Hydrogel/microcarrier cell scaffolds for rapid expansion of satellite cells from large yellow croakers: Differential analysis between 2D and 3D cell culture.

Cell culture meat is based on the scaled-up expansion of seed cells. The biological differences between seed cells from large yellow croakers in the two-dimensional (2D) and three-dimensional (3D) culture systems have not been explored. Here, satellite cells (SCs) from large yellow croakers (Larimichthys crocea) were grown on cell climbing slices, hydrogels, and microcarriers for five days to analyze the biological differences of SCs on different cell scaffolds. The results exhibited that SCs had different cell morphologies in 2D and 3D cultures. Cell adhesion receptors (Itgb1andsdc4) and adhesion spot markervclof the 3D cultures were markedly expressed. Furthermore, myogenic decision markers (Pax7andmyod) were significantly enhanced. However, the expression of myogenic differentiation marker (desmin) was significantly increased in the microcarrier group. Combined with the transcriptome data, this suggests that cell adhesion of SCs in 3D culture was related to the integrin signaling pathway. In contrast, the slight spontaneous differentiation of SCs on microcarriers was associated with rapid cell proliferation. This study is the first to report the biological differences between SCs in 2D and 3D cultures, providing new perspectives for the rapid expansion of cell culture meat-seeded cells and the development of customized scaffolds.

Altered asymmetry of functional connectome gradients in major depressive disorder.

Introduction: Major depressive disorder (MDD) is a debilitating disease involving sensory and higher-order cognitive dysfunction. Previous work has shown altered asymmetry in MDD, including abnormal lateralized activation and disrupted hemispheric connectivity. However, it remains unclear whether and how MDD affects functional asymmetries in the context of intrinsic hierarchical organization. Methods: Here, we evaluate intra- and inter-hemispheric asymmetries of the first three functional gradients, characterizing unimodal-transmodal, visual-somatosensory, and somatomotor/default mode-multiple demand hierarchies, to study MDD-related alterations in overarching system-level architecture. Results: We find that, relative to the healthy controls, MDD patients exhibit alterations in both primary sensory regions (e.g., visual areas) and transmodal association regions (e.g., default mode areas). We further find these abnormalities are woven in heterogeneous alterations along multiple functional gradients, associated with cognitive terms involving mind, memory, and visual processing. Moreover, through an elastic net model, we observe that both intra- and inter-asymmetric features are predictive of depressive traits measured by BDI-II scores. Discussion: Altogether, these findings highlight a broad and mixed effect of MDD on functional gradient asymmetry, contributing to a richer understanding of the neurobiological underpinnings in MDD.

The heritability and structural correlates of resting-state fMRI complexity.

The complexity of fMRI signals quantifies temporal dynamics of spontaneous neural activity, which has been increasingly recognized as providing important insights into cognitive functions and psychiatric disorders. However, its heritability and structural underpinnings are not well understood. Here, we utilize multi-scale sample entropy to extract resting-state fMRI complexity in a large healthy adult sample from the Human Connectome Project. We show that fMRI complexity at multiple time scales is heritable in broad brain regions. Heritability estimates are modest and regionally variable. We relate fMRI complexity to brain structure including surface area, cortical myelination, cortical thickness, subcortical volumes, and total brain volume. We find that surface area is negatively correlated with fine-scale complexity and positively correlated with coarse-scale complexity in most cortical regions, especially the association cortex. Most of these correlations are related to common genetic and environmental effects. We also find positive correlations between cortical myelination and fMRI complexity at fine scales and negative correlations at coarse scales in the prefrontal cortex, lateral temporal lobe, precuneus, lateral parietal cortex, and cingulate cortex, with these correlations mainly attributed to common environmental effects. We detect few significant associations between fMRI complexity and cortical thickness. Despite the non-significant association with total brain volume, fMRI complexity exhibits significant correlations with subcortical volumes in the hippocampus, cerebellum, putamen, and pallidum at certain scales. Collectively, our work establishes the genetic basis and structural correlates of resting-state fMRI complexity across multiple scales, supporting its potential application as an endophenotype for psychiatric disorders.

Uptake of gadolinium and dexamethasone in rat inner ear and facial nerve using different administrations.

