Gene transfection techniques have potential therapeutic value in reducing the inflammatory response in atherosclerosis. Atherosclerosis is a chronic inflammatory disease. Its pathological process involves multiple types of cells and signaling pathways. In recent years, researchers have used gene transfection techniques to introduce specific genes into vascular or immune cells in order to inhibit inflammatory responses, stabilize plaques, and slow down the process of atherosclerosis. Research progress has shown that gene transfection can exert anti-inflammatory effects through various mechanisms. IL-10 transfection suppresses atherosclerosis by activating the STAT3 pathway, reducing TNF-α and IL-6 expression in macrophages. Conversely, eNOS transfection enhances nitric oxide bioavailability, inhibiting endothelial cell adhesion molecule expression (e.g., VCAM-1) and monocyte recruitment. Other studies have regulated the expression of inflammation-related genes by transfecting miRNA (tiny RNA), thus inhibiting the inflammatory response of atherosclerosis. Despite preclinical efficacy, clinical translation is hindered by suboptimal vector tropism (e.g., viral vectors exhibit off-target hepatotoxicity) and immune-mediated clearance of non-viral vectors (e.g., liposomes trigger complement activation). Long-term risks of insertional mutagenesis (retroviral vectors) and epigenetic silencing of transgenes further limit durability. This paper discusses the role and mechanism of gene transfection in reducing the inflammatory response in atherosclerosis.

Background Polydatin, a natural component of Polygonum cuspidatum, exhibits potent anti-metabolic properties. The treatment with Poly (10 µm/L) effectively reversed the high glucose (HG)-induced reduction in acetylcholine (ACh)-elicited vasodilation in the aortas of Sprague-Dawley rats. Methods Male Sprague-Dawley rats were used to evaluate the effects of polydatin on endothelial function under HG conditions. Endothelium-dependent relaxation (EDR) was assessed in isolated thoracic aortic rings using ACh, with or without L-NAME or tempol. Human umbilical vein endothelial cells (HUVECs) were also treated under normal glucose (NG), HG, or HG + polydatin conditions. Gene expression (NLRP3, VCAM-1, GAPDH) was measured by RT-PCR, while protein levels of eNOS, iNOS, NLRP3, VCAM-1, and GAPDH were analyzed by western blotting. Results HG significantly impaired ACh-induced EDR in rat aortic rings, while polydatin (10 µmol/L) restored vascular responsiveness. Mechanistically, polydatin upregulated eNOS and suppressed iNOS expression, and its vasoprotective effects were partially inhibited by L-NAME, indicating nitric oxide (NO) pathway involvement. In both aortic tissues and HUVECs, HG markedly increased NLRP3 and VCAM-1 expression, which was effectively reversed by polydatin, indicating its anti-inflammatory action. Conclusion Polydatin counteracts hyperglycemia-induced endothelial dysfunction by enhancing eNOS-dependent NO signaling to restore vasodilatory capacity, while inhibiting NLRP3 inflammasome activation and downstream VCAM-1 expression to attenuate vascular inflammation. These dual mechanisms position polydatin as a therapeutic agent for preserving vascular function in diabeticconditions.

Background: Ameloblastoma is a benign tumor that can cause deformity and functional disorders in the craniomaxillofacial region. The invasion process of ameloblastoma requires degradation of the extracellular matrix (ECM) and basement membrane to support tumor cell proliferation. SDC-1 (CD-138) functions as a heparan sulfate proteoglycan that regulates cellular adhesion and extracellular matrix attachment, while E-Cadherin (E-Cad) serves as a calcium-dependent transmembrane glycoprotein critical for epithelial morphogenesis and homotypic cellular adhesion. Aim: The present study was designed to evaluate differences in SDC-1 and E-Cad expression patterns according to ameloblastoma histopathological classification. Materials and Methods: This research is an analytical observational study with a cross-sectional approach. The research sample used 24 post-operative paraffin blocks from ameloblastoma patients from the period 2015–2023 who were histopathologically diagnosed. SDC-1 and E-Cad expression was analyzed using immunohistochemical methods. Statistical analysis used the Tukey HSD test. This research has received ethical approval from the local ethics committee. Results: The lowest expression of SDC-1 and E-Cad was found in the follicular type, while the mixed type (follicular-plexiform) showed the highest expression values. The Tukey HSD test showed significant differences in SDC-1 expression between the mixed type and the plexiform type (p=0.040) and follicular type (p=0.032). E-Cad expression also showed significant differences between the follicular type and mixed type (p=0.032). Conclusion: There are significant differences in SDC-1 and E-Cad expression between follicular type and mixed type ameloblastoma, while no significant differences were found between follicular type and plexiform type. These results indicate that histopathological variation is related to cell adhesion molecule expression in ameloblastoma.

