Glial cells play essential roles in maintaining neural tissue homeostasis and limiting the spread of injury-induced neuroinflammation, yet their dysfunction can also exacerbate neurodegenerative, neuroimmune, and neurodevelopmental disorders. Therapeutic targeting of specific glial cell populations would open up new treatment possibilities, but currently available viral and non-viral delivery vehicles are limited by carrier toxicity as well as poor delivery efficiency and specificity. To work towards new glia-targeted, non-viral delivery vehicles, we performed an in silico analysis on neural cell specific RNA-Seq datasets in mice to identify surface molecules differentially enriched on neurons, astrocytes, and microglia. We identified Slc2a5 (Glut5) as a microglia-enriched transporter and validated its microglia specific expression in healthy murine neural tissue using RNA in situ hybridization. By employing a sequential thiol-ene and enzymatic catalyzed reaction scheme, we synthesized polyelectrolytic dendrimers with multivalent presentation of fructose, the natural ligand for Glut5, and formulated nano-sized polyionic complexes (PICs) loaded with protein or nucleic acid cargo by mixing oppositely charged dendrimers. Fructose functionalized PICs lacking cationic surface charge enabled fructose-dependent intracellular protein delivery to Glut5-expressing human breast cancer cells (MCF-7) and mouse fibroblasts, while restricting uptake by Glut5-negative mouse astrocytes, confirming transporter-dependent selectivity in vitro . Fructose functionalized PICs resulted in minimal neuroinflammation when injected into mouse striatum at 1 mg/ml but elicited concentration-dependent neural tissue toxicity at higher doses. Fructose-PICs failed to achieve microglia specific intracellular delivery of functional proteins when injected into healthy neural tissue but aided in directing protein delivery to microglia and astrocytes at ischemic stroke lesions. Together, our findings demonstrate proof-of-principle for using in silico RNA-seq screening workflows to identify cell specific surfaceome targets and incorporating that insight into a modular biomaterial platform for targeted drug delivery.

Acute ischemic cardio-cerebrovascular events are critical clinical emergencies characterized by sudden interruption of arterial blood supply to the myocardium or cerebral tissue, predominantly presenting as acute myocardial infarction and ischemic stroke. Individuals affected by these events exhibit a significantly elevated risk of recurrence, particularly during the critical timeframe spanning the initial weeks to months following the primary incident. Accumulating evidence reveals that, in the aftermath of acute ischemic events, endothelial senescence and sustained endothelial dysfunction are mediated by trained immunity, alongside signaling cascades activated by exosome-derived ligands and neutrophil extracellular trap (NET)-derived cell-free DNA-most notably encompassing the Notch1 pathway and the high mobility group box 1-receptor for advanced glycation end products (HMGB1-RAGE) axis. Furthermore, neuroendocrine responses coupled with glucose metabolic dysregulation contribute to systemic inflammation and promote atherosclerotic progression. Current preclinical models highlight the therapeutic efficacy of multifaceted interventions, ranging from targeted interventions and immunomodulation to chemokine-receptor blockade. Consequently, this review elucidates the underlying mechanisms promoting post-ischemic plaque destabilization and systematically evaluates therapeutic strategies designed to minimize recurrence and optimize long-term patient outcomes.

Dysphagia constitutes a growing global health burden, particularly among geriatric and post-stroke populations. Although traditionally managed through biomechanical interventions, emerging evidence underscores the microbiota-immune axis as a critical modulator of systemic resilience and clinical outcomes. This review delineates how dysphagia drives systemic dysbiosis via three primary mechanisms: dietary modification, descending migration of oral pathogens along the oral-gut-lung axis, and iatrogenic pharmacological effects. A core pathological consequence is the depletion of microbial metabolites, especially short-chain fatty acids (SCFAs), which undermines neurological recovery and musculoskeletal integrity through the gut-brain and gut-muscle axes. Such dysbiosis further weakens intestinal barrier function, precipitating endotoxin translocation, chronic systemic inflammation, and elevated risk of life-threatening complications like aspiration pneumonia. Consequently, nursing practice should integrate microbiome-targeted strategies. Key interventions encompass nutritional modulation with specific probiotics (e.g., Lactobacillus rhamnosus GG) and prebiotics to restore SCFA levels, enhanced oral care to minimize pathogen reservoirs, and pharmacological stewardship to mitigate iatrogenic microbial disruption. Adopting these tailored approaches, these can transit nursing care from compensatory support to actively promoting physiological recovery and immune resilience in dysphagia patients.