BACKGROUND: The pathway by which drugs are injected subcutaneously behind the ear to act on the inner ear has not been fully elucidated. OBJECTIVES: To compare the uptake of gadopentetate dimeglumine (Gd-DTPA) and dexamethasone (Dex) in the cochlea and facial nerve of rats following different administrations. MATERIALS AND METHODS: Magnetic resonance imaging was applied to observe the distribution of Gd-DTPA in the facial nerve and inner ear. We observed the uptake of Dex after it was injected with different methods. RESULTS: Images of the intravenous (IV) and intramuscular (IM) groups showed that the bilateral cochlea of the rat was visualized almost simultaneously. While in the left post-auricular (PA) injection group, it was asynchronous. The maximum accumulation (Cmax) of the Gd in the left facial nerve of the PA group (35.406 ± 5.32) was substantially higher than that of the IV group (16.765 ± 3.7542) (p < .01). CONCLUSIONS: Compared with systemic administration, PA has the advantages of long Gd and Dex action time and high accumulation concentration to treat facial nerve diseases. SIGNIFICANCE: The distribution of Gd and Dex in the inner ear and facial nerve of rats following PA injection might be unique.

Research progress of prodrugs for the treatment of cerebral ischemia.

It is well-known that pharmacotherapy plays a pivotal role in the treatment and prevention of cerebral ischemia. Nevertheless, existing drugs, including numerous natural products, encounter various challenges when applied in cerebral ischemia treatment. These challenges comprise poor brain absorption due to low blood-brain barrier (BBB) permeability, limited water solubility, inadequate bioavailability, poor stability, and rapid metabolism. To address these issues, researchers have turned to prodrug strategies, aiming to mitigate or eliminate the adverse properties of parent drug molecules. In vivo metabolism or enzymatic reactions convert prodrugs into active parent drugs, thereby augmenting BBB permeability, improving bioavailability and stability, and reducing toxicity to normal tissues, ultimately aiming to enhance treatment efficacy and safety. This comprehensive review delves into multiple effective prodrug strategies, providing a detailed description of representative prodrugs developed over the past two decades. It underscores the potential of prodrug approaches to improve the therapeutic outcomes of currently available drugs for cerebral ischemia. The publication of this review serves to enrich current research progress on prodrug strategies for the treatment and prevention of cerebral ischemia. Furthermore, it seeks to offer valuable insights for pharmaceutical chemists in this field, offer guidance for the development of drugs for cerebral ischemia, and provide patients with safer and more effective drug treatment options.

In Situ Preparation of Star-Shaped Protein-"Smart" Polymer Conjugates with pH and Thermo-Dual Responsibility for Bacterial Separation.

To achieve effective separation and enrichment of bacteria, a novel synthetic scheme was developed to synthesize star-style boronate-functionalized copolymers with excellent hydrophilicity and temperature and pH responsiveness. A hydrophilic copolymer brush was synthesized by combining surface-initiated atom-transfer radical polymerization with amide reaction using bovine serum albumin as the core. The copolymer brush was further modified by introducing and immobilizing fluorophenylboronic acids through an amide reaction, resulting in the formation of boronate affinity material BSA@poly(NIPAm-co-AGE)@DFFPBA. The morphology and organic content of BSA@poly(NIPAm-co-AGE)@DFFPBA were systematically characterized. The BSA-derived composites demonstrated a strong binding capacity to both Gram-positive and Gram-negative bacteria. The binding capabilities of the affinity composite to Staphylococcus aureus and Salmonella spp. were 195.8 × 1010 CFU/g and 79.2 × 1010 CFU/g, respectively, which indicates that the novel composite exhibits a high binding capability to bacteria and shows a particularly more significant binding capacity toward Gram-positive bacteria. The bacterial binding of BSA@poly(NIPAm-co-AGE)@DFFPBA can be effectively altered by adjusting the pH and temperature. This study demonstrated that the star-shaped affinity composite had the potential to serve as an affinity material for the rapid separation and enrichment of bacteria in complex samples.

Probabilistic activity driven model of temporal simplicial networks and its application on higher-order dynamics.

