Cells

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene, which encodes a cAMP-activated chloride channel essential for epithelial function. Beyond its canonical role, evidence suggests CFTR also influences mitochondrial function. Previous studies have identified CFTR- and Cl-dependent genes, including MTND4 and CISD1, which are downregulated in CF cells and play a critical role in mitochondrial function. CF cells exhibit altered mitochondrial complex I (mCx-I) activity and impaired electron transport chain function, although the underlying mechanisms remain unclear. In this study, the impact of the CFTR modulators lumacaftor (VX-809) and ivacaftor (VX-770) on mitochondrial morphology and function was investigated in heterozygous ΔF508/W1282X CF IB3-1 cells. Combined treatment with VX-809 (10 μM, CFTR corrector) and VX-770 (0.1 μM, CFTR potentiator) induced a fragmented mitochondrial morphology in both CF and CF expressing wt-CFTR cells, without affecting cell viability or mitochondrial membrane potential (ΔΨm). While individual treatments differentially modulated ROS production and ΔΨm, these effects were not statistically significant under combined treatment. These results highlight a previously unrecognized role for CFTR modulators in shaping mitochondrial morphology. A better understanding of these effects may reveal novel mechanisms underlying the regulation of mitochondrial structure and function.

Recent technological breakthroughs have enabled multidimensional phenotyping, with unprecedented single-cell resolution and genome-wide coverage, across multiple osteoarthritis (OA)-relevant tissues, such as articular cartilage, synovium, infrapatellar fat pad, and subchondral bone. The majority of the single nucleotide variations (SNVs) that have been associated with OA are located in non-protein coding regions and confer risk for disease by altering the expression level, instead of the amino acid sequence of the gene product. These data have shaped the concept of OA as a polygenic disease, where genetic factors disrupt the chromatin landscape in disease-relevant cells, leading to aberrant expression of effector genes. Pharmacologic manipulation of the OA-driving epigenetic landscape has recently emerged as an attractive path for the development of disease-modifying drugs. Novel clustered regulatory interspaced short palindromic repeats (CRISPR)-based technologies provide opportunities for precise epigenetic editing at the desired genomic regions and may allow a targeted transcriptional regulation of disease-relevant genes in disease-relevant cells. The aim of the present narrative review is to summarize the emerging data on the role of epigenetic factors and chromatin structure as calibrators of the risk for developing OA and to discuss the opportunities and challenges arising from the use of chromatin landscape to guide drug discovery.

Objectives: Pleural mesothelioma (PM) is a rare cancer that often develops after a decades-long latency period and confers a grim prognosis. Novel, biomarker-based therapeutic modalities are expected to improve the outcome of patients with advanced PM. CUDC-907 (fimepinostat) is a dual inhibitor that affects both histone deacetylases and PI3K enzymes. Its antitumor activity was described in several cancer types, but it has not yet been explored in PM. Materials and Methods: The sensitivity of 22 PM cell lines—including 18 models established in our laboratory—to cisplatin and CUDC-907 was determined using a cell viability assay. BAP1, PTEN, and c-Myc expression, as well as MYC copy number variation, were measured. The effect of combination treatment with cisplatin was assessed with cell viability, cell cycle, and 3D spheroid formation assays. Results: Most PM cell lines were sensitive to CUDC-907 treatment, and the CUDC-907 response was significantly higher in cell lines with higher c-Myc expression due to MYC copy number gain or amplification. Importantly, all cisplatin-insensitive cell lines were sensitive to CUDC-907. Combination treatment with cisplatin synergistically decreased cell viability and induced G2/M arrest or cell death. We tested cisplatin-sensitive P31WT and cisplatin resistant P31cis isogeneic pair and found that in both 2D and 3D assays the cisplatin-resistant cells showed a higher sensitivity to CUDC-907 single treatment. Combining CUDC-907 with cisplatin further decreased cell growth even in cisplatin-resistant cells. Conclusions: The majority of PM cell models are sensitive to CUDC-907, which may be a potent therapeutic agent in PM.