砂河 孝行

Long-lasting neurological issues, including cognitive impairment, anxiety, and depression, that persist after recovery from acute inflammatory diseases, such as infections, have become a significant social problem, particularly following the coronavirus disease 2019 pandemic. Various diagnostic techniques and biomarkers have been explored to objectively evaluate brain symptoms associated with infection-induced local or systemic inflammatory responses (i.e. immune fatigue); however, their detection capabilities remain limited. Here we investigated whether magnetic resonance imaging (MRI) combined with a quantum-sensed molecule, parahydrogen-polarised [1-13C] pyruvate, could detect persistent brain metabolic alterations in a murine pseudo-infection model induced by polyinosinic-polycytidylic acid (Poly(I: C)), a Toll-like receptor 3 ligand. Significant alterations in brain pyruvate metabolism favouring glycolysis were observed in both the acute and late phases of the pseudo-infection model, with a 12.7% and 2.5% decrease in bicarbonate flux, and a 58.4% and 32.2% increase in lactate flux on day 3 and week 2, respectively. These brain metabolic changes were accompanied by diminished dopamine signal markers in the striatum and nigra/ventral tegmental areas and reduced spontaneous nocturnal locomotor activity. A biochemical analysis of energy metabolic markers consistently supported the reprogramming of brain glucose metabolism, showing the suppression of oxidative phosphorylation during the acute phase and promotion of glycolysis during the late phase of Poly(I: C) treatment. Hyperpolarised 13C MRI of pyruvate metabolism is a promising non-invasive imaging biomarker for brain issues during the late phase of systemic infections and other neurodegenerative and psychiatric diseases, particularly in conditions lacking discernible morphological abnormalities.

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.

Fibrosis is the ultimate outcome of various chronic diseases that affect multiple organs, including the liver, lungs, heart, and kidneys. This pathological process is characterized by the excessive accumulation of extracellular matrix produced by activated myofibroblasts in response to chronic injury, as part of a degenerative process of dysregulated tissue repair. While numerous pathways have been implicated in the development of fibrosis, the precise mechanisms that drive and exacerbate organ fibrosis remain inconclusive. Consequently, there are currently very limited treatments for organ fibrosis. In recent years, immune cells have been identified as critical mediators of the fibrotic cascade, capable of inducing tissue damage or promoting repair. Harnessing immune cells and immunotherapeutic approaches to intervene in the fibrotic process is a promising avenue towards new treatment options. In this review, we explore the pathophysiology of fibrosis in various organs, with a specific focus on the role of immune cells in both the development and regression of fibrosis as well as the latest preclinical findings with relation to immunotherapeutic treatment approaches. Understanding the role of immune responses in fibrotic diseases will aid in the development of immunotherapeutic strategies that target key pro-fibrotic cytokines and immune cells, with the aim of preventing fibrosis or promoting its regression.