Moderate inflammation is essential for standard wound healing. In pathological conditions, such as diabetes, protracted and refractory wounds are associated with excessive inflammation, manifested by persistent proinflammatory macrophage states. However, the mechanisms are still unclear. Herein, we perform a metabolomic profile and find a significant phenylpyruvate accumulation in diabetic foot ulcers. Increased phenylpyruvate impairs wound healing and augments inflammatory responses, whereas reducing phenylpyruvate via dietary phenylalanine restriction relieves uncontrolled inflammation and benefits diabetic wounds. Mechanistically, phenylpyruvate is ingested into macrophages in a scavenger receptor CD36-dependent manner, binds to PPT1, and inhibits depalmitoylase activity, thus increasing palmitoylation of the NLRP3 protein. Increased NLRP3 palmitoylation is found to enhance NLRP3 protein stability, decrease lysosome degradation, and promote NLRP3 inflammasome activation and the release of inflammatory factors, such as interleukin (IL)-1β, finally triggering the proinflammatory macrophage phenotype. Our study suggests a potential strategy of targeting phenylpyruvate to prevent excessive inflammation in diabetic wounds.

The continuous imbalance of the diabetic wound microenvironment is an important cause of chronic nonhealing, which manifests as a vicious cycle between excessive accumulation of reactive oxygen species (ROS) and abnormal healing. Regulating the microenvironment by suppressing wound inflammation, oxidative stress, and bacterial infection is a key challenge in treating diabetic wounds. In this study, ROS‐responsive hydrogels are developed composed of silk fibroin methacrylated (SFMA), modified collagen type III (rCol₃MA), and lipid nanoparticles (LNPs). The newly designed hydrogel system demonstrated stable physicochemical properties and excellent biocompatibility. Moreover, the release of antimicrobial peptide (AMP) and puerarin (PUE) demonstrated remarkable efficacy in eradicating bacteria, regulating inflammatory responses, and modulating vascular functions. This multifunctional hydrogel is a simple and efficient approach for the treatment of chronic diabetic infected wounds and holds tremendous potential for future clinical applications.

Diabetic wound healing remains a significant clinical challenge because of hyperglycaemia-induced cellular senescence, impaired angiogenesis, and chronic inflammation. To address these issues, we developed a multifunctional hydrogel (GelMA/PNS/Alg@IGF-1) that integrates gelatine methacryloyl (GelMA), Panax notoginseng saponins (PNS), and sodium alginate microspheres encapsulating insulin-like growth factor-1 (IGF-1). This hydrogel was engineered to achieve gradient and sustained release of bioactive agents to target senescence and promote vascular repair. In vitro studies demonstrated that the hydrogel significantly reduced oxidative stress, suppressed senescence markers and senescence-associated secretory phenotypes, and restored endothelial cell function under high-glucose conditions by inhibiting NF-κB pathway activation. Transcriptomic analysis revealed the modulation of pathways linked to inflammation, apoptosis, and angiogenesis. This hydrogel accelerated diabetic wound closure in a rat model in vivo and enhanced collagen deposition, granulation tissue formation, and neovascularization. Furthermore, the hydrogel mitigated oxidative stress and cellular senescence and promoted tissue remodelling. The synergistic effects of PNS and IGF-1 within the hydrogel established a pro-regenerative microenvironment to address both pathological ageing and vascular dysfunction. These findings highlight GelMA/PNS/Alg@IGF-1 as a promising therapeutic platform for diabetic wound management, as this material offers dual anti-senescence and proangiogenic efficacy to overcome the complexities of chronic wound healing.

Purpose: Previous study reported that Piezo1 was highly expressed in glioma and promoted the proliferation of glioma cells, suggesting that Piezo1 overexpression might contribute to the poor prognosis of patients. Thus, this study aimed to identify whether Piezo1 may become a new prognostic biomarker for glioma patients. Patients and Methods: Firstly, Piezo1 expression of gliomas was analyzed through GEO and Oncomine dataset, and verified by qRT-PCR and immunohistochemistry (IHC) methods. A total of 183 glioma patients were included in this study between January 2010 and December 2014. Kaplan-Meier survival analyses, Cox regression analyses and ROC curve analyses were performed to assess the diagnostic and prognostic values of Piezo1 in glioma patients. Results: In this study, Piezo1 was identified to be highly expressed in gliomas, and increased with WHO grade. Chi-square test results showed that Piezo1 expression was significantly related to age (P=0.00), WHO grade (P=0.00), Histopathology (P=0.00), IDH1 mutation (P=0.00) and chemotherapy (P=0.00). Kaplan-Meier analysis showed that the overall survival (OS) of patients with high Piezo1 expression was significantly worse than that of patients with low Piezo1 expression (HR=3.39, 95% CI=2.40– 4.81, P< 0.0001). A multivariate Cox regression analysis revealed that Piezo1 might be an independent prognostic factor for glioma patients (HR=1.34, 95% CI=1.23– 1.47, P=0.000). The area under the ROC curve (AUC) of 1-, 3-, and 5-year overall survival for Piezo1 overexpression was 0.820 (P=0.000), 0.849 (P=0.000), and 0.861 (P=0.000), respectively. Conclusion: Piezo1 was overexpressed in glioma samples. Piezo1 overexpression as an independent prognostic factor adversely affects the prognosis of patients, which could be a new novel prognostic indicator in glioma patients.

The development of therapeutic strategies to improve wound healing in individual diabetic patients remains challenging. Stem cell-derived exosomes represent a promising nanomaterial, and microRNAs (miRNAs) can be isolated from them. It is important to identify the potential therapeutic role of specific miRNAs, given that miRNAs can play a therapeutic role. qPCR, flow cytometry, and western blotting were used to verify the effect of epidermal stem cell-derived exosomes (EpiSC-EXOs) on M2 macrophage polarization and SOCS3 expression. By screening key miRNAs targeting SOCS3 in EpiSC-EXOs by high-throughput sequencing, we verified the mechanism in vitro. Finally, an animal model was used to verify the effect of promoting healing. The use of EpiSC-EXOs reduced SOCS3 expression and promoted M2 macrophage polarization. The abundant miR-203a-3p present in the EpiSC-EXOs specifically bound to SOCS3 and activated the JAK2/STAT3 signaling pathway to induce M2 macrophage polarization. Treatment of the db/db mouse wound model with miR-203a-3p agomir exerted a pro-healing effect. Our results demonstrated that the abundant miR-203a-3p present in EpiSC-EXOs can promote M2 macrophage polarization by downregulating SOCS3 and suggested that diabetic wounds can obtain better healing effects through this mechanism.