BackgroundSpinal cord injury (SCI) initiates a secondary-injury cascade involving mitochondrial dysfunction, metal dyshomeostasis, neuroinflammation, and regulated cell death. Cuproptosis, a copper-dependent form of regulated cell death driven by lipoylated mitochondrial protein aggregation, has reframed copper dyshomeostasis as a potential molecular vulnerability rather than a passive trace-metal disturbance.Main bodyThis targeted narrative review critically synthesizes the FDX1–lipoylation–DLAT/DLST cuproptosis pathway, copper trafficking and redistribution after SCI, and the evidence boundary between spinal cord ischemia–reperfusion injury (SCIRI) and traumatic SCI. We evaluate two distinct but interacting regulatory layers: non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, circular RNAs, and extracellular-vesicle RNAs; and epigenetic regulation, including DNA methylation, histone modifications, and RNA modifications. Evidence is graded to distinguish established canonical biochemistry, the strongest direct preclinical mechanistic evidence in spinal-cord models, associative or hypothesis-generating traumatic-SCI evidence, non-SCI mechanistic validation, and testable hypotheses.ConclusionAt present the ncRNA–epigenetics–cuproptosis axis represents a molecular-neurobiological framework that still requires experimental validation rather than a clinically actionable pathway. The highest-priority next step is temporally and spatially resolved traumatic SCI validation that combines copper mapping, cell-type-specific cuproptosis execution assays, immune profiling, and genetic or pharmacological rescue experiments.
BackgroundGlioma is a molecularly heterogeneous tumor of the central nervous system with variable clinical behavior, immune contexture, and therapeutic response. Palmitoylation is a reversible lipid modification that regulates membrane localization, synaptic signaling, inflammatory pathways, and oncogenic signaling; however, the prognostic and functional relevance of palmitoylation-related long non-coding RNAs (PRlncRNAs) in glioma remains incompletely defined.MethodsTranscriptomic and clinical data for 429 glioma patients were obtained from TCGA. Thirty palmitoylation-related genes were used to identify PRlncRNAs through co-expression analysis. A prognostic signature was constructed using univariate Cox regression, LASSO-Cox regression, and multivariate Cox regression. The model was evaluated by Kaplan-Meier analysis, ROC curves, time-dependent ROC analysis, Cox regression, C-index analysis, nomogram modeling, calibration curves, and an institutional clinical cohort of 46 paired glioma and adjacent tissues. Functional enrichment, immune deconvolution, tumor microenvironment scoring, TIDE-based immunotherapy prediction, TMB/MSI analysis, and pRRophetic-based drug-sensitivity analysis were performed. U87 and U251 glioma cells, LYRM4-AS1 knockdown, in vitro functional assays, and nude-mouse xenografts were used for biological validation.ResultsA six-PRlncRNA signature consisting of POLR2J4, LYRM4-AS1, BX640514.2, AL592295.6, AL390755.1, and AC018730.1 stratified glioma patients into high- and low-risk groups with significantly different overall survival. The risk score remained an independent prognostic factor and showed strong predictive performance for 1-, 3-, and 5-year survival. Risk-associated genes were enriched in extracellular matrix organization, leukocyte-mediated immunity, neuroactive ligand-receptor interaction, MAPK signaling, cytokine-receptor interaction, cell-cycle programs, and ECM-receptor interaction. High-risk tumors displayed increased stromal, immune, and ESTIMATE scores, higher expression of multiple immune checkpoint genes, higher TIDE scores, and elevated TMB/MSI levels. Clinical validation confirmed differential expression of the six PRlncRNAs and the prognostic value of the risk score. Functionally, LYRM4-AS1 knockdown inhibited glioma cell proliferation, EdU incorporation, migration, invasion, and colony formation, while suppressing xenograft growth, increasing TUNEL-positive apoptotic cells, and reducing Ki-67, CD31, and MMP9 expression.ConclusionThis study identifies a palmitoylation-related lncRNA signature that integrates molecular signaling, immune remodeling, and prognosis in glioma. LYRM4-AS1 acts as a functional driver of glioma progression and may represent a candidate biomarker and therapeutic target at the crossroads of neural tumorigenesis and immune-microenvironmental regulation.
