Luyang Tao

Objectives: This study aims to investigate the characteristics of event-related potentials (ERP) in patients with traumatic subarachnoid hemorrhage (tSAH) during the clinical stable phase, with the aim of obtaining neuroelectrophysiological indicators that can objectively assess cognitive dysfunction caused by this injury. Methods: A total of 16 healthy volunteers and 33 tSAH patients in the stable phase were recruited. Demographic and clinical data were collected, MMSE assessments were completed, and EEG data for P300, mismatch negativity (MMN), and contingent negative variation (CNV) were recorded using a 32-lead ERP system. ERP analysis was performed by comparing the tSAH group with the healthy control (HC) group and by further dividing the tSAH group into a cognitive impairment subgroup (CI, n = 18) and a normal cognition subgroup (NC, n = 15) based on MMSE scores, with a focus on the mean amplitude and peak latency within specific time windows and their correlation with cognitive behavioral measures. Results: The results showed no significant differences in demographic characteristics between the two groups, while the MMSE scores of the tSAH group were significantly lower than those of the HC group. Compared with HC, the mean amplitude of P300 in response to the target stimuli was significantly reduced in multiple brain regions in the tSAH group and attenuated the negativity of mean CNV amplitudes across multiple brain regions, while no significant differences in mean MMN amplitudes were detected across electrodes and no significant differences were observed in peak latencies of P300 and MMN. The CI group was slightly older than the NC group; after controlling for the effect of age, the Mini-Mental State Examination (MMSE) scores of the CI group were significantly lower than those of the NC group, but no significant differences were found between the two groups in mean amplitudes and peak latencies of P300 and MMN or in mean CNV amplitudes. Conclusions: This study indicates that tSAH may be one of the relevant risk factors for post-traumatic cognitive dysfunction. ERP findings suggest that the allocation of relevant cognitive resources is attenuated in this population, but no differences were detected in the temporal sequence of neural processing. No significant abnormalities were observed during auditory deviance detection corresponding to the MMN time window, and no significant differences in ERP characteristics were found among the subgroups. This study found that tSAH can cause selective cognitive electrophysiological impairment, but ERP electrophysiological changes do not fully match cognitive impairment classified based on clinical scales.

Interleukin-33 (IL-33), an alarmin cytokine of the IL-1 family, has emerged as a pivotal regulator of neuroimmune interactions in the central nervous system (CNS). Acting through its receptor ST2, IL-33 orchestrates diverse immune responses by modulating microglial polarization, shaping T cell differentiation, activating type 2 innate lymphoid cells (ILC2s), and engaging mast cell-macrophage regulatory circuits. Across distinct neurological disorders, including epilepsy, stroke, traumatic brain injury (TBI), Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), cerebral malaria, and glioma, IL-33 exerts both protective and pathogenic effects in a context-dependent manner. In epilepsy, IL-33 modulates neuroinflammation and neuronal excitability; in stroke, it attenuates acute neurovascular injury while influencing post-stroke remodeling; in AD, it enhances amyloid-β clearance and mitigates chronic neuroinflammation; in MS, it regulates autoimmune demyelination via T cell and innate immune pathways. These shared yet disease-specific mechanisms underscore IL-33's central role in neuroimmune homeostasis and its potential as a precision therapeutic target. Future research integrating multi-disease models, temporal disease staging, and single-cell multi-omics will be essential to define the conditions under which IL-33 modulation yields maximal therapeutic benefit.

Morphine addiction is driven in part by persistent reward-associated memory, yet the molecular mechanisms linking translational control to cellular stress responses remain unclear. In the present study, using a mouse morphine-induced conditioned place preference and N2a cell model, we investigated apoptosis-related alterations in the medial prefrontal cortex and the involvement of eIF4E-dependent translational regulation and BDNF/TrkB signaling. Morphine-induced conditioned place preference was associated with an increase in TUNEL-positive cells in the medial prefrontal cortex, accompanied by upregulation of Bax and downregulation of Bcl-2. In N2a cells, morphine induced apoptosis in a dose-dependent manner. Morphine also increased neuronal eIF4E expression in both mPFC tissue and N2a cells, accompanied by upregulation of BDNF and TrkB. Inhibition of the eIF4E/eIF4G interaction with 4EGI-1 significantly affected morphine-induced CPP formation and altered apoptosis-related markers and BDNF/TrkB expression. Notably, intra-mPFC administration of 4EGI-1 suppressed morphine-induced CPP without affecting anxiety-like behavior, locomotor activity, or general learning and memory performance. These findings suggest that eIF4E-dependent translational regulation is functionally associated with morphine-induced reward memory and apoptosis, potentially in association with changes in BDNF/TrkB molecular expression. This study offers novel insight into the molecular basis of morphine addiction and highlights a potentially targetable translational regulatory pathway for therapeutic intervention.