Patients with liver cirrhosis who develop minimal hepatic encephalopathy (MHE) show mild cognitive impairment associated with increased peripheral inflammation, including elevated interleukin-17 (IL-17). In animal models, this inflammation promotes neuroinflammation and disrupts glutamatergic neurotransmission in the hippocampus, contributing to cognitive deficits. This study investigated whether IL-17 is directly involved in cognitive impairment in hyperammonemic rats and explored the mechanisms involved. Hyperammonemic rats received intravenous anti-IL-17 treatment at days 3-5 after induction of hyperammonemia. Cognitive assessment and blood-brain barrier integrity, neuroinflammation, and glutamatergic neurotransmission in the hippocampus were performed after four weeks. Increased peripheral IL-17 activated its receptor in endothelial cells, enhancing NADPH oxidase activity and increasing Myosin light chain kinase (MLCK) levels. This reduced the tight junction proteins occludin and ZO-1, weakening the blood-brain barrier and facilitating immune cell infiltration and IL-17 entry into the hippocampus. Consequently, microglia became activated, increasing TNFα and IL-1β levels and altering membrane expression of glutamate receptors, leading to cognitive impairment. Blocking IL-17 prevented these pathological changes and produced sustained protection against cognitive deficits. These findings support a role of IL-17 in early transmission of peripheral inflammation into the brain initiating hippocampal neuroinflammation and cognitive impairment in MHE and propose anti-IL-17 therapies for MHE.

Background: Intracellular Ca[2+] dysregulation and neurovascular dysfunction are increasingly recognized as important mechanisms underlying neurodegenerative disorders, including Alzheimer's disease (AD). Restoration of pathological Ca[2+] imbalance has therefore emerged as a potential therapeutic strategy. Although ginsenoside compound K (CK) has demonstrated neuroprotective and anti-inflammatory properties, its role in Ca[2+] homeostasis remains unclear. Methods: SH-SY5Y neuronal cells, U373 astrocytes, BV2 microglia, bEND brain endothelial cells, and MOVAS vascular smooth muscle cells were exposed to trimethyltin chloride (TMT, 5 μM, 24 h). Cell viability, real-time cell confluence, intracellular Ca[2+] influx, and endoplasmic reticulum (ER) Ca[2+] store release were evaluated. Ca[2+] dynamics were analyzed using Fura-2 fluorescence, and signaling associated with CK-mediated Ca[2+] regulation was investigated using pharmacological inhibitors. Orai1 protein expression was evaluated by Western blot analysis in SH-SY5Y and U373 cells. Results: TMT increased store-operated Ca[2+] entry (SOCE)-mediated Ca[2+] influx in SH-SY5Y neuronal cells without significant cytotoxicity. In contrast, TMT reduced both Ca[2+] influx and cell viability in U373 astrocytes, BV2 microglia, and MOVAS cells, whereas bEND cells showed minimal changes. CK restored abnormal Ca[2+] responses in a cell type-specific manner, reducing elevated Ca[2+] influx in neuronal cells while restoring suppressed Ca[2+] signaling in astrocytes. Consistent with these functional findings, Orai1 protein expression was increased by TMT in SH-SY5Y cells and attenuated by CK, whereas TMT reduced Orai1 expression in U373 cells, which was restored by CK. Pharmacological analyses suggested involvement of PKA- and LTCC-associated signaling in neuronal cells and PLC- and PLD-associated signaling in astrocytes. In both cell types, CK-associated Ca[2+] responses were sensitive to NAC and the SOCE inhibitor BTP2, supporting ROS- and SOCE-associated mechanisms. Additional controls showed no significant inhibitor effects under control or CK-only conditions, strengthening the pharmacological interpretation of responses under TMT-containing conditions. Conclusions: TMT-induced Ca[2+] dysregulation differed markedly by cell type. CK restored disrupted Ca[2+] homeostasis in association with distinct pharmacological signaling profiles in neuronal and astrocytic cells. These findings suggest that CK may function as a cell type-specific Ca[2+] homeostatic regulator under neurotoxic stress conditions and highlight the importance of differential Ca[2+] regulation in neurodegenerative disease models.

