Pancreatic ductal adenocarcinoma remains one of the most formidable challenges in oncology, with limited treatment options and a poor prognosis. Understanding the key pathways affecting cancer progression is crucial for the development of therapeutic strategies. Here, we reveal a pivotal role of Prolyl 3-hydroxylase 1 in pancreatic ductal adenocarcinoma using transcriptome sequencing, proteomic analyses and engineered mouse model. Mechanistically, our findings indicate that this effect is, at least in part, through the regulation of Polo-like kinase 1 and Polo-like kinase 1-mediated β-catenin signaling. Restoration of either Prolyl 3-hydroxylase 1 or Polo-like kinase 1 expression in Prolyl 3-hydroxylase 1-deficient cells reverses the defects of β-catenin signaling, facilitates tumor cell proliferation and elicits macrophage infiltration. In addition, pharmacological inhibition of Polo-like kinase 1 strongly increases the therapeutic efficacy of chemotherapeutic response against pancreatic ductal adenocarcinoma, alleviating tumor burden in mice. Our findings suggest a promising therapeutic strategy for treating pancreatic ductal adenocarcinoma.

Citrus aurantium L. (Citrus aurantium) is rich in flavonoids and bioactive phytochemicals, but its industrial utilization is limited by suboptimal flavor quality and instability during processing. Herein, monoculture fermentation using Lactiplantibacillus plantarum (a lactic acid bacterium) or Bifidobacterium animalis subsp. lactis (a lactic acid bacterium), together with their synergistic co-fermentation, was employed to investigate flavor and functional modifications in C. aurantium juice. Compared with monoculture fermentation, co-fermentation increased total flavonoid and phenolic contents by 23.7-50.4% and 43.6-65.0%, respectively, while β-glucosidase activity, ABTS and DPPH radical-scavenging activities increased by 10.9-27.3%, 12.6-24.4%, and 12.7-26.4%, respectively. Electronic-nose and headspace solid-phase microextraction-gas chromatography-mass spectrometry analyses revealed that co-fermentation generated a distinct volatile profile characterized by enrichment of aroma-related compounds and altered representation of compounds associated with earthy and camphor-like notes. Untargeted metabolomics revealed extensive remodeling of phenolic, amino acid, and lipid metabolism. The relative abundance of limonin showed a marginal, non-significant decrease of 3.9%, while indoline and L-tyrosine increased by 3.9% and 3.8%, respectively (p < 0.001). These changes were accompanied by significant enrichment of the flavone and flavonol biosynthesis pathway (p = 0.0082). Correlation analysis further revealed strong associations between key differential metabolites and functional indicators. Collectively, these findings demonstrate that synergistic probiotic co-fermentation drives metabolic remodeling and flavonoid biotransformation in C. aurantium juice, providing a promising strategy for developing high-value functional citrus beverages. Future studies should further evaluate sensory acceptability, storage stability and industrial feasibility to facilitate commercial application.

Hexaploid wheat has a large genome, making it difficult for transgenes to produce phenotypes due to gene redundancy and tight linkage among genes. Multiple gene copies typically necessitate multiple targeting events during gene editing, followed by several generations of self-crossing to achieve homozygous genotypes. The high cost of transgenesis in wheat is another issue, which hinders the easy availability of gene-edited materials in wheat. In this study, we developed a comprehensive approach to improve wheat gene editing efficiency. First, we established a protoplast-based system to evaluate the relative efficiency of gene editing targets, which enabled the rapid and effective selection of optimal sgRNAs. We then compared two transformation strategies: biolistic bombardment and Agrobacterium-mediated transformation for generating edited wheat lines. Although biolistic bombardment showed higher initial editing efficiency, Agrobacterium-mediated transformation proved more effective for obtaining homozygous mutants. Notably, we discovered that deploying the same sgRNA through different vectors enhanced editing efficiency, whereas overlapping but distinct sgRNAs exhibited interference effects. Finally, we optimized the VITF-edit (virus-induced transgene free editing) technique using BSMV delivery to establish a relatively simple and easily applied wheat gene editing method for general laboratories.

