Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with an extremely low survival rate. New and effective approaches for treatment are therefore urgently needed. Here, we successfully developed M1-like macrophage-derived extracellular vesicles (M1EVs) that overcome multiple challenges via guidance from two macrophage-related observations in clinical specimens from GBM patients: enrichment of M2 macrophages in GBM; and origination of a majority of infiltrating macrophage from peripheral blood. To maximize the synergistic effect, we further functionalized the membranes of M1EVs with two hydrophobic agents (the chemical excitation source CPPO (C) and the photosensitizer Ce6 (C)) and loaded the hydrophilic hypoxia-activated prodrug AQ4N (A) into the inner core of the M1EVs. After intravenous injection, the inherent nature of M1-derived extracellular vesicles CCA-M1EVs allowed for blood-brain barrier penetration, and modulated the immunosuppressive tumor microenvironment via M2-to-M1 polarization, which increased hydrogen peroxide (H2O2) levels. Furthermore, the reaction between H2O2 and CPPO produced chemical energy, which could be used for Ce6 activation to generate large amounts of reactive oxygen species to achieve chemiexcited photodynamic therapy (CDT). As this reaction consumed oxygen, the aggravation of tumor hypoxia also led to the conversion of non-toxic AQ4N into toxic AQ4 for chemotherapy. Therefore, CCA-M1EVs achieved synergistic immunomodulation, CDT, and hypoxia-activated chemotherapy in GBM to exert a potent therapeutic effect. Finally, we demonstrated the excellent effect of CCA-M1EVs against GBM in cell-derived xenograft and patient-derived xenograft models, underscoring the strong potential of our highly flexible M1EVs system to support multi-modal therapies for difficult-to-treat GBM.
Microwave resonance sensors integrated in an ultra-compact planar circuit enable real-time and label-free biosensing, offering significant potential for in vitro diagnostics and home healthcare. However, the detection of weak biological signals at low concentrations has fundamental limitations due to the large disparity between the microwave wavelength and the molecular scale of biomolecules. Here, we realize an electromagnetic (EM) skyrmion mode in a microwave plasmonic resonator with an electrical size of 1/50 wavelength. The combination of strong EM field confinement and a high quality factor of 185 yields markedly enhanced wave-matter interactions, resulting in a 105-fold sensitivity improvement over the traditional microstrip ring resonator operating at the same frequency. The sensing capability is experimentally validated through the detection of diabetic nephropathy (DN), with a reporting limit for DN-associated proteins down to 12.5 pmol in amount of substance and 125 nmol/L in concentration at an operating wavelength of 0.33m. These findings constitute a major advance in microwave resonance sensing, dramatically advancing its detection limits and paving the way for rapid and early diagnostic platforms in integrated systems.
OBJECTIVES:Exclusive enteral nutrition (EEN) is a well-established therapy for inducing remission in luminal Crohn's disease (CD), but its role in biologic-refractory patients remains unclear. This study aimed to evaluate the efficacy of EEN in biologic-refractory CD in adults and identify factors influencing treatment outcomes. METHODS:A single-center retrospective study was conducted on adult CD patients who received EEN between January 2021 and December 2024. Patients with active disease despite prior biologic therapy were included, along with a biologic-naïve subgroup for comparison. Clinical and laboratory data were analyzed, and remission rates were compared, stratified by the number of failed biologics. Logistic regression identified predictors of EEN efficacy. RESULTS:Among 224 patients, 94 were biologics-refractory, and 130 were biologics-naïve. Clinical remission at week 6 was achieved in 63.8% of biologic-refractory versus 73.8% of biologic-naïve patients (P = 0.11). Remission rates in patients failing one or two biologics were similar to biologic-naïve patients, but were significantly lower in those failing more than three biologics (P < 0.01). Multivariate analysis identified gastrointestinal bleeding (OR = 0.08; 95% [CI] = [0.03-1.20], P = 0.03) and failure of more than three biologics (OR = 0.11; 95% [CI] = [0.02-0.50], P < 0.01) as independent risk factors for nonremission. CONCLUSIONS:EEN is an effective salvage therapy for biologic-refractory CD in adults, but its efficacy diminishes with increased biologic failures. Additionally, active CD with gastrointestinal bleeding is associated with a lower likelihood of achieving clinical remission.
