Parkinson's disease (PD), the second most common neurodegenerative condition, develops because of abnormal protein misfolding and aggregation of α-synuclein with its subsequent intercellular spread. Such pathological changes lead to disruption of neuronal homeostasis and contribute to neuronal degeneration. During normal conditions, α-synuclein clearance is controlled by different types of lysosomal degradation, namely, macro autophagy, chaperone-mediated autophagy (CMA), micro autophagy, and the ubiquitin-proteasome system. Malfunction of these systems results in increased α-synuclein secretion due to exosome-dependent, direct, and damage-induced mechanisms, which, in turn, promotes enhanced intercellular propagation, inflammation, mitochondrial dysfunction, blood-brain barrier leakage, and neuronal cell death. Although several approaches targeting α-synuclein clearance have shown biological activity in preclinical or early clinical studies, consistent disease-modifying efficacy has not yet been established, owing to challenges including target specificity, blood brain barrier penetration, biological heterogeneity, and the limited sensitivity of clinical endpoints. Recent research indicates that successful treatment is more related to restoring the balance of these two processes than to manipulating one of them.In this review, it is proposed that a systems-level approach can be taken where PD is understood as a disease characterized by the imbalance in proteostasis. Potential treatment modalities include small molecules targeting lysosome function (ambroxol, rapamycin, TFEB activators), CMA enhancers, gene therapy, and antibodies against extracellular α-synuclein. Furthermore, new modalities like molecular glue degraders, allostery-based stabilization of α-synuclein tetramers, engineered decoy particles, and bispecific antibodies represent some other possible routes towards multimodal disease modification.
Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder with progressive cognitive decline and neuronal loss. This study investigated the neuroprotective effects of AMBMP Hydrochloride, a Wnt/β-catenin agonist, in a streptozotocin (STZ)-induced mice model of AD, elucidating the interplay between dysregulated Wnt/β-catenin signaling and Toll-Like Receptor 4 (TLR4)-mediated inflammation, with Palmitic acid used as a TLR4 pathway modulator. Mice received bilateral intracerebroventricular (i.c.v.) injections of STZ (3 mg/kg) on Day 1 and Day 3, followed by administration of Donepezil (3 mg/kg)/ AMBMP Hydrochloride (5 mg/kg and 10 mg/kg)/Palmitic acid (TLR4 agonist, 20 mg/kg) via the intraperitoneal (i.p.) route from Day 4 to Day 22. STZ-treated mice exhibited significant cognitive dysfunction, characterized by impaired performance in the Morris Water Maze (MWM) task along with increase in acetylcholinesterase (AChE) activity, oxidative stress (thiobarbituric acid reactive substances; TBARS), neuroinflammation [tumor necrosis factor alpha (TNF-α)/Interleukin-6 (IL-6)/Interleukin-1 beta (IL-1β) and nuclear factor kappa B (NF-κB)] and decreased reduced glutathione (GSH) levels. However, AMBMP Hydrochloride significantly improved behavioral and biochemical alterations possibly through modulation of Wnt/β-catenin signaling and attenuation of TLR4-mediated inflammation. Interestingly, Palmitic acid co-treatment was found to counteract these protective effects, further pointing to a role of TLR4 in the pharmacological effect of AMBMP Hydrochloride. In summary, we confirmed that AMBMP Hydrochloride exhibits potent neuroprotective effects associated with modulating Wnt/β-catenin/TLR4 signaling, offering a promising therapeutic approach against Alzheimer-Type Dementia. Future studies should delve deeper into the molecular mechanisms and translational promise of AMBMP hydrochloride, paving the way for its development as a potential candidate for AD management.
