口丸 高弘

SIGNIFICANCE: Cervical cancer progresses through cervical intraepithelial neoplasia (CIN), which are precursor lesions of cervical cancer. In low-grade CIN, atypical cells are generated inside the squamous epithelium, which causes the accuracy of cytodiagnosis for cervical cancer not to be very high. The grade of CIN can be estimated by the depth of atypical cell infiltration from the basal layer to the surface, rather than the abnormality of cells. Therefore, a noninvasive method is required to evaluate the depths of abnormal cells hidden at depth. AIM: Cancerous tissues beneath healthy tissues were experimentally identified using circularly polarized light scattering (CiPLS). This method enabled the changes in the size of the cell nuclei within the penetration depth in tissue to be investigated. APPROACH: Artificial unexposed cancerous tissues were prepared that consisted of healthy/cancerous/healthy layers with various thicknesses of the topmost healthy layer and the cancerous layer. A polarization imaging camera with a quarter-wave plate was used to create distribution images of the circular polarization of the scattered light. RESULTS: CiPLS images indicated that the thickness variation of the top healthy layer (the depth of the cancerous layer) caused significant changes in the degree of circular polarization. CONCLUSIONS: The depth of unexposed cancer lying within the optical penetration depth can be evaluated using a circular polarization imaging system based on the CiPLS method. These findings will lead to the development of a noninvasive optical diagnostic method for early-stage cervical cancer, potentially improving early detection and treatment outcomes.

Cardiac fibroblasts (CFs) are the predominant non-myocyte cell type in the heart and play central roles in extracellular matrix remodeling and intercellular signaling during cardiac physiology and pathology. However, the bioenergetic basis underlying CF functions remains poorly understood, mainly due to the lack of tools for visualizing intracellular adenosine triphosphate (ATP) dynamics with high spatiotemporal resolution. Here, we established immortalized murine cardiac fibroblasts stably expressing the genetically encoded ATP indicator GO-ATeam2 based on Förster Resonance Energy Transfer (FRET). The resulting CF7/GO-ATeam2 cell line allows real-time and quantitative monitoring of cytosolic ATP levels in living cells. CF7/GO-ATeam2 cells exhibited robust proliferation and quick responses to change of cytosolic ATP level. We demonstrated dynamic cytosolic ATP imaging upon pharmacological perturbations of oxidative phosphorylation and glycolysis, as well as under growth factor stimulation. Our work provides the CF7/GO-ATeam2 platform, a versatile cellular resource for dissecting the metabolic regulation of cardiac fibroblasts, offering new opportunities to explore energy dynamics in cardiac physiology and disease.

Fibroblast growth factor-23 (FGF23) is a bone-derived hormone that promotes urinary phosphate excretion in response to phosphate loading. While essential for phosphate homeostasis, elevated FGF23 increases phosphate concentration in the renal tubular fluid, promoting calcium-phosphate crystal formation and tubular injury. Here we show that bone resorption mobilizes phosphate into the circulation and mimics the pathophysiology of dietary phosphate loading. Enhanced bone resorption, induced by soluble receptor activator of NF-κB ligand (sRANKL) administration or microgravity exposure on the International Space Station, increased circulating FGF23 levels and caused renal tubular injury in mice. Pre-treatment with bisphosphonate, an inducer of osteoclast apoptosis, prevented sRANKL-induced increases in FGF23 and tubular damage. These findings suggest that bone mineral loss may contribute to renal tubular injury in clinical settings, including immobilization, osteoporosis, and chronic kidney disease-mineral bone disorder.

The ring finger protein 213 (RNF213) gene, identified in 2011 as a susceptibility gene for moyamoya disease (MMD), has since been recognized as a key factor in a broader spectrum of vascular disorders. The p.R4810K mutation in RNF213 is particularly common among Japanese MMD patients, although a smaller percentage of healthy individuals also carry the mutation, indicating that environmental factors, alongside genetic predisposition, likely influence disease onset. RNF213, a large E3 ubiquitin ligase, plays essential roles in vascular homeostasis, immune response, and endoplasmic reticulum stress reaction. Its mutation disrupts normal angiogenesis, contributing to abnormal vascular remodeling in conditions such as pulmonary hypertension and coronary artery disease. This review examines the multifaceted role of RNF213 and its p.R4810K mutation in the pathogenesis of MMD and other vascular conditions, collectively referred to as RNF213-associated vascular diseases. While research has begun to clarify the mutation's effects on angiogenesis and the involved pathways, the roles of RNF213 and its mutation in vascular integrity remain unclear. This comprehensive overview underscores the complex interaction between genetic and environmental factors in RNF213-related vascular diseases and calls for further research to elucidate these mechanisms and develop targeted therapeutic interventions.