Bin Zhou

Embolization of hemorrhagic small vessels with collateral circulation remains challenges, as conventional liquid agents often cause nontarget embolization and particulate agents are prone to recanalization. Herein, we develop an injectable embolic system (PP/DMSO/I) based on hydration-driven self-gelling polyethylenimine/poly(acrylic acid) (PP) particles that seamlessly combines the controllable embolic size of particulate agents with the stable occlusion of liquid agents. Upon intravascular delivery, DMSO transports size-sieved PP particles to the target blood vessel, where they aggregate due to size-restricted trapping, achieving precise embolization without distal migration. Subsequent solvent exchange with blood triggers rapid hydration and fusion of PP particles into a continuous and adaptive hydrogel in situ that definitively occludes the lumen. In a typical hemorrhagic collateral circulation model (hemorrhagic point in anastomotic arcade between mesenteric artery of the rabbit), PP/DMSO/I achieves superior hemostasis (blood loss: 2.1 ± 0.3 g), significantly outperforming commercial particulate embolic agent (3.7 ± 0.4 g) and matching the efficacy of commercial liquid embolic agents (2.3 ± 0.4 g and 2.1 ± 0.6 g). Crucially, unlike commercial liquid embolic agent, it eliminated the risk of nontarget embolization and distal infarction. This hydration-driven self-gelling particulate embolic system represents a paradigm shift in embolization therapy, offering a precise, durable, and safe solution for managing hemorrhage in complex vascular networks.

Background: Hepatocellular carcinoma (HCC), the major form of primary liver cancer, contributes markedly to cancer-related mortality worldwide and remains a serious global health concern, particularly affecting individuals with underlying chronic liver disorders. In hepatocellular carcinoma, insufficient radiofrequency ablation (iRFA) has been reported to drive local tumor relapse and distant spread, possibly by aggravating the immunosuppressive features of the tumor microenvironment. The present work seeks to clarify the underlying pathways driving the development of an immunosuppressive milieu after RFA and to identify potential therapeutic approaches to counteract this process.

Introduction: Neuroinflammation is a pivotal factor in the pathophysiology process of ischemic stroke. Undue inflammatory responses are the main cause of neuronal death and infarct enlargement after reperfusion, but there is currently no effective clinical treatment method. Pyroptosis plays an important role in post-stroke neuroinflammation. Inhibiting pyroptosis may be a potential method for treating ischemic stroke. Ursolic acid (UA) is a natural antioxidant with an antipyroptotic effect, but the mechanism of UA in cerebral ischemia-reperfusion injury remains unknown.Methods: We evaluated UA’s neuroprotective effects in a transient middle cerebral artery occlusion (tMCAO) mouse model via oral administration. TTC staining was carried out to measure infarct volume. Neuronal damage was assessed through TUNEL and FJC staining. Open field test and novel object recognition test were conducted to evaluate anxiety-like behavior and hippocampal-related memory. Double-immunofluorescence was conducted to detect pyroptotic microglia. In vitro, BV-2 microglial cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) were treated with UA. Cell viability was measured utilizing CCK-8 assay. RT-qPCR was used to measure NLRP3, IL-1β, and IL-18 mRNA levels. ELISA was utilized to measure IL-1β and IL-18 concentration. PMA was used as an agonist in rescue experiment. Immunostaining was used to observe nuclear/cytoplasmic distribution of NF-κB. Western blot was used to evaluate the protein expression of pyroptosis markers.Results: UA significantly reduced infarct volume, alleviated neuronal damage, and improved cognitive and functional recovery in tMCAO mice. Additionally, UA downregulated the density of NLRP3, Caspase-1, and GSDMD positive microglia and the production of IL-1β and IL-18 in the ischemic penumbra of tMCAO mice. These effects were replicated in OGD/R-challenged BV-2 cells. Mechanistically, UA suppressed NF-κB activation, and PMA treatment reversed its therapeutic benefits in both models.Discussion: Our findings demonstrate that UA attenuates microglial pyroptosis by inhibiting NF-κB signaling, thereby reducing neuroinflammation and ischemic brain injury. This study highlights UA’s potential as a therapeutic agent for ischemic stroke.

Jingpei Guo, Xiaoting Zhang, Junbin Liu, Ke Zhang, Bin Zhou, 1 Center of Interventional Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong

Background: Incomplete radiofrequency ablation (iRFA) in hepatocellular carcinoma (HCC) often leads to local recurrence and distant metastasis of the residual tumor. This is closely linked to the development of a tumor immunosuppressive environment (TIME). In this study, underlying mechanisms and potential therapeutic targets involved in the formation of TIME in residual tumors following iRFA were explored. Then, TAK-981-loaded nanocomposite hydrogel was constructed, and its therapeutic effects on residual tumors were investigated. Results: This study reveals that the upregulation of small ubiquitin-like modifier 2 (Sumo2) and activated SUMOylation is intricately tied to immunosuppression in residual tumors post-iRFA. Both knockdown of Sumo2 and inhibiting SUMOylation with TAK-981 activate IFN-1 signaling in HCC cells, thereby promoting dendritic cell maturation. Herein, we propose an injectable PDLLA-PEG-PDLLA (PLEL) nanocomposite hydrogel which incorporates self-assembled TAK-981 and BSA nanoparticles for complementary localized treatment of residual tumor after iRFA. The sustained release of TAK-981 from this hydrogel curbs the expansion of residual tumors and notably stimulates the dendritic cell and cytotoxic lymphocyte-mediated antitumor immune response in residual tumors while maintaining biosafety. Furthermore, the treatment with TAK-981 nanocomposite hydrogel resulted in a widespread elevation in PD-L1 levels. Combining TAK-981 nanocomposite hydrogel with PD-L1 blockade therapy synergistically eradicates residual tumors and suppresses distant tumors. Conclusions: These findings underscore the potential of the TAK-981-based strategy as an effective therapy to enhance RFA therapy for HCC. Graphic

Imaging strategies for the specific detection and therapeutic monitoring of myocarditis are still lacking. Stimulator of interferon genes (STING) is a signal transduction molecule involved in an innate immune response. Here, we evaluated the feasibility of the recently developed STING-targeted radiotracer [¹⁸F]FBTA for positron emission tomography (PET) imaging to detect myocardial inflammation and monitor treatment in myocarditis mice. [¹⁸F]FBTA-PET imaging was performed in myocarditis mice and normal mice to verify the specificity of [¹⁸F]FBTA for the diagnosis of myocarditis. We also performed PET imaging in mice with myocarditis treated to verify the ability of [¹⁸F]FBTA in therapeutic monitoring. The expression of STING and inflammatory cell types was confirmed by flow cytometry and immunohistochemistry. [¹⁸F]FDG-PET imaging of myocarditis was used as a contrast. [¹⁸F]FBTA-PET imaging showed that the average radioactive uptake was significantly higher in the hearts of the myocarditis group than in the control group. STING was highly overexpressed in cardiac inflammatory cells, including macrophages, dendritic cells (DCs), and T cells. However, there was no significant difference in cardiac radiotracer uptake of [¹⁸F]FDG between the myocarditis group and the control group. Moreover, cardiac uptake of [¹⁸F]FBTA was significantly reduced in cyclosporin A-treated myocarditis mice and myocardial STING expression was also significantly reduced after the treatment. Overall, we showed that a STING-targeted PET tracer [¹⁸F]FBTA can be used to monitor changes in the inflammatory microenvironment in myocarditis. Besides, [¹⁸F]FBTA-PET is also suitable for real-time monitoring of myocarditis treatment, representing a promising diagnostic and therapeutic monitoring approach for myocarditis.