Network modeling characterizes the underlying principles of structural properties and is of vital significance for simulating dynamical processes in real world. However, bridging structure and dynamics is always challenging due to the multiple complexities in real systems. Here, through introducing the individual's activity rate and the possibility of group interaction, we propose a probabilistic activity-driven (PAD) model that could generate temporal higher-order networks with both power-law and high-clustering characteristics, which successfully links the two most critical structural features and a basic dynamical pattern in extensive complex systems. Surprisingly, the power-law exponents and the clustering coefficients of the aggregated PAD network could be tuned in a wide range by altering a set of model parameters. We further provide an approximation algorithm to select the proper parameters that can generate networks with given structural properties, the effectiveness of which is verified by fitting various real-world networks. Finally, we construct the co-evolution framework of the PAD model and higher-order contagion dynamics and derive the critical conditions for phase transition and bistable phenomenon using theoretical and numerical methods. Results show that tendency of participating in higher-order interactions can promote the emergence of bistability but delay the outbreak under heterogeneous activity rates. Our model provides a basic tool to reproduce complex structural properties and to study the widespread higher-order dynamics, which has great potential for applications across fields.

Is Intravenous Dextrose Infusion During Emergence From Anesthesia Effective in Improving the PONV in Gynecologic Laparoscopy? A Randomized Controlled Trial.

STUDY OBJECTIVE: This study aimed to explore the relationship between intravenous 5% dextrose infusion during emergence from anesthesia to postoperative nausea and vomiting (PONV) in patients after gynecologic laparoscopic surgery. DESIGN: This was a double-blind randomized controlled trial. Participants were randomized into the experimental group and control group using a computer-generated random number generator. Intervenors and measurers were blinded to group assignments of the study. SETTING: A single academic tertiary medical center. PATIENTS: Patients undergoing gynecologic laparoscopic surgery. INTERVENTIONS: On completion of surgery, participants were randomized into the test group (receive 5% dextrose) and control group (receive Ringer's lactate solution). MEASUREMENTS AND MAIN RESULTS: The primary outcome of the present study was the incidence of PONV. Other outcomes included postoperative rescue analgesic and rescue antiemetic, postoperative pain response, and recovery time of postanesthesia care unit. Baseline characteristics were statistically similar between the 2 groups of participants. There were 49 of 105 patients experienced PONV within 24 hours postoperatively. The overall incidence of PONV within 24 hours postoperatively was not significantly different (45.5% vs 48%; relative risk [RR], 0.95; 95% confidence interval [CI], 0.67-1.37; p = .794). However, fewer patients experienced PONV in the test group than in the control group during 0 to 1 hours (6.0% vs 20.0%; RR, 0.85; 95% CI, 0.73-0.99; p = .024) and 1 to 3 hours (14.5% vs 32.0%; RR, 0.80; 95% CI, 0.64-0.99; p = .033) postoperatively. In addition, recovery time in the postanesthesia care unit was less in the test group (17.07 ± 6.36 vs 22.04 ± 7.33; mean difference, -4.97; 95% CI, -7.62 to -2.32; p <.001) and pain score was lower in the test group during 0 to 0.5 hours postoperatively (2.29 ± 1.74 vs 3.08 ± 1.64; mean difference, -0.79; 95% CI, -1.45 to -0.13; p = .019). CONCLUSION: In patients after gynecologic laparoscopic surgery, postanesthesia 5% dextrose infusion may be useful in improving the early management of PONV and pain response and may warrant further study.

Radiomic profiling for insular diffuse glioma stratification with distinct biologic pathway activities.

Current literature emphasizes surgical complexities and customized resection for managing insular gliomas; however, radiogenomic investigations into prognostic radiomic traits remain limited. We aimed to develop and validate a radiomic model using multiparametric magnetic resonance imaging (MRI) for prognostic prediction and to reveal the underlying biological mechanisms. Radiomic features from preoperative MRI were utilized to develop and validate a radiomic risk signature (RRS) for insular gliomas, validated through paired MRI and RNA-seq data (N = 39), to identify core pathways underlying the RRS and individual prognostic radiomic features. An 18-feature-based RRS was established for overall survival (OS) prediction. Gene set enrichment analysis (GSEA) and weighted gene coexpression network analysis (WGCNA) were used to identify intersectional pathways. In total, 364 patients with insular gliomas (training set, N = 295; validation set, N = 69) were enrolled. RRS was significantly associated with insular glioma OS (log-rank p = 0.00058; HR = 3.595, 95% CI:1.636-7.898) in the validation set. The radiomic-pathological-clinical model (R-P-CM) displayed enhanced reliability and accuracy in prognostic prediction. The radiogenomic analysis revealed 322 intersectional pathways through GSEA and WGCNA fusion; 13 prognostic radiomic features were significantly correlated with these intersectional pathways. The RRS demonstrated independent predictive value for insular glioma prognosis compared with established clinical and pathological profiles. The biological basis for prognostic radiomic indicators includes immune, proliferative, migratory, metabolic, and cellular biological function-related pathways.