Background/Objectives: Schizophrenia is a complex psychiatric disorder characterized by positive, negative, and cognitive symptoms, as well as disturbances of the self and metacognitive dysfunction. Increasing evidence suggests that these dimensions contribute substantially to psychosocial functioning and recovery, yet they are often investigated separately. This narrative review aims to integrate current knowledge on self-disturbances and metacognition in schizophrenia and discuss their relevance for contemporary therapeutic approaches. This review proposes an integrative conceptual framework positioning disturbances of the minimal self and metacognitive dysfunction as complementary dimensions that may contribute to schizophrenia psychopathology and may have relevance for recovery-oriented interventions. Methods: A narrative review of the peer-reviewed literature was conducted. Classical theoretical papers, recent empirical studies, systematic reviews, and meta-analyses addressing self-disturbances, metacognition, and therapeutic interventions in schizophrenia spectrum disorders were analyzed. Results: Current evidence indicates that disturbances of the minimal self and metacognitive dysfunction may represent complementary and interacting dimensions of schizophrenia psychopathology. Self-disturbances affect the subjective sense of identity, agency, and self-presence, whereas metacognitive deficits impair the integration of information about oneself and others into coherent mental representations. These impairments are associated with poorer psychosocial functioning, reduced quality of life, and limited recovery. Interventions targeting metacognitive functioning, including Metacognitive Reflection and Insight Therapy, Metacognitive Training, and cognitive remediation, have shown promising effects on functional outcomes and recovery. Conclusions: Integrating phenomenological concepts of self-disturbance with contemporary metacognitive models may provide a broader understanding of schizophrenia than symptom-based approaches alone. In clinical practice, instruments such as the Examination of Anomalous Self-Experience (EASE) and Metacognition Assessment Scale-Abbreviated (MAS-A) may complement standard assessment by providing information about anomalous self-experiences, insight, and psychosocial functioning. However, the additional diagnostic value of combining these assessments with established clinical procedures has not yet been clearly demonstrated. They should therefore be regarded as supplementary tools that may inform clinical formulation and individualized, recovery-oriented treatment planning rather than as standalone diagnostic measures.

Non-invasive brain stimulation (NIBS), including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), has been widely used as an adjunctive intervention for upper limb motor recovery after stroke; however, the treatment completion rates and comparative safety profiles across different NIBS modalities have not been systematically evaluated. This systematic review and network meta-analysis aimed to assess and compare the treatment completion rates of various NIBS interventions for post-stroke upper limb rehabilitation. We systematically searched six databases and trial registries (PubMed, Embase, Cochrane CENTRAL, CINAHL, WHO ICTRP, and ClinicalTrials.gov) for randomized controlled trials (RCTs) published up to January 20, 2025, with an updated search conducted to April 15, 2026. Random-effects single-arm meta-analyses using the Freeman-Tukey double arcsine transformation were performed to pool completion rates, and a Bayesian random-effects network meta-analysis estimated relative risks (RRs) with 95% credible intervals (CrIs); treatments were ranked using surface under the cumulative ranking curve (SUCRA) values. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. The protocol was registered with PROSPERO (CRD420261309536). Fifty-five RCTs comprising 68 comparisons and 2,640 participants were included. The pooled intervention group completion rate was 94.9% (95% CI: 93.3-96.4%; I[2] = 46.8%). The network meta-analysis showed no statistically significant differences in completion rate between any NIBS intervention and sham/control (all 95% CrIs included 1.00). SUCRA rankings indicated that intermittent theta burst stimulation (iTBS; 71.1%), bilateral rTMS (BL-rTMS; 60.9%), and dual transcranial direct current stimulation (Dual-tDCS; 58.1%) ranked highest. The overall adverse event (AE) rate was 16.4% (95% CI: 8.5-26.2%) in intervention groups, predominantly mild headache and skin tingling, with an AE-related dropout rate of only 1.1%. Subgroup analyses showed higher completion rates for tDCS (96.8%) than rTMS (93.9%), with the chronic phase highest (97.1%) and the mixed phase lowest (89.1%). The LFK index was 0.04, indicating no publication bias. In conclusion, NIBS for post-stroke upper limb rehabilitation demonstrates favorable tolerability and safety, with an overall completion rate of approximately 95%. Exploratory SUCRA rankings placed iTBS, BL-rTMS, and Dual-tDCS in the top three positions; however, these rankings should be considered hypothesis-generating rather than definitive, as four interventions were informed by only a single study, absolute differences in completion rates were minimal, and all pairwise credible intervals included 1.00. These observed phase-specific differences suggest that stroke phase may be an important factor to consider when designing adherence strategies, although prospective evaluation of tailored interventions is needed.