IntroductionTherapeutic options for the acute phase of ischemic stroke remain limited. Transcranial direct current stimulation (tDCS) and mitochondrial transplantation have emerged as promising neuroprotective approaches, but their individual efficacy is variable. We hypothesized that combining these two therapies would produce additive benefits for post-stroke recovery.MethodsFocal cortical ischemia was induced in mice using photothrombotic technique. Mice were randomly assigned to receive sham treatment, tDCS, mitochondrial transplantation, or combined treatment. Grid-walking, cylinder tests and 2,3,5-triphenyltetrazolium chloride staining were used to assess motor recovery and infarct volume, respectively. Immunofluorescence staining, and western blotting were performed to determine mitochondrial internalization and polarization of astrocytes in vivo and in vitro.ResultsCombining tDCS with mitochondrial transplantation resulted in a significantly greater reduction in infarct volume and improvement in locomotor function compared to either treatment alone. Interestingly, tDCS specifically enhanced the uptake of exogenous mitochondria by astrocytes. This was associated with a significant increase in beneficial A2 astrocytes and decrease in detrimental A1 astrocytes. Mechanistically, the combined treatment led to a marked upregulation of CD38 in astrocytes, suggesting their involvement in the tDCS-facilitated mitochondrial endocytosis. Suppression of CD38 expression by short interfering RNA attenuated astrocyte mitochondrial endocytosis and A2 phenotype induced by tDCS.ConclusionOur findings demonstrate that combining tDCS with mitochondrial transplantation conferred superior neuroprotection against ischemic brain damage than either treatment alone, and may represent a promising strategy for ischemic stroke treatment.
BackgroundAutism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication differences and restricted, repetitive behaviors. Convergent evidence implicates prefrontal cortex (PFC) circuit dysregulation and chronic neuroimmune activation in ASD. Despite increasing off-label use of guanfacine in children and adolescents with autism, its molecular and immunological rationale remains incompletely synthesized.ObjectiveTo synthesize current evidence regarding the molecular, neurophysiological, and immunological mechanisms through which guanfacine may influence ASD-related neural and immune dysfunction.MethodsIn this narrative review, we integrated evidence from pharmacology, systems neuroscience, immunology, and clinical studies to examine two converging mechanisms by which guanfacine may act in ASD and related conditions.ResultsGuanfacine suppresses cAMP signaling through α2A-adrenoceptor activation, producing dual neuronal and immune effects. In PFC pyramidal neurons, reduced cAMP signaling promotes closure of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, strengthening network firing that supports working memory, attention, and emotion regulation. In parallel, activation of α2A-adrenoceptors on microglia and macrophages reduces production of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, and interleukin-6, while promoting anti-inflammatory phenotypes through nuclear factor kappa B suppression and peroxisome proliferator-activated receptor gamma activation. Evidence from human studies and ASD models indicates that α2A-adrenoceptor signaling, HCN channel function, and microglial reactivity are altered in autism and converge on synaptic refinement, dendritic spine stability, and PFC-dependent behavior. We further review clinical evidence for guanfacine in individuals with autism and in related conditions, including attention-deficit/hyperactivity disorder, post-traumatic stress disorder, traumatic brain injury, post-COVID cognitive impairment, delirium, and age-related cognitive decline.ConclusionCollectively, the available evidence supports a mechanistic framework linking guanfacine, HCN channel modulation, and neuroimmune regulation, thereby bridging neuroinflammation and PFC function in ASD. The broader α2A–HCN–microglia axis may represent a promising therapeutic target for PFC- and neuroimmune-related features of ASD; however, adequately powered autism-specific randomized trials and biomarker-informed stratification strategies are needed to establish clinical efficacy and validate this framework.
Vitrification is a fast-cooling cryopreservation technique that limits ice crystal formation and cryoprotectant toxicity. We adapted an established vitrification method used on oocytes and blastocysts and optimized it for the cryopreservation of single and multi-rosette cortical organoids. Vitrified and rewarmed organoids were compared to unvitrified controls using immunofluorescence, qRT-PCR, and electrophysiological recordings. Vitrified and rewarmed organoids generated using two different protocols showed similar levels of proliferating cells, cell death and cell-type specific markers as unvitrified controls. We also found via multielectrode array and patch-clamp recordings that the vitrified and rewarmed organoids showed similar activity to unvitrified controls. Preliminary evidence suggests that vitrified cortical organoids could be stored for over a year and shipped long distance with little detriment to the hCOs after rewarming. Our vitrification cryopreservation method allows for the long-term storage of hCOs at ultralow temperatures and rewarming with minimal impact on cell-type specification or electrophysiology. This method provides a useful alternative approach for bio-banking and cross-institutional collaboration using cortical organoids as a model system.