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental condition characterized by impaired social communication and repetitive behaviors. The triggers and mechanisms underlying ASD are complex, including inflammatory-immune microenvironment, lipid metabolic disturbances, impaired synaptic remodeling, and neuronal apoptosis. As a critical regulator of the neuroimmune milieu, interleukin-33 (IL-33) has been found to be significantly changed in the serum of individuals with ASD and in BTBR mice, suggesting a potential role in disease onset and progression; however, the underlying mechanisms remain largely undefined. In this study, we demonstrate that exogenous IL-33 exerts multifaceted neuroprotective effects, including suppressing neuroinflammatory responses, enhancing lipid metabolic reprogramming, promoting synaptic remodeling, reducing neuronal apoptosis, and subsequent improvement in social deficits and repetitive stereotyped behaviors. Integrative spatial metabolomics and transcriptomics analyses further reveal that IL-33 treatment reverses the expression levels of the differentially expressed genes (i.e., T-bet and ALOX15 ). Mechanistically, IL-33 administration significantly downregulates multiple factors associated with the inflammatory–immune microenvironment (e.g., T-bet, RUNX1, RORγt, IL-17, TGF-β, SMADs, FOXP3, and GATA3), while simultaneously modulating lipid metabolism-related regulators, such as ALOX15 and PPARβ. Notably, adeno-associated virus (AAV)-mediated knockdown of T-bet attenuates the anti-inflammatory and neuroprotective effects of IL-33. Furthermore, pharmacological inhibition of ALOX15 using ML351 abolishes IL-33-induced enhancement of complement-mediated synaptic pruning. Collectively, these findings identify a previously unrecognized IL-33/T-bet/ALOX15 signaling axis that coordinates neuroimmune regulation and lipid metabolic reprogramming to facilitate synaptic remodeling. This pathway ultimately contributes to the alleviation of core behavioral deficits in BTBR mice. Our study not only provides novel mechanistic insights into ASD pathophysiology but also highlights the IL-33/T-bet/ALOX15 axis as a promising therapeutic target for intervention.

Ferroptosis is a form of regulated cell death driven by iron-dependent lipid peroxidation, which plays a pivotal role in regulating the inflammatory-immune microenvironment of central nervous system (CNS) diseases. Mounting evidence indicates that dysregulated iron metabolism and an imbalance in antioxidant defenses can induce ferroptosis in neurons and glial cells while simultaneously remodeling immune cell function, thereby establishing a bidirectional feedback loop that amplifies neuroinflammation and tissue damage. In neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), pro-inflammatory cytokines such as TNF-α and IL-1β released by activated microglia upregulate neuronal iron transporters (e.g., DMT1 and TfR1), promoting iron accumulation and ferroptotic cell death. In turn, damage-associated molecular patterns released from ferroptotic cells further potentiate immune activation, forming a self-amplifying cycle. In contrast, within the glioma microenvironment, CD8 ⁺ T cell-derived IFN-γ suppresses SLC7A11 expression in tumor cells, leading to glutathione depletion and glutathione peroxidase 4 inactivation, thereby triggering ferroptosis and modulating anti-tumor immunity. Although targeting ferroptosis or neuroimmune pathways has shown therapeutic promise in mitigating neurological deficits and enhancing anti-tumor responses, the underlying mechanisms governing ferroptosis-immune crosstalk remain inadequately characterized. Herein, this review systematically summarizes the key biological characteristics of ferroptosis and immune responses, with particular emphasis on their interplay across major CNS disorders (i.e., AD, PD, ALS, multiple sclerosis, stroke, and glioma). Furthermore, we discuss emerging therapeutic strategies encompassing small molecules, immunomodulatory approaches, and nanotechnology-based interventions, highlighting the ferroptosis-immune axis as a promising therapeutic target for CNS diseases.

Background: Severe endometrial injury constitutes a significant risk to female fertility, often leading to the development of intrauterine adhesions. Pyroptosis, a form of programmed cell death associated with inflammation, is initiated by the cleavage of gasdermin family proteins by caspase, which has been implicated in endometrial injury. In recent years, hydrogen sulfide (H2S), a gaseous signaling molecule, exerts significant regulatory effects on pyroptosis in diverse pathological processes. The aim of this study is to elucidate the role of H2S in facilitating functional recovery of the endometrium following injury in a murine model. Methods: A prospective laboratory based randomized control trial was performed to evaluate the protective role of H2S in endometrial injury. Ethanol-induced endometrial injury mouse models were established and H2S donor sodium hydrosulfide (NaHS) was randomly administered to the injured mice. Western blot analysis was conducted to assess changes in the expression of endogenous H2S metabolism and pyroptosis-related markers and histological analysis (Hematoxylin & Eosin and Masson staining) was employed to examine alterations in endometrial morphology. Finally, a fertility test was performed to evaluate the restoration of the uterine function. Results: Following endometrial injury, the expression of key endogenous H2S enzymes-cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (MST)-is significantly reduced, while the levels of pyroptosis-related proteins are elevated (p < 0.05). However, treatment with H2S resulted in an increase in the expression of endogenous H2S enzymes and a decrease in pyroptosis-associated proteins compared to the Model group (p < 0.05). Moreover, endometrial morphology and embryo count showed the most pronounced improvement in the H2S treatment group (p < 0.05). Conclusions: This study confirms the therapeutic efficacy of H2S in facilitating the recovery of injured endometrium and revealed its potential therapeutic mechanism, offering a promising therapeutic avenue for patients with severe endometrial injury.

