Inflammation-induced proliferation of airway smooth muscle cells (ASMCs) and subsequent airway remodeling is a hallmark of chronic obstructive lung disease (COPD). The role of midkine (MK) in COPD is unclear. In this work, we explored the role of MK-Notch2 signaling in COPD by inhibiting the expression of MK using lentivirus shRNA in ASMCs in vitro and instillation of AAV9-MK in the airway of a COPD rat model in vivo. The results demonstrated that LPS decreased ASMC migration and proliferation, increased apoptosis and induced the expression of MK and Notch2 signaling molecules. Inhibition of MK exacerbated the changes in migration and proliferation but decreased the expression of MK and Notch2 signaling molecules. Rats treated with smoke fumigation and LPS showed features of COPD. The small airways of COPD rats were remodeled and lung function was significantly reduced. The expressions of TGF-β, ICAM-1, HA, MMP-9, PC-III, and LN in BALF and the expression of MK and Notch2 signaling molecules were significantly increased in the COPD rats compared with controls. Inhibition of MK reversed these changes. In conclusion, the MK-Notch2 pathway plays a key role in airway remodeling induced by ASMC proliferation. Targeting the MK-Notch2 pathway may be a new strategy for improving airway remodeling and preventing progressive decline of pulmonary function in COPD.

The singular forms of programmed cell death (PCD), including pyroptosis, apoptosis, and necroptosis, are inadequate for comprehensively elucidating the complex pathological mechanisms underlying ischemic diseases. PANoptosis is a unique lytic, innate immune, and inflammatory cell death pathway, initiated by innate immune sensors and driven by caspases and RIPKs through PANoptosome complexes. In diseases like cerebral ischemia, retinal ischemia, myocardial ischemia, renal ischemia, and spinal cord ischemia, targeting key regulatory factors of PANoptosis can help mitigate tissue damage. Therefore, the therapeutic potential of PANoptosis in ischemic diseases—from molecular mechanisms to clinical applications—merits further investigation. However, effectively regulating PANoptosis to achieve therapeutic outcomes remains a critical scientific challenge that must be addressed. This review focuses on the molecular mechanisms of PANoptosis in ischemic diseases and its potential therapeutic implications, aiming to provide new insights and a theoretical foundation for precision treatment in these conditions.

Lower-limb ischemia–reperfusion injury (LL-IRI) is a frequent and serious complication following reperfusion therapy for lower-limb arterial occlusion. It can be caused by trauma, arterial stenosis, thrombotic occlusion, and atherosclerosis. As a prevalent peripheral vascular disease, LL-IRI results in local tissue damage and triggers systemic inflammatory responses that can lead to multiple-organ dysfunction syndrome, as well as multiorgan failure and death in severe cases. Despite its clinical significance, the mechanisms underlying IRI remain poorly understood, and no specific targeted drugs or effective emergency interventions are currently available. Therefore, this review provides a comprehensive analysis of the domestic and international literature published over the past decade regarding the disease definition, pathogenesis, and therapeutic advances in LL-IRI. It summarizes current pharmacological and non-pharmacological interventions, including antioxidant stress management, anti-inflammatory approaches, and oxidative stress reduction strategies. This review aims to advance the exploration of LL-IRI pathogenesis and proposes novel therapeutic perspectives for innovative drug development.

Although reactive oxygen species (ROS)-mediated PANoptosis plays a pivotal role in the pathological dysfunction of lower limb ischemia/reperfusion injury (LL-IRI), its exact mechanism remains unclear. Real-time detection of H₂O₂ will help to reveal the complicated relationship between ROS, PANoptosis and LL-IRI. In this work, we designed and synthesized a novel near-infrared fluorogenic (NIRF) probe, BFP-H₂O₂, which exhibited a pronounced fluorescence-enhanced response to H₂O₂ at 650 nm. BFP-H₂O₂ was successfully applied to a TAK1i/LPS-induced PANoptosis cell model, revealing up-regulation of H₂O₂ during PANoptosis. To the best of our knowledge, there were no suitable chemical tools available for high-throughput screening of anti-PANoptosis compounds from Plantagodepressa Willd (PW). Leveraging BFP-H₂O₂, aucubin (AU) from PW was identified for the first time as the most promising anti-PANoptosis active ingredient. Additionally, BFP-H₂O₂ enabled visual imaging of the dynamic changes of H₂O₂ in the LL-IRI mice model. Particularly importantly, it was confirmed that AU could effectively inhibit H₂O₂-mediated oxidative stress and attenuate PANoptosis in gastrocnemius muscle tissues during LL-IRI. This work not only afforded a reliable chemical tool for screening anti-PANoptosis drugs, but also further elucidated the mechanism of PANoptosis and LL-IRI and advanced the development of therapeutic drugs for PANoptosis-related diseases.

Traditional particulate embolic agents are small in diameter, but can easily embolize the ends of blood vessels, resulting in ischemia and necrosis of normal tissues and organs. The metal spring embolic agent has a larger diameter, but it cannot be degraded and can easily cause permanent damage to blood vessels. Ideally, a bleeding embolism should achieve rapid hemostasis without causing long-term necrosis of organs and tissues. In this study, a modified sodium alginate hydrogel (MSAH) was prepared by mixing an oxidized sodium alginate (OSA) aqueous solution with a carboxymethyl chitosan (CMC) aqueous solution at a ratio of 1:6 in a 38°C bath for 8 min. The feasibility of this modified hydrogel was then tested in an internal iliac artery hemorrhage model using New Zealand rabbits. The MSAH had good adhesion. The hydrogel was injected through a single curved 4F catheter without obvious effects on uterine smooth muscle cell proliferation and apoptosis. The blood flow of the internal iliac artery was restored by long-term degradation of the sodium alginate hydrogel, and no ischemia and necrosis were observed by histopathology. The MSAH prepared using a mixture of OSA and CMC had good adhesion, biocompatibility, and injectability and could be used for target-vessel embolization in an internal iliac artery hemorrhage model. The MSAH can achieve main artery embolization without affecting the peripheral artery blood supply, resulting in both short-term rapid hemostasis and long-term degradation, with no target organ necrosis.

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