Cerebral ischemia-reperfusion injury (CIRI) drives neuronal death through secondary molecular events that persist after blood flow is restored. How neurons commit to survival or death before individual death programs engage remains unclear. Liquid-liquid phase separation and its stress granules (SGs) offer one regulatory platform. Under CIRI stress, SGs assemble around G3BP1 and concentrate stalled mRNP complexes with RNA-binding proteins such as TDP-43, FUS, and DDX3X. The physical state of the condensate sets its function. Liquid-state SGs are cytoprotective. In a mechanism so far demonstrated outside CIRI itself, they sequester executioner caspase-3 and caspase-7. They also upregulate GPX4 protein through a G3BP1-IGF2BP1-m6A hub that limits ferroptosis. They further reduce DDX3X availability for NLRP3 inflammasome assembly, an effect now supported by direct evidence in ischemic brain tissue. When injury exceeds what liquid condensates can buffer, oxidative modification drives an irreversible liquid-to-solid transition. Cytoplasmic mislocalization of TDP-43 after nuclear pore damage, progressive FUS aggregation under sustained oxidative stress, and chaperone depletion accelerate this shift. The result is proteostasis collapse through joint failure of the ubiquitin-proteasome system and selective autophagy. Rodent occlusion models place this bifurcation in early reperfusion, broadly within the first day, though estimates remain approximate and the human interval is undefined. Muscone and icariin may stabilize acute-phase condensates, while melatonin and HDAC6 inhibition may resolve subacute aggregates. The account moves from the biophysical basis of SG formation through the distinct ischemic and reperfusion phases of assembly. It then covers the bifurcating protective and pathological trajectories before turning to therapeutic strategies and their translational limitations. This review argues that the SG checkpoint is an underappreciated node in CIRI. Progress requires defining its time window in human neurons, resolving SG behavior across the neurovascular unit, and validating topology-targeting approaches in primates.
Octopamine is involved in a variety of physiological and behavioral mechanisms throughout the Drosophila melanogaster life cycle. Octopaminergic neurons in both the central and the peripheral nervous system target a multitude of neurons and even non-neuronal tissues, making it challenging to analyze individual mechanisms of octopamine function. One approach to deconstructing this complex system is to examine the postsynaptic components of signal transmission, the six distinct G-protein-coupled octopamine receptors. Here, we compiled and validated a complete set of potential mutant lines of all known octopamine receptors (Oamb, Octα2R, Octβ1R, Octβ2R, Octβ3R, and Oct-TyrR) that were generated using the same genetic tool: the recently established Trojan Exon system. It integrates the Gal4/UAS binary expression strategy while simultaneously impairing receptor function. We generated a comprehensive anatomical map of receptor expression in the larva and, at the same time, analyzed the function of individual octopamine receptors during larval development, chemosensory perception, and locomotion. All octopamine receptors are expressed in the central and peripheral nervous system. Octβ2R stands out with a pronounced expression in the somatic muscles. We also observed a previously undescribed role of Octβ1R, Octβ3R, and Oct-TyrR in larval hatching and in the survival of larvae and pupae. Combined with tissue- and stage-specific gene expression data, this validated set of transgenic lines provides a basis for further functional studies of the octopaminergic system.
Abnormal epigenetic modifications are involved in central nervous system (CNS) diseases. Histones play a crucial role in chromatin structure and function, whose post-translational modifications significantly impact gene expression and chromatin dynamics. Histone acetylation, governed by the balance between histone acetyltransferases (HATs) and histone deacetylases (HDACs), is one of the key modulators of chromatin accessibility and transcriptional activity. Lysine acetyltransferase 5 (KAT5, aka TIP60), a member of the MYST subfamily of HATs, is involved in many cellular processes, including DNA repair, apoptosis, and cell cycle control. Notably, the dysfunction of KAT5 has been implicated in several CNS diseases. In this review, we explored the roles of KAT5 in CNS pathophysiology, emphasizing its involvement in neurological disorders and its potential as a therapeutic target. This review sheds light on the epigenetic mechanisms in CNS diseases mediated by KAT5 and provides valuable information for potential treatment strategies.
