VISTA antibody-loaded Fe3O4@TiO2 nanoparticles for sonodynamic therapy-synergistic immune checkpoint therapy of pancreatic cancer.

Breaking the poor permeability of immune checkpoint inhibitors (ICIs) caused by the stromal barrier and reversing the immunosuppressive microenvironment are significant challenges in pancreatic cancer immunotherapy. In this study, we synthesized core-shell Fe3O4@TiO2 nanoparticles to act as carriers for loading VISTA monoclonal antibodies to form Fe3O4@TiO2@VISTAmAb (FTV). The nanoparticles are designed to target the overexpressed ICIs VISTA in pancreatic cancer, aiming to improve magnetic resonance imaging-guided sonodynamic therapy (SDT)-facilitated immunotherapy. Laser confocal microscopy and flow cytometry results demonstrate that FTV nanoparticles are specifically recognized and phagocytosed by Panc-2 cells. In vivo experiments reveal that ultrasound-triggered TiO2 SDT can induce tumor immunogenic cell death (ICD) and recruit T-cell infiltration within the tumor microenvironment by releasing damage-associated molecular patterns (DAMPs). Furthermore, ultrasound loosens the dense fibrous stroma surrounding the pancreatic tumor and increases vascular density, facilitating immune therapeutic efficiency. In summary, our study demonstrates that FTV nanoparticles hold great promise for synergistic SDT and immunotherapy in pancreatic cancer.

Cancer-associated fibroblasts reprogram cysteine metabolism to increase tumor resistance to ferroptosis in pancreatic cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) is an insidious, rapidly progressing malignancy of the gastrointestinal tract. Due to its dense fibrous stroma and complex tumor microenvironment, neither of which is sensitive to radiotherapy, pancreatic adenocarcinoma is one of the malignancies with the poorest prognosis. Therefore, detailed elucidation of the inhibitory microenvironment of PDAC is essential for the development of novel therapeutic strategies. Methods: We analyzed the association between cancer-associated fibroblasts (CAFs) and resistance to ferroptosis in PDAC using conditioned CAF medium and co-culture of pancreatic cancer cells. Abnormal cysteine metabolism was observed in CAFs using non-targeted metabolomics analysis with liquid chromatography-tandem mass spectrometry (LC-MS/MS). The regulatory effects of cysteine were investigated in PDAC cells through measurement of cell cloning, cell death, cell function, and EdU assays. The effects of exogenous cysteine intake were examined in a mouse xenograft model and the effects of the cysteine pathway on ferroptosis in PDAC were investigated by western blotting, measurement of glutathione and reactive oxygen species levels, among others. Results: It was found that CAFs played a critical role in PDAC metabolism by secreting cysteine, which could increase tumor resistance to ferroptosis. A previously unrecognized function of the sulfur transfer pathway in CAFs was identified, which increased the extracellular supply of cysteine to support glutathione synthesis and thus inducing ferroptosis resistance. Cysteine secretion by CAFs was found to be mediated by the TGF-ß/SMAD3/ATF4 signaling axis. Conclusion: Taken together, the findings demonstrate a novel metabolic relationship between CAFs and cancer cells, in which cysteine generated by CAFs acts as a substrate in the prevention of oxidative damage in PDAC and thus suggests new therapeutic targets for PDAC.

MMP-9 inhibition alleviates postoperative cognitive dysfunction by improving glymphatic function via regulating AQP4 polarity.

Postoperative cognitive dysfunction (POCD) is a common complication after surgery, characterized by deficits in memory, attention and cognitive flexibility. However, the underlying mechanisms of POCD remain unclear. Neuroinflammation and blood-brain barrier disruption have been implicated as potential pathological processes. This study explores the neuroprotective effects and mechanisms of the matrix metalloproteinase（MMP-9）inhibitor GM6001 against POCD. We hypothesize GM6001 may reduce neuroinflammation and preserve blood-brain barrier integrity through direct inhibition of MMP-9. Moreover, GM6001 may stabilize aquaporin-4 polarity and glymphatic clearance function by modulating MMP-9-mediated cleavage of dystroglycan, a key protein for aquaporin-4 anchoring. Our results demonstrate GM6001 alleviates postoperative cognitive deficits and neuroinflammation. GM6001 also preserves blood-brain barrier integrity and rescues aquaporin-4 mislocalization after surgery. This study reveals a novel dual role for MMP-9 inhibition in cognitive protection through direct anti-neuroinflammatory effects and regulating aquaporin-4 membrane distribution. Targeting MMP-9 may represent a promising strategy to prevent postoperative cognitive dysfunction by integrating multiple protective mechanisms.