Phytoremediation associated with plant-beneficial bacteria has gained considerable attention for its efficiency in remediating cadmium (Cd)-contaminated soil. In this study, we isolated an endophytic bacterium, PEB-9, from pigeon pea, which was identified as Bacillus cereus and exhibited strong plant growth-promoting traits along with high Cd resistance in vitro. Pot experiments demonstrated that PEB-9 inoculation increased in pigeon pea biomass (11.45-19.29 %), Cd accumulation (43.89-69.90 %), and the Cd transfer factor (4.17-16.89 %) in Cd-stress soil (2-10 mg/kg), with soil remediation efficiency improving by 11.1-15.4 %. Under Cd stress, PEB-9-treated pigeon pea exhibited significant improvement in the activities of superoxide dismutase, peroxidase, and catalase, while a notable decrease in malondialdehyde content, indicating a reduction in Cd cytotoxicity. Additionally, the chlorophyll content in PEB-9-treated plants was significantly higher than that in the control group. Furthermore, PEB-9 inoculation enhanced bioavailable Cd, soil enzymes activity and nutrient content, including available nitrogen, phosphorus, and organic matter, while also boosting the relative abundance of stress-resistant bacterial groups, such as Proteobacteria and Actinobacteria. Correlation analysis indicated that soil nutrient changes induced by PEB-9 significantly influenced bacterial community structure, thereby regulating plant physiological responses, and improving Cd remediation efficacy of pigeon pea. These findings offer a valuable basis for the practical implementation of PEB-9 in remediating Cd-contaminated soils.

L. rhamnosus FSJ13 enhanced FGF21 expression, thereby inhibiting the TGF-β/Smad2/3 signaling pathway and subsequently attenuating pancreatic fibrosis.

Ruthenium-based metallodrugs have garnered attention as a promising alternative for anticancer therapy, aiming to overcome chemoresistance and severe side effects linked to platinum-based drugs. However, ruthenium complexes tested in clinical trials to date have yielded unsatisfactory results. This study synthesized a positively charged ruthenium complex (Ru-2) that effectively penetrated cancer cells and exhibited superior cytotoxicity to cisplatin in vitro against cancer cell lines and organoids. Ru-2 selectively targeted mitochondria, disrupting their function by depolarizing mitochondrial membrane potential, elevating reactive oxygen species production, and impairing both oxidative phosphorylation and the tricarboxylic acid cycle. Furthermore, Ru-2 triggered endoplasmic reticulum (ER) stress and apoptosis. Integrative transcriptomic and proteomic analyses, performed using RNA sequencing and mass spectrometry, identified key molecular changes in cancer cells treated with Ru-2. For enhanced in vivo application, we developed a transferrin-based nanomedicine formulation, TF/Ru-2, incorporating Ru-2 into transferrin. In vivo studies demonstrated that both Ru-2 and TF/Ru-2 exhibited superior antitumor efficacy and improved biosafety compared to cisplatin. This study presents a novel ruthenium complex and a transferrin-based drug delivery platform with significant potential for future cancer therapies.

The micro-nano structure of drug delivery systems, which realize the release of the drug in stages, represent a promising therapeutic approach for tumor chemotherapy. In this study, we developed a drug delivery system in which nano-PLGA was coated on the surface of attapulgite microspheres (ATT-MS) loaded with doxorubicin hydrochloride (DOX). Nano-PLGA surrounding ATT-MS formed a satellite structure, which improved the drug release rate by blocking the drug release channels with the nano-PLGA. The drug delivery system achieves a high DOX encapsulation efficiency (98%) and enables passive, tumor-selective drug release. The zeta potential and drug release curve showed that DOX in this drug delivery system is more readily released in the tumor microenvironment. The fluorescence imaging and western blot analysis showed that the drug delivery system has the potential to improve tumor resistance. Moreover, the in vivo experiment showed that the system not only maintained the anticancer activity but also reduced the organ damage. In conclusion, this micro-nano structure of the drug delivery system may provide a novel approach to effectively deliver DOX to the tumor and reduce systemic toxicity.