Postoperative cognitive dysfunction (POCD) remains a clinically important problem after surgery, particularly in older and neurologically vulnerable patients. Its interpretation is complicated by heterogeneous cognitive definitions and follow-up periods, while the underlying biology appears to involve interacting inflammatory, metabolic, glial, and synaptic disturbances rather than a single pathogenic cascade. Esketamine has therefore attracted interest as a potential perioperative neuroprotective agent, but the strength of evidence differs markedly across the mechanisms proposed to explain its effects. We conducted a structured narrative review with evidence mapping of clinical and experimental studies identified in PubMed/MEDLINE and the Web of Science Core Collection, using a literature cutoff of 1 May 2026. Direct perioperative clinical and preclinical studies were distinguished from non-perioperative esketamine research, ketamine/enantiomer studies, and contextual POCD/PND biology, with greater mechanistic weight assigned to experiments incorporating pathway perturbation or rescue. The direct preclinical literature favors a multi-branch model of esketamine action. Functional evidence supports contributions from TLR4/MyD88–p38 signaling, STING/TBK1-associated inflammatory cell death, and PARP1-related autophagic regulation, while changes in NF-κB signaling, microglial BDNF–TrkB activity, and ROCK2/ADD1-associated synaptic remodeling are supported mainly by convergent molecular and functional findings. NLRP3 remains relevant to postoperative neuroinflammation but has not been established as a required upstream mediator of esketamine action, and proposed effects on the blood–brain barrier, antioxidant pathways, cholinergic signaling, and neurogenesis remain less directly supported in perioperative cognitive models. Clinical findings are less uniform. Some randomized trials suggest reductions in postoperative delirium or early postoperative cognitive decline in selected populations, whereas other adequately designed studies are neutral, and evidence for sustained cognitive protection is limited. Peripheral inflammatory, neuronal-injury, and neurotrophic biomarkers indicate biological activity but do not establish central target engagement or cognitive mediation. Taken together, the current literature supports a biologically plausible, multi-target model for esketamine, but not an established preventive effect against perioperative neurocognitive disorders.
Human studies have demonstrated that repetitive head acceleration events (HAEs) disrupt metabolic homeostasis, raising the question of whether similar biochemical cascades scale across diverse platforms, from human to rodent to cell, for other traumatic brain injuries (TBIs). This study analyzed molecular disruptions in (i) humans with repetitive HAEs, (ii) mice with singular blast-elicited HAE with loss of consciousness, and (iii) a human 3D in vitro model of blunt injury. Humans exhibited metabolic, protein glycation, and epigenetic regulation abnormalities, with 30 pre-season metabolites predicting post-season levels with 89% accuracy. In vivo and in vitro RNA sequencing studies revealed convergence in 211 genes, with 123 metabolic genes mirroring human results. Regression analysis reflected an unprecedented 86% information scaling between platforms, namely, cell culture data predicted 86% of the information in the murine data. Athlete data linked these pathways to HAEs and motor behavior, highlighting convergent molecular disruptions across TBI models in metabolic homeostasis required for neural information processing. This approach across three platforms has not been shown before for brain-related disorders.
Women are twice as likely to develop Alzheimer’s disease (AD) as men. Despite substantial progress in understanding the pathogenesis of sporadic AD, sex-specific mechanisms remain insufficiently explored, and preclinical research has historically been biased toward male subjects. Furthermore, there is often a delay of more than 10 years between the onset of neuropathological changes and clinical diagnosis. This latent pre-symptomatic period, during which pathological alterations may still be reversible, represents a promising window for therapeutic intervention. In this context, synaptic dysfunction and neuroinflammatory alterations are among the earliest detectable AD-associated impairments and have recently emerged as promising therapeutic targets. This mini-review summarizes the currently limited knowledge on sex-related differences in synaptic functions during pre-symptomatic stage of AD pathology in both pre-clinical and clinical studies. We further position sex as a critical biological variable impacting neuronal activity, either directly or indirectly through microglia-neuron crosstalk. Finally, we emphasize the importance and rationale for integrating sex-specific neuroimmune mechanisms into early-stage research to guide design of targeted, sex-tailored therapeutic strategies that modulate neuron-microglia interactions before clinical onset.
