Renal ischemia-reperfusion injury (IRI) is a significant cause of acute kidney injury with high mortality rates, poor prognosis, and limited therapeutic options. TRIM7, an E3 ubiquitin ligase, plays a role in regulating various cellular processes, including antiviral immune responses and autophagy in different diseases. However, the specific role of TRIM7 in renal IRI has not been well understood. In this study, overexpression of TRIM7 significantly mitigated the inflammation and apoptosis subjected to ischemia injury, whereas TRIM7 knockout exerted the opposite effect both in vivo and in vitro. Mechanistically, we discovered that TRIM7 interacted with CMPK2 and negatively regulate its expression. Inhibiting CMPK2 activity reversed the increased inflammation and apoptosis seen in renal epithelial cells lacking TRIM7. Overall, our findings demonstrate that TRIM7 plays a role in suppressing inflammation and apoptosis during renal IRI by modulating CMPK2 expression. This study uncovers a novel function of TRIM7 in renal IRI and presents a potential new drug target for treating it clinically.

Depression is a leading global mental health issue, and social determinants of health (SDOH) influence its onset and progression. The role of neighborhood-level social vulnerability index (SVI), a comprehensive measure encompassing multiple SDOH indicators, in depression prevalence remains uncertain. Utilizing data from the US CDC, we employed mixed-effects linear regression models to explore this association and applied LASSO regression to analyze the relative importance of SVI domains and indicators Our analysis revealed that neighborhoods with higher SVI exhibited a significantly higher prevalence of depression, with an adjusted beta of 2.625 (95% CI: 2.518, 2.724) for continuous SVI, and the prevalence increased progressively from the second to the fourth SVI quartile (p for trend <0.001) Among all domains, race & ethnicity status (β = -9.090) and socioeconomic status (β = 8.252) demonstrated the strongest associations with depression prevalence, and we also observed a significant interaction between environmental burden and SVI (p for interaction <0.001). These findings indicate that higher SVI is associated with higher depression prevalence, with racial & minority and socioeconomic statuses emerging as key drivers of this relationship.

Myocardial infarction (MI) remains a severe threat to global health. The loss of cardiomyocytes and structural damage to the ventricles following MI lead to cardiac dysfunction. Current myocardial repair scaffolds promote tissue regeneration by mimicking the natural structure of myocardial tissue, yet suffer from the limitation of focusing on a single dimension of repair, failing to address the complex pathological microenvironment after MI characterized by ischemia, inflammation, and stress mismatch. To overcome this, our study has developed a multiscale bionic fibrous scaffold. The scaffold combines directional freezing with electrospinning technology. While constructing oriented channels that mimic natural myocardial tissue, it embeds nanofibers into the channel walls to form synapse-like microstructures. In vivo and in vitro experiments demonstrate that this scaffold synergistically promotes myocardial repair through multiple mechanisms: providing mechanical support, promoting angiogenesis, and regulating macrophage polarization. It significantly improves cardiac ejection function and inhibits ventricular remodeling. This repair mechanism results from the nanofiber synapse structure activating downstream intracellular signaling networks through its integrin binding sites, thereby regulating cellular behavior. In summary, this study provides a novel strategy for developing myocardial repair materials that synergistically regulate multicellular tissues and match complex pathological microenvironments.