Sepsis is a condition resulting from the uncontrolled immune response to infection, leading to widespread inflammatory damage and potentially fatal organ dysfunction. Currently, there is a lack of specific prevention and treatment strategies for sepsis across different age groups. Programmed Cell Death (PCD) can regulate the enrichment of effector immune cells or regulatory immune cells, providing a new perspective for immunotherapy. Within the framework of computational biology and machine learning strategies, and against the backdrop of global multicenter sepsis cohort data, this study aims to deeply mine and screen specific biomarkers related to the immune microenvironment and programmed cell death in populations across different life stages (neonates, children, and adults). This will provide foundational data for precision treatment and drug development in artificial intelligence-assisted sepsis diagnosis and treatment management. Gene expression data from sepsis patients across global multicenter populations, including China, Europe, and the United States, were obtained from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were identified. A literature review was conducted to obtain 18 PCD-related genes, which were intersected with DEGs to identify DEGs associated with specific types of PCD. Nine machine learning algorithms (Logistic Regression LR, Decision Tree DT, Gradient Boosting Machine GBM, K-Nearest Neighbors KNN, LASSO, Principal Component Analysis PCA, Random Forest RF, Support Vector Machine SVM, and XGBoost) were applied to training and testing datasets with 10-fold cross-validation to select three optimized algorithm models. The SHAP algorithm was further used to quantify the contribution of each gene based on cell death features to the prediction of sepsis. Key PCD patterns were identified based on model evaluation metrics (Accuracy, Precision, Recall, F1 score, and Receiver Operating Characteristic Curve ROC), and their associated DEGs were obtained through intersection, followed by immune-related analysis of DEGs. The study included a total of 1507 sepsis cases and 484 controls globally, with 90 neonatal cases and 95 controls, 527 children cases and 101 controls, and 890 adult cases and 288 controls. The best model for predicting sepsis across different populations was GBM.The key PCD patterns selected by machine learning for different age groups were Pyroptosis (neonates), Ferroptosis (children), and Autophagy (adults). (1) In neonatal sepsis, the models constructed by GBM, XGBoost, and RF algorithms performed the best, and identified 5 key DEGs associated with Pyroptosis (CHMP7, NLRC4, AIM2, GZMB, PRKACA), with NLRC4 showing the best predictive ability (AUC = 0.902, P < 0.05), significantly positively correlated with neutrophils and negatively correlated with CD8 + T cells. (2) In the children sepsis population, models constructed using the Gradient Boosting Machine (GBM), Support Vector Machine (SVM), and Least Absolute Shrinkage and Selection Operator (LASSO) algorithms demonstrated the best performance. Six key DEGs associated with Ferroptosis were identified (AKR1C3, GCLM, PEBP1, CARS, MAP1LC3B, SCL11A2), among which MAP1LC3B, playing a role in mitochondrial reactive oxygen species energy metabolism, showed the strongest predictive ability (AUC = 0.883, P < 0.05). It was significantly positively correlated with M0-type macrophages and significantly negatively correlated with activated CD4 + memory T cells. (3) In the adult sepsis population, models constructed using GBM, SVM, and LASSO algorithms showed the best performance. Three key DEGs associated with Autophagy were identified (TSPO, HTRA2, USP10), with TSPO, which mediates oxidative stress regulation, iron homeostasis, and cholesterol transport, showing the strongest predictive ability (AUC = 0.825, P < 0.05). It was significantly positively correlated with M1-type macrophages and significantly negatively correlated with CD8 + T cells. This study, through the integrated application of computational biology and machine learning algorithms, discovered biomarkers of PCD patterns that affect cytokine storm-mediated inflammation and immunosuppressive effects in sepsis populations across different age groups (neonates, children, and adults). These findings have specific clinical application and drug development value, providing a scientific basis for the global application of artificial intelligence-assisted sepsis diagnosis and treatment management.