Neuroinflammatory mechanisms are increasingly recognized in biologically defined subgroups of psychiatric disorders, yet the cellular interfaces linking peripheral immune activation to brain dysfunction remain incompletely understood. This review examines the blood-brain barrier (BBB) and neurovascular unit (NVU) as dynamic immunometabolic structures whose stability depends on mitochondrial bioenergetics, redox signaling, calcium handling, mitophagy, and innate immune regulation. We integrate human postmortem, neuroimaging, cerebrospinal fluid and circulating biomarker findings with mechanistic evidence from cellular and animal models to examine whether mitochondrial dysfunction may be associated with BBB vulnerability, endothelial activation, altered tight-junction organization, and neuroinflammatory signaling. We discuss how this mitochondrial-BBB axis may contribute to transdiagnostic phenotypes such as cognitive impairment, anhedonia, fatigue, negative symptoms, affective dysregulation, and treatment resistance. Candidate biomarkers, including inflammatory mediators, BBB permeability markers, mitochondrial DNA, bioenergetic readouts, mitophagy markers, and neuroimaging measures, are considered as tools for patient stratification rather than diagnosis. Finally, we evaluate therapeutic implications, including mitochondrial-targeted interventions, BBB-protective strategies, anti-inflammatory approaches, metabolic modulation, and precision psychiatry frameworks. We argue that the mitochondrial regulation of BBB homeostasis represents a promising but still emerging framework for understanding neuroinflammatory psychiatric phenotypes and designing biomarker-guided studies.
Engineered exosomes demonstrate good biocompatibility, barrier-crossing ability, and programmable drug-loading capacity. Recently, they have steadily emerged as a promising area of study for precision intervention in sensorineural hearing loss. This review focuses on numerous main topics, including the selection of exosome sources and donor-cell pretreatment techniques, surface targeting strategies, therapeutic cargo loading methods, the mechanisms by which exosomes cross the blood-labyrinth barrier, and recent advancements in research on the role of exosomes in hair cell protection, spiral ganglion neuron protection, supporting-cell plasticity, and cochlear microenvironment remodeling. This review also examines the key challenges in the clinical translation of exosomes. It comprehensively reviews direct cochlear exosome evidence for hair cell protection and auditory protection, separating these results from indirect non-cochlear exosome evidence and theoretical engineering approaches for spiral ganglion neuron protection, supporting-cell-mediated regeneration-related mechanisms, and cochlear neurovascular microenvironment remodeling. In addition to outlining a framework that combines targeted delivery and functional regulation for sensorineural hearing loss, this review highlights the hearing-protective potential of engineered exosomes in preclinical models and requires further experimental validation. Despite the positive outlook, there are still notable issues with the durability of therapeutic effects, mechanistic clarity, and clinical translatability. Future studies should prioritize standardization of extracellular vesicle reporting, dose reproducibility, clinically relevant models, and long-term functional outcomes.
Microglia are brain-resident myeloid cells that maintain central nervous system homeostasis and respond dynamically to neuronal injury, protein aggregation, and alterations in the local metabolic environment. Single-cell and single-nucleus studies demonstrate that microglial responses in neurodegenerative diseases are highly heterogeneous and cannot be adequately explained by the classical M1/M2 polarization model. Increasing evidence further indicates that metabolic remodeling is not merely a consequence of activation but a determinant of microglial migration, phagocytosis, inflammatory signaling, redox balance, organelle function, and interactions with surrounding neural cells. In this review, we propose a microglial immunometabolic trajectory framework in which metabolic states are viewed as branching and potentially reversible determinants of cellular function rather than fixed stages of a universal disease pathway. We summarize how glucose metabolism, mitochondrial function, lipid metabolism, amino acid metabolism, lysosomal activity, and redox regulation shape microglial plasticity. We further examine relationships among transcriptionally defined states, including disease-associated microglia, microglia associated with neurodegeneration, lipid-droplet-accumulating microglia, and other disease-enriched populations, while emphasizing that transcriptional similarity does not necessarily imply metabolic function or lineage progression. Comparative evidence from Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis indicates that common metabolic regulators, including HIF-1α, mTOR, PKM2, TREM2, APOE, and NLRP3, exert disease-specific effects with unequal mechanistic support. We further distinguish associative metabolic signatures from intervention-based causal evidence and discuss limitations of animal models, immortalized cell lines, postmortem tissue, and induced pluripotent stem cell-derived microglia. Finally, we highlight the need for cell-specific, state-resolved, and temporally precise metabolic interventions that restore defined microglial functions without compromising physiological immune surveillance.
