ペルオキシソーム病

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 80-85% of cases. Despite therapeutic advances, drug resistance and suboptimal outcomes persist, underscoring the need for novel molecular targets. Peroxisome proliferator-activated receptors (PPARα, PPARβ/δ, PPARγ) are ligand-activated transcription factors that regulate lipid metabolism and inflammation. Their expression is dysregulated in NSCLC, but functional studies have yielded conflicting results: all three isoforms can exert either tumor-suppressive or tumor-promoting effects depending on cellular context, metabolic state, and genetic background. This context-dependent duality has created uncertainty in the field, even as the intersection of metabolism and anti-tumor immunity becomes increasingly recognized as a driver of NSCLC progression. PPARs sit at this intersection, integrating metabolic, inflammatory, and immune signals, which has renewed interest in their therapeutic potential. Clinically available PPAR agonists (e.g., fibrates, thiazolidinediones) are being investigated in exploratory combinations with immune checkpoint or targeted therapies, though their success may depend on biomarker-guided patient selection. This review critically discusses the isoform-specific functions and molecular mechanisms of PPARs in NSCLC, summarizes preclinical and clinical advances in PPAR-targeted strategies for prevention and treatment, and highlights key translational gaps. We aim to provide a conceptual framework for developing precision therapies that account for the context-dependent nature of PPAR signaling.

Ischemia-Reperfusion Injury-related Acute Kidney Injury (IRI-AKI) is a significant clinical challenge. Despite extensive research into the underlying mechanism for IRI-AKI, the development of effective therapeutic interventions remains challenging due to self-perpetuating positive-feedback loops between oxidative stress and inflammation pathways. Mitochondrial dysfunction has been acknowledged as a significant player in the early stages of IRI in causing cellular damage. However, antioxidant therapy has only yielded modest improvements in outcomes. Interestingly, Mesenchymal Stem/Stromal Cells (MSCs) have shown potential in the treatment of AKI through their anti-inflammatory properties, though their ability to disrupt the oxidative stress-inflammation axis remains incompletely understood. In a clinically relevant surgical model of IRI-AKI, we investigated precision delivery of MSCs directly into the kidney, via its arterial blood supply, to ensure spatial in vivo coupling of these cells with injured renal cells. Here, we observed that MSCs, specifically BM-MSCs, mitigated mitochondrial dysfunction during the early stages of IRI-AKI, leading to reduced inflammation, preventing cellular injury and recovery of renal function. Mechanistic studies demonstrated the importance of Connexin 43 (Cx43)-mediated gap junctions in facilitating mitochondrial transfer from MSCs to damaged renal epithelial cells, resulting in activation of PGC1α signaling, a reduction in mitochondrial reactive oxygen species (ROS), and promotion of mitogenesis. These findings highlight the mechanism by which spatially coupled MSCs can restore cellular mitochondrial homeostasis by disrupting the oxidative stress-inflammation axis and paving the way for the development of disease etiology-based therapeutics for treating IRI-AKI.

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants increasingly detected in maternal serum, breast milk, drinking water, and indoor environments, raising concern for fetal and early postnatal exposure during critical periods of lung development. Although epidemiologic and experimental studies link early-life PFAS exposure with altered immune function, impaired lung maturation, and later respiratory vulnerability, the molecular pathways underlying these effects remain incompletely defined. In this mini-review, we propose peroxisome proliferator-activated receptor gamma (PPARγ) as a central integrator of developmental lung reprogramming by PFAS. PPARγ regulates key processes required for normal alveolar maturation, including epithelial-mesenchymal interactions, lipofibroblast differentiation, epithelial barrier integrity, macrophage polarization, and inflammatory homeostasis. Recent evidence, including our own, indicates that in the developing lung PFAS exposure is associated with suppression of pulmonary PPARγ expression and signaling while relatively sparing PPARα, and that pharmacologic modulation of PPARγ significantly alters PFAS-induced epithelial inflammatory responses. We discuss how PFAS-mediated disruption of PPARγ signaling, potentially through direct pulmonary effects as well as indirect placental and endocrine mechanisms, may link structural and immune reprogramming by altering lipofibroblast identity, impairing alveolar maturation, altering epithelial permeability, and promoting macrophage programs that amplify later allergic susceptibility. We further highlight developmental timing, exposure mixture, and sex-divergent outcomes as emerging modifiers of this pathway. Defining how PFAS perturbs PPARγ-dependent developmental programs may provide a practical mechanistic framework for understanding environmentally programmed respiratory disease.

Exercise has a positive effect on various cardiovascular diseases. However, it is not uncommon to experience arrhythmia events during or after exercising. To determine how to maximize the benefits of exercise while ensuring safety. We conducted a study involving 40 adult male Sprague-Dawley rats. These rats underwent exercise of different intensities for 8 weeks. We recorded electrophysiological stimulation to track the occurrence and duration of atrial fibrillation and other electrophysiological data. Additionally, we analyzed and observed the histology of cardiomyocytes. The results revealed a relationship between exercise intensity and the incidence of atrial fibrillation and myocardial lipid deposition. As exercise intensity increased, there was an increase in myocardial fibrosis, mitochondrial activity, and autophagy and a decrease in reactive oxygen species. The expression of Na/Ca Exchanger (NCX1) and Kv1.5 proteins in rat atrial cardiomyocytes exhibited varying degrees of change. The increase in myocardial lipid level after exercise is thought to significantly affect myocardial fibrosis, which may be related to the upregulation of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha expression. Sustained and moderate-intensity exercise is more suitable for improving myocardial metabolic energy supply and treating atrial arrhythmias.

OBJECTIVES: Serum from patients with hypertension (HT) causes endothelial cell (EC) damage, leading to senescence and dysfunctional phenotype. This study investigated whether serum from patients treated with the antihypertensive drugs could normalize EC activity. METHODS: This study involved 71 patients with newly diagnosed HT, who were randomly assigned to one of three groups based on the antihypertensive treatment: amlodipine, nebivolol, or perindopril. Serum samples collected before and 6 weeks after treatment were applied to ECs in vitro to assess their angiogenic activity, cellular senescence, mitochondrial metabolism, and oxidative stress. RESULTS: Results showed that exposure of ECs to serum from patients treated for 6 weeks significantly altered EC function, with varying effects among the drugs. Serum from nebivolol-treated patients produced the most consistent benefits, reducing EC proliferation and HIF-1α expression, likely due to lower levels of angiogenic factors such as angiopoietin-1, basic fibroblast growth factor (bFGF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF). Additionally, this serum contained reduced levels of pro-inflammatory cytokines (E-selectin, P-selectin, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor α (TNFα)) and lower TGF-β1, which are linked to HT-related EC senescence. Nebivolol treatment decreased senescence biomarkers such as SA-β-Gal, 53BP1, and p16, with SA-β-Gal reduction comparable to that of TGF-β1 neutralizing antibodies. Oxidative stress was reduced, indicated by lower oxidized DNA product levels. CONCLUSIONS: Nebivolol was the most effective at reducing the factors, associated with HT induced cellular senescence of endothelium, through reducing TGF-β1.