Perioperative neurocognitive disorder (PND) manifests as neurocognitive alterations induced by anesthesia and surgical stress. High-risk factors, including advanced age, obesity, diabetes, and preoperative neurological dysfunction, accelerate PND progression, with neuroinflammation serving as a core pathological mechanism throughout PND pathogenesis. Semaglutide regulates neuroinflammation in patients with diabetes and stroke, yet its role in PND remains undefined.A lipopolysaccharide (LPS)-induced inflammatory neurocognitive impairment mouse model was established via intracerebroventricular injection. Mice were treated with semaglutide alone or combined with the O-GlcNAc transferase inhibitor OSMI-1 and AKT-silencing adeno-associated viruses. Behavioral, biochemical and immunofluorescence assays were performed to evaluate cognitive function and molecular changes. Semaglutide significantly rescued LPS-induced cognitive deficits and restored hippocampal O-GlcNAcylation. Mechanistically, LPS inhibited AKT O-GlcNAc modification and AKT-mTOR pathway activity, facilitated mTOR-gephyrin binding, disrupted GABAAR distribution, aggravated neuronal apoptosis, and impaired synaptic plasticity. Semaglutide reversed these abnormalities by elevating AKT O-GlcNAcylation to activate the AKT-mTOR pathway, which triggered mTOR-gephyrin dissociation, restored synaptic GABAAR localization, attenuated neuronal damage, and rescued synaptic plasticity.Semaglutide ameliorates PND via AKT O-GlcNAcylation-mediated AKT-mTOR activation and subsequent neuroprotective effects.
Celiac disease (CD) is a chronic immune-mediated enteropathy triggered by gluten ingestion in genetically susceptible individuals. While traditionally associated with gastrointestinal (GI) symptoms, CD is increasingly recognized as a systemic disorder with significant neurological involvement. A growing body of evidence links CD to a broad spectrum of neurological manifestations, including gluten ataxia (GA), peripheral neuropathy (PN), epilepsy, migraine, myoclonic disorders, and cognitive impairment. These symptoms may precede or occur independently of GI symptoms, complicating diagnosis and delaying treatment. The underlying mechanisms are multifactorial, involving autoantibody cross-reactivity, neuroinflammation, increased permeability of the intestinal and blood–brain barrier (BBB), gut dysbiosis, and micronutrient deficiencies. This review synthesizes current insights into the pathophysiological basis of CD-related neurological disorders. We also explore the therapeutic impact of a strict gluten-free diet (GFD) on CD-related neurological manifestations. Early recognition of neurological signs and their prompt management are essential to mitigate irreversible neural injury and improve long-term outcomes in these patients. Given the potential for symptom reversibility with dietary treatment, routine screening for CD should be considered in patients presenting with idiopathic neurological syndromes, even in the absence of GI symptoms.
Objectives To evaluate the causal association between sleep traits and epilepsy risk using Mendelian randomization, and to investigate the mechanism of a prioritized epilepsy-risk variant through gene-level enrichment analysis and functional validation. Methods Large-scale European GWAS datasets were analysed using multiple Mendelian randomization methods, including inverse variance weighted, MR–Egger and weighted median models, with heterogeneity and sensitivity analyses. Epilepsy-associated loci were mapped to protein-coding genes and flanking regions based on GRCh37 annotation, and primary and sensitivity-analysis gene sets were constructed from gene-level summary results for functional enrichment analysis. Guided by locus-level prioritization and the biological plausibility of CACNA1A, rs2228130 was selected for functional validation in CRISPR-ABE-edited human iPSC and knock-in mouse models to assess inhibitory synaptic transmission, sleep-related phenotypes and seizure susceptibility. Results Longer sleep duration was significantly associated with lower epilepsy risk (OR = 0.9937, p < 1 × 10⁻⁵), supporting a protective genetic causal association. The association between insomnia and epilepsy showed substantial heterogeneity (Q = 9352.91) and should be interpreted cautiously. Gene-level enrichment analysis indicated that epilepsy-associated candidate genes converged primarily on broad biological regulation, developmental processes and multicellular organismal processes, without stable dominant enrichment of GABAergic synapse or circadian rhythm pathways. Functional validation showed that rs2228130 did not affect neuronal differentiation but impaired inhibitory synaptic transmission, accompanied by abnormal network activity, altered sleep-related phenotypes and increased seizure susceptibility. Knock-in mice exhibited more frequent epileptiform discharges, reduced non-rapid eye movement sleep, decreased slow-wave activity and altered expression of rhythm-related genes. Pharmacological and sleep-related interventions partially ameliorated these abnormalities. Significance This study supports a protective genetic causal association between longer sleep duration and lower epilepsy risk, and suggests that epilepsy-related genetic risk converges primarily on broad functional networks. Within this framework, functional validation of CACNA1A rs2228130 identifies inhibitory synaptic dysfunction as a key mechanistic node linking genetic risk to sleep- and epilepsy-related phenotypes, providing a rationale for epilepsy prevention and treatment through sleep optimization and targeted modulation of critical downstream pathways. Plain Language Summary We used large-scale genetic data and experimental models to examine how sleep is related to epilepsy. Genetic evidence showed that longer sleep duration was associated with lower epilepsy risk. Although broad gene-level analyses did not identify a stable dominant signal for GABAergic synapse or circadian rhythm pathways, functional studies of the epilepsy-risk variant CACNA1A rs2228130 showed that it disrupted inhibitory synaptic transmission, altered sleep-related phenotypes and increased seizure susceptibility. In mouse models, drug treatment and sleep-related intervention partly improved these abnormalities, suggesting that sleep optimization and targeted downstream regulation may help reduce epilepsy risk. rs2228130-associated changes in inhibitory transmission, sleep and seizure susceptibility Mendelian randomization supports a protective genetic association between longer sleep duration and lower epilepsy risk. CACNA1A rs2228130 is associated with impaired inhibitory synaptic transmission and rhythm-related molecular changes. Pharmacological and sleep-related interventions partially reverse rs2228130-related sleep and seizure phenotypes.