Oxygen evolution reaction (OER) and oxygen reduction reaction (ORR) are cathodic reactions of rechargeable zinc air batteries (ZABs), and their slow kinetics and multiple complex processes directly determine the overall energy efficiency and cycle life of ZABs. Exploring high activity, high stability and low cost non precious metal electrocatalysts for ZABs and their preparation method is of great significance. In this paper, a composite catalyst named Co/CoO@PNC has been prepared by scalable high gravity-hydrothermal method with a distinctive core shell structure of Co/CoO active particles uniformly loaded on polyaniline-derived one-dimensional nitrogen doped carbon material. The synergistic effect between each component enables Co/CoO@PNC to exhibit excellent bifunctional OER/ORR catalytic activity, which has a lower value of Delta E of 0.703 V. When Co/ CoO@PNC is used as the catalyst of rechargeable ZABs, the power density is 156.5 mW/cm2, with a specific capacity of 821 mAh/g and strong charging and discharging ability, better than Pt/C + RuO2. After more than 250 h of charge and discharge cycles, there is no significant decrease in performance. This article provides a high performance bifunctional OER/ORR catalyst without precious metals and its low-cost, simple and scalable preparation method.

Allergic asthma is a significant global health issue characterized by chronic airway inflammation. Current treatments only alleviate symptoms but fail to cure the disease due to its complex pathology. Lipid mediators from arachidonate metabolism are pivotal in immune regulation in asthma. Previously, coactosin-like protein (CLP) is identified as a regulator of leukotriene production in vitro. However, its role in asthma is unclear. In this study, it is found that CLP-deficient (Cotl1-/-) mice challenged with house dust mite (HDM) exhibits exacerbated airway inflammation, macrophage polarization, and type 2 immune responses. CLP deficiency increased prostaglandin D2 (PGD2) in bronchoalveolar lavage (BAL) and alveolar macrophages (AMs), activating the PGD2 receptor chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) on immune cells. Notably, HDM exposure reduced pulmonary CLP levels in wild-type (WT) mice, and overexpression of CLP in Cotl1-/- macrophages decreased HDM-induced PGD2 in BAL and alleviated inflammation. Cotl1-/- AMs exacerbated HDM-induced airway inflammation compared to WT AMs, and this effect is dependent on CRTH2 signaling. These findings reveal that CLP modulates macrophage polarization and suppresses the PGD2-CRTH2 pathway to alleviate airway inflammation, highlighting CLP as a promising therapeutic target for asthma.

OBJECTIVE:This study investigated whether parameter-optimized paired associative stimulation (PAS) could enhance neurological recovery after cerebral ischemia by modulating oxidative stress and inflammation in a rat middle cerebral artery occlusion (MCAO) model. METHODS:Twenty-four Sprague-Dawley rats were randomly divided into Sham, Model, PAS-ISI-10 ms, and PAS-ISI-15 ms groups. The MCAO model was established using the intraluminal filament method. PAS intervention (90 paired pulses/day for 28 days) was initiated 24 h postischemia. Neurological function was assessed using Longa scores, grip strength, and corner tests. Cerebral infarction (TTC staining), neuronal survival (Nissl staining), apoptosis (TUNEL), neuroregeneration markers (GAP43, BDNF, MAP2, and Syn), oxidative stress (GSH-Px and MDA), and inflammatory cytokines (IL-1β, IL-6, and TNF-α) were evaluated. RESULTS:The PAS-ISI-10 ms group demonstrated significantly better neurological recovery than PAS-ISI-15 ms ( P  < 0.05), with reduced infarct volume ( P  < 0.01) and lower apoptosis rates ( P  < 0.01). Neuroregenerative markers showed greater upregulation in the 10 ms group ( P  < 0.05). Oxidative stress markers were significantly improved in PAS groups (GSH-Px increased P  < 0.01; MDA decreased P  < 0.01), with more pronounced effects in the 10ms condition. Proinflammatory cytokines were markedly reduced in both PAS groups ( P  < 0.05), showing stronger suppression in the 10ms group. CONCLUSION:Parameter-optimized PAS with 10-ms ISI promotes neurological recovery after cerebral ischemia through coordinated antioxidant, anti-inflammatory, and neuroregenerative mechanisms. These findings provide evidence for optimizing noninvasive neuromodulation strategies in stroke rehabilitation.