BackgroundFOLFOX, a commonly prescribed chemotherapeutic regimen, associated with significant neurotoxicity, that necessitates stop administration in some cases, hence, this study aimed to investigate the molecular mechanisms underlying FOLFOX-induced neurotoxicity in the brain and sciatic nerve, and determining its cerebral concentration via HPLC technique.Methods48 rats were divided into four groups: normal control, Oxaliplatin (6 mg/kg), 5-Fluorouracil (50 mg/kg), and a combination group (oxaliplatin 6 mg/kg + 5-fluorouracil 50 mg/kg). Behavioral tests in addition to samples collection from cerebral tissues, sciatic nerves, and blood were conducted. Tissue histological and biochemical changes were determined, including oxidative stress markers (Nrf2, SOD2, HO-1), apoptotic proteins (Bax, cCaspase-3, Bcl-2), and inflammatory biomarkers (COX-II, TNF-α, IL-6, NF-κβ). A new HPLC method was developed and validated to quantify oxaliplatin and 5-fluorouracil (5-Flu) concentrations in the brain tissue.ResultsBoth oxaliplatin and 5-Flu induced a substantial oxidative stress, evidenced by reduced expression of Nrf2, SOD2, and HO-1 proteins, associated with a significant upregulation of the pro-apoptotic proteins Bax and cleaved caspase-3, and downregulation of the anti-apoptotic protein Bcl-2. Inflammatory markers were increased in all treated groups, and the highest levels were observed in the combination group. HPLC analysis confirmed a significantly higher concentration of both drugs in the cerebral tissue of the combination group. Histopathological findings revealed neuronal damage and inflammation associated by increased Glial fibrillary acidic protein (GFAP) and decreased neural cell adhesion molecule (NCAM) expression. Behavioral assessments demonstrated markedly reduced pain thresholds in treated animals.ConclusionThis study identified a novel mechanisms underlying FOLFOX neurotoxicity involving activation of the pro-apoptotic BAX/cCaspase-3 pathway and suppression of the Nrf2/KEAP-1/SOD2/HO-1 antioxidant defense mechanism. These disorders induced a neuronal injury, evidenced by altered GFAP and NCAM expression. The findings highlight the synergistic role of FOLFOX components in driving oxidative stress, apoptosis, and inflammation, collectively contributing to neurotoxicity.

Abstract Cells sense their microenvironment and neighboring cells by exerting finely tuned mechanical forces through receptor–ligand interactions, which shape mechanophenotypes critical to biological development, immunity, and disease. Profiling these mechanophenotypes requires ligands with variable avidities. However, conventional strategies based on discrete valency changes lack the precision for continuous modulation, limiting the resolution of subtle mechanotypic differences. Here, we introduce a bivariate strategy to construct heteromultivalent ligands that independently modulate both unit affinity and valency within a single DNA nanoscaffold. By co‐assembling two aptamers with distinct binding affinities, each targeting different epitopes of the same receptor, we generate ligand architectures with tunable avidities through precise stoichiometric modulation. This strategy produces a continuous avidity spectrum, overcoming the limitations of traditional homovalent systems, which are constrained by the discrete nature of valency adjustments. These heteromultivalent ligands enhance the sensitivity of force measurements, revealing subtle mechanical differences in cells with varying epithelial cell adhesion molecule (EpCAM) expressions, and enabling efficient, sequential sorting of phenotypically similar subpopulations via simple flow rate adjustments. These findings underscore the critical importance of avidity modulation in multivalent interaction engineering and mechanical cell profiling, showcasing the advantages of molecularly assembled heteromultivalent interactions over conventional homovalent strategies.