Weight fluctuations preceding and succeeding heart failure diagnosis: Implications for all-cause mortality.

OBJECTIVE: This study aims to explore the ramifications of weight fluctuations preceding and succeeding the identification of heart failure (HF) on all-cause mortality. METHODS: The research cohort comprised individuals engaged in the Kailuan Group's health assessments from 2006 to 2018, who were subsequently diagnosed with HF. The moment of HF recognition marked the commencement of the monitoring period, culminating either at the instance of comprehensive mortality or at the conclusion of the monitoring phase (December 31, 2021). RESULTS: Throughout an average monitoring span of 5.8±3.5 years, from the 3115 qualified participants, 957 instances (30.7%) encountered comprehensive mortality. The COX proportional hazards regression model's outcomes revealed that, post the adjustment for potential confounders, in comparison to the Q3 category, the Q1 category had the highest hazard ratios (95% confidence intervals) of 1.71 (1.43-2.05). CONCLUSION: Weight reduction before and post the HF diagnosis stands as an autonomous risk determinant for comprehensive mortality.

Preparation of Novel Sea Cucumber Intestinal Peptides to Promote Tibial Fracture Healing in Mice by Inducing Differentiation of Hypertrophic Chondrocytes to the Osteoblast Lineage.

SCOPE: Hypertrophic chondrocytes have a decisive regulatory role in the process of fracture healing, and the fate of hypertrophic chondrocytes is not only apoptosis. However, the mechanism of sea cucumber (Stichopus japonicus) intestinal peptide (SCIP) on fracture promotion is still unclear. This study aims to investigate the effect of sea cucumber intestinal peptide on the differentiation fate of hypertrophic chondrocytes in a mouse tibial fracture model. METHODS AND RESULTS: Mice are subjected to open fractures of the right tibia to establish a tibial fracture model. The results exhibit that the SCIP intervention significantly promotes the mineralization of cartilage callus, decreases the expression of the hypertrophic chondrocyte marker Col X, and increases the expression of the osteoblast marker Col I. Mechanically, SCIP promotes tibial fracture healing by promoting histone acetylation and inhibiting histone methylation, thereby upregulating pluripotent transcription factors induced the differentiation of hypertrophic chondrocytes to the osteoblast lineage in a manner distinct from classical endochondral ossification. CONCLUSION: This study is the first to report that SCIP can promote tibial fracture healing in mice by inducing the differentiation of hypertrophic chondrocytes to the osteoblast lineage. SCIP may be considered raw material for developing nutraceuticals to promote fracture healing.

Eigenmode-based approach reveals a decline in brain structure-function liberality across the human lifespan.

While brain function is supported and constrained by the underlying structure, the connectome-based link estimated by current approaches is either relatively moderate or accompanied by high model complexity, with the essential principles underlying structure-function coupling remaining elusive. Here, by proposing a mapping method based on network eigendecomposition, we present a concise and strong correspondence between structure and function. We show that the explanation of functional connectivity can be significantly improved by incorporating interactions between different structural eigenmodes. We also demonstrate the pronounced advantage of the present mapping in capturing individual-specific information with simple implementation. Applying our methodology to the human lifespan, we find that functional diversity decreases with age, with functional interactions increasingly dominated by the leading functional mode. We also find that structure-function liberality weakens with age, which is driven by the decreases in functional components that are less constrained by anatomy, while the magnitude of structure-aligned components is preserved. Overall, our work enhances the understanding of structure-function coupling from a collective, connectome-oriented perspective and promotes a more refined identification of functional portions relevant to human aging, holding great potential for mechanistic insights into individual differences associated with cognition, development, and neurological disorders.

Enhanced brain structure-function tethering in transmodal cortex revealed by high-frequency eigenmodes.