Cerebral small-vessel disease (CSVD) represents a major etiology of vascular cognitive impairment (VCI), driven by pathological processes such as cellular senescence and neuroinflammation. Among these, microglia-the brain's specialized immune cells-play a key role in driving neuroinflammation through their senescence, thereby exacerbating cognitive dysfunction. Although signal transducer and activator of transcription 6 (STAT6) activation has been implicated in alleviating neuroinflammation and cognitive deficits in CSVD, the underlying mechanisms remain unclear. This study sought to elucidate the roles of STAT6 and autophagy in the process of microglial senescence induced by CSVD. Using stroke-prone renovascular hypertensive rats (RHRSP) and chronic hypoxia-treated BV2 cells to assess cognitive function, microglial senescence, and autophagy, we observed that phosphorylation-mediated STAT6 activation significantly suppressed microglial senescence. Mechanistically, we found that phosphorylated STAT6 (pSTAT6) enhanced autophagy, which reduced the burden of senescent microglia and thereby ameliorated CSVD-induced VCI. These findings provide insights into the potential of targeting the STAT6 pathway in VCI associated with CSVD.
White-matter (WM) injury contributes to disability across multiple sclerosis, traumatic brain injury, Alzheimer’s disease and related dementias, and small-vessel disease. We use microglial state programs as an organizing axis for WM injury-to-repair logic, while emphasizing that WM outcomes are multicellular and involve oligodendrocyte-lineage cells, astrocytes, axons/neurons, and vascular factors. Microglia span an injury–repair continuum, from inflammatory programs that increase oxidative stress and debris burden to repair-competent programs that support debris handling, remyelination, and axonal integrity. Near-infrared photobiomodulation (PBM; 800–1100 nm) is most consistently associated with modulation of mitochondrial redox/bioenergetic pathways and inflammatory tone. CCO-centered mechanistic framing is best established near 800–850 nm, whereas longer wavelengths (e.g., 1064–1070 nm) may involve additional initiating mechanisms with downstream convergence on shared redox/bioenergetic and inflammatory pathways. Across demyelination and spinal cord injury models, appropriately dosed PBM has been reported to reduce inflammatory glial readouts and to associate with improved myelin/axon-related endpoints and functional measures, although mechanistic certainty varies across models. Human evidence remains early but broadly supports safety; a randomized trial in moderate traumatic brain injury reported treatment-related changes in diffusion-MRI WM metrics, while small dementia and chronic-injury studies report heterogeneous cognitive and physiological signals. Given dose dependence and depth-limited transcranial delivery, we synthesize mechanism-informed, dose-aware reporting guidance and WM-anchored outcome frameworks that pair diffusion MRI/DTI with interpretable biomarkers (e.g., NfL, GFAP, sTREM2) and thermally controlled sham designs. We also note potential indirect/systemic contributions that could help reconcile depth–dose constraints with deeper WM effects.
The detection and characterization of hypoxia through functional imaging represents a critical frontier in oncology, cardiology, and neurology. Despite extensive efforts, the clinical translation of a robust hypoxia imaging biomarker remains hindered by suboptimal signal limiting diagnostic accuracy. Here, we report the development of a 64Cu-based radiotracer (64Cu-CysPhe), which exploits the cellular copper uptake pathway involving the human copper transporter 1 (hCtr1). This targeted mechanism facilitates selective tracer accumulation in hypoxic tissues. In-vivo PET-MRI imaging in a murine breast cancer model demonstrated tumor-to-muscle ratios exceeding 3.0 up to 24 h post-injection. Notably, immunohistochemical analyses revealed that 64Cu-CysPhe preferentially localizes to hypoxic tumor regions while excluding necrotic cores, thereby providing information about a tumor’s immediate microenvironment. Comparative analysis with established radiotracers, including 64Cu-ATSM and 18F-FDG, confirmed the sensitivity of 64Cu-CysPhe in detecting hypoxic tumor regions. These findings establish 64Cu-CysPhe as a promising candidate for non-invasive imaging of tumors.
