Chronic wounds infected with multidrug-resistant bacteria pose a significant challenge to global health, as traditional monotherapies often fail to eradicate pathogens and restore the damaged wound microenvironment. Engineering innovative nanocomposites that integrate synergistic therapeutics and controlled release is a pivotal strategy for advanced wound management. Here, we developed a novel multi-drug metal-organic framework (MOF) nanocomposite, BBR + FA@UiO, by covalently grafting ferulic acid (FA) onto UiO-66-NH₂ and physically loading berberine (BBR). Drawing from "Jun–Chen–Zuo–[Shi]" hierarchy of Traditional Chinese Medicine (TCM), this design used the MOF as a robust porous carrier “[Shi]” for the antibacterial drug "Jun" (BBR) and antioxidant drug "Chen/Zuo" (FA). BBR + FA@UiO exhibits potent, synergistic antibacterial and antibiofilm activity against critical clinical pathogens like MRSA and Pseudomonas aeruginosa, through a pH/ROS-responsive release mechanism in the infected site. Functionally, BBR + FA@UiO activates the Nrf2/Keap1 pathway in macrophages, thereby mitigating oxidative stress and enhancing mitochondrial function. Consequently, proliferation and migration of Human Umbilical Vein Endothelial Cells (HUVECs) are restored through promoting angiogenesis. In vivo, BBR + FA@UiO significantly accelerates healing by eradicating bacteria, enhancing collagen deposition, and improving vascularization, driven by the coordinated activation of the Nrf2/HO-1 antioxidant axis and pro-regenerative Wnt/β-catenin and TGF-β signaling pathways. Demonstrating excellent biocompatibility and no systemic toxicity, this work establishes BBR + FA@UiO as a new therapeutic approach that merges TCM with advanced MOFs for comprehensive wound care.

Background Pancreatic cancer is highly lethal and has a poor prognosis. Research has highlighted the role of circular RNAs and m6A methylation in cancer progression. METTL3, a key m6A methyltransferase, is linked to various cancers, but its interaction with circular RNAs in pancreatic cancer is unclear. This study examined the role of circCEACAM5 in pancreatic cancer, particularly its regulation by METTL3-mediated m6A methylation and interaction with effectors such as DKC1. Methods circCEACAM5 expression in pancreatic cancer tissues and cell lines was evaluated via RT‒qPCR. Its characteristics were validated through Sanger sequencing, stability assays, and FISH. Functional assays (CCK-8, EdU, Transwell, and flow cytometry) were conducted in AsPC-1 cells, and in vivo tumor models were established. m6A modification was analyzed via bioinformatics tools and m6A-specific immunoprecipitation, while RNA pull-down assays were used to examine the interaction of circCEACAM5 with METTL3 and DKC1. Results circCEACAM5 was significantly upregulated in pancreatic cancer and correlated with poor clinical outcomes. CircCEACAM5 promoted cell proliferation, invasion, and migration while inhibiting apoptosis both in vitro and in vivo. METTL3-mediated m6A methylation of circCEACAM5 was confirmed, and METTL3 knockdown reversed the effects of circCEACAM5 silencing on the malignant behavior of pancreatic cancer cells. circCEACAM5 interacted with DKC1, and DKC1 overexpression reversed the effects of circCEACAM5 knockdown on the malignant behavior of pancreatic cancer cells. Conclusion METTL3-mediated m6A methylation of circCEACAM5 drives pancreatic cancer progression by increasing DKC1 expression, suggesting potential new therapeutic targets for this aggressive malignancy.

