搜索结果：Experimental neurology

Hypoglossal neuropathy is the most common lower cranial neuropathy detected as a delayed sequelae of Human Papillomavirus (HPV) -driven oropharyngeal cancer (OPC). Needle electromyography (EMG) is the gold standard for electrodiagnostic testing, but it is invasive and relies on subjective interpretation of the EMG signal. This study explores the potential of non-invasive high-density surface electromyography (HDSEMG) to detect and quantify hypoglossal neuropathy in OPC survivors. In an exploratory study, examine the feasibility of HDSEMG for rapid, non-invasive screening of hypoglossal nerve (CN XII) function and estimate the prevalence of hypoglossal neuropathy before and after oropharyngeal radiotherapy, and associate with patient-reported and clinician-graded functional outcomes. Machine learning performance will be measured through sensitivity, specificity, and F1 score, with a target area under the curve > 0.7 based on literature-reported EMG sensitivity and specificity. This protocol will recruit patients aged ≥ 18 years who receive radiation therapy for OPC at MD Anderson Cancer Center (MDACC) between 2024-2025 and consent to experimental HDSEMG testing. Sanchez Research Lab (The University of Utah, Salt Lake City, UT) will perform data analysis. Clinical data-including electrical impedance measurement (EIM), patient-reported outcomes, dysphagia grading, tongue functions, fibrosis grading, and needle EMG-will be collected from n = 36 patients. Features extracted from HDSEMG will be correlated with other clinical outcomes and used to train a machine learning classifier to quantify the severity of hypoglossal neuropathy.

The core pathogenesis of carotid atherosclerosis (CAS) lies in the rupture of vulnerable plaques, with macrophages (MC) playing a critical role in plaque progression and destabilization. However, the functional characteristics of MC subpopulations in CAS remain poorly understood. This study systematically investigates the cellular composition of CAS and the regulatory mechanisms of MC by integrating single-cell RNA sequencing (scRNA-seq), in vitro models, and spatial transcriptomics. Differentially expressed genes upregulated in MC were significantly enriched in multiple signaling pathways, including Lipid and Atherosclerosis, Lysosome, and Antigen Processing and Presentation. Gene Set Variation Analysis (GSVA) revealed higher MC scores for Angiogenesis and Lipid Metabolism in the atherosclerotic core (AC). A total of seven distinct MC subtypes were identified. Pseudotime analysis indicated that IGSF21+ MC constitute the initial cell population, while FABP4+ MC represent the terminal cells along the trajectory. An in vitro atherosclerosis model was established to validate the diagnostic value of SPP1, FTH1, and FTL. Spatial transcriptomics further revealed the spatial connection patterns of the SPP1 signaling pathway network across different cell types. This study provides novel molecular insights into the pathogenesis of CAS and lays the groundwork for developing diagnostic biomarkers and therapeutic targets.

Transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES) have been extensively used in experimental and clinical research in psychiatry, neurology, and rehabilitation. Several advanced approaches for delivering transcranial electromagnetic stimulation have been proposed to maximize the temporal and spatial precision of conventional stimulation protocols or to optimize stimulation parameters for enhanced efficacy during neuromodulation. Here, we thematically reviewed several advanced neuromodulatory approaches: (1) using prior or real-time brain states to guide the delivery of stimulation through priming protocols or brain-state-dependent stimulation interfaces (temporal precision); (2) facilitating the stimulation target engagement, either from a single brain region to an interregional brain connection using cortico-cortical paired associative stimulation or dual-site in/anti-phase transcranial alternating current stimulation, or from a superficial brain target to a deep brain region using temporal interference stimulation (spatial precision); and (3) strengthening or accelerating the plasticity modulation outcomes using high-dose protocols (dose optimization). While results from these efforts are promising, challenges exist in terms of the optimal timing of brain states and stimulation parameters, treatment durability, as well as the complexity in aggregating different advanced approaches. Future research should focus on exploring the underlying mechanisms, optimizing parameters, and assessing the efficacy in well-designed proof-of-concept experiments and clinical trials.