Cells sense their microenvironment and neighboring cells by exerting finely tuned mechanical forces through receptor-ligand interactions, which shape mechanophenotypes critical to biological development, immunity, and disease. Profiling these mechanophenotypes requires ligands with variable avidities. However, conventional strategies based on discrete valency changes lack the precision for continuous modulation, limiting the resolution of subtle mechanotypic differences. Here, we introduce a bivariate strategy to construct heteromultivalent ligands that independently modulate both unit affinity and valency within a single DNA nanoscaffold. By co-assembling two aptamers with distinct binding affinities, each targeting different epitopes of the same receptor, we generate ligand architectures with tunable avidities through precise stoichiometric modulation. This strategy produces a continuous avidity spectrum, overcoming the limitations of traditional homovalent systems, which are constrained by the discrete nature of valency adjustments. These heteromultivalent ligands enhance the sensitivity of force measurements, revealing subtle mechanical differences in cells with varying epithelial cell adhesion molecule (EpCAM) expressions, and enabling efficient, sequential sorting of phenotypically similar subpopulations via simple flow rate adjustments. These findings underscore the critical importance of avidity modulation in multivalent interaction engineering and mechanical cell profiling, showcasing the advantages of molecularly assembled heteromultivalent interactions over conventional homovalent strategies.

SummaryControlled signaling activity is vital for normal tissue homeostasis and oncogenic signaling activation facilitates tumorigenesis. Here we use single-cell transcriptomics to investigate the effects of pro-proliferative signaling on epithelial homeostasis using the Drosophila follicle cell lineage. Notably, EGFR-Ras overactivation induces cell cycle defects by activating the transcription factors Pointed and E2f1 and impedes differentiation. Hh signaling simultaneously promotes an undifferentiated state and induces differentiation via activation of EMT-associated transcription factors zfh1 and Mef2. As a result, overactivation of Hh signaling generates a transcriptional hybrid state comparable to epithelial-mesenchymal-transition. Co-overactivation of Hh signaling with EGFR-Ras signaling blocks differentiation and induces key characteristics of tumor cells including a loss of tissue architecture caused by reduced expression of cell adhesion molecules, sustained proliferation and an evasion of cell cycle checkpoints. These findings provide new insight into how non-interacting signaling pathways converge at the transcriptional level to prevent malignant cell behavior.