While the link between brain structure and function remains an ongoing challenge, the prevailing hypothesis is that the structure-function relationship may itself be gradually decoupling from unimodal to transmodal cortex. However, this hypothesis is constrained by the underlying models which may neglect requisite information. Here we relate structural and functional connectivity derived from diffusion and functional MRI through orthogonal eigenmodes governing frequency-specific diffusion patterns. We find that low-frequency eigenmodes contribute little to functional interactions in transmodal cortex, resulting in divergent structure-function relationships. Conversely, high-frequency eigenmodes predominantly support neuronal coactivation patterns in these areas, inducing structure-function convergence along a unimodal-transmodal hierarchy. High-frequency information, although weak and scattered, could enhance the structure-function tethering, especially in transmodal association cortices. Our findings suggest that the structure-function decoupling may not be an intrinsic property of brain organization, but can be narrowed through multiplexed and regionally specialized spatiotemporal propagation regimes.

A novel mutation in COL1A1 causing osteogenesis imperfecta/hearing loss

Abstract Objectives: To screen the COL1A1 and COL1A2 gene mutation sites in a family with type I osteogenesis imperfecta (OI)/hearing loss and analyze the characteristics and recovery of hearing loss in patients with osteogenesis imperfecta. Methods: The basic clinical data of Ol proband and her parents were collected, and the COL1A1 and COL1A2 genes were detected in peripheral blood by PCR amplification and generation Sanger sequencing. Literature of stapedial surgery in patients with osteogenesis imperfecta was collected. Results: The heterozygous mutation of the 26 exon c.1922_1923 ins C in the Ol progenitor COL1A1 gene led to the amino acid frameshift mutation of p.Pro 601FS, which was not detected in the phenotypic parents. The homozygous of exon 28 c.1782>G in COL1A2 was detected in the proband and her parents, resulting in changes in the protein p.Pro 549Ala. Conclusion: The clinical symptoms of the Ol proband is caused by heterozygous mutation of the 26 exon c.1922_1923 ins C in COL1A1 gene. Stapedial surgery can provide short-term and long-term hearing benefits for Ol patients with hearing loss. Level of evidence: Level 4.

Novel Canthin-6-one Derivatives: Design, Synthesis, and Their Antiproliferative Activities via Inducing Apoptosis, Deoxyribonucleic Acid Damage, and Ferroptosis.

A series of novel canthin-6-one (CO) derivatives (8a-l) were designed and synthesized by introducing different amide side chains at the C-2 position, and their water solubility, antiproliferative activity, and preliminary mechanism were investigated. Most compounds displayed high cytotoxicity exhibiting low-micromolar IC50 values against four human cancer cell lines, especially HT29 cells. Meanwhile, the water solubility of active CO derivatives was significantly improved. Among these compounds, compound 8h with the N-methyl piperazine group exhibiting the highest antiproliferative capability with an IC50 value of 1.0 µM against HT29 cells, which was 8.6-fold lower than that of CO. Furthermore, 8h could upregulate the levels of reactive oxygen species, leading to mitochondrial damage. In addition, 8h could promote cell apoptosis and DNA damage by regulating the expression of apoptosis-associated proteins (Bcl-2 and cleaved-caspase 3) and the DNA damage-associated protein (H2AX). Most importantly, 8h also exerted ferroptosis by reducing the GSH level and GPX4 expression as well as increasing the lipid peroxidation level. Thus, the novel CO derivative 8h with N-methylpiperazine represents a promising anticancer candidate and warrants a more intensive study.

A novel mutation in COL1A1 causing osteogenesis imperfecta/hearing loss.

OBJECTIVES: To screen the COL1A1 and COL1A2 gene mutation sites in a family with type I osteogenesis imperfecta (OI)/hearing loss and analyze the characteristics and recovery of hearing loss in patients with osteogenesis imperfecta. METHODS: The basic clinical data of OI proband and her parents were collected, and the COL1A1 and COL1A2 genes were detected in peripheral blood by PCR amplification and generation Sanger sequencing. Literature of stapedial surgery in patients with osteogenesis imperfecta was collected. RESULTS: The heterozygous mutation of the 26 exon c.1922_1923 ins C in the OI progenitor COL1A1 gene led to the amino acid frameshift mutation of p.Pro 601FS, which was not detected in the phenotypic parents. The homozygous of exon 28 c.1782>G in COL1A2 was detected in the proband and her parents, resulting in changes in the protein p.Pro 549Ala. CONCLUSION: The clinical symptoms of the OI proband is caused by heterozygous mutation of the 26 exon c.1922_1923 ins C in COL1A1 gene. Stapedial surgery can provide short-term and long-term hearing benefits for OI patients with hearing loss. LEVEL OF EVIDENCE: Level 4.