Epilepsy is frequently associated with behavioral and emotional difficulties. Among antiseizure medications, Levetiracetam, Perampanel, and Brivaracetam are notorious to cause behavioral adverse drug reactions, including increased anger, irritability, and aggression. While these effects are often described in self-report data, experimental studies examining aggressive behavior in patients with epilepsy are scarce. This study aims to assess aggression in patients with epilepsy and compare it to healthy controls, using self-report measures and two experimental provocation paradigms. Thirty seven patients with epilepsy treated with Levetiracetam, Perampanel, or Brivaracetam (with an overrepresentation of patients treated with Levetiracetam) and 38 healthy controls completed the Buss and Perry Aggression Questionnaire, Barratt Impulsiveness Scale, Beck's Depression Inventory, and Affective Style Questionnaire. Aggressive behavior and reaction were investigated using a modified version of the Taylor Aggression Paradigm and the Technical Provocation Paradigm, alongside with emotional state ratings during the paradigms. Patients with epilepsy reported higher aggression, impulsivity, and depression in the self-report questionnaires compared to healthy controls. However, behaviorally, patients did not show increased aggression. Instead, they showed reduced emotional reactivity to provocation, with lower changes in the emotional state ratings. Higher desire for revenge and higher frustration during the task predicted stronger aggressive responses in the patient group, but not in the control group. Our findings suggest reduced emotional responsiveness to provocation, and a discrepancy between self-perceived and observed aggression in patients with epilepsy. Aggressive responses in this group appeared to be influenced by situational emotions such as revengefulness and frustration. These results underline the need to differentiate between subjective and observable behavioral changes in patients with epilepsy, and of considering the impact of psychiatric comorbidities and emotion regulation difficulties.

Subarachnoid hemorrhage (SAH), accounting for approximately 5% of all stroke cases, triggers hemorrhagic brain injury where early brain injury (EBI) emerges as a pivotal prognostic determinant. EBI is characterized by multiple pathophysiological processes including oxidative stress (OS), neuroinflammation, neuronal apoptosis, and blood-brain barrier (BBB) disruption following SAH. This study investigated the neuroprotective effects of 3,4-dihydropyrimidin-2(1H)-one derivatives (DHPMs) against neural dysfunction and EBI in a murine SAH model, compared with edaravone (EDA). We hypothesized that DHPMs alleviate SAH-induced neurological damage, dysfunction, and apoptosis through scavenging excess reactive oxygen species (ROS) generated post-SAH, a mechanistic premise systematically validated through experimental analyses. We hypothesized that male C57BL/6 mice weighing between 22 g and 30 g were arbitrarily classified into one of seven cohorts: sham, SAH, SAH + vehicle, SAH + DHPMs 50 mg/kg, SAH + DHPMs 300 mg/kg, SAH + DHPMs 500 mg/kg, and SAH + EDA 10 mg/kg. The intravascular threading method was utilized to induce SAH in the mice. DHPMs were intraperitoneally administered at 50 mg/kg, 300 mg/kg, and 500 mg/kg 15 min after SAH, while EDA was intraperitoneally provided at 10 mg/kg. The modified Garcia score (MGS) and balance beam test (BBT) were employed for behavioral activity assessment at 24 h and 72 h post-SAH, with neurological scores recorded for mice. Subsequently, mice were euthanized to evaluate SAH grade and severity, followed by determination of the optimal drug dosage according to the group exhibiting the most significant behavioral improvement. We computed the brain water content using the dry and wet protocol 24 h post-SAH, while Evans blue was employed to assess BBB leakage. Using Western blot, we also detected pathway-associated proteins, inflammation-related proteins, apoptosis-related proteins, and tight junction (TJ) proteins at the protein level in experimental SAH in mice. Frozen brain tissue sections of mice were prepared for immunofluorescence (IF) staining to observe the changes of microglia, astrocytes, and neurons before and after SAH administration in mice. Our experiment found that the intervention of 300 mg/kg DHPMs after SAH could improve the neurological score of mice, similar to the effects observed with EDA 10 mg/kg intervention. Additionally, DHPMs intervention was found to reduce brain edema and BBB damage 24 h post-SAH, surpassing the efficacy of EDA. Furthermore, the administration of 300 mg/kg DHPMs was linked to augmented Nrf2, apoptosis proteins Bax, Caspase-3, CHOP-1, inflammation proteins interleukin (IL)-1β, IL-18, TJ proteins Occludin, claudin-5, and zonulaoccludens-1 (ZO-1) protein expressions, and diminished heme oxygenase 1 (HO-1) and apoptosis protein Bcl-2 protein expressions. We demonstrated that DHPMs have the potential to safeguard neurological function, mitigate brain edema and BBB disruption, and alleviate OS, inflammation, and apoptosis following SAH.