Curculigoside (CUR), a flavonoid derived from traditional Chinese medicine, has shown potential in alleviating depressive symptoms. However, the mechanisms underlying its antidepressant effects remain unclear. The aim of this study was to investigate the effect of CUR on depressive-like behavior in the chronic social defeat stress (CSDS) model and its potential mechanism of action on pyramidal neuronal excitability and synaptic transmission. We injected 20 mg/kg of CUR intraperitoneally for seven days and found that CUR significantly alleviated emotional deficits in mice subjected to CSDS. CUR restored the activity of pyramidal neurons in the medial prefrontal cortex (mPFC) and ventral CA1 (vCA1) regions, which were suppressed by CSDS during depression-like behaviors. Through network pharmacology and molecular docking, we identified CUR’s pharmacological targets and found that its antidepressant effects are partly mediated by modulating the cAMP-PKA signaling pathway. CUR treatment ameliorated synaptic transmission dysfunction in both the mPFC and vCA1. CUR regulated the cAMP-PKA signaling pathway and GluA1 subunit trafficking, thereby contributing to the restoration of synaptic function. CUR alleviated depression-like behaviors induced by CSDS by modulating the excitability and synaptic transmission of pyramidal neurons in the mPFC and vCA1 through activation of the cAMP-PKA-GluA1 signaling pathway. These findings provide new insights into CUR’s antidepressant mechanisms and highlight its potential as a therapeutic agent for depression.
Alzheimer’s disease (AD) involves complex lysosomal proteolytic dysfunction, but the specific roles of cathepsin family proteins remain unclear. This study aimed to systematically evaluate the association of cathepsins with AD risk and to explore underlying mechanistic pathways integrating neuroimaging, cognitive, and genetic evidence. We analyzed data from 52,988 UK Biobank participants. Plasma levels of 11 cathepsins were measured via Olink proteomics. Associations with AD diagnosis, cognitive performance, and brain structural measures were assessed using multivariable regression. Mediation analysis tested pathways through cognition and brain structure. Bidirectional two-sample Mendelian randomization (MR) was used to assess potential directional associations, and colocalization analysis was performed to identify shared genetic signals. Among the cathepsins analyzed, CTSL was the most coherent signal across observational analyses, showing associations with AD diagnosis, poorer cognitive performance, and reduced volume in AD-vulnerable regions including the hippocampus. Exploratory mediation analyses identified indirect associational patterns involving cognition and brain structure. Bidirectional MR provided genetic evidence for a positive directional association of genetically predicted CTSL with AD diagnosis (β = 1.2666 on the log-odds scale, p < 0.001) and for a reverse association of AD liability with higher CTSL levels (β = 0.5556, p < 0.001). Colocalization initially suggested a shared signal in the APOE/ZNF285 region, but this signal was not independent of APOE after sensitivity analysis. CTSL emerged as a candidate plasma molecule associated with AD across observational and genetic analyses. These findings support further longitudinal and experimental evaluation of CTSL, while the mechanistic interpretation remains preliminary.