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Epigenetic dysregulation, particularly in Group 3 and Group 4 tumors, is a major driver of tumorigenesis despite relatively few recurrent driver mutations. DNA methylation, histone modification, chromatin remodeling, and non-coding RNAs orchestrate aberrant transcriptional programs governing tumor initiation, progression, and cellular identity. Single-cell and multi-omic studies have revealed epigenetic heterogeneity, cellular plasticity, and microenvironmental interactions underlying therapeutic resistance. Epigenetic alterations provide valuable diagnostic and prognostic biomarkers. DNA methylation profiling is the gold standard for molecular classification, while epigenetic signatures and cerebrospinal fluid circulating tumor DNA support precision diagnosis and disease monitoring. This review integrates recent advances in MB epigenetics into a framework linking cellular plasticity and the tumor microenvironment to biomarker-driven precision therapies. Several comprehensive reviews have summarized the epigenetic landscape of medulloblastoma, focusing primarily on DNA methylation, histone modifications, chromatin remodeling, and subgroup-specific epigenetic alterations. While these studies have substantially advanced our understanding of epigenetic mechanisms, the rapid emergence of single-cell sequencing, spatial transcriptomics, multi-omic integration, and three-dimensional chromatin mapping has reshaped the current view of medulloblastoma biology. These technologies provide unprecedented resolution for dissecting intratumoral heterogeneity, developmental trajectories, and dynamic epigenetic regulation not fully addressed in earlier reviews. In this review, we integrate these recent advances into a unified framework connecting classical epigenetic mechanisms with emerging multidimensional epigenomic technologies. We discuss how these insights facilitate biomarker discovery, improve molecular classification, and accelerate precision epigenetic therapies, highlighting future directions for translational research.
Glioblastoma (GBM) remains one of the most lethal malignancies in adults, with a median survival of 15 months under the current standard of care. The lack of effective targeted therapies is a critical gap, particularly for the mesenchymal subtype of glioblastoma (MES-GBM), which accounts for up to 49% of GBM cases and carries the worst prognosis. Although direct RAS mutations are rare in GBM, mutations in upstream ERK MAPK pathway regulators such as loss-of-function of neurofibromin 1 (NF1) and gain-of-function mutations in epidermal growth factor receptor (EGFR) are highly prevalent in MES-GBM and drive constitutive pathway hyperactivation, chemoresistance, and aggressive tumor behavior. These mutations render the ERK MAPK pathway a compelling, yet underexplored, therapeutic target in GBM. RAS(ON) multi-selective inhibitors, which act upstream by blocking active RAS-GTP across multiple isoforms and mutations, represent a new therapeutic opportunity. Daraxonrasib (RMC-6236), a potent RAS(ON) multi-selective inhibitor currently in Phase III clinical trials for pancreatic cancer, has demonstrated blood-brain barrier (BBB) penetrance in non-GBM brain metastasis models, broad efficacy across RAS-driven cancers, and a favorable tolerability profile in clinical studies. As daraxonrasib targets active RAS regardless of mutation status, it is mechanistically suited for NF1-mutant GBM, in which RAS itself is wild-type but constitutively activated. Beyond direct tumor cell effects, hyperactive RAS signaling in GBM drives pro-tumoral reprogramming of microglia and tumor-associated macrophages (TAMs), creating an immunosuppressive microenvironment that further promotes MES-GBM transition and treatment resistance. RAS(ON) inhibition therefore holds potential to simultaneously suppress tumor proliferation and remodel the tumor microenvironment (TME) toward an anti-tumor state. In this review, we discuss the potential effect of daraxonrasib as an emerging targeted therapeutic candidate in MES-GBM, highlighting the need of further research and clinical evaluation to better determine its therapeutic efficacy dedicated GBM preclinical models.