Traumatic brain injury (TBI) patients may suffer from several long-term complications after injury such as impaired motor skills, cognitive decline, and sensory abnormalities including chronic pain. Disruption of endogenous pain modulatory pathways likely contributes to the development of chronic pain in a wide range of conditions including TBI. Aerobic exercise has been shown to impact pain syndromes. Here, we investigate the effect of exercise on nociceptive outcome measures after TBI using a lateral fluid percussion (LFP) model and voluntary running wheels in male and female rats. We tested mechanical nociceptive reactivity with von Frey fibers and descending control of nociception (DCN) using hindpaw sensitization with prostaglandin E2 followed by a capsaicin-test stimulus to the forepaw. Pharmacological studies included administration of noradrenergic (NA) and serotoninergic receptor antagonists. Neuropathological studies quantified neuroinflammatory changes and axonal damage. We found that exercise decreased the duration of hindlimb hyperalgesia from ∼5 weeks to 2-3 weeks in female and male TBI rats, respectively. These gains were reversed by administration of the α1-adrenoceptor (α1-AR) antagonist, prazosin. Exercise also prevented the loss of DCN for at least 180 days post-injury in both male and female TBI rats. The intact DCN response in male and female TBI rats provided by exercise could be blocked using prazosin. Surprisingly, exercise-mediated restoration of the DCN response in male TBI rats was not blocked by the 5-HT7 receptor antagonist, SB-267790, despite this being the receptor system through which serotonin reuptake inhibitors restore DCN after TBI in male rats. Assessment of neuropathology, conducted acutely after TBI, revealed that both astrocyte and microglial responses to injury were significantly greater in male TBI compared with female TBI rats, regardless of exercise. The effect of exercise on the extent of neuroinflammation after injury was minimal in TBI rats of both sexes. Exercise significantly reduced axonal loss in the corpus callosum in both male and female TBI rats compared with sedentary TBI rats. However, the extent of axonal loss after TBI in both exercise and sedentary male rats was greater than in female exercise and sedentary groups, respectively. These results demonstrate that exercise is a promising treatment for chronic nociception after TBI in both male and female rats. It also highlights that dysfunction of endogenous pain modulatory pathways in male TBI rats involving a transition from NA to serotonergic antinociception can be blocked by exercise, possibly by reducing axonal loss.

A persistent barrier to optimizing the utilization of deceased donor kidneys, nearly 30% of which are discarded, is the absence of objective, molecularly resolved metrics of organ quality. To address this gap, we integrated high-resolution proteoform imaging mass spectrometry (PiMS) of donor kidney biopsies with deep LC-MS-based intact proteoform profiling of recipient peripheral blood mononuclear cells (PBMCs) and standard clinical assays. This approach enables direct delineation of proteoform landscapes and reveals immunological and cell stress signatures. Across donor types, living donor (LD) kidneys were enriched for proteoforms associated with oxidative metabolism and cellular homeostasis, whereas kidneys from donation after brain death (DBD), donation after circulatory death (DCD), and discarded organs exhibited elevated abundance of stress-responsive proteoforms, including acetylated CRYAB, PARK7, S100A4, and ACTG1. Despite more pronounced early allograft dysfunction in DCD recipients, DCD tissue proteoform landscapes were globally more similar to LD than to DBD kidneys, indicating distinct injury biology not captured by clinical metrics or peptide-centric proteomics. To extend these findings beyond the graft, we performed the first paired tissue and PBMC proteoform profiling across donor types. Baseline PBMC proteoform differences were minimal; however, by day 7 post-transplant, recipients of deceased donor kidneys exhibited platelet activation, cytoskeletal stress, and inflammatory signaling. Several PBMC-derived proteoforms correlated with serum creatinine, highlighting their potential as early, objective indicators of graft adaptation. Collectively, this proof-of-concept study defines conserved injury-associated proteoforms across tissue and immune compartments and support the idea that proteoform-resolved analysis may provide a mechanistically grounded, objective framework for assessing donor kidney quality and early graft function.

Chiari I malformation (CM1), the most common structural hindbrain disorder in humans, is traditionally characterized by the downward displacement of the cerebellar tonsils through the foramen magnum. However, this definition does not reflect the variability in clinical presentation, natural history and treatment response of this disorder. Some individuals with minimal tonsillar descent have severe