We aimed to assess differences in auditory deviance detection and the underlying sources' effective connectivity between participants with juvenile myoclonic epilepsy (JME) (N = 60) and healthy controls (N = 39). 256-channel EEG data were recorded during an auditory roving oddball paradigm. Dynamic causal modeling (DCM) was used to estimate effective connectivity between brain regions involved in generation of auditory mismatch negativity (MMN) and P3a component of event-related potentials (ERPs). Between-group statistics were used to compare the MMN and P3a amplitudes. DCM and Parametric Empirical Bayes (PEB) were used to model experimental perturbations in cortical connectivity and assess between-group differences. Hypothesis-driven correlation tests between the sensor space MMN and P3a amplitudes, as well as DCM connectivity estimates, with heavy executive function load cognitive tests were also evaluated. MMN and P3a amplitudes were significantly smaller in the JME patients group compared to controls. DCM and PEB analyses revealed group-level differences in cortical connectivity as the result of experimental effects (i.e., differential response to the deviant stimuli in relation to the standard ones): (1) Significantly reduced extrinsic connectivity for JME participants versus controls between right superior temporal gyrus (r-STG) and right inferior frontal gyrus (r-IFG), as well as (2) Increase in intrinsic (within a region) excitability in left STG. Weak-to-moderate associations were found between the electrophysiological variables under study and neuropsychological tests of executive function. Reduced auditory deviance detection, as well as a decreased right-sided feedforward connectivity in our JME cohort, correlated with cognitive test performance. These findings reflect aberrant neurophysiology underlying JME warranting potential interventions.

This review explores the role of autoimmune mechanisms in drug-resistant epilepsy (DRE), with emphasis on etiology, mechanisms of drug resistance, and potential immunomodulatory interventions. A structured review of clinical and experimental studies was conducted to assess current knowledge on the interplay between molecular mechanisms and immune responses in DRE. Particular attention was given to the involvement of the mTOR pathway, blood-brain barrier (BBB) dysfunction, astrocyte activation, and overexpression of efflux transporters, as well as the presence of neuronal autoantibodies such as N-methyl-D-aspartate receptor (NMDAR) and GluR3. The available evidence suggests that, although conventional pharmacologic approaches fail in a subset of patients, immunologic diagnostics and targeted therapies - including intravenous immunoglobulin, corticosteroids, rituximab, and plasmapheresis - may provide clinical benefit. Seizure reduction has been reported in selected patients; however, therapeutic response remains heterogeneous and is limited by small study populations. In conclusion, early identification of autoimmune mechanisms in DRE may help optimize treatment strategies, improve patient outcomes, and reduce the long-term clinical and societal burden of the disease.

This study investigated the feasibility, reliability, and validity of abbreviated versions of four neurocognitive tasks-typically used to assess attention, working memory, and executive functions (i.e., the Oddball, n-Back, Stroop, and Flanker tasks). To reduce the effects of response variability and physiological noise, neurocognitive assessments typically require numerous stimulus trials per task, causing each task to often exceed 20 minutes in duration. Such long durations can contribute to participant fatigue and practical constraints, especially when multiple neurocognitive tasks are administered in a single session to evaluate neurocognitive performance across domains. To address this, we evaluated whether abbreviated versions of the tasks-each limited to a maximum duration of four minutes-could serve as reliable alternatives. A total of 57 healthy young adult participants completed the four aforementioned tasks administered through a custom-built, cross-platform mobile application. Response accuracy and reaction times were then analyzed to assess cognitive performance. Statistical analyses confirmed significant expected effects between different stimuli and experimental conditions within each task. Moreover, high split-half intraclass correlation coefficients (ICCs) indicated excellent internal consistency, demonstrating that the abbreviated versions yielded stable and reproducible results across all tasks. These findings support the use of the presented abbreviated tasks as efficient proxy measures for defined facets of executive functions, offering practical alternatives without compromising data integrity.

