Xinjiang Medical University

Neuroexcitotoxicity mediated by NMDA receptor is a central contributor to ischemic stroke pathology. Neuroprotective effect and mechanism of the new compound GW201, which targets NMDA receptor, were studied. We evaluated the neuroprotective effects of GW201 using in vivo and in vitro models of ischemic stroke, including the middle cerebral artery occlusion/reperfusion (MCAOi/r) model, permanent MCAO (pMCAO) model and primary neuronal oxygen-glucose deprivation (OGD) model. Pharmacodynamic studies examined the dose-response relationship and therapeutic time window of GW201 neuroprotective effects. Electrophysiological membrane clamp experiments assessed the NMDA receptor subunit selectivity of GW201 and its influence on neuronal currents under ischemia-mimicking conditions. The mechanism of its action was further analysed using molecular docking technology. Live-cell fluorescence imaging was employed to evaluate the impact of GW201 on intracellular calcium levels in simulated ischemic stroke. Furthermore, bioinformatics analysis of the GEO database identified 16 significant calcium-related genes, with their regulation by GW201 validated in the MCAOi/r model. Across all models tested, GW201 exhibited marked neuroprotective effects. Membrane clamp studies identified GW201 as an allosteric modulator of the NMDA receptor GluN2A subunit reducing current amplitude under high glutamate/NMDA + glycine conditions and subsequently lowering intracellular calcium levels. Bioinformatics analysis revealed 16 calcium-related genes, with GW201 significantly modulating Ccl3, Stat3, Anxa1, Anxa2, Mgp, S100A8, S100A9 and Cacna1a. These results suggest that the neuroprotective effects of GW201 are mediated by its ability to allosterically modulate NMDA receptor activity, reducing calcium overload, influence downstream gene expression and suppress inflammatory responses.

To investigate the triglyceride-glucose index (TyG) as a predictor of glycaemic variability phenotypes in patients with type 2 diabetes mellitus (T2DM) using continuous glucose monitoring (CGM)-derived metrics, guiding personalized management. This cross-sectional study analysed 279 T2DM patients who underwent 14-day CGM monitering from community hospitals in Ningbo, China. Participants were stratified by TyG tertiles. Spectral clustering with complexity-invariant dynamic time warping identified distinct glycaemic variability glucotypes. Comprehensive CGM metrics spanning time-domain, frequency-domain, event-based, and circadian rhythm domains were evaluated. Multivariable logistic regression assessed associations between TyG and glycaemic phenotypes. Across TyG tertiles, we observed progressive increases in HbA1c (6.8 ± 1.5%, 7.2 ± 1.2%, 7.3 ± 1.3%, p = 0.011), fasting glucose (6.1 ± 1.1, 7.2 ± 1.6, 8.5 ± 2.8 mmol/L, p < 0.001), and triglycerides (0.9 ± 0.2, 1.4 ± 0.4, 2.7 ± 1.0 mmol/L, p < 0.001). Most notably, patients in the highest TyG tertile exhibited sustained hyperglycaemia with lower TIR (81.8% to 72.8 to 70.3%, p = 0.001), elevated TAR (15.9% vs. 29.1%, p < 0.001), and paradoxically reduced TBR (2.3% to 1.4% to 0.6%, p = 0.014) and CV (26.2% to 25.8% to 23.8%, p = 0.021). Frequency domain analysis demonstrated that elevated TyG was associated with high-level, low-frequency glucose oscillations. Higher TyG tertiles demonstrated increased prevalence of severe variability glucotype (32.3% to 53.8% to 63.4%), with TyG emerging as the strongest independent predictor (OR = 1.87, 95% CI: 1.42-2.50, p < 0.001). Elevated TyG identifies a distinct glycaemic phenotype characterized by high-level, low-frequency oscillations, sustained hyperglycaemia, and minimal hypoglycaemic risk. T2DM patients with high TyG levels may be appropriate candidates for more intensified glucose-lowering strategies.