Blood vessel embolization is a well-established treatment modality for liver cancer. Novel shear-thinning hydrogels (STH) have been developed to address the need for safer and more effective local delivery of embolic agents and therapeutics. However, embolization therapies are currently optimized in animal models, which often differ from humans at the cellular, tissue, and organ levels. We aim to evaluate the efficacy of novel embolic agents such as STH using a human-relevantin vitromodel that recapitulates human hepatocellular carcinoma capillary networks. A vascularized human liver-tumor-on-a-chip model was developed to assess embolic agent performance. The effects of drug-eluting STH (DESTH) on tumor cell viability, surface marker expression, vasculature morphology, and cytokine responses were evaluated. To study the effects of embolization on microvasculature morphology independent of the chemotherapy compound, we evaluated the effect of different drug-free embolic agents on the vascular tumor microenvironment under flow conditions. DESTH treatment induced tumor cell death, downregulated the expression of epithelial cell adhesion molecules in HepG2, increased levels of cytokines such as interleukin-4 (IL-4), granulocyte-macrophage colony-stimulating factor, and vascular endothelial growth factor, and decreased albumin secretion. Furthermore, different embolic agents exert distinct effects on microvascular morphology, with STH causing complete regression of the microvascular networks. This vascularized liver tumor-on-a-chip model enables human-relevant, real-time assessment of embolic agent efficacy and vascular response and can be applied for the development of innovative and effective embolization therapies for liver cancer.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths, with a five-year survival rate around 12%. In PDAC, cancer-associated fibroblasts (CAFs) play a vital role in promoting the desmoplastic and immunosuppressive tumor microenvironment (TME), and have emerged as relevant cancer targets. CAFs produce intratumoral hyaluronic acid (HA) whose accumulation induces high interstitial fluid-pressure (IFP) which can interfere with drug delivery. Moreover, HA has been linked with tumor escape from immune surveillance. Systemic administration of Hyaluronidase, via the PEGPH20 formulation, has reduced stromal HA, normalized IFP, and consequently improved the efficiency of the cytotoxic compound, gemcitabine, leading to increased survival in mice. In this study we have decided to eliminate HA by a different approach involving its synthesis rather than inducing its degradation. To this end, we have genetically targeted the three genes encoding HA synthases (Has1, 2, 3). Has1 and Has3 null alleles were generated by CRISPR technology in mouse embryos since they are nor essential for embryonic development. To eliminate Has2, we used existing conditional Has2lox alleles (Matsumoto et al. 2019, PMID XXXX) along an inducible allele, Rosa26-CreERT2, encoding an inducible Cre-ERT2 recombinase to allow the systemic ablation of the conditional Has2lox alleles in adult mice upon exposure to a Tamoxifen-containing (TAM) diet. These alleles were added to the standard KPF strain (KRas +/FSFG12V;P53F/F;Pdx1-FlpO) to determine the effect of HA elimination in tumor-bearing mice. Exposure of these adult animals to the TMA diet induced significant levels of HA depletion leading to reprogramming of tumoral, stromal and immune cells leading to significantly reduced tumor progression. Tumor cells were more differentiated as illustrated by higher expression of cytokeratin19 and additional epithelial cell adhesion molecules. Furthermore, these tumor cells displayed reduced proliferative capacity, mor limited EMT, migration and invasive capacity. Interestingly, they also exhibited upregulated Kras expression. At the stroma level, we observed less fibrotic tissue, decreased collagen deposition, reduced CAFs activation,and changes in the CAF populations, with high content of iCAFs (Inflammatory CAFs) and very low content in myCAFs (Myofibroblast CAFs). More importantly, we also observed infiltration of CD8+ T cells. Notably, HA depletion enhanced the efficacy of gemcitabine, the anti-CTLA-4 and the panras inhibitor darasonrasib, either alone or in combination of anti-CTLA-4. In summary, HA depletion in PDAC produced multiple changes at different levels that opens up new opportunities for therapeutic interventions. Citation Format: Pian Sun, Ángeles Durán, Federico Virga, María Diaz-Meco, Jorge Moscat, Carmen Guerra, Mariano Barbacid. Targeting hyaluronic acid in pancreatic ductal adenocarcinoma uncovers novel therapeutic opportunities [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B031.

Inflammation is the initial immune response activated to protect an organism's integrity after cell or tissue damage caused by infectious agents or physical trauma, such as exposure to ionizing radiation. The mechanisms behind ionizing radiation-induced inflammation are not fully understood in untransformed human cells, especially at high dose exposures that can also cause cell death. Radiation-induced genotoxic stress triggers the cellular DNA damage response, and interactions between this pathway and inflammation may be crucial in determining the fate of irradiated cells. We studied how primary human vascular endothelial cells, telomerase-immortalized foreskin microvascular cells, blood mononuclear cells, and primary skin fibroblasts respond to radiation doses from 2 to 10 Gy for up to 24 h after exposure, prior to cell death. In endothelial cells, exposure to 10 Gy, but not lower doses, caused a temporary increase in the transcription of genes coding for inflammatory factors before the activation of DNA damage response genes. This early inflammatory reaction depends on ATM activity, which coordinates the DNA damage response, and is not observed in blood cells or fibroblasts. Additionally, we saw an increase in cytokine production and adhesion molecule expression in endothelial cells. This inflammatory response may contribute to changes in the immune microenvironment of irradiated cells.

Targeting the VIP-VPAC Pathway in Melanoma Models Inhibits Tumor Growth and Liver Metastasis.