BACKGROUND:While physical activity (PA) may influence abdominal aortic aneurysm (AAA) risk, prior studies relied on self-reported data, and genetic interactions remain unexplored. We investigated PA and AAA associations using accelerometer and questionnaire data and assessed genetic predisposition. METHODS:We included 392 737 UK Biobank participants with questionnaire-based PA data and 92 101 with accelerometer-based data, all free of baseline AAA. PA was categorized into light-intensity, moderate-intensity, vigorous-intensity, moderate- to vigorous-intensity, and total PA. Incident AAA was ascertained using International Classification of Diseases, Tenth Revision (ICD-10), and Office of Population, Censuses and Surveys Classification of Interventions and Procedures (OPCS-4) codes. Dose-response associations were examined using restricted cubic splines. Genetic susceptibility was assessed using polygenic risk scores. Associations were estimated using Cox proportional hazards models and isotemporal substitution models. RESULTS:Among cohorts with questionnaire- (n=392 737; median follow-up, over 13.5 years) and accelerometer- (n=92 101; median follow-up, 7.9 years) based PA data, there were 2181 and 402 incident cases, respectively. Higher moderate-intensity PA, vigorous-intensity PA, and total PA were inversely associated with AAA risk. Protective associations were strongest in patients with low genetic risk and high PA. A nonlinear relationship was observed for moderate-intensity PA and moderate- to vigorous-intensity PA, with maximal risk reduction at 402.6 and 428.1 minutes per week, respectively, beyond which no additional benefit was observed. An isotemporal substitution model showed that replacing light-intensity PA with moderate-intensity PA/vigorous-intensity PA reduced AAA risk, with greater benefit for vigorous-intensity PA. CONCLUSION:PA engagement is associated with a reduction in AAA burden, regardless of genetic risk. We identified distinct time thresholds for achieving maximum benefit among PA intensities, highlighting its potential role in exercise-based AAA prevention strategies.

OBJECTIVE:This study aims to investigate the role of neurotrophin-4 (NTF4) in gestational diabetes mellitus (GDM) and to elucidate the underlying mechanism by which NTF4 regulates high glucose-induced apoptosis and inflammation in HTR-8/SVneo cells via the PI3K/AKT signaling pathway. METHODS:Transcriptomic analysis combined with public database screening revealed that NTF4 is significantly upregulated in placental tissues from GDM patients. In a high glucose-induced HTR-8/SVneo cell model, NTF4 was silenced using small interfering RNA to evaluate the effects on cell proliferation, apoptosis, and inflammatory responses. Cell proliferation was evaluated using the CCK-8 assay, apoptosis by flow cytometry, inflammatory cytokine secretion by ELISA, and cell migration and invasion by Transwell assays. Western blotting was performed to detect protein levels. Additionally, the PI3K-specific inhibitor LY294002 was used to determine the pathway dependence of NTF4-mediated effects. RESULTS:NTF4 is upregulated in GDM placentas and high glucose-induced HTR-8/SVneo cells. Knockdown of NTF4 significantly ameliorated high glucose-induced cell damage by enhancing cell viability, suppressing apoptosis, and inflammation. Mechanistic investigations revealed that NTF4 contributes to cellular injury by activating the PI3K/AKT signaling pathway, while the PI3K inhibitor LY294002 further amplified the protective effects of NTF4 silencing. CONCLUSIONS:This study identified the role of NTF4 in promoting trophoblast injury by activating the PI3K/AKT signaling pathway in high-glucose-stimulated HTR-8/SVneo cells, which provides a preliminary experimental basis for exploring its potential role in the pathogenesis of GDM.

Culturing cardiomyocytes in vitro with robust contractile capacity remains challenging due to the complex and diverse factors influencing contraction, such as cellular maturity, spatial distribution, and structural orientation. Herein, biomass-derived micropatterned hydrogels are fabricated via UV-induced polymerization, providing an anisotropic microenvironment for cardiomyocyte culture. This enables the precise regulation of mitochondrial networks within individual cardiomyocytes and the oriented organization of multicellular ensembles. As the elastic modulus of the tunicate cellulose nanocrystals (TCNCs) reinforced hydrogel is 50 kPa, the single-cell mitochondrial area increases to 560 μm2, providing the energy foundation necessary for cardiomyocyte contraction. Moreover, the orientation degree of cardiomyocytes reaches 80% by precisely tuning the width of the surface microgroove to 40 μm, thereby facilitating the synchronized contractile activity in vitro for more than 10 consecutive days. Finally, flower-shaped bio-actuators driven by oriented cardiomyocytes are constructed to mimic the opening and closing motion of flowers. This work not only establishes a versatile biomimetic platform for engineering anisotropic microenvironments to support in vitro cardiomyocyte culture and maturation but also demonstrates significant potential for applications in biological microactuators.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is associated with the complete loss of cognition, and its pathogenesis has been suggested to be closely linked to oxidative stress in the early stage. However, there is currently a lack of effective methods to provide direct evidence for dynamic development of the oxidative stress status during AD progression. Herein, through manipulating the multiple energy transfer between 4f electronic levels of lanthanide ions (Ln3+), we proposed an energy interception strategy to construct activatable NIR-IIb nanoprobe for visualizing oxidative stress level. By utilizing an organic molecule, A1094 that absorbs light at wavelength matching the emission of Nd3+ and Yb3+, NIR-IIb emission from Er3+ can be modulated upon the response of A1094 to oxidative species. This nanoprobe can not only clearly outline and distinguish oxidative stress regions in AD brains with adjacent age but also provide fast feedback on the efficacy of early interventional treatment for AD.