Schizophrenia (SCZ) is hypothesized to arise from neural circuit dysfunction, but the role of non-neuronal cells remains poorly defined. While astrocytic connexin 43 (Cx43) facilitates both gap junction (GJ) coupling and hemichannel (HC)-mediated gliotransmitter release, its specific role in SCZ remains unclear. Here, we report elevated Cx43 expression in the prefrontal cortex of individuals with SCZ and investigate its functional relevance in an MK801-induced mouse model. In this model, medial prefrontal cortex (mPFC) Cx43 upregulation was associated with enhanced HC activity without affecting GJ coupling. Pharmacological blockade of Cx43 HC with TAT-Gap19 rescued SCZ-like behavioral and synaptic alterations, whereas astrocyte-specific Cx43 overexpression (Cx43 OE) in the mPFC of naive mice recapitulated behavioral abnormalities. Mechanistically, increased HC activity was linked to excessive astrocytic glutamate release, which was directly visualized using ex vivo two-photon imaging with an astrocyte-specific glutamate sensor and normalized by TAT-Gap19. Together, our results integrate human expression data with experimental evidence to implicate astrocytic Cx43 HC dysregulation in prefrontal circuit dysfunction relevant to SCZ and suggest that glial HC signaling warrants further investigation in SCZ pathophysiology.

The hippocampus has a critical role in the online processing of information; encoding, storage, and retrieval of episodic memory; and novelty detection. These functions have been classically associated with a trisynaptic circuit connecting the entorhinal cortex, the dentate gyrus, area CA3, and area CA1. Until recently, the role of area CA2, located between CA3 and CA1, has been underappreciated. However, increased evidence indicates that, despite its small size,1 area CA2 has a critical role in in regulating activity throughout the hippocampal circuit and has a unique importance in social recognition memory.2-8 Area CA2 has widespread connectivity with other hippocampal regions2 and has unique structural features, electrophysiologic responses, pattens of receptor expression, and subcortical inputs. Pyramidal CA2 neurons are more resistant to excitotoxicity than those in other hippocampal subfields.9 However, area CA2 is susceptible to accumulation of alpha-synuclein10,11 and tau.12 Experimental studies show loss or impaired function of a critical subpopulation of local inhibitory CA2 interneurons in several disorders, including temporal lobe epilepsy,13 Alzheimer disease (AD), multiple sclerosis, schizophrenia, and autism spectrum disorder.14.

Parkinson's disease (PD) is defined by the presence of motor symptoms, such as bradykinesia. However, it also involves less well-understood cognitive deficits, including impairments in time processing: the ability to perceive, estimate, and produce time intervals accurately. In this review, we summarize the existing literature on time processing in PD, with an emphasis on the different tasks used to study it, as well as on the cognitive processes and neurophysiological mechanisms contributing to time processing deficits in PD. FINDINGS: show that temporal processing deficits in PD span both motor and cognitive/perceptual domains. While dopamine replacement therapy can improve motor timing, its effects on cognitively controlled tasks-particularly those requiring attention and longer intervals-are limited. These deficits reflect dysfunction across basal ganglia, prefrontal, cerebellar, and other brain circuits, and may involve additional neurotransmitter systems such as acetylcholine, serotonin, and noradrenalin. The variety of experimental tasks used to study timing reveals the need for more precise assessments that clearly separate motor and cognitive components. Furthermore, different cognitive processes, such as explicit, implicit, sub-second, and supra-second timing as well as attention and working memory, are involved in time processing in PD. Temporal dysfunction in PD is multidimensional, resulting from a complex system of interacting neural processes. A more complete understanding of time processing in PD is needed, focusing on exploration of the non-dopaminergic aspects of time processing, and improving the design of timing tasks to better identify specific deficits and treatment targets.