Recursive splice sites are rare motifs postulated to facilitate splicing across massive introns and shape isoform diversity, especially for long, brain-expressed genes. The necessity of this unique mechanism remains unsubstantiated, as does the role of recursive splicing (RS) in human disease. From analyses of rare copy number variants (CNVs) from almost one million individuals, we previously identified large, heterozygous deletions eliminating an RS site (RS1) in the first intron of CADM2 that conferred substantial risk for attention deficit hyperactivity disorder (ADHD) and other neurobehavioral traits. CADM2 encodes a neuronally expressed cell adhesion molecule that has repeatedly been associated with ADHD and numerous similar traits. To explore the molecular impact of RS ablation in CADM2 , we used CRISPR to model patient deletions and to target a smaller region (~500 base pairs) containing RS1 in both human induced neurons (iNs) and rats. Transcriptome analyses in unedited iNs provided a catalog of CADM2 transcripts, including novel transcripts that retained RS exons. Intriguingly, ablating RS1 altered the gradient of RNA abundance across the first intron of CADM2 , decreased the level of CADM2 expression, and impacted transcript usage. Decreased CADM2 expression was reflected in reduced exon usage downstream of the RS1 site and global alteration to genes involved in neuronal processes including synapse and axon development. Given the scale of our analyses and the widespread association of CADM2 with neurobehavioral traits, we sought to validate these findings using in vivo models and found that rodent models harboring Cadm2 RS1 deletions exhibited significant changes in relevant behaviors and functional brain connectivity. In summary, our analyses demonstrate a functional role for RS as a noncoding regulatory mechanism in a gene associated with a spectrum of neuropsychiatric and behavioral traits.

Introduction: Cutaneous melanoma, a highly aggressive malignant tumor, continues to pose significant challenges in early diagnosis and prognosis assessment. Although anoikis-related genes (ARGs) play crucial roles in tumor progression, systematic molecular diagnostic biomarkers remain lacking. Objective: This study aims to elucidate the molecular mechanisms and diagnostic value of ARGs in cutaneous melanoma using advanced bioinformatics and machine learning approaches. Methods: Multiple melanoma datasets from The Cancer Genome Atlas and GEO databases (GSE3189, GSE15605, GSE19234, GSE65904, and GSE66839) were integrated to analyze ARG expression patterns. Differential expression analysis identified candidate genes significantly associated with cutaneous skin melanoma. A total of 113 machine learning models were employed to screen and validate candidate genes, with receiver operating characteristic curves evaluating diagnostic value. Core genes were identified through protein-protein interaction (PPI) networks. The immune infiltration correlations of core genes were analyzed, and their tissue-level expression was validated using immunohistochemistry. Results: Twenty-two ARGs were significantly enriched in cancer signaling pathways, including phosphoinositide 3-kinase-protein kinase B, hypoxia-inducible factor 1, and programmed death-ligand 1. Nine candidate genes were identified through differential and intersection analysis, and eight model genes were further screened using machine learning. Seven genes exhibited high diagnostic efficacy in both training and external validation sets (area under the curve [AUC] >0.7). Survival analysis revealed that high expression of carcinoembryonic antigen-related cell adhesion molecule (CEACAM)5, CEACAM6, epidermal growth factor receptor (EGFR), stratifin (SFN), and Polo-like kinase 1 (PLK1) correlated with poor prognosis. PPI analysis confirmed these as core regulatory factors, and immune infiltration analysis revealed strong associations with dendritic cells, T cells, and macrophages. The five-gene combination yielded excellent diagnostic performance, with AUCs of 0.969 (training) and 0.971 (validation). Immunohistochemistry confirmed their elevated expression in melanoma tissues. Conclusion: This study identified five key ARGs, CEACAM5, CEACAM6, EGFR, SFN, and PLK1, as significantly upregulated in cutaneous melanoma and associated with poor prognosis. Their combined diagnostic power suggests strong potential as clinical pathological biomarkers.

The highly fibrotic microenvironment of pancreatic ductal adenocarcinoma (PDAC) poses significant challenges for effective treatment, particularly in drug delivery and tumor progression. Our study investigates the role of collagen dynamics in PDAC, revealing that TGF-β1 negatively regulates the expression of L1 cell adhesion molecule (L1CAM), leading to a more invasive tumor phenotype. We identify a subset of PDAC cells with low L1CAM expression (L1low) that actively influences collagen deposition and remodeling, as evidenced by the upregulation of collagen 17A1 (COL17A1) and matrix metalloproteinase 2 (MMP2), both associated with poor prognosis. In vivo studies demonstrate that L1low cells correlate with increased collagen deposition, reduced sensitivity to gemcitabine, and heightened liver metastasis. The secretion of COL17A1 and MMP2 by these cells enhances their migratory capabilities and contributes to the formation of a fibrotic stroma that facilitates tumor progression. This interaction underscores the critical role of collagen in shaping the tumor microenvironment and promoting aggressive tumor behavior. Notably, treatment with Tranilast significantly reduced collagen deposition and MMP2 levels while promoting L1CAM expression, suggesting a therapeutic avenue for counteracting the aggressive characteristics of L1low cells. By modulating collagen dynamics and enhancing drug delivery, Tranilast may improve treatment outcomes for patients with low L1CAM-expressing tumors. Understanding the mechanisms by which L1low cells contribute to collagen secretion and tumor aggressiveness is essential for developing effective interventions in pancreatic cancer.