AQP4 is an Emerging Regulator of Pathological Pain: A Narrative Review.

Pathological pain presents significant challenges in clinical practice and research. Aquaporin-4 (AQP4), which is primarily found in astrocytes, is being considered as a prospective modulator of pathological pain. This review examines the association between AQP4 and pain-related diseases, including cancer pain, neuropathic pain, and inflammatory pain. In cancer pain, upregulated AQP4 expression in tumor cells is linked to increased pain severity, potentially through tumor-induced inflammation and edema. Targeting AQP4 may offer therapeutic strategies for managing cancer pain. AQP4 has also been found to play a role in nerve damage. Changes in AQP4 expression have been detected in pain-related regions of the brain and spinal cord; thus, modulating AQP4 expression or function may provide new avenues for treating neuropathic pain. Of note, AQP4-deficient mice exhibit reduced chronic pain responses, suggesting potential involvement of AQP4 in chronic pain modulation, and AQP4 is involved in pain modulation during inflammation, so understanding AQP4-mediated pain modulation may lead to novel anti-inflammatory and analgesic therapies. Recent advancements in magnetic resonance imaging (MRI) techniques enable assessment of AQP4 expression and localization, contributing to our understanding of its involvement in brain edema and clearance pathways related to pathological pain. Furthermore, targeting AQP4 through gene therapies and small-molecule modulators shows promise as a potential therapeutic intervention. Future research should focus on utilizing advanced MRI techniques to observe glymphatic system changes and the exchange of cerebrospinal fluid and interstitial fluid. Additionally, investigating the regulation of AQP4 by non-coding RNAs and exploring novel small-molecule medicines are important directions for future research. This review shed light on AQP4-based innovative therapeutic strategies for the treatment of pathological pain. Dark blue cells represent astrocytes, green cells represent microglia, and red ones represent brain microvasculature.

Electroacupuncture modulates gut microbiota in mice: A potential target in postoperative cognitive dysfunction.

The detailed mechanism of inflammation in postoperative cognitive dysfunction (POCD) is unclear. This study aimed to determine whether electroacupuncture (EA) ameliorates POCD by modulating gut microbial dysbiosis. Compared to the control group, mice in the EA group were treated at the acupoints Zusanli (ST36), Quchi (L111), Baihui (GV20), and Dazhui (GV14) 1 week before appendectomy. Novel object recognition and the Morris water maze tests were used to assess learning and spatial reference memory deficits, whereas hippocampus samples and stool samples were collected for central inflammatory tests and 16S-rRNA sequencing of intestinal flora, respectively. In amyloid precursor protein/presenilin 1 (APP/PS1) mice, EA enhanced spatial memory and learning deficits. The fecal microbial community was altered in APP/PS1 mice in the absence of EA following surgery. Among them, Coprococcus and Bacteroidetes were more abundant in the EA groups than in the control groups; however, Actinobacteriota, Helicobacteraceae, and Escherichia/shigella constitute the minor bacterial colonization in the EA groups. Furthermore, we found a significant negative correlation between Firmicutes and escape latency (Pearson correlation coefficient - 0.551, p < 0.01) and positive correlation between Proteobacteria and escape latency (Pearson correlation coefficient 0.462, p < 0.05). Electron microscopy revealed signs of blood-brain barrier (BBB) impairments and immunofluorescence images showed glial cells activated in the hippocampus of APP/PS mice without EA, and serum diamine oxidase levels were increased in these mice; whereas EA treatment significantly relieved the above pathological changes. Our findings implied that EA decreases hippocampal inflammation of APP/PS1 by upregulating benificial  gut microbiota, reducing BBB and intestinal barrier dysfunction, thus alleviates postoperative cognitive dysfunction. This may provide a novel target in POCD management.

Biophilic virtual reality on children's anxiety and pain during circumcision: A randomized controlled study.

