The First People's Hospital of Lianyungang

The catalytic strategies selectively eradicate tumors, but their efficacy is hindered by antioxidant defense mechanisms of tumor microenvironment (TME) and insufficient catalytic efficiency. Herein, we present a multifunctional manganese oxide nanosphere (MnO_x NSs)-based antitumor platform that synergizes ultrasound (US)-triggered reactive oxygen species (ROS) generation with oxygen-independent sulfate radical (SO₄^•-) production to amplify oxidative damage. Under US irradiation, MnO_x NSs generate hydroxyl radicals (•OH) and singlet oxygen (¹O₂) via sonodynamic effects, and Mn²⁺/Mn³⁺ species activate peroxymonosulfate (PMS) to produce SO₄^•- and •OH without oxygen reliance. Notably, US-induced electron-hole separation enables redox cycling between Mn³⁺/Mn⁴⁺ and Mn²⁺/Mn³⁺, creating a self-sustaining catalytic loop for continuous reactive species generation. Concurrently, enzyme-mimicking activities of MnO_x NSs alleviating hypoxia and depleting glutathione in TME, thereby disrupting redox homeostasis. The TME remodeling, combined with oxidative storm induction, triggers ferroptosis which is driven by lipid peroxidation. In vitro and in vivo studies validate the efficacy and biosafety of this approach, demonstrating significant tumor suppression through synergistic oxidative storm and ferroptosis induction. This work highlights a paradigm-shifting strategy that integrates multi-catalytic reactivity, TME modulation, and regulated cell death pathways, offering a robust solution to overcome therapeutic barriers in antioxidant-rich tumors. The findings underscore the potential of manganese-based nanoplatforms in advancing next-generation catalytic oncology therapies.

Sepsis-associated encephalopathy (SAE) is a common and serious complication of sepsis, characterized by neuroinflammation and cognitive dysfunction, yet its molecular mechanisms remain unclear. This study aimed to investigate the role of heat shock protein 90α (HSP90α) in microglial NLRP3 inflammasome activation and cognitive impairment in SAE, and to explore the therapeutic potential of a small molecule compound, nicotinamide N-oxide (NAMO). SAE models were established using cecal ligation and puncture (CLP) in mice and LPS/ATP stimulated primary microglial cells/BV-2 cells. A combination of H&E/Nissl/TUNEL staining, transcriptomics, immunoblotting, qPCR, immunofluorescence, ELISA, mtDNA release, co-immunoprecipitation, molecular docking, AAV stereotaxic delivery, and pharmacological/siRNA interventions were utilized. Results showed that HSP90α expression was significantly upregulated in microglia during SAE. HSP90α facilitated NLRP3 inflammasome activation and exacerbated cognitive dysfunction in SAE by inducing mitochondrial dysfunction and promoting the release of mitochondrial DNA (mtDNA). Mechanistically, HSP90α interacted with PPP3CA, which facilitated Drp1 dephosphorylation at Ser637, triggering mitochondrial fragmentation and mtDNA release. Importantly, we identified that NAMO binds directly to HSP90α, inhibits the HSP90α-PPP3CA-Drp1 axis, reduces mtDNA release, and suppresses NLRP3 inflammasome activation. Administration of NAMO significantly alleviated cognitive impairment in SAE mice. Collectively, our findings reveal a novel HSP90α-PPP3CA-Drp1-mtDNA-NLRP3 signaling pathway in microglial activation and cognitive injury during SAE, and propose NAMO as a promising therapeutic candidate for SAE intervention.

Sepsis frequently gives rise to acute hepatic injury, representing a prevalent and critical pathological manifestation associated with high morbidity and mortality, yet effective therapeutic strategies remain limited. In this study, sepsis-induced acute liver injury was modeled in mice using cecum ligation and puncture (CLP) surgery. The therapeutic potential and underlying mechanisms of Nicotinamide nitrogen oxide (NAMO) were evaluated via intraperitoneal injection at doses of 40, 80, and 160 mg/kg. Histological analysis revealed that increasing doses of NAMO led to more orderly hepatocyte arrangement and significantly reduced vacuolar degeneration and inflammatory cell infiltration. NAMO treatment significantly downregulated the mRNA expression of pro-inflammatory cytokines (iNOS, IL-1β, TNF-α, and IL-6) and upregulated the anti-inflammatory cytokine IL-10. Additionally, NAMO enhanced the activity of antioxidant enzymes (CAT, GSH, and T-AOC), while reducing levels of lipid peroxidation markers (MDA) and reactive oxygen species (ROS) in both liver tissues and hepatocytes. Furthermore, NAMO restored the protein expression of mitochondrial regulatory factors NRF1 and PGC-1α and preserved intracellular ATP levels, indicating improved mitochondrial function. Mechanistic investigations showed that NAMO exerted its protective effects by modulating mitochondrial homeostasis and oxidative stress through the SIRT3/AKT signaling pathway being blocked. In conclusion, by minimizing oxidative stress and inflammation, keeping mitochondrial integrity, and managing the SIRT3/AKT pathway, NAMO shields with sepsis-induced acute liver injury. The results indicate that NAMO holds significant potential as a therapeutic agent for managing hepatic impairment associated with sepsis.