In Alzheimer's disease (AD), senescent astrocytes fuel neuroinflammation and neuronal damage via the senescence-associated secretory phenotype (SASP). Calcium signaling plays a crucial role in this process, but the underlying molecular mechanisms remain elusive. We retrieved scRNA-seq data from the Gene Expression Omnibus (GEO) for AD and control brains. After cell-type annotation, we resolved astrocyte sub-clusters. Pseudotime trajectory and differential-expression analyses identified SORBS1 as a key senescence-related gene, which we followed with gene-set enrichment analysis. Next, we established an in vitro AD model by treating astrocytes with amyloid-β (Aβ). We evaluated astrocyte senescence using SA-β-gal staining, qRT-PCR, Western blot (WB) for senescence markers, and ELISA for SASP cytokines. We measured concentration of Ca2+ with Fluo-4 AM probes. Subsequently, bioinformatic screening predicted FBXO22 as an interactor of SORBS1 and BAG3 as a ubiquitination substrate of FBXO22. We validated these interactions using Co-IP and in vitro ubiquitination assays. Finally, we constructed an astrocyte-neuron co-culture model. We detected neuronal cell viability, AChE activity, AD phenotype-related protein expression, apoptosis, and levels of inflammatory factors using MTT assay, specific kits, WB, flow cytometry, and ELISA, respectively, to assess neuronal damage. ScRNA-seq analysis revealed a marked reduction in astrocyte expression in AD brains, which may result from cellular senescence. The SASP gene SORBS1 was selectively up-regulated in astrocytes and significantly enriched in calcium-signaling pathways. Functional assays confirmed that SORBS1 accelerated astrocyte senescence. Mechanistically, SORBS1 interacted with FBXO22 to promote the ubiquitin-dependent degradation of BAG3, thereby amplifying calcium signaling, accelerating astrocyte senescence, and contributing to AD-related neuronal damage. We uncover a novel mechanism by which the SORBS1/FBXO22/BAG3 axis drives astrocyte senescence through the regulation of calcium signaling, thereby influencing AD-related neuronal damage. This finding provides a potential therapeutic target for AD treatment by targeting astrocyte senescence.
Brain cancers hijack biological systems involved in neural development and synaptic plasticity. Medulloblastoma (MB), the most common malignant brain tumor in children, is thought to arise from disruptions in neurodevelopmental programs. Glutamatergic transmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) has been implicated in synaptic communication between adult brain tumors and surrounding neurons; however, the possible role of AMPARs in MB remains largely unexplored. Here, we analyzed the expression of genes encoding AMPAR subunits, GRIA1–4, in datasets of MB tumors and cell lines, revealing distinct expression patterns and associations with overall survival (OS) across molecular subgroups and histological variants. Expression levels differed among MB molecular subgroups. Analysis using single-cell RNA sequencing (scRNA-seq) was consistent with enrichment of GRIA1 in Group 3 and GRIA4 in sonic hedgehog (SHH) MB. Higher GRIA1, GRIA2, and GRIA4 transcription was associated with more favorable patient outcomes in specific MB subgroups. In contrast, high expression of GRIA3 in SHH, or of either GRIA3 or GRIA4 in Group 3 MB, was associated with worse prognosis. Particularly robust but opposing associations with patient survival were found for GRIA3 and GRIA4 in SHH MB. Analysis of GRIA mRNA levels in MB cell lines using both quantitative reverse transcription polymerase chain reaction (qRT-PCR) and data from The Human Protein Atlas, supported some of the gene expression patterns observed in tumors. Together, these findings suggest that GRIA genes and their corresponding AMPAR subunits may have subgroup-specific prognostic relevance in MB.
Chronic subdural hematoma (cSDH) is now better understood as a biologically active inflammatory disorder rather than purely a consequence of trauma. With recurrence occurring in up to 30
Juvenile myoclonic epilepsy (JME) is one of the most common idiopathic generalized epilepsy syndromes, yet its molecular pathogenesis remains incompletely understood. Circular RNAs (circRNAs) are stable non-coding RNAs with important regulatory roles and increasing relevance in neurological disorders. In this study, we investigated for the first time the association between selected circRNAs (hsa_circ_0000218, hsa_circ_0000229, hsa_circ_0000249, hsa_circ_0002010, and hsa_circ_0000143) and JME. Total RNA was isolated from peripheral blood samples of 41 patients with JME and 41 healthy controls, followed by RNase R treatment and quantitative real-time PCR analysis. Expression levels of hsa_circ_0002010 and hsa_circ_0000143 were significantly upregulated in patients with JME compared with controls (both p < 0.001), whereas hsa_circ_0000249 was significantly downregulated (p < 0.001). No significant differences were observed for hsa_circ_0000218 or hsa_circ_0000229. Sex-specific analyses revealed differential expression patterns, and hsa_circ_0002010 and hsa_circ_0000249 were associated with drug resistance. Our findings suggest that certain circRNAs may be involved in molecular pathways related to JME and may provide preliminary information to inform future studies exploring their potential relevance in JME.