INTRODUCTION: The aim of this study was to evaluate the effects of the biophilic virtual reality (BVR) method on children's pain and anxiety undergoing circumcision. MATERIALS AND METHODS: This randomized controlled study used a parallel trial design guided by the CONSORT checklist. A total of 106 children were included in the analysis. Intraoperative anxiety was assessed by using the simplified Chinese version of the modified Yale Preoperative Anxiety Scale (CmYPAS), Visual Analogue Scale (VAS), heart rate (HR), and Anxiety index (Ai). Intraoperative pain was assessed by using the Faces Pain Scale-Revised (FPS-R), and Pain index (Pi). The Pearson correlation analysis was used to analyze the relationship between Ai and the CmYPAS. The primary outcomes were CmYPAS, VAS, and FPS-R, which were analyzed using the Kruskal-Wallis test. RESULTS: Baseline variables were not significantly different between the BVR group (34 patients), the indoor virtual reality (IVR) group (36 patients), and the blank control group (36 patients). The CmYPAS scores during surgery were significantly lower in the BVR group and the IVR group versus the blank control group (25.0[22.9-29.2], 22.9[22.9-29.2], 33.3[33.3-38.5] respectively; P < 0.001). The VAS scores during surgery were significantly lower in the BVR group and the IVR group versus the blank control group (5.0[3.0-7.0], 3.0[2.0-5.0], 6.0[5.0-8.8] respectively; P < 0.001). The FPS-R scores during surgery were significantly lower in the BVR group and IVR group versus the blank control group (2.0[1.8-4.2], 3.0[2.0-4.8], 5.5[5.0-8.0], respectively; P < 0.001). At removal of the foreskin, Pi were significantly lower in the BVR group and IVR group versus the blank control group (6.9[4.1], 7.7[3.3], 9.8[6.2] respectively; P = 0.033). The Ai scores at each time point were significantly lower in the BVR group and IVR group versus the control (P = 0.015, P = 0.006 respectively). The correlation analysis of Ai (at removal of the foreskin) and CmYPAS scores in children showed that the Pearson correlation coefficient was 0.194 (P = 0.046). DISCUSSION: This is the first RCT to investigate the effects of BVR in children undergoing circumcision. This study demonstrates a reduction in pediatric intraoperative pain and anxiety with the use of virtual reality (VR). CONCLUSION: Intraoperative VR may be an effective noninvasive modality for reducing pain and anxiety during circumcision. Pi and Ai might be used to assess subjective pain and anxiety in patients.

Two central circadian oscillators OsPRR59 and OsPRR95 modulate magnesium homeostasis and carbon fixation in rice.

Photosynthesis, which provides oxygen and energy for all living organisms, is circadian regulated. Photosynthesis-associated metabolism must tightly coordinate with the circadian clock to maximize the efficiency of the light-energy capture and carbon fixation. However, the molecular basis for the interplay of photosynthesis and the circadian clock is not fully understood, particularly in crop plants. Here, we report two central oscillator genes of circadian clock, OsPRR95 and OsPRR59 in rice, which function as transcriptional repressors to negatively regulate the rhythmic expression of OsMGT3 encoding a chloroplast-localized Mg2+ transporter. OsMGT3-dependent rhythmic Mg fluctuations modulate carbon fixation and consequent sugar output in rice chloroplasts. Furthermore, sugar triggers the increase of superoxide, which may act as a feedback signal to positively regulate the expression of OsPRR95 and OsPRR59. Taken together, our results reveal a negative-feedback loop that strengthens the crosstalk between photosynthetic carbon fixation and the circadian clock, which may improve plan adaptation and performance in fluctuating environments.

Carbon-nitrogen trading in symbiotic nodules depends on magnesium import.

Symbiotic nitrogen fixation provides large amounts of nitrogen for global agricultural systems with little environmental or economic costs. The basis of symbiosis is the nutrient exchange occurring between legumes and rhizobia, but key regulators controlling nutrient exchange are largely unknown. Here, we reveal that magnesium (Mg), an important nutrient factor that preferentially accumulates in inner cortical cells of soybean nodules, shows the most positive correlation with nodule carbon (C) import and nitrogen (N) export. We further identified a pair of Mg transporter genes, GmMGT4 and GmMGT5, that are specifically expressed in the nodule cortex, modulating both nodule Mg import and C-N transport processes. The GmMGT4&5-dependent Mg import activates the activity of a plasmodesmata-located ß-1,3-glucanase GmBG2 and consequently keeps plasmodesmata permeable for C-N transport in nodule inner cortical cells. Our studies discovered an important regulating pathway for host plants fine-tuning nodule C-N trading to achieve optimal growth, which may be helpful for optimizing nutrient management for soybean production.