The filtration function of glomeruli requires slit diaphragms formed by interdigitating podocyte foot processes, which are actin-based membrane protrusions. Failure in the maintenance of these cytoskeletal structures leads to foot process effacement, proteinuria, and progression to chronic kidney disease. We report WNK1 kinase activity is required for normal glomerular function in vivo and test the hypothesis that WNK1 kinase activity affects the structure of podocyte foot processes through modulation of actomyosin activity and focal adhesion complexes. Perturbation of cytoskeletal structure and focal adhesion signalosomes with WNK1 kinase inhibition supports a role for WNK1 in the maintenance of podocyte foot processes and sarcomere-like structures (SLSs) that are induced in models of podocyte injury. Applicability of WNK1 kinase activity modulation toward treatment of podocyte injury was assessed using primary and immortalized podocyte cell lines developed from control and Col4a3-/- Alport Syndrome model mice. Collectively, the results provide compelling evidence that WNK1 kinase signalosome activity, which includes regulation of nascent focal adhesion formation and NMII activity at membrane protrusions and extensions, is necessary for physiological maintenance of slit diaphragms.

Early HMGB1 Inhibition Reduces Hippocampal Injury During Adolescence in a Young Mouse Model of Radiation-Induced Brain Injury.

A synergistic protective network of Polygonatum sibiricum-derived carbon nanoparticles against ethanol-induced and oxidative hepatic injury in HepG2 cells.

Acoustic hydrogen delivery to treat PANoptosis induced by myocardial ischemia/reperfusion injury in rats.

T-2 toxin is a typical mycotoxin that seriously threatens human and animal health. Liver is the major target organ of T-2 toxin. To elucidate the precise hepatotoxicity mechanism and discover a natural antagonist of T-2 toxin. T-2 toxin (0, 0.5, 1, 2 mg/kg BW)-induced liver injury model, Ferrostatin-1 (1 mg/kg·BW) interference model, Parkin-/- mice model, Nrf2-activating model (tBHQ, 20 mg/kg·BW) and lycopene (5 mg/kg·BW) treatment model were constructed. Proteomics revealed that ferroptosis is a critical hepatotoxicity mechanism of T-2 toxin. Blocking ferroptosis alleviated the liver damage and mitophagy under T-2 toxin threat. However, these processes were exacerbated in Parkin-/- mice. In vivo mouse model confirmed that Nrf2 activation increased PINK-Parkin mediated mitophagy and alleviated T-2 toxin-induced ferroptosis, suggesting that Nrf2/mitophagy axis was involved in T-2 toxin-induced hepatic ferroptosis. Further analysis revealed that lycopene promoted Nrf2 nuclear translocation and PINK-Parkin mediated mitophagy to mitigate T-2 toxin-induced hepatic ferroptosis.

ABSTRACT This study presents a machine learning-based framework for predicting driver injury severity (DIS) in urban traffic crashes, using ten years (2011–2020) of police-reported data from Imphal, India. Focusing on morning and nighttime accidents, six ML models were trained and evaluated based on accuracy, precision – recall analysis, including AUC-PR (area under the Precision – Recall curve), recall (sensitivity) for the fatal class, and precision for the fatal class, under multiple train/test splits and cross-validation schemes. The best-performing models—Random Forest for morning crashes and LightGBM for night—were identified and further analyzed using SHAP-based sensitivity methods to determine key predictors. Results revealed that model performance and variable impact were sensitive to training ratio and cross-validation strategy. Two-wheeler involvement and narrow-road conditions were among the most significant factors. Overall, the study contributes to data-driven traffic injury modeling and highlights the potential of explainable artificial intelligence (XAI) as a decision-support tool for improving urban transport safety management.

This study aims to elucidate the synergistic protective mechanism of the AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) in ischemia-reperfusion injury -associated acute kidney injury (IRI-AKI). By establishing a hypoxia/reoxygenation (H/R) injury model using human proximal tubule cells (HK-2) and IRI-AKI rat model, and employing molecular techniques including qRT-PCR, western blotting, serum biochemical assays, renal tissue hematoxylin and eosin staining, immunofluorescence, and transmission electron microscopy (TEM), we demonstrated that AICAR activates AMPK, leading to the significant downregulation of TXNIP and NLRP3, blocks Caspase-1-dependent release of IL-1β and IL-18, and ultimately suppresses pyroptosis, thereby alleviating renal inflammatory injury. Furthermore, AICAR restored mitochondrial membrane potential and ATP levels in H/R-treated HK-2 cells, reduced reactive oxygen species production in renal tissues of IRI-AKI rats, and elevated levels of antioxidant enzymes. Concurrently, utilizing targeted metabolomics technology, we discovered that AICAR effectively restores the levels of multiple metabolites associated with glycolysis, the TCA cycle, the urea cycle, and tryptophan metabolism and alleviates lipid deposition in IRI-AKI. This confirms that AICAR alleviates IRI-AKI by activating AMPK to restore impaired cellular energy metabolism, improve mitochondrial function, and ameliorate oxidative stress. Notably, this study is the first to reveal that AICAR, via AMPK activation, synchronously regulates dual protective pathways: "pyroptosis inhibition" and "energy metabolism remodeling." This synergistic protective mechanism may represent the core advantage distinguishing AICAR from other potential therapeutic strategies, highlighting its substantial translational potential as a multi-mechanism synergistic therapeutic agent. Our findings provide an innovative dual-regulatory ("pyroptosis-energy metabolism") therapeutic strategy for the clinical prevention and treatment of IRI-AKI.