Traumatic spinal cord injury (SCI) shows pronounced biological sex differences in incidence and short-term outcomes, yet mechanistic studies and therapeutic development are not consistently sex-informed. Here we summarize evidence that sex hormones, sex-chromosome effects and immune–glial interactions shape key components of the secondary injury cascade, including blood–spinal cord barrier (BSCB) disruption, neuroinflammation, oxidative stress, cell death and remyelination. Estrogens and progesterone generally support barrier stabilization, temper leukocyte infiltration, bias microglia/macrophages toward reparative programs, and promote neurotrophin signaling and myelin repair. In males, post-injury androgen deficiency together with stronger early innate immune activation may exacerbate oxidative damage, demyelination and scar formation, potentially limiting plasticity. Clinical evidence remains limited and confounded, but available data support the need for adequately powered, sex-stratified trials, particularly for time-sensitive hormonal and immunomodulatory interventions. Incorporating sex as a biological variable in experimental design and translation may improve target selection, dosing and therapeutic windows for SCI.
Down syndrome (DS), or trisomy 21 (T21), represents the most common genetic cause of intellectual disability worldwide and is associated with a wide range of medical, developmental, and neurodegenerative conditions, including a universal predisposition to early-onset Alzheimer’s disease (AD). Since its establishment in 2014, the Trisomy 21 Research Society (T21RS) has provided a global forum for advancing DS research across disciplines and promoting translational efforts to improve health and quality of life. Every two years, T21RS hosts an international scientific meeting that brings together researchers, clinicians, self-advocates, families, and industry stakeholders. In 2024, the 5th T21RS International Conference was held in Rome, Italy, from June 5 to 8, under the theme “Promoting Research Excellence in Down Syndrome.” The meeting brought together about 500 scientists from 26 countries across five continents, and more than 900 attendees overall, including families and caregivers. The scientific program featured 5 keynote lectures, 2 satellite meetings, 17 symposia, 7 nano symposia, 2 workshops, and 1 industry-focused session, totaling more than 150 oral presentations. More than 230 abstracts were presented as posters. The conference covered research across the lifespan of individuals with DS, spanning genomic and epigenetic regulation, molecular and cellular mechanisms, preclinical and experimental models, cognition and behavior, neurodevelopment, aging and neurodegeneration, co-occurring medical conditions, and therapeutic interventions. Dedicated sessions focused on capacity-building in DS research and societal engagement were established. Significantly, T21RS promoted inclusivity by supporting 60 young investigator fellowships, providing childcare awards, and organizing a two-day program for families and caregivers in collaboration with Italian DS associations. This proceeding summarizes the main scientific highlights of the 5th T21RS International Conference, reflecting the latest advances in DS biology, clinical research, biomarker development, and therapeutic innovation.
Intracellular glucocorticoid metabolism plays a critical role in shaping glucocorticoid receptor signaling in the brain. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) catalyzes the NAD+-dependent oxidation of active glucocorticoids to inactive 11-keto forms, yet its expression and functional capacity in the adult brain are generally considered negligible, except for discrete brainstem nuclei. Here, we examined HSD11B2 expression in the adult rat brain at the mRNA and protein levels using quantitative real-time PCR, Western blotting, and immunohistochemistry. To assess catalytic function, HSD11B2 was immunoprecipitated from hippocampal lysates and assayed in vitro in the presence of NAD+, using cortisol as a substrate. Hsd11b2 mRNA and HSD11B2 protein were detected across all brain regions examined. Immunohistochemistry indicated predominant HSD11B2 immunoreactivity in hippocampal neurons. Both hippocampal homogenates and HSD11B2 immunoprecipitates displayed NAD+-dependent glucocorticoid dehydrogenase activity, consistent with enzymatic functionality. Collectively, these findings provide molecular and functional evidence for HSD11B2 expression and activity in the adult rat brain and motivate further studies to define its cellular localization and to clarify how local glucocorticoid inactivation influences hippocampal signaling and physiology.