Cell adhesion molecule-1 is a promising target for chimeric antigen receptors in lung adenocarcinoma.

Bladder cancer (BC) ranks as the 10th leading cause of cancer-related deaths in the United States. Despite significant advancements in managing BC, including antibody-drug conjugates and immune checkpoint blockers, a significant percentage of patients fail these treatments. This underscores the pressing need to develop methods for identifying novel therapeutic targets, predicting therapy responses, and optimizing personalized treatment strategies for patients. Patient-derived xenograft (PDX) models have the potential to address these challenges. However, these models suffer from limitations, including a consistent rate of tumor acceptance, extended time for tumor growth, and the absence of the donor's immune system. This study aimed to address these challenges through a comprehensive comparison of different PDX implantation methods, culminating in the establishment of a PDX cell line for utilization in invivo BC preclinical models. Flow cytometry analysis and total RNA sequencing were used for comparative analysis of original tumor tissue, PDX tumor, and PDX257S cell line. Tumor tissue processing techniques were optimized to enhance the rate of PDX tumor acceptance and shorten the time to tumor development. Furthermore, a PDX cell line, PDX257S, was successfully established and confirmed to exhibit more aggressive and tumorigenic characteristics compared to the original donor tumor tissue. The PDX257S cell line demonstrated faster tumor growth, higher expression of human epithelial cell adhesion molecule, increased mutation burden in BC-associated genes, and significant alterations in BC-related gene expression, compared to the original tumor. The PDX257S cell line was also used to establish a double humanized BC murine model that minimized graft-versus-host disease and is a potential platform for testing novel immune therapeutics. In summary, this study offers an optimized protocol for the consistent establishment of BC PDX tumors. Furthermore, it has also established a novel double-humanized model, demonstrating the potential for drug screening and clinical prognosis in the context of BC treatment.

The growing epidemic of diabetes mellitus and its associated complications presents a major global health challenge. Diabetic nephropathy (DN) is a critical microvascular complication of diabetes, accounts for approximately one-third of all related cases worldwide and frequently progresses to end-stage renal disease (ESRD) and premature mortality. Extensive experimental evidence underscores the pivotal role of chronic inflammation driven by the activation of the nuclear transcription factor NF-κB in the pathogenesis of DN. Triggered by various factors including hyperglycemia, NF-κB activation leads to the expression of numerous pro-inflammatory cytokines, chemokines and cell adhesion molecules, resulting in the pathological hallmarks of DN: podocyte injury, excessive extracellular matrix accumulation, glomerulosclerosis, epithelial-mesenchymal transition, renal tubular atrophy and increased proteinuria. Consequently, NF-κB emerges as a promising therapeutic target for DN. Naturally occurring phytoconstituents, as inhibitors of the NF-κB pathway and are gaining significant attention due to their lower toxicity, enhanced safety, greater efficacy and cost-effectiveness. This review summarizes the role of NF-κB in the pathophysiology of DN and examines recent research on medicinal plants and phytoconstituents that target the NF-κB signaling pathway in both in vitro and in vivo and in silico models. Furthermore, we elucidate their mechanisms of action and evaluate their potential as effective therapeutic agents for mitigating DN-related inflammation and complications. This provides a theoretical framework for the development of novel anti-nephropathic drugs that may overcome the limitations of current medications.