Deep brain stimulation is an established therapy for neurological disorders such as Parkinson's disease, but its underlying mechanisms and tissue effects remain incompletely understood. A particular challenge arises from the foreign body response to implanted electrodes, which leads to scar formation and encapsulation, altering the electrical properties of the surrounding tissue. This study aims to characterize the electrode-tissue interface during long-term stimulation and to improve model-based estimation of the stimulation volume using subject-specific dielectric properties. Continuous deep brain stimulation was delivered for six weeks using a fully implantable stimulator in a unilateral 6-hydroxydopamine Parkinson rat model. In vivo impedance spectroscopy and post mortem histology were performed to assess encapsulation tissue properties. Principal component analysis was applied to identify group differences in the impedance spectra. Encapsulation layer thickness was quantified histologically and incorporated into subject-specific numerical models to resolve the non-identifiability between layer thickness and dielectric parameters. Dielectric properties were estimated by fitting simulated spectra to experimental measurements. Impedance spectra differed significantly between stimulated and non-stimulated animals, indicating that impedance spectroscopy can distinguish tissue responses to chronic stimulation. Incorporating subject-specific encapsulation parameters substantially altered estimates of the stimulation volume compared to conventional assumptions. By integrating in vivo measurements, histology, and computational modeling, this study replaces generic interface assumptions with subject-specific electrode-tissue properties. The results identify measurable markers of encapsulation tissue and demonstrate that conventional modeling approaches overestimate the stimulation volume when generic interface assumptions are used.
Incorporating subject-specific electrode-tissue properties improves the reliability of deep brain
stimulation simulations and supports individualized stimulation strategies.

Tremor arises from mechanical, reflex, or central oscillatory mechanisms. Transcranial magnetic stimulation (TMS) can transiently perturb ongoing tremor and enables the quantitative assessment of phase resetting, offering circuit-level insight into tremor types. Although numerous studies have applied TMS-induced resetting, the findings have not been systematically reviewed. This study systematically reviews human studies evaluating TMS-induced tremor resetting across tremor types. A systematic search of PubMed and Google Scholar identified human studies using TMS to perturb tremor or rhythmic movement. Search terms included "tremor resetting," "resetting of tremor," "tremor phase shift," "tremor phase reset," "transcranial magnetic stimulation," and "central oscillator." Inclusion criteria were human participants, experimental TMS perturbation, and quantitative tremor phase/resetting outcomes. Exclusion criteria were animal studies, therapeutic repetitive TMS trials without resetting analyses, and isolated case reports. Two researchers independently screened and extracted data. The PRISMA 2020 guidelines were followed. Twenty-one studies were identified, three of which were excluded from the primary synthesis (two case reports and one qualitative-only design). Eighteen studies remained, which addressed essential tremor (ET) (n = 6), Parkinson's disease tremor (PDT) (n = 7), orthostatic tremor (OT) (n = 4), palatal tremor (n = 1), dystonic tremor (DT) (n = 1), and voluntary rhythmic movement (n = 4). M1 stimulation reset ET, postural PDT, OT, palatal tremor, DT, and voluntary rhythmic movements. Rest PDT had inconsistent resetting by M1 stimulation and no resetting by cerebellar stimulation. Cerebellar stimulation reset postural PDT but not ET. The resetting index was associated with the stimulus intensity and duration of the silent period. TMS-induced resetting is a strong physiological tool for differentiating tremor circuits. M1 acts as a major convergence node, while cerebellar involvement is tremor-specific. Methodological heterogeneity and small samples limit the comparability of study results. Advances in targeting technologies and closed-loop and phase-locked protocols could enhance the diagnostic and therapeutic utility of resetting paradigms.