Exosomes serve as intercellular communication vectors and are involved in a broad range of physiological functions. Although exosome-based therapies have demonstrated diverse functional potential, the regulatory mechanisms underlying their biogenesis and secretion remain poorly understood. Here, we report that TEAD1 functions as a molecular switch, dramatically enhancing the synthesis and secretion of exosomes. Mechanistically, TEAD1 enhances exosome secretion by promoting the expression of exosome secretion-associated proteins RAB11, CD9, and SNAP23. We found that TEAD1 enhances exosome secretion from adipose-derived mesenchymal stem cells, thereby promoting skin wound healing in diabetic mice. Similarly, TEAD1 promotes the release of exosomes from bone marrow-derived mesenchymal stem cells, thereby facilitating spinal cord injury (SCI) repair. Our study elucidates a novel role for TEAD1 in driving exosome secretion in different cell types, highlighting the therapeutic potential of TEAD1 in enhancing tissue regeneration, particularly in diabetic wound healing and SCI repair.

Hydrogen sulfide (H2S), known as a metabolic modulator, is a gaseous signaling molecule with functions similar to those of nitric oxide and carbon monoxide, all of which possess vasodilatory, antioxidant, and other properties. In the central nervous system, H2S is a signaling molecule that is crucial for neuroprotection and the control of neurological processes. The paraventricular nucleus (PVN) of the hypothalamus is an important central nucleus that regulates and integrates cardiovascular and peripheral sympathetic activity. This study aimed to investigate whether intra-PVN injection of the endogenous H2S synthase CBS activator S-adenosylmethionine (SAMe) or the endogenous H2S synthase CBS inhibitor hydroxylamine (HA) modulates H2S expression in the PVN, whether microglia in the PVN are targeted by H2S, and whether PVN H2S further induces alterations in blood pressure(BP) by affecting endoplasmic reticulum(ER) stress in the PVN of spontaneously hypertensive rats (SHR). Healthy male Wistar-Kyoto (WKY) rats and SHR were fed a normal diet for 8weeks, followed by intra-PVN injections of SAMe, HA, or vehicle for 4weeks. Plasma norepinephrine levels and mean arterial pressure were elevated in the SHR group. The expression of factors related to ER stress, such as p-PERK, GRP78, and p-IRE1α, was also elevated. Levels of these parameters were lower in the SHR+SAMe group, whereas the SHR + HA group presented with higher levels of these indicators. These findings suggest that endogenous H2S attenuates sympathetic activity and hypertensive responses in the PVN, in part by modulating ER stress.

High-grade meningiomas remain clinically challenging due to their aggressive behavior and limited therapeutic options. Although mutations and dysregulation of KMT2 family members have been implicated in various cancers, their functional significance in meningioma remains unclear. While NF2 alterations are the most common drivers of meningioma pathogenesis, the mechanisms regulating NF2 transcription in NF2-intact tumors are poorly understood. Here, we demonstrate that KMT2C expression is markedly reduced in high-grade meningiomas and that loss of KMT2C promotes proliferation and invasion in NF2-wild-type meningioma cells. Mechanistically, KMT2C deficiency suppresses NF2 transcription and inactivates Hippo signaling, leading to enhanced oncogenic activity and increased sensitivity to ferroptosis. Loss of KMT2C impairs the acetyltransferase activity of CBP/EP300, resulting in a global reduction of H3K27ac and transcriptional silencing of NF2. Pharmacological restoration of histone acetylation with the HDAC inhibitor Trichostatin A (TSA) effectively suppressed tumor growth. Collectively, our findings identify KMT2C as a key epigenetic regulator linking promoter histone acetylation, NF2-Hippo pathway activity, and ferroptosis susceptibility. These results provide mechanistic insights into high-grade meningioma progression and highlight ferroptosis induction and epigenetic modulation as promising therapeutic strategies for NF2-wild-type, KMT2C-deficient meningiomas.