Objectives Chronic kidney disease (CKD) is a global public health concern, characterized by a gradual decline in kidney function, with death of renal tubular epithelial cells (RTECs) as a key pathological mechanism. This study investigated the protective effect of ligustroflavone in CKD and its potential molecular mechanisms.Methods In vivo, the unilateral ureteral obstruction (UUO) and folic acid-induced nephropathy (FAN) mouse models were employed to assess the effects of ligustroflavone. In vitro, RTECs were treated with erastin. Western blotting, qRT-PCR, immunofluorescence (IF), and immunohistochemistry (IHC) were performed to detect renal tubular injury both in vivo and in vitro.Results In vivo, ligustroflavone treatment significantly improved renal tubular damage and interstitial fibrosis in mice. Furthermore, our results demonstrated that ligustroflavone alleviated ferroptosis of RTECs by inhibiting GSK3β activity and reducing lipid peroxidation in mice. In vitro, ligustroflavone treatment inhibited erastin-induced ferroptosis in RTECs. In addition, ligustroflavone inhibited activation of myofibroblasts induced by ferroptosis of RTECs. Mechanistically, ligustroflavone exerted it’s protect effects through the GSK3β/NRF2 pathway by inhibiting GSK3β and activating NRF2, thereby promoting GPX4 expression and suppressing ferroptosis.Conclusions In summary, ligustroflavone inhibits ferroptosis in RTECs and confers protection in CKD. These findings suggest that ligustroflavone holds promise as a potential therapeutic agent for CKD.
Background Therapeutic hypothermia (TH) is an important treatment after cardiac arrest to mitigate cerebral ischemia-reperfusion (I/R) injury, but its underlying mechanism remains unclear. Studies have shown that cold-inducible RNA binding protein (CIRP), as a stress-response protein, plays a key role in improving neurological outcomes following TH treatment in cases of global ischemia. Objective This in vitro study aimed to investigate the role of CIRP in primary hippocampal neuronal injury induced by oxygen-glucose deprivation/reoxygenation (OGD/R) and to explore the underlying mechanisms. Materials and Methods Primary hippocampal neurons were cultured and an OGD/R model was established. After OGD/R injury, neurons were resuscitated in normal or hypothemia (32 °C) condition for 6 h. Adenovirus transfection were used to regulate the expression of CIRP. The ultrastructure of neurons was visualized by transmission electron microscope (TEM). Flow cytometry were use to detect OGD-induced neuronal apoptosis. Reverse transcription polymerase chain reaction (RT-PCR) and western blot were used to detect the expression of CIRP mRNA and protein levels. Meanwhile, the enzyme-linked immunosorbent assay (ELISA) was used to evaluate the levels of malondialdehyde (MDA), superoxide dismutase (SOD) and gutathione (GSH). Results Hypothermia treatment could induce CIRP over-expression in neurons and reverse the down-regulation of CIRP induced by OGD/R. In addition, over-expression of CIRP could reduce the release of reactive oxygen species (ROS) induced by OGD/R through reducing MDA levels and increasing the level of SOD and GSH, and alleviated OGD/R-induced neuronal apoptosis by down regulating Caspase-3 and cleaved Caspase-3 expression and up regulating Bcl-2 expression. Furthermore, CIRP silencing enhanced neuronal OGD/R-induced apoptosis and oxidative stress. Meanwhile, as expected, neurons were seriously damaged and mitochondrial membrane ruptured after OGD/R injury, which were attenuated by CIRP over-expression or TH. Conclusions Our results showed that CIRP at least partially resisted OGD/R-induced neuronal injury by exhibiting anti-apoptotic and anti-oxidative properties. To sum up, targeting CIRP may represent potential therapeutic implications in the treatment of brain I/R injury.