Posterior circulation ischemic vertigo (PCIV) is a common clinical condition with limited effective treatments. Baicalein, a flavonoid derived from Scutellaria baicalensis, possesses anti-inflammatory and neuroprotective properties; however, its effects on PCIV remain unclear. This study aimed to investigate the function of baicalein on brain tissue injury in a rat model of PCIV and to explore its underlying mechanism. In this experimental study, 80 rats were randomly divided into sham operation, PCIV, Baicalin, TAK242, and Baicalin+TAK242 groups. The latency to escape from electrical stimulation, blood flow in the vestibular nucleus, and hemorheological indices were measured. Pathological changes and neuronal apoptosis were assessed by HE staining and TUNEL staining, respectively. Western blotting was used to evaluate the protein expression of toll-like receptor 4 (TLR4), phosphorylated nuclear factor-kappa B p65 (p-NF-κB p65), and phosphorylated inhibitor of kappa B alpha (p-IκBα) in rat brain tissue. The Baicalin, TAK242, and Baicalin+TAK242 groups showed significantly lower values for latency to escape electrical stimulation, reduction rate of vestibular nucleus blood flow, whole blood viscosity, plasma viscosity, hematocrit, erythrocyte aggregation index, erythrocyte deformability index, erythrocyte sedimentation rate, number of TUNELpositive cells, levels of LAC, LDH, IL-1β, IL-6, TNF-α, and protein expression of TLR4, p-NF-κB p65, and p-IκBα. The reductions in these indicators were more pronounced in the Baicalein+TAK242 group compared to the Baicalein or TAK242 groups alone. The brain structure and the number of nerve cells were partially restored in the Baicalein and TAK242 groups compared to the PCIV group, and this restoration was more evident in the Baicalein+TAK242 group. The number of nerve cells in the Baicalin+TAK242 group were significantly reduced. Baicalein alleviates vertigo symptoms, improves vestibular nucleus blood circulation, inhibits inflammatory responses, and reduces brain tissue damage in PCIV rats, at least in part through inhibition of the TLR4/NF-κB pathway.

Electrical brain stimulation (EBS) has been studied as a tool to improve speech perception. Available EBS methods compromise between precision and power and rarely consider temporal dynamics. Noninvasive EBS delivers currents to wide areas but may lack regional specificity and is susceptible to current shunting through the skin. We introduce a novel minimally-invasive electrical brain stimulation approach using clinically implanted epicranial electrodes and cranial bolts, circumventing the current shunting limitations of traditional transcranial stimulation. Two types of contacts were used in five epilepsy patients (one female) over six experimental sessions undergoing intracranial monitoring: epicranial electrodes (served as reference electrodes for clinical recordings) and cranial bolts (holding fixtures for depth electrodes). Participants monaurally listened to pseudo-randomly presented sentences from matrix sentence speech-in-noise task in 3 conditions: no-stimulation, 50 ms, or 200 ms stimulation lag relative to sentence onset. EBS parameters were 100 Hz, biphasic, amplitude-balanced, square-wave pulses where the amplitude (1-6 mA) was modulated by the ongoing speech envelope. Accuracy in the task improved in 5 of 6 sessions while not reaching significance across sessions possibly limited due to the limited number of sessions and trials (p = 0.087 and 0.068 for 50 ms and 200 ms delay, linear mixed-effects model). In 5/6 sessions, there was increased accuracy with 50 ms delay, and in 3 of those, there was further improvement with 200 ms delay. We successfully demonstrated the dynamic EBS patterns delivered through minimally-invasive electrodes during speech perception with 83% responder rate for improvement in speech perception with short latency (50 ms) and 50% with longer latency (200 ms) stimulation.