With rising life expectancy and global population aging, cognitive decline has become a major and growing public health challenge. Advances in nutritional neuroscience highlight the gut microbiota–immune–brain axis as a key biological pathway through which diet may influence cognitive function during aging. The gut microbiota, a metabolically active ecosystem, responds dynamically to habitual dietary patterns and produces bioactive metabolites capable of modulating immune signaling, neuroinflammation, and neuronal function. Diets rich in microbiota-modulating foods (e.g., dietary fiber, polyphenols, prebiotics, and probiotics) promote beneficial microbial communities. These communities support short-chain fatty acid production, maintain intestinal barrier integrity, and regulate systemic immune responses, processes increasingly associated with cognitive resilience in aging populations. In contrast, Western-style dietary patterns characterized by high intakes of saturated fats and refined sugars are linked to microbial dysbiosis, impaired gut barrier function, metabolic endotoxemia, and chronic low-grade inflammation, which may contribute to neuroinflammatory pathways involved in cognitive decline. This narrative review synthesizes evidence from observational studies, dietary intervention trials, and mechanistic animal models to examine how diet-driven alterations in gut microbiota composition and microbial metabolites interact with and modulate immune pathways to influence brain function in aging populations. Although emerging evidence supports the biological plausibility of this axis in cognitive health, current evidence remains constrained by methodological heterogeneity, short intervention durations, limited functional insight, and substantial inter-individual variability in microbiota responsiveness. In particular, much of the mechanistic understanding derives from preclinical research, while human evidence remains largely associative and insufficient to establish causal pathways. Future research should integrate longitudinal cohort designs, harmonized cognitive assessment tools, and repeated profiling of microbial and host metabolites to clarify the functional and causal links between diet, microbial metabolism, immune regulation, and brain aging. A more integrated understanding of these interactions may help inform targeted, microbiome-informed nutritional strategies for supporting healthy cognitive aging, while maintaining appropriate caution in clinical interpretation.
The ability to sense environmental temperature is fundamental to animal survival, physiological homeostasis, and adaptation to changing environments. Animals rely on temperature-responsive molecules to detect changes in environmental and internal temperatures to maintain their thermal homeostasis. Among these molecules, the best-characterized group belongs to the transient receptor potential (TRP) channel superfamily, commonly referred to as thermoTRPs. ThermoTRPs have been extensively studied and are well established as thermoreceptors. In recent years, cryo-electron microscopy (cryo-EM) has enabled the structural characterization of numerous thermoTRP channels in their closed-state and agonist-induced open state, providing unprecedented insights into their architecture and gating mechanisms. Despite these advances, the molecular mechanisms by which thermoTRPs undergo temperature-induced activation remain poorly understood. This review focuses on six pioneering cryo-EM studies reporting temperature-induced open structures to summarize current structural evidence and discuss potential mechanisms by which temperature drives channel opening in thermoTRPs.
Synaptic transmission is dynamically regulated by neuromodulators. One well-studied example is cannabinoid receptor type 1 (CB1R)-mediated suppression of neurotransmitter release by reducing presynaptic Ca2+ influx. Recently, GPR55 was shown to regulate transmitter release through a mechanism distinct from that of CB1R. However, the presynaptic role of cannabinoid receptor type 2 (CB2R) remains unclear. Here we studied this issue using cerebellar Purkinje cells (PCs), which are known to express both CB2R and GPR55 and amenable to direct patch-clamp recordings from axon terminals. At naïve PC synapses onto target neurons, application of a CB2R agonist did not affect synaptic transmission. The lack of effect was ascribed to minimal endogenous CB2R at distal axon terminals of PCs. Exogenous expression of CB2R enabled suppression of synaptic transmission upon pharmacological activation. Direct voltage-clamp recordings of presynaptic Ca2+ current and membrane capacitance changes at boutons demonstrated that CB2R activation reduced presynaptic Ca2+ influx without affecting the total amount of readily releasable vesicles, leading to less vesicle exocytosis through lowered release probability. Notably, replacement of two intracellular loops of CB2R with those of GPR55 converted the site of action for synaptic suppression from Ca2+ channel inhibition to the reduction of the readily releasable vesicles, as GPR55 does. These findings indicate that, when sufficiently present at axon terminals, CB2R suppresses transmitter release through reduction of Ca2+ influx like CB1R, and suggest that intracellular loops of cannabinoid receptors determine whether transmitter release is suppressed through inhibition of presynaptic Ca2+ channels or reduction of the readily releasable pool of vesicles.