Tumor microenvironment (TME)-induced nanocatalytic therapy is a trending strategy for tumor-targeting therapy, but the low catalytic efficiency remains to limit its therapeutic effect. The single-atom catalysts (SACs) appear as a novel type of nanozymes that possesses incredible catalytic activity. Here, we developed PEGylated manganese/iron-based SACs (Mn/Fe PSACs) by coordinating single-atom Mn/Fe to nitrogen atoms in hollow zeolitic imidazolate frameworks (ZIFs). Mn/Fe PSACs catalyze cellular hydrogen peroxide (H₂O₂) converting to hydroxyl radical (•OH) through a Fenton-like reaction; it also enhances the decomposition of H₂O₂ to O₂ that continuously converts to cytotoxic superoxide ion (•O₂⁻) via oxidase-like activity. Mn/Fe PSACs can reduce the depletion of reactive oxygen species (ROS) by consuming glutathione (GSH). Here, we demonstrated the Mn/Fe PSACs-mediated synergistic antitumor efficacy among in vitro and in vivo experiments. This study proposes new promising single-atom nanozymes with highly efficient biocatalytic sites and synergistic therapeutic effects, which will give birth to abundant inspirations in ROS-related biological applications in broad biomedical fields.

Aflatoxin B1 (AFB1) is a naturally-occurring mycotoxin and recognized as the most toxic foodborne toxin, particularly causing damages to kidney. Glomerular podocytes are terminally differentiated epithelial cells. AFB1 induces podocyte inflammation, proteinuria and renal dysfunction. Studying the mechanism of AFB1-induced podocyte inflammation and murine kidney dysfunction, we detected that AFB1 increased ubiquitin-dependent degradation of the transcription factor RelA through enhanced interaction of RelA with E3 ubiquitin ligase tripartite motif containing 7 (TRIM7) in mouse podocyte clone-5 (MPC-5) and mouse glomeruli. Reduction of RelA resulted in decreasing microRNA-9 (miR-9) and activating the chemokine receptor 4 (CXCR4), thioredoxin interacting protein (TXNIP), and NOD-like receptor pyrin domain-containing 3 (NLRP3) signaling axis (CXCR4/TXNIP/NLRP3 pathway), leading to podocyte inflammation. We also determined that downregulation of miR-9 led to CXCR4 expression and the downstream TXNIP/NLRP3 pathway activation. Overexpression of miR-9 or deletion of CXCR4 suppressed AFB1-induced CXCR4/TXNIP/NLRP3 pathway, resulting in alleviating podocyte inflammation and kidney dysfunction. Our findings indicated that ubiquitin-dependent proteolysis of RelA, downregulation of miR-9, and activation of CXCR4/TXNIP/NLRP3 pathway played an essential role in AFB1-induced glomerular podocyte inflammation. Our study revealed a novel mechanism, via RelA, for the control of AFB1’s nephrotoxicity, leading to an effective protection of food safety and public health.

The T-2 toxin, a major secondary metabolite of Fusarium Gramineae, is considered a great risk to humans and animals due to its toxicity, such as inducing emesis. The mechanism of emesis is a complex signal involving an imbalance of hormones and neurotransmitters, as well as activity of visceral afferent neurons. The T-2 toxin has been proven to induce emesis and possess the capacity to elevate expressions of intestinal hormones glucagon-like peptide-_17–36 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), both of which are important emetic factors. In addition, the activation of calcium-sensitive receptor (CaSR) and transient receptor potential (TRP) channels are engaged in intestinal hormone release. However, it is unknown whether hormones GLP-1 and GIP mediate T-2 toxin-induced emetic response through activating CaSR and TRP channels. To further assess the mechanism of T-2 toxin-induced emesis, we studied the hypothesis that T-2 toxin-caused emetic response and intestinal hormones GLP-1 and GIP released in mink are associated with activating calcium transduction. Following oral gavage and intraperitoneal injection T-2 toxin, emetic responses were observed in a dose-dependent manner, which notably corresponded to the secretion of GLP-1 and GIP, and were suppressed by pretreatment with respective antagonist Exending_9–39 and Pro3GIP. Additional research found that NPS-2143 (NPS) and ruthenium red (RR), respective antagonists of CaSR and TRP channels, dramatically inhibited both T-2 toxin-induced emesis response and the expression of plasma GLP-1 and GIP. According to these data, we observed that T-2 toxin-induced emetic response corresponds to secretion of GLP-1 and GIP via calcium transduction.