Cisplatin (Cis) chemotherapy-induced hepatotoxicity frequently leads to treatment interruption or dose reduction, ultimately compromising therapeutic outcomes. Asperosaponin VI (AVI), a bioactive triterpenoid saponin extracted from Dipsacus asperoides, has demonstrated anti-inflammatory and antioxidant properties in various pathological conditions. However, its hepatoprotective efficacy against cisplatin-induced hepatotoxicity and underlying molecular mechanisms remain poorly understood. This study utilized both in vitro (LO2 human hepatocytes) and in vivo (C57BL/6mice n&#x2009;=&#x2009;4 per group) experimental approaches to investigate the protective effects of AVI against cisplatin-induced acute hepatotoxicity. Cell viability was assessed using CCK-8 assay, while hepatic injury was evaluated through histopathological examination, biochemical markers (ALT, AST, GSH), and TUNEL staining. The involvement of the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway was confirmed using Brusatol, a specific Nrf2 inhibitor. AVI (400&#x2009;&#x3bc;M in vitro; 20&#x2009;mg/kg in vivo) significantly attenuated cisplatin-induced cytotoxicity in LO2cells and reduced hepatic injury in mice. Treatment with AVI markedly decreased serum transaminase levels (ALT: 68.3&#x2009;&#xb1;&#x2009;30.4 vs. 358.1&#x2009;&#xb1;&#x2009;67.5&#x2009;U/L, p&#x2009;<&#x2009;0.001; AST: 129.0&#x2009;&#xb1;&#x2009;45.9 vs. 374.4&#x2009;&#xb1;&#x2009;49.5&#x2009;U/L, p&#x2009;<&#x2009;0.001), ameliorated oxidative stress, and suppressed inflammatory responses. AVI significantly upregulated Nrf2and HO-1 protein expressions while downregulating pro-inflammatory mediators (TNF-&#x3b1;, IL-1&#x3b2;, IL-6) and apoptotic markers (Caspase-1, Caspase-3, NLRP3). Pharmacological inhibition of Nrf2 with Brusatol abolished the protective effects of AVI. AVI effectively protects against cisplatin-induced hepatotoxicity through activation of the Nrf2/HO-1 signaling pathway, suggesting its potential as a novel hepatoprotective agent in cisplatin-based chemotherapy.

Neuromyelitis optica (NMO) is a severe autoimmune disorder of the central nervous system (CNS) characterized by aquaporin-4 antibody (AQP4-IgG)-mediated astrocyte injury. IL-1&#x3b2;-mediated inflammatory signaling plays a critical role in amplifying astrocyte damage and propagating CNS inflammation in NMO. However, the astrocyte-intrinsic mechanisms linking IL-1&#x3b2; signaling to downstream pathways, such as STING activation, remain poorly understood. To address this knowledge gap, in this study, we aim to elucidate the astrocyte-intrinsic mechanisms, specifically the IL-1&#x3b2;-IL-1R STING signaling axis, that contribute to NMO pathogenesis, and to evaluate the therapeutic potential of IL-1&#x3b2;-targeting antisense oligonucleotides (ASOs). Using a multi-level experimental system comprising in vitro primary astrocytes, ex vivo organotypic cerebellar slices, and in vivo NMO mouse models, we systematically investigated the critical role of the astrocytic IL-1&#x3b2;-IL-1R STING signaling axis in NMO pathogenesis. Utilizing diverse interventions-including an IL-1&#x3b2;-neutralizing antibody, astrocyte-specific IL-1&#x3b2; knockout, the IL-1R inhibitor Anakinra, STING genetic ablation, and IL-1&#x3b2; ASOs-in conjunction with behavioral, histopathological, and molecular analyses, we comprehensively delineated the impact of this signaling pathway on NMO pathology. These data support the translation of targeted therapeutic strategies. IL-1&#x3b2; signals through the IL-1 receptor (IL-1R) to induce STING-dependent proinflammatory cytokine production in astrocytes. This inflammatory cascade can be suppressed by the IL-1R antagonist anakinra or genetic ablation of STING. Therapeutic administration of lead IL-1&#x3b2; targeting ASO reduces IL-1&#x3b2; expression, preserves AQP4 levels and myelin integrity, and improves functional outcomes. The IL-1&#x3b2;-IL-1R STING signaling axis is a central contributor to NMO pathogenesis and supports IL-1&#x3b2; ASO therapy as a promising potential disease-modifying approach. ANN NEUROL 2026.

