Free Radical Biology and Medicine最新文献

Breast cancer remains a major global health challenge, with triple-negative breast cancer (TNBC) posing a particular therapeutic dilemma due to its lack of targetable receptors and reliance on chemotherapy, which is often thwarted by drug resistance. To overcome these limitations, we developed a novel metal-polyphenol nano-platform (DLF@NPs) via a one-pot coordination assembly of L-dopa (L-DA), doxorubicin (DOX), and ferrous ions (Fe²⁺). This GSH/pH-dual-responsive nanoparticle exploits the overexpression of L-type amino acid transporter 1 (LAT1) on breast cancer cells for targeted delivery and tumor-specific enrichment, effectively addressing the off-target toxicity and resistance associated with free DOX. Upon internalization into the acidic and high-GSH tumor microenvironment, DLF@NPs rapidly disassemble, releasing their payload. The liberated DOX not only exerts its apoptotic effect but also activates NADPH oxidases (NOXs) to elevate intracellular H₂O₂ levels. This endogenous H₂O₂ supply fuels a Fenton reaction catalyzed by the co-released Fe²⁺, generating highly toxic hydroxyl radicals. Furthermore, L-DA reduces the resultant Fe³⁺ back to Fe²⁺, establishing a catalytic cycle that robustly amplifies reactive oxygen species (ROS). The resultant ROS burst synergizes with DOX by inducing severe mitochondrial damage, leading to potentiated apoptosis. In summary, this work proposes a novel targeted nanoplatform that utilizes the synergy between chemodynamic therapy and chemotherapy to provide a promising strategy for combating drug-resistant breast cancer.

G protein-coupled receptor kinase 4 (GRK4) plays a vital role in the regulation of blood pressure. Several GRK4 gene variants have attracted attention because of their association with hypertension. However, the role of GRK4 R65L in hypertension is still unclear. In the present study, we report that global and renal tubule-targeted GRK4 R65L over-expression in mice caused salt-sensitive hypertension, accompanied by a rightward shift of the plot of urine sodium excretion against systolic blood pressure, that were improved by AAV9-mediated renal GRK4 depletion. RNA sequencing showed that the expression of the long chain L-2-hydroxyacid oxidase 2 (Hao2) gene ranked first in up-regulated candidates involved in the regulation of sodium-water metabolism. The salt-sensitive hypertension and increased renal oxidative stress in GRK4 R65L mice were mitigated by AAV9-mediated renal Hao2 depletion or administration of the potent antioxidant tempol. Immunoprecipitation-mass spectrometry showed an increased interaction between triosephosphate isomerase 1 (TPI1) and GRK4 in the kidneys of high salt-fed GRK4 R65L mice, accompanied by increased TPI1 phosphorylation and nuclear translocation, which were decreased, along with renal Hao2 expression, after GRK4 depletion. Renal H3K27ac levels and binding to the Hao2 promoter were increased but the levels of nuclear dihydroxyacetone phosphate (DHAP), a downstream molecule of TPI1, were decreased in high salt-fed GRK4 R65L mice. DHAP reduced the levels of H3K27ac and Hao2 in GRK4 R65L transfected-HK-2 cells. The H3K27ac inhibitor C646 mitigated the salt-sensitive hypertension in GRK4 R65L mice, accompanied by decreased H3K27ac and Hao2 expressions, and oxidative stress. Our results demonstrated that in high salt fed-GRK4 R65L mice, elevated renal TPI1 nuclear phosphorylation decreased DHAP levels and increased H3K27ac expression, which increased Hao2 expression and oxidative stress, caused a rightward shift of the pressure-natriuresis plot, and subsequently caused salt-sensitive hypertension.

Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent in type 2 diabetes (T2D), yet disease-modifying therapies remain limited. Here we identify an adipose-cardiac communication axis in which stressed adipocytes export extracellular vesicles (AdEVs) laden with oxidatively damaged mitochondrial proteins that are associated with impaired cardiomyocyte bioenergetics and increased apoptosis. Single-nucleus RNA-seq of human subcutaneous adipose tissue from patients with T2D-HFpEF revealed metabolic stress in adipocytes, characterized by enriched mitochondrial oxidative stress genes and reduced metabolic flux. The severely affected AD3 subpopulation exhibits mitochondrial impairments, potentially accompanied by increased AdEV release. In parallel, circulating AdEVs were elevated and their mitochondrial cargo showed greater oxidative modification; AdEV abundance tracked systemic protein carbonyls and clinical markers of cardiac load. In vitro, lipotoxic adipocytes released AdEVs enriched for mitochondrial components with increased protein carbonylation. When applied to human cardiomyocytes (AC16 and human induced pluripotent stem cell-derived cardiomyocytes), these AdEVs increased reactive oxygen species (ROS), dissipated mitochondrial membrane potential, fragmented mitochondrial networks, reduced oxygen consumption and ATP production, and activated intrinsic apoptosis and heart-failure marker expression. Inhibition of EV biogenesis (GW4869) or scavenging of mitochondrial ROS (Mito-TEMPO) blunted these effects. Collectively, our data support a model in which oxidatively modified mitochondrial cargo within AdEVs links adipose stress to cardiomyocyte dysfunction in T2D-HFpEF and suggest that AdEV release and mitochondrial ROS may represent tractable therapeutic targets.