Macrophage (M-), granulocyte (G-), and granulocyte–macrophage (GM-) colony-stimulating factors (CSFs) regulate myeloid cell function, yet their relative roles during inflammation remain poorly defined. To uncover how CSFs shape spatial immune niches in Crohn’s disease, we performed Xenium single-cell spatial transcriptomics on ileal tissues, revealing cell-type–specific expression and source–target interactions for each CSF. GM-CSF, unlike M-CSF or G-CSF, was locally enriched in ulcerated regions where lymphocytes adjacent to macrophage aggregates signaled through STAT5 phosphorylation. To study functional consequences, we developed a csf2rb−/−zebrafish model of intestinal injury. Using this model, we found that loss of GM-CSF signaling exacerbated epithelial damage and inflammation, whereas recombinant human GM-CSF limited injury by restraining ILC1 expansion, sustaining ILC3 maintenance, and promoting IL-22 production. Cross-species single-cell analysis revealed conserved ILC gene modules and GM-CSF–dependent transcriptional networks linking lymphoid and myeloid populations. These findings establish GM-CSF as a critical spatial regulator of myeloid– lymphoid crosstalk and intestinal immune homeostasis in Crohn’s disease.

Taurine and tauroursodeoxycholic acid are used for treating cerebral ischemia. In this study, we used the combination of taurine and tauroursodeoxycholic acid to establish a model of ischemia-reperfusion injury and evaluate the effect and target of the drug combination using the neurovascular unit (NVU) model of hypoxia and reoxygenation in vitro. Results showed that the combined application of these two drugs improved the survival of neurons, astrocytes, and endothelial cells; reduced inflammatory damage, levels of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-1β, oxidative stress response, and the release of malondialdehyde and nitric oxide; and enhanced the activity of superoxide dismutase. Simultaneously, they acted on the blood-brain barrier (BBB) and improved the transendothelial electrical resistance value, reduced lactate dehydrogenase levels, improved the activity of γ-glutamyl transferase, and protected the integrity of the BBB against damage caused by oxygen-glucose deprivation/reoxygenation. At the same time, they prevented neuronal apoptosis, reduced the expression of Bax and caspase-3, and increased the expression of Bcl-2. These two drugs regulated the expression of connexin 43 (CX43) and aquaporin 4 (AQP4) in astrocytes, reducing the level of AQP4, and improving the activity of CX43. In addition, the drug combination increased the expression of tight junction proteins in endothelial cells, such as zona occludens-1, occluding, and claudin-5, and decreased the expression of matrix metalloproteinase (MMP)2 and MMP9. Furthermore, they acted together on the p38 mitogen-activated protein kinase (MAPK) signaling pathway, and the addition of the p38 inhibitor SB203580 partially inhibited the expression of p38MAPK. Thus, the combined action of these drugs protected the NVU.

Soft tissue injuries induce lumbar instability and intervertebral disc degeneration: A mechanobiological study based on a rabbit model.

Targeting the interaction between the C-terminal domain of the GluA2 subunit of AMPA receptors and BRAG2 presents a highly promising therapeutic approach for acute ischemic stroke. The membrane-permeable peptide Tat-GluA2-3Y has shown potential by competitively binding to BRAG2 to inhibit GluA2 endocytosis; however, its clinical application is limited due to poor stability in vivo. To address this limitation, we developed stapled peptides based on GluA2-3Y, leading to the identification of the lead compound P3LC7LC-P, which exhibits high-affinity binding to BRAG2. Functionally, P3LC7LC-P offers strong neuroprotection in two injury models: oxygen-glucose deprivation-induced and glutamate-induced neurotoxicity. Notably, P3LC7LC-P significantly improved plasma stability compared to Tat-GluA2-3Y, with a half-life exceeding 372.7 min. In the transient middle cerebral artery occlusion (tMCAO) model, P3LC7LC-P reduced cerebral infarction areas to 21.00% at a dose of 8 mg/kg. These findings highlight P3LC7LC-P as a promising candidate for the development of novel therapies for ischemic stroke.