Assessment and prognostic value of serum uric acid and neuron-specific enolase on the efficacy of intravenous thrombolytic therapy in cerebral infarction.

Assessment and prognostic value of serum uric acid (SUA) and neuron-specific enolase (NSE) on the efficacy of intravenous thrombolytic therapy in cerebral infarction. A retrospective analysis was performed on clinical data of 159 patients with acute cerebral infarction who received rt-PA intravenous thrombolytic therapy from 2015 to 2020 and patients with an mRS>2 points were assigned to the poor prognosis group and with mRS≤2 to the good prognosis group. The receiver operating characteristic curve (ROC) was used to examine the prognostic value of SUA and NSE in intravenous thrombolytic therapy for acute cerebral infarction, and logistic regression analysis was utilized to elucidate the predictive features. SUA levels were adversely correlated with prognosis, whereas NSE was positively correlated with prognosis (r=0.465 and -0.501, P=0.000 and 0.000). The ROC curve showed that the predictive accuracy of SUA was 77.4% and of NSE was 71%. SUA≤337.5 mmol/l and NSE≥24.50 ng/ml are considered viable criteria to predict the curative effect and prognostic value of intravenous thrombolytic therapy for acute cerebral infarction. SUA and NSE demonstrate great potential to accurately predict the therapeutic effect and prognosis of intravenous thrombolytic therapy for acute cerebral infarction.

Hierarchical Macroporous Agarose Materials with Polyethyleneimine-Assisted Multiple Boronate Affinity Binding Sites for the Separation of Neomycin.

Quantification of neomycin residues in food samples demands an efficient purification platform. Herein, hierarchical macroporous agarose monoliths with multiple boronate affinity sites were established for selective separation of neomycin. The silica core was synthesized by "one-step" Stöber procedures followed by modification with amino group and incorporation of polyethyleneimine. A versatile macroporous agarose monolith was prepared by emulsification strategies and functionalized with epoxy groups. After introducing polyethyleneimine-integrated silica nanoparticles onto the agarose monolith, fluorophenylboronic acids were immobilized. The physical and chemical characteristics of the composite monolith were analyzed systematically. After optimization, neomycin showed high binding ability of 23.69 mg/g, and the binding capacity can be manipulated by changing the pH and adding monosaccharides. The composite monolith was subsequently utilized to purify neomycin from the spiked model aquatic products followed by high-performance liquid chromatography analysis, which revealed a remarkable neomycin purification effect, indicating the great potential in the separation of neomycin from complicated aquatic products.

Circular RNA circADAM9 Promotes Inflammation, Oxidative Stress, and Fibrosis of Human Mesangial Cells via the Keap1-Nrf2 Pathway in Diabetic Nephropathy.

OBJECTIVE: Circular RNAs (circRNAs) have been discovered as potential biomarkers for diabetic nephropathy (DN). In this study, the potential roles of circADAM9 in high glucose (HG)-induced cell injury of human mesangial cells (HMCs) were investigated, and the underlying mechanism was elucidated. METHODS: DN cell model in vitro was simulated by HG treatment of HMCs. Endogenous expressions of circADAM9, miR-545-3p, and ubiquitin-specific protease 15 (USP15) were determined by real-time polymerase chain reaction. Cell proliferation and migration were evaluated using Cell Counting Kit-8 and wound healing assays. The inflammatory response was assessed by enzyme-linked immunosorbent assay. Oxidative stress was examined using commercially available kits. Dual-luciferase reporter and RNA pull-down assays were conducted to confirm the interaction among circADAM9, miR-545-3p, and USP15. RESULTS: CircADAM9 was upregulated in DN samples and HG-treated HMCs, while its downregulation inhibited cell proliferation, inflammation, fibrosis, and oxidative stress. Further investigation revealed that circADAM9 exerted this influence by targeting the miR-545-3p/USP15 axis, thereby regulating the KELCH-like ECh-associated protein 1/nuclear factor erythroid 2 related factor 2 (Keap1/Nrf2) pathway. MiR-545-3p knockdown or USP15 overexpression reversed the effect of circADAM9 silencing in HG-induced HMCs. CONCLUSION: These results indicate that the circADAM9/miR-545-3p/USP15/Keap1/Nrf2 signaling axis is critical for HG-induced cell injury in HMCs and might represent a novel therapeutic target for DN treatment.