Cerebral ischemia-reperfusion injury (CIRI) causes severe neuronal damage following restoration of cerebral blood flow, and mitochondrial dysfunction acts as a core pathological driver of this process. Molecular hydrogen (H&#x2082;) has exhibited promising neuroprotective effects in multiple neurological disease models, yet it remains unclear whether H2 alleviates CIRI by modulating mitophagy and its upstream regulatory signaling pathways. In vivo experiments were performed using male C57BL/6 mice subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) with mice randomly divided into three groups: Sham group, MCAO/R group, and MCAO/H&#x2082; group. In vitro, human neuroblastoma SH-SY5Y cells were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R), with four experimental groups: Control group, OGD/R group, OGD/R + H&#x2082; group, and OGD/R + H&#x2082;+ML385 group (5 &#x3bc;M ML385, a specific Nrf2 inhibitor, pretreated for 1 h before OGD). Neurological function was assessed via neurological deficits score (zea-Longa); Cerebral infarct volume was measured by TTC staining; Neuronal histopathological damage and apoptosis were evaluated via HE, Nissl, and TUNEL staining; Cell viability was detected using CCK-8 assay; Cell apoptosis, mitochondrial reactive oxygen species (ROS) levels, and mitochondrial membrane potential (MMP) were analyzed by flow cytometry; Protein expression levels were quantified by Western blotting. In vivo experiments demonstrated that H&#x2082; inhalation markedly alleviated neurological deficits, reduced cerebral infarct volume and histopathological damage, inhibited neuronal apoptosis, and promoted mitophagy in MCAO/R mice. In SH-SY5Y cells, H&#x2082; treatment significantly improved cell viability, attenuated oxidative stress and mitochondrial dysfunction, and enhanced mitophagy via activation of the PINK1/Parkin pathway. Mechanistically, H&#x2082; maintained cellular redox homeostasis, cleared damaged mitochondria, upregulated the Nrf2/HO-1 antioxidant pathway, and suppressed NF-&#x3ba;B-mediated inflammatory signaling. Notably, inhibition of Nrf2 with ML385 significantly reversed the mitochondrial protective and anti-apoptotic effects of H&#x2082; in OGD/R-exposed cells. Our findings revealed that H2 exerts significant neuroprotective effects against CIRI by attenuating oxidative stress, inhibiting neuronal apoptosis, and improving mitochondrial function. These effects are closely associated with the activation of the Nrf2/PINK1/Parkin-mediated mitophagy pathway, highlighting H&#x2082; as a potential therapeutic method for CIRI.

Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disorder with limited treatment options. Macropinocytosis is one of the key cellular processes involved in nutrient consumption from the extracellular environment under stress conditions. Here, we studied the role of macropinocytosis in experimental pulmonary fibrosis models. We found that macropinocytosis is increased in human lung fibroblasts (HLFs) derived from IPF patients. The inhibition of macropinocytosis with 5-(n-ethyl-n-isopropyl)-amiloride (EIPA) inhibited profibrotic responses in IPF-derived and TGF-&#xf062;1-stimulated HLFs and reduced pulmonary fibrosis in bleomycin (Bleo)-injured mice. EIPA exerted its antifibrotic effects by regulating amino acid (AA) uptake, mammalian target of rapamycin complex 1 (mTORC1) activation and mesenchyme homeobox1 (MEOX1) expression in activated HLFs. Fittngly, genetic inhibition of macropinocytosis also ameliorated lung fibroblast activation and pulmonary fibrosis in mice. Using IPF-derived precision cut lung slices (PCLS), we observed robust repression of profibrotic gene expression programs in EIPA-treated PCLS across different fibroblast subpopulations. Finally, we found that imipramine (Imi), a tricyclic antidepressant approved by the Food and Drug Administration (FDA), effectively inhibited macropinocytosis and ameliorated profibrotic responses in lung fibroblasts, Bleo-injured mice and IPF-derived PCLS. Taken together, our results suggest macropinocytosis inhibition can be considered as a potential therapeutic strategy to treat pulmonary fibrosis.