P-glycoprotein (P-gp) is expressed on brain microvessel endothelial cells of blood-brain barrier (BBB) and elevated after cerebral ischemia. In this study, we explored the influence and potential mechanisms of P-gp on BBB function in experimental ischemic stroke in vivo and in vitro. Middle cerebral artery occlusion/reperfusion (MCAO/R) was created in mice. Oxygen-glucose deprivation/reoxygenation (OGD/R) was performed in brain microvascular vessel-derived endothelial cells (bEnd.3) to mimic ischemia/reperfusion injury in vitro. P-gp-specific siRNA and pharmacological inhibitor cyclosporine A were used to inhibit P-gp, whereas pcDNA3.1 was utilized to overexpress P-gp. Twenty-four hours after reperfusion, acute ischemic stroke outcome, BBB integrity and permeability, autophagic proteins and relative signaling pathways were evaluated. P-gp levels were markedly elevated in mouse brain and endothelial cells following MCAO/R and OGD/R, respectively. P-gp siRNA silencing or pharmacologically inhibiting (cyclosporine A) reduced infarct volume and brain edema, attenuated brain pathology, and improved neurological behavior in association with attenuated accumulation of neutrophils and macrophages, reduced expression levels of inflammatory cytokines (TNF-α and IL-1β), matrix metalloproteinases (MMP-2 and MMP-9) and adhesion molecules (ICAM-1 and VCAM-1). P-gp silence also counteracted BBB leakage, restored the expressions of tight junction proteins (Claudin-5, Occludin and ZO-1), activated autophagic proteins (upregulated LC3-II/LC3-I and Beclin 1, and downregulated P62), and diminished Akt/mTOR signal activity in mice following MCAO/R. In the endothelial cell OGD/R assay, P-gp silence downregulated the expressions of inflammatory cytokines and adhesion molecules, inhibited leukocytes adhesion and migration, increased tight junction protein levels, and activated autophagy, all were reversible by forceful P-gp expression. Additionally, treatment with an autophagy inhibitor (3-methyladenine) abolished protections against ischemic stroke and tight junction proteins reduction followed by P-gp silence. In conclusion, increased P-gp expression after ischemic injury resulted in BBB dysfunction and hyperpermeability by suppressing Akt/mTOR-induced endothelial autophagy.

Background:Pyruvate metabolism presents a novel, therapeutically targetable metabolic vulnerability in hepatocellular carcinoma (HCC). In this study, we sought to identify HCC molecular subtypes and develop prognostic signatures based on pyruvate metabolism-related genes (PMRGs) to inform personalized therapeutic approaches. Methods:Transcriptional profiles and clinical data of HCC patients were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Consensus clustering was employed for molecular classification, while a least absolute shrinkage and selection operator (LASSO) Cox regression model was constructed for risk score calculation. The relationship between the risk score and HCC prognosis, immune landscape, gene expression, and drug sensitivity was analyzed. Results:Twenty PMRGs were identified as significantly associated with HCC prognosis. Consensus clustering of these genes revealed two distinct molecular subtypes that stratified patients into groups with favorable and unfavorable outcomes. A novel six-gene signature, comprising ACACA, ACAT1, CYP1, DLAT, LDHA, and ME1, was developed for HCC prognostication. The receiver operating characteristic (ROC) curve demonstrated robust survival prediction in all cohorts, allowing the stratification of patients into high- and low-risk groups with markedly different overall survival (OS). The signature-derived nomogram displayed appreciable clinical net benefit. Enrichment analysis revealed activation of PMRGs and enrichment of diverse metabolic processes and signaling pathways in the high-risk group. Moreover, the prognostic signature showed significant correlations with immune landscapes and therapeutic responses, enabling prediction of immunotherapy responsiveness. Conclusions:Collectively, a unique PMRG-based signature effectively predicts prognosis in HCC patients and provides valuable insights into chemotherapy and immunotherapy strategies for these individuals.

Type 1 diabetes (T1D) is an autoimmune disorder characterized by the destruction of insulin-producing pancreatic β cell. It contributes to high mortality, frequent diabetic complications, poor quality of life in patients and also puts a significant economic burden on health care systems. Therefore, the development of new therapeutic strategies is urgently needed. Recently, certain dietary compounds with potential applications in food industry, particularly polyphenols and polysaccharides, have gained increasing attention with their prominent anti-diabetic effects on T1D by modulating β cell function, the gut microbiota and/or the immune system. In this review, we critically discuss the recent findings of several dietary polyphenols and polysaccharides with the potential to protect against T1D and the underlying anti-diabetic mechanisms. More importantly, we highlight the current trends, major issues, and future directions of industrial production of polyphenols- and polysaccharides-based functional foods for preventing or delaying T1D.