Cartilage is severely limited in self-repair after damage, and tissue engineering scaffold transplantation is considered the most promising strategy for cartilage regeneration. However, scaffolds without cells and growth factors, which can effectively avoid long cell culture times, high risk of infection, and susceptibility to contamination, remain scarce. Hence, we developed a cell- and growth factor-dual free hierarchically structured nanofibrous sponge to mimic the extracellular matrix, in which the encapsulated core-shell nanofibers served both as mechanical supports and as long-lasting carriers for bioactive biomass molecules (glucosamine sulfate). Under the protection of the nanofibers in this designed sponge, glucosamine sulfate could be released continuously for at least 30 days, which significantly accelerated the repair of cartilage tissue in a rat cartilage defect model. Moreover, the nanofibrous sponge based on carboxymethyl chitosan as the framework could effectively fill irregular cartilage defects, adapt to the dynamic changes during cartilage movement, and maintain almost 100 % elasticity even after multiple compression cycles. This strategy, which combines fiber freeze-shaping technology with a controlled-release method for encapsulating bioactivity, allows for the assembly of porous bionic scaffolds with hierarchical nanofiber structure, providing a novel and safe approach to tissue repair.

The blood-brain barrier (BBB) impedes the transportation of drugs to the brain, thereby constraining the efficacy of treatments for brain diseases. Here, a pH-sensitive nanocarrier coated with a brain metastatic tumor cell membrane (CA-iRGD-CS@M) is designed to enhance drug delivery across the BBB by simultaneously improving cellular uptake and accelerating lysosomal escape. The cell membrane coating can recognize brain microvessel endothelial cells (BMECs) to improve cellular uptake. The pH-sensitive nanocarrier (CA-iRGD-CS) as the core of CA-iRGD-CS@M undergoes charge reversal triggered by the acidic environment of lysosomes, leading to the disruption of the coated cell membrane and further promoting the escape of the detached core from lysosomes into the brain parenchyma. Facilitated by the targeting ligand iRGD, the detached core containing the photothermal agent (CuS) can target the tumor site and fulfill deep penetration, thereby achieving efficient NIR-II photothermal therapy.

The blood-brain barrier (BBB) presents a major challenge in the theranostics of brain diseases by impeding the delivery of drugs to the brain. Currently the most common strategy for transferring substances across the BBB is receptor-mediated transcytosis, which is restricted by several key factors, including insufficient endocytosis by brain microvessel endothelial cells (BMECs) due to underexpressed pinocytotic vesicles, lysosomal retention, and limited exocytosis to the brain parenchyma. We report a hybrid cell membrane (HCM)-coated and 2-methacryloyloxyethyl phosphorylcholine (MPC)-modified nanocarrier to promote drug delivery across the BBB by modulating the transcytosis process. The HCM incorporates a brain metastatic tumor cell membrane for recognition of BMECs and a GFP-293-S cell membrane expressing Spike protein to facilitate membrane fusion between the nanocarrier and BMECs, thereby bypassing vesicle-dependent endocytosis and enhancing cellular uptake. Membrane fusion reduces the chance of lysosomal retention, and MPC modification enhances exocytosis into the brain parenchyma via the interaction of MPC with transporters expressed on the abluminal endothelial membrane. The nanocarrier achieves significantly improved delivery of CuS, a photothermal agent, to the brain and thus enables highly efficient therapy of brain glioma.