Neuropilins (NRPs), particularly NRP-1, are multifunctional co-receptors involved in neuroinflammatory and neuroprotective processes. Altered NRP expression has been observed in multiple sclerosis (MS) lesions and peripheral circulation, suggesting early involvement in disease progression. This review addresses the dual role of NRPs in MS and experimental autoimmune encephalomyelitis (EAE), emphasizing expression patterns, signaling pathways, and therapeutic interventions. NRP-1 is expressed by endothelial cells, microglia, and macrophages, while Sema3A, a key ligand, is produced by reactive astrocytes and contributes to a non-regenerative microenvironment. NRP-1 is involved in regulating blood-brain barrier (BBB) integrity, contributes to leukocyte trafficking, and modulates inflammatory signaling via the IFN-γ-STAT1-CXCL10 axis. In EAE, endothelial-specific NRP-1 deletion reduces disease severity, demyelination, and immune infiltration. Immunologically, NRP-1 governs interactions among T cells, dendritic cells, and macrophages, facilitating regulatory T cell (Treg) function and peripheral tolerance. Trogocytosis-mediated NRP-1 transfer from dendritic cells to T cells and polysialylated NRP-2 on dendritic cells further influence immune modulation. Tuftsin, a tetrapeptide targeting NRP-1, promotes anti-inflammatory microglial polarization and Treg activation, improving EAE outcomes. Therapeutic interventions, such as Bu-Shen-Yi-Sui Capsule (BSYSC), FTX-101 (a Sema3A-NRP-1 inhibitor), and tuftsin restore BBB function, reduce inflammation, enhance remyelination, and improve clinical scores. NRP-1 signaling thus exhibits context-dependent dual roles: promoting inflammatory cascades while enabling neuroprotection through regulatory immune networks and oligodendrocyte precursor cell support, highlighting NRP-1 as a therapeutic target in MS.
Emerging evidence indicates that circular RNAs (circRNAs) can encode functional peptides, which participate in the regulation of both physiological and pathological processes. CircRNA-derived peptides are involved in the regulation of various cellular functions and signaling pathways by interacting with specific biological molecules. These peptides can influence tumor progression by modulating key signaling pathways and by promoting or inhibiting malignant phenotypes through defined mechanisms. Consequently, the suppression of particular circRNA-encoded peptides may contribute to the inhibition of glioma progression or facilitate tumor elimination. Given that the expression of certain circRNAs is elevated in glioma tissues and associated cells, they hold potential as diagnostic biomarkers and therapeutic targets. This review provides a comprehensive overview of circRNA-encoded peptides, focusing on their regulatory roles and functional mechanisms in glioma. We discuss how these small peptides contribute to glioma pathophysiology and consider their prospective applications in diagnosis, prognosis, and targeted therapy.
Diabetic ischemic stroke leads to more severe brain damage. While the urokinase-type plasminogen activator receptor (PLAUR) is implicated in inflammation and cell migration, its precise role in diabetic stroke remains unclear. A streptozotocin-induced diabetic tMCAO mouse model was employed to simulate diabetic ischemic stroke. PLAUR expressions in mouse brain tissues were analyzed using microarray, Western blot, and immunofluorescence. PLAUR mRNA expression in endothelial cells (bEnd.3) was analyzed by RT-qPCR. We assessed cerebral infarct volume, brain water content, neurological deficits, and BBB integrity. Neutrophil infiltration (flow cytometry), inflammatory mediators, microglial polarization, and metabolic reprogramming (glycolytic proteins, ECAR/OCR) were investigated in vivo and in vitro. To test whether neutrophils are essential for PLAUR-mediated injury, we performed neutrophil depletion experiments using anti-Ly6G antibody, alone or combined with PLAUR knockdown. Neutrophil extracellular trap (NET) formation (CitH3 expression) and its impact on endothelial permeability and microglial polarization were also examined. PLAUR was significantly upregulated in the brains of diabetic stroke mice, particularly in microglia. PLAUR knockdown resulted in smaller infarct volumes, improved functional recovery, and maintained BBB integrity by restoring tight junction proteins. PLAUR knockdown was associated with reduced neutrophil infiltration, decreased pro-inflammatory mediator (MPO, MMP3) and attenuated pro-inflammatory M1 microglial polarization. PLAUR silencing also reduced NETosis in vivo and in isolated neutrophils. Neutrophil depletion alone significantly reduced infarct volume, improved neurological outcomes, and restored tight junction proteins; notably, PLAUR knockdown provided no additional benefit when neutrophils were already depleted, indicating that neutrophils are essential downstream effectors of PLAUR-mediated injury. Furthermore, PLAUR knockdown reversed the glycolytic shift in microglia. PLAUR is upregulated in diabetic ischemic stroke and its knockdown is associated with reduced neuroinflammation, preserved BBB integrity, decreased neutrophil infiltration, attenuated NETosis, and shifts in microglial polarization and metabolism. Therefore, targeting PLAUR represents a promising therapeutic strategy for attenuating brain injury in diabetic stroke.
