibitors such as enzalutamide are initially effective in castration resistant prostate cancer through suppression of AR signaling pathway, acquired resistance invariably develops, presenting a significant therapeutic challenge. Understanding the mechanisms of enzalutamide resistance (ENZR) is essential for developing improved therapeutic strategies. Here, we demonstrated that ZNF711 was significantly overexpressed in ENZR, and high ZNF711 levels correlated with poor clinical outcomes. Functionally, ZNF711 promoted ENZR progression both in vitro and in vivo. Mechanistically, ZNF711 directly bound to the AR promoter, transcriptionally upregulating AR expression. ZNF711 knockdown markedly reduced AR chromatin occupancy at target loci. Additionally, ZNF711 formed a complex with BMI1 and AR, enhancing AR signaling pathway by suppressing CpG methylation at the promoter of AR and its downstream target genes (e.g., KLK3, TMPRSS2), thereby potentiating AR transcriptional activity. Notably, targeting ZNF711 with antagonistic chimeric siRNA restored enzalutamide sensitivity in vivo. Collectively, our findings establish ZNF711 as a critical regulator of ENZR that promotes resistance by dually modulating the AR signaling pathway via transcriptional activation and epigenetic demethylation. Targeting the ZNF711-AR axis represents a novel therapeutic strategy to overcome ENZR in prostate cancer.

The IQGAP protein family-comprising IQGAP1, IQGAP2, and IQGAP3-exhibits structural similarity but fulfils distinct cellular functions. We previously demonstrated that IQGAP1 is recruited to Marburg virus (MARV)-induced inclusion bodies (IBs) and associates with motile nucleocapsids. To further elucidate the roles of IQGAP proteins in the MARV life cycle, we generated Huh-7 cell lines with single, combined, or triple knockouts (KOs) of IQGAP isoforms. Loss of IQGAP proteins consistently reduced cellular permissiveness to MARV infection and impaired multiple key viral processes: (i) transcription and replication efficiency was diminished predominantly by IQGAP3 KO; (ii) virus release was most notably reduced in IQGAP3 KO cells, whereas cell-to-cell spread was more strongly impaired in IQGAP1 KO cells; and (iii) although actin tails continued to form at nucleocapsids in triple KO cells, long distance nucleocapsid transport was altered, with reduced spatial displacement efficiency observed in both IQGAP1 KO and IQGAP3 KO cells. The expression of individual IQGAPs in triple KO cells demonstrated their functionality and ability to partially restore the phenotype of wild-type cells. These findings identify IQGAPs as critical host factors that support MARV transcription/replication, nucleocapsid transport, and viral spread, likely through modulation of actin dynamics.