Myocardial infarction (MI) is followed by irreversible damage to the myocardium, which eventually evolves into ventricular remodeling and heart failure. An imbalanced inflammatory response after MI can exacerbate myocardial injury. Current strategies to modulate inflammation and thereby improve myocardial tissue repair are limited. Material surface microstructures can modulate the immune microenvironment and thus influence the tissue damage repair process. Therefore, modulation of the postinfarction immune microenvironment through the hierarchical structure of materials becomes a feasible strategy. In this study, hierarchically structured hydrogels were prepared using a polysaccharide gel matrix and a protein fiber network to modulate the postinfarction immune microenvironment. The hierarchical structure of the hydrogel was able to recruit macrophages and further promote the multicellular response of endothelial cells and cardiomyocytes, resulting in angiogenesis and cardiomyocyte survival by modulating macrophage conversion to the M2 type. In the MI model, the hierarchically structured hydrogels effectively reduced the infarct area, increased the ventricular wall thickness, and improved cardiac contractile function. This study is based on the structural modification of materials to facilitate myocardial defect repair, which is expected to provide ideas for the current treatment paradigm after myocardial injury.

Emerging evidence suggests that autophagy is activated during exercise, mediating the benefits of exercise. However, the molecular mechanisms underlying the regulation of skeletal muscle autophagy during exercise are incompletely understood. Here, we show lactate severs as a positive regulator of autophagy in myocytes and its levels increase rapidly in response to a single bout of exercise. Mice with low lactate levels due to the lack of myocyte lactate dehydrogenase A exhibit significant abnormalities in skeletal muscle, including impaired autophagy. Our mechanistic study demonstrates that lactate enhances autophagy by inactivating mTOR complex 1 (mTORC1) through promoting mTOR lactylation at lysine 921 (K921) in myocytes. Accordingly, mutation of mTOR at K921 site causes sustained mTORC1 activation, leading to defects in skeletal muscle autophagy. Thus, our work uncovers a previously undescribed physiological action of lactate in the regulation of mTORC1-controlled skeletal muscle autophagy during acute exercise, which involves a lactylation-based post-translational modification mechanism.

Background: Recent studies have shown an association between atherogenic index of plasma (AIP) and nonalcoholic fatty liver disease (NAFLD), but the association in a population of pregnant women remains unclear. Objectives: Our study aimed to examine the association between AIP and NAFLD in pregnant Korean women. Methods: Our study used publicly available data from Korea, which recruited singleton pregnant women between November 2014 and September 2016 who were at 10-14 weeks of gestation. The presence of NAFLD was diagnosed by liver ultrasound. AIP was calculated as log10 (TG/HDL). Participants were grouped according to AIP tertile: T1 (< 0.16, n = 195), T2 (0.16-0.32, n = 195), and T3 (>0.32, n = 196). Logistic regression models were used to estimate the relationship between AIP and NAFLD. Subgroup and sensitivity analyses were conducted to explore the stability of this relationship. Restricted cubic spline (RCS) curve fitting was employed to investigate potential non-linear associations. Results: After excluding data on missing variables, 586 singleton pregnant women were finally included. The subjects included in the study had an average AIP of 0.22 (0.11, 0.37), and NAFLD occurred in 110 (18.8%) pregnant women. We observed a positive linear association between AIP and NAFLD (OR = 1.33, 95% CI: 1.19-1.48), which persisted after adjusting for potential confounders (OR = 1.2, 95% CI: 1.06-1.37). When AIP was used as a categorical variable, after adjusting for covariates, the NAFLD risk was significantly higher in the highest tertile of AIP than in the lowest group (OR = 2.02, 95% CI: 1.11-3.68). Their correlations were stable across subgroups and sensitivity analyses. Conclusion: In this secondary analysis of a prospective cohort study of pregnant Korean women, AIP was found to be positively associated with NAFLD. These outcomes might be used to screen for NAFLD in pregnant women.