Background: Traumatic brain injury (TBI) is one of the leading causes of injury and disability worldwide. Pyroptosis, a specific type of programmed cell death (PCD) triggered by inflammatory signals, plays a significant part in the pathological process after TBI. Copper ions play an important role in anti-inflammation and anti-oxidative stress. There is a more active copper metabolism in neurons after injury, and that neurons may require more copper ions and downstream copper-based enzymes to maintain normal physiological functions. Given these understandings of the roles of pyroptosis and copper ions in TBI pathology, this study aims to elucidate the interplay between copper ions and pyroptosis following TBI, with the goal of identifying novel therapeutic targets for TBI management. Methods: We developed an electrostatic spinning scaffold loaded with copper oxide (CuO@PCL/gelatiin, CuO@PG) to achieve small-dose local administration and avoid toxic side effects. The membranes underwent preparation and characterization through various techniques including Fourier transform infrared spectroscopy, measurement of water contact angle, antibacterial experiment, scanning electron microscopy, and assessment of in vitro release of copper. In addition, we used a controlled cortical impact to establish a TBI model in mice to examine the effect of CuO@PG on TBI-induced pyroptosis and the ability of the membranes to heal brain injury. Results: CuO@PG inhibited TBI-induced neuronal pyroptosis. CuO@PG can inhibit the expression of the pyroptosis-related proteins. Moreover, CuO@PG also alleviates brain edema and the degree of neurodegeneration in the acute phase of TBI. The neuroprotective effect of CuO@PG was further confirmed by wire-grip test, open field test, Morris water maze test. Lastly, the beneficial results were significantly inhibited by the use of the copper chelator tetrathiomolybdate. Conclusions: In this study, we successfully constructed electrostatically spun scaffolds loaded with copper oxide to achieve slow, continuous and low-dose copper supply to the local brain, which provides a new theoretical basis for the imbalance of copper homeostasis in the brain after TBI.

Nearly half of mild traumatic brain injury (mTBI) patients continue to experience residual neurological dysfunction, which may be attributed to exposure to stress. Ferroptosis, a newly discovered form of cell death, is increasingly recognized for its involvement in the pathophysiology of TBI. Understanding the mechanisms by which stress influences mTBI, particularly through ferroptosis, is crucial for the effective treatment and prevention of mTBI patients who are sensitive to stressful events. In our study, a mouse mTBI model was established. An acute restraint stress (RS) and a chronic unpredictable mild stress (CUMS) model then were applied to make acute and chronic stress, respectively. We found acute RS significantly delayed the recovery of reduced body weight and short-term motor dysfunctions and exacerbated cell insults and blood–brain barrier leakage caused by mTBI. Further studies revealed that acute RS exacerbates neuronal ferroptosis, pyroptosis, and apoptosis by promoting iron overloading in the neocortex following mTBI. Interestingly, the inhibition of ferroptosis with iron chelators, including deferoxamine and ciclopirox, reversed pyroptosis and apoptosis. Moreover, CUMS aggravated neurological dysfunctions (motor function, cognitive function, and anxiety-like behavior) and exacerbated brain lesion volume. CUMS also exacerbates ferroptosis, pyroptosis, and apoptosis by intensifying iron deposition, along with decreasing the expression of neuronal brain-derived neurotrophic factor and glucocorticoid receptor in the neocortex post mTBI. These effects were also mitigated by iron chelators. Our findings suggest that alleviating ferroptosis induced by iron deposition may represent a promising therapeutic approach for mTBI patients who have experienced stressful events.

Interleukin (IL)‐38 is a newly discovered cytokine of the IL‐1 family, which binds various receptors (i.e., IL‐36R, IL‐1 receptor accessory protein‐like 1, and IL‐1R1) in the central nervous system (CNS). The hallmark physiological function of IL‐38 is competitive binding to IL‐36R, as does the IL‐36R antagonist. Emerging research has shown that IL‐38 is abnormally expressed in the serum and brain tissue of patients with ischemic stroke (IS) and autism spectrum disorder (ASD), suggesting that IL‐38 may play an important role in neurological diseases. Important advances include that IL‐38 alleviates neuromyelitis optica disorder (NMOD) by inhibiting Th17 expression, improves IS by protecting against atherosclerosis via regulating immune cells and inflammation, and reduces IL‐1β and CXCL8 release through inhibiting human microglial activity post‐ASD. In contrast, IL‐38 mRNA is markedly increased and is mainly expressed in phagocytes in spinal cord injury (SCI). IL‐38 ablation attenuated SCI by reducing immune cell infiltration. However, the effect and underlying mechanism of IL‐38 in CNS diseases remain inadequately characterized. In this review, we summarize the biological characteristics, pathophysiological role, and potential mechanisms of IL‐38 in CNS diseases (e.g., NMOD, Alzheimer's disease, ASD, IS, TBI, and SCI), aiming to explore the therapeutic potential of IL‐38 in the prevention and treatment of CNS diseases.