Acutely denervated muscle EVs reshape neuronal mitochondrial metabolism via retrograde signaling to rescue peripheral nerve injury.

To clarify the relationship between acute kidney injury (AKI) and vancomycin use in patients with renal impairment and to establish a risk score for AKI. In this retrospective, multicentre, observational cohort study, trough and peak blood samples were collected from patients who initiated vancomycin therapy. The cumulative incidence of AKI within 14 days was compared among three groups classified according to renal function (estimated glomerular filtration rate ≥ 60, 30-59 and <30 mL/min/1.73 m2). The risk score and predicted probability of AKI incidence were calculated. AKI was defined in accordance with the Kidney Disease Improving Global Outcomes criteria. The incidence of AKI was 11.7% (99/847). No statistically significant difference was detected in the cumulative incidence of AKI among the three groups (P = 0.103). Cox proportional hazard analysis showed that the use of tazobactam/piperacillin [HR: 3.3, 95% CI (2.18-4.99), 2 points], vasopressors/inotropes [HR: 3.0, 95% CI (2.02-4.51), 2 points] and area under the concentration-time curve (AUC) on Day 2 [500-600 µg·h/mL: HR, 2.4, 95% CI (1.50-3.89), 1 point; >600 µg·h/mL: HR, 4.4, 95% CI (2.62-7.37), 3 points] were significantly related to the development of AKI. The predicted probabilities of AKI incidence were <5% (low-risk), 5% to <20% (moderate-risk), 20% to <40% (high-risk) and 40% to 67% (very high-risk), with total points of 0, 1-2, 3-4 and ≥5, respectively. A risk prediction model was developed for AKI based on AUC exposure and concomitant medications, and no difference in AKI risk was observed across renal function categories.

CaMKII-based gene therapy protects retinal ganglion cells in a broad range of disease: ischemic retinopathy and congenital glaucoma.

PPARa-FSP1 axis modulates lipid peroxidation-induced neuronal ferroptosis to promote functional recovery in mouse model of traumatic spinal cord injury.

Mitophagy dysfunction is a critical contributor to retinal pigment epithelial (RPE) cell damage during the progression of retinal degenerative diseases, including age-related macular degeneration (AMD). In this study, we investigated the effects of paeoniflorin (PF) on mitophagy in RPE cells, with a particular focus on the CUL3/LKB1/AMPK/ULK1 signaling pathway. ARPE-19 cells were treated with different concentrations of PF to evaluate cytotoxicity, and its protective effects were further examined in H₂O₂-induced oxidative stress models in vitro and in sodium iodate (NaIO₃)-induced RPE injury models in vivo. Protein levels of CUL3, apoptosis-related factors, mitophagy markers, and components of the LKB1/AMPK/ULK1 pathway were assessed by western blotting, and mitophagy was visualized using MitoTracker labeling. Cycloheximide (CHX) and coimmunoprecipitation (Co-IP) assays were performed to analyze the interaction between CUL3 and LKB1. PF treatment enhanced mitophagy in H₂O₂-stimulated ARPE-19 cells, whereas Parkin knockdown markedly attenuated this effect. In oxidatively damaged cells, PF promoted AMPK and ULK1 phosphorylation, increased mitophagy-associated protein expression, and alleviated mitochondrial dysfunction; these protective effects were abolished by pharmacological inhibition of AMPK or ULK1. In addition, CUL3 overexpression significantly attenuated PF-induced mitophagy activation and reduced PF-associated phosphorylation of LKB1, AMPK, and ULK1. Mechanistically, PF downregulated CUL3 expression, while CUL3 promoted the ubiquitination and degradation of LKB1. Silencing CUL3 induced mitophagy in H₂O₂-treated cells, whereas concurrent knockdown of CUL3 and LKB1 abolished this effect. In vivo, PF mitigated RPE cell loss, enhanced mitophagy, and activated the CUL3/LKB1/AMPK/ULK1 signaling pathway in the retinal tissues of NaIO₃-induced mice. Collectively, these findings indicate that PF protects against RPE injury in an NaIO₃-induced AMD-like model by downregulating CUL3 expression and activating LKB1/AMPK/ULK1-mediated mitophagy.

Airway injury induces alveolar epithelial responses mediated by macrophages.

Sirt3-Bnip3 signaling axis alleviates myocardial ischemia/reperfusion-induced cardiac injury via regulating GSDME.

Targeting PDK4 attenuates neointimal hyperplasia and regulates VSMC phenotypic Switching, Apoptosis, and autophagy.

Screening and identification of a novel PGAM5-specific inhibitor for attenuating multi-organ injury.