Background Autoimmune diseases are closely linked to cardiovascular diseases. This study aimed to assess the relationship between cardiovascular health (CVH) defined by Life's Essential 8 (LE8), genetic predisposition, and the risk of 19 autoimmune disorders. Methods and Results A total of 247 660 participants without prior autoimmune diseases from the UK Biobank were included. CVH was assessed using LE8 scores, categorized into low, moderate, and high. Cox proportional hazards models estimated the association between CVH, genetic susceptibility, and autoimmune disorder risk. Over 13.2 years of follow‐up, 11 422 incident autoimmune disorders occurred. Higher CVH levels were associated with reduced risks of overall autoimmune disorders (hazard ratio, 0.68 [95% CI, 0.62–0.74]) and specific conditions, including Graves disease, inflammatory bowel disease, polymyalgia rheumatica, psoriasis, rheumatoid arthritis, and type 1 diabetes. Dose–response analyses revealed a linear negative relationship between continuous LE8 scores and the risks of Graves disease, inflammatory bowel disease, polymyalgia rheumatica, psoriasis, rheumatoid arthritis, and type 1 diabetes (Pnonlinear>0.05). Genetic predisposition to autoimmune disorders (including ankylosing spondylitis, celiac disease, Graves disease, inflammatory bowel disease, polymyalgia rheumatica, psoriasis, rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, systemic sclerosis, and type 1 diabetes) significantly modified these associations (Pinteraction<0.05), with protective effects more pronounced in women, participants aged <65 years, and those with low genetic risk. Conclusions LE8 scores inversely and linearly predicted autoimmune disease incidence. Prioritizing CVH optimization through LE8 adherence may reduce the global autoimmune disease burden.

Hepatocellular carcinoma (HCC) stands as the prevailing manifestation of primary liver cancer and continues to pose a formidable challenge to human well-being and longevity, owing to its elevated incidence and mortality rates. Nevertheless, the quest for reliable predictive biomarkers for HCC remains ongoing. Recent research has demonstrated a close correlation between ferroptosis and disulfidptosis, two cellular processes, and cancer prognosis, suggesting their potential as predictive factors for HCC. In this study, we employed a combination of bioinformatics algorithms and machine learning techniques, leveraging RNA sequencing data, mutation profiles, and clinical data from HCC samples in The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and the International Cancer Genome Consortium (ICGC) databases, to develop a risk prognosis model based on genes associated with ferroptosis and disulfidptosis. We conducted an unsupervised clustering analysis, calculating a risk score (RS) to predict the prognosis of HCC using these genes. Clustering analysis revealed two distinct HCC clusters, each characterized by significantly different prognostic and immune features. The median RS stratified HCC samples in the TCGA, GEO, and ICGC cohorts into high-and low-risk groups. Importantly, RS emerged as an independent prognostic factor in all three cohorts, with the high-risk group demonstrating poorer prognosis and a more active immunosuppressive microenvironment. Additionally, the high-risk group exhibited higher expression levels of tumor mutation burden (TMB), immune checkpoints (ICs), and human leukocyte antigen (HLA), suggesting a heightened responsiveness to immunotherapy. A cancer stem cell infiltration analysis revealed a higher similarity between tumor cells and stem cells in the high-risk group. Furthermore, drug sensitivity analysis highlighted significant differences in response to antitumor drugs between the two risk groups. In summary, our risk prognostic model, constructed based on ferroptosis-related genes associated with disulfidptosis, effectively predicts HCC prognosis. These findings hold potential implications for patient stratification and clinical decision-making, offering valuable theoretical insights in this field.