Necrotizing enterocolitis (NEC) is a life-threatening disease in premature infants, characterized by high mortality. Recent studies increasingly highlight the role of gut dysbiosis in NEC pathogenesis. Although probiotics have shown some efficacy in preventing NEC, further research is needed to determine potential strains and approaches. In this study, we demonstrated that the novel probiotic strain Lactobacillus gasseri (L. gasseri) FWJL-4, isolated from the feces of healthy infants, significantly enhanced intestinal barrier function, providing substantial protection against NEC. This protective effect was attributed to elevated intestinal acetate levels. Notably, acetate supplementation alone was sufficient to mitigate NEC, mimicking the protective effects of L. gasseri FWJL-4. Mechanistically, we revealed that L. gasseri FWJL-4 inhibited necroptosis and preserved the number of the goblet cells and enterocytes through the production of the short-chain fatty acid acetate, via activation of the acetate receptors G protein-coupled receptor (GPR) 41 and GPR43. Our findings suggest that L. gasseri FWJL-4 enhances intestinal barrier function to protect against NEC, underscoring the potential of probiotic manipulation as a promising strategy for NEC prevention.

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Autophagy plays a crucial role in cancer cell survival by facilitating the elimination of detrimental cellular components and the recycling of nutrients. Understanding the molecular regulation of autophagy is critical for developing interventional approaches for cancer therapy. In this study, we report that migfilin, a focal adhesion protein, plays a novel role in promoting autophagy by increasing autophagosome–lysosome fusion. We found that migfilin is associated with SNAP29 and Vamp8, thereby facilitating Stx17-SNAP29-Vamp8 SNARE complex assembly. Depletion of migfilin disrupted the formation of the SNAP29-mediated SNARE complex, which consequently blocked the autophagosome-lysosome fusion, ultimately suppressing cancer cell growth. Restoration of the SNARE complex formation rescued migfilin-deficiency–induced autophagic flux defects. Finally, we found depletion of migfilin inhibited cancer cell proliferation. SNARE complex reassembly successfully reversed migfilin-deficiency–induced inhibition of cancer cell growth. Taken together, our study uncovers a new function of migfilin as an autophagy-regulatory protein and suggests that targeting the migfilin–SNARE assembly could provide a promising therapeutic approach to alleviate cancer progression.

Cisplatin-induced renal tubular injury largely restricts the wide-spread usage of cisplatin in the treatment of malignancies. Identifying the key signaling pathways that regulate cisplatin-induced renal tubular injury is thus clinically important. PARVB, a focal adhesion protein, plays a crucial role in tumorigenesis. However, the function of PARVB in kidney disease is largely unknown. To investigate whether and how PARVB contributes to cisplatin-induced renal tubular injury, a mouse model (PARVB cKO) was generated in which PARVB gene was specifically deleted from proximal tubular epithelial cells using the Cre-LoxP system. In this study, we found depletion of PARVB in proximal tubular epithelial cells significantly attenuates cisplatin-induced renal tubular injury, including tubular cell death and inflammation. Mechanistically, PARVB associates with transforming growth factor-β-activated kinase 1 (TAK1), a central regulator of cell survival and inflammation that is critically involved in mediating cisplatin-induced renal tubular injury. Depletion of PARVB promotes cisplatin-induced TAK1 degradation, inhibits TAK1 downstream signaling, and ultimately alleviates cisplatin-induced tubular cell damage. Restoration of PARVB or TAK1 in PARVB-deficient cells aggravates cisplatin-induced tubular cell injury. Finally, we demonstrated that PARVB regulates TAK1 protein expression through an E3 ligase ITCH-dependent pathway. PARVB prevents ITCH association with TAK1 to block its ubiquitination. Our study reveals that PARVB deficiency protects against cisplatin-induced tubular injury through regulation of TAK1 signaling and indicates targeting this pathway may provide a novel therapeutic strategy to alleviate cisplatin-induced kidney damage.