Kawasaki disease (KD) is an acute vasculitis and its pathogenesis is complex. Caveolin-1 (Cav-1) is the main structural protein of caveolae and is involved in the pathogenesis of many vascular diseases. A clinical study revealed that the Cav-1 serum level in children significantly increases in the acute phase of KD, but the role of Cav-1 in KD is still unclear. We aimed to explore whether and how Cav-1 is involved in the KD pathogenesis. KD vasculitis was induced by Lactobacillus casei cell wall extract intraperitoneal injection in mice, and Cav-1 expression was inhibited by adeno-associated viruses (AAV)-Cav-1 shRNA. Cardiovascular lesions was assessed via haematoxylin and eosin staining. Proinflammatory cytokine and matrix metalloproteinase-9 levels were measured via quantitative real-time polymerase chain reaction. Endothelial cell adhesion molecule expression was evaluated by immunohistochemistry. Cav-1 expression and nuclear factor kappa-B pathway activation were evaluated by Western blotting. Mice with Lactobacillus casei cell wall extract-induced KD vasculitis exhibited severe heart vessel inflammation and increased Cav-1, proinflammatory cytokine, matrix metalloproteinase-9, and endothelial cell adhesion molecule expression, which were reversed after Cav-1 inhibition. Moreover, nuclear factor kappa-B activation of KD vasculitis model mice was suppressed after Cav-1 inhibition. Cav-1 participates in KD vasculitis pathogenesis by regulating the nuclear factor kappa-B signalling pathway.

Radiation-induced brain injury (RIBI) is a common brain injury following radiotherapy to the head and neck region, which is often accompanied by severe cognitive dysfunction, seriously affecting the quality of life of patients. Studies have established that excessive free radicals produced by radiation are mainly responsible for RIBI. However, there are currently no clinically effective drugs for RIBI treatment. Although nanocatalyst-mediated catalytic therapy is a powerful tool for the treatment of oxidative damage, it is limited by poor targeting and the blood-brain barrier (BBB). Herein, we develop metal armor-decorated neutrophil micromotors (Neumotor) to achieve brain targeting and penetration, which are composed of cryo-shocked neutrophils (CS-Neu) retaining cell membrane integrity and possessing high expression of cell adhesion molecules and chemokine receptors due to a pretreatment strategy, surface thioketal-linked platinum nanoclusters (PtNCs) with catalytic activity. Notably, Neumotor preserves the inflammation-targeting capability of neutrophils and additionally exhibits multienzyme-mimicking activity, reactive oxygen species-responsive release of PtNCs, and self-propulsive functions. Thus, the Neumotor effectively achieves brain targeting and penetration, neutralizes irradiation-caused excess free radicals, mitigates inflammatory damage, BBB disruption, and neuronal injury, ultimately ameliorating cognitive, memory, and spatial perception deficits in RIBI mice. This study not only presents a distinct application for neutrophils but also proposes a feasible catalytic therapy strategy for RIBI.

The primary cause of branchio-oto-renal syndrome (BORS) is mutations in the EYA1 gene. The aim of this study was to investigate the clinical characteristics associated with induced podocyte reappearance in children with BORS and EYA1 mutations. We collected clinical and genetic data from a 4-year-old girl diagnosed with BORS and her family. Induced pluripotent stem cells (iPSC) were derived from peripheral blood mononuclear cells of both the patient and healthy individuals, which were differentiated into podocytes in vitro. RNA-seq was used to analyze differentially expressed genes in both groups. Here, the proband, along with his brother and mother, exhibited symptoms of BORS. WES analysis identified a heterozygous splicing variant at the EYA1 locus: c.1050 + 5G > A, inherited from his mother. The proband was initially glucocorticoid-resistant. After tacrolimus treatment, his urine protein/creatinine ratio significantly improved. Compared to healthy individuals, patient-derived podocytes displayed increased motility and pronounced cytoskeletal rearrangement. RNA-Seq results indicated significant downregulation of cell adhesion molecule and cytoskeletal rearrangement signaling pathway expression in patient-derived podocytes. Dexamethasone was ineffective in ameliorating the pathological damage induced by puromycin aminonucleoside in patient-derived podocytes. In BORS patients, podocytes exhibit cytoskeletal reorganization and enhanced motility in vitro while showing resistance to steroid treatment. These findings were consistent with the clinical features observed in the patient, suggesting that this unique cellular disease model merits further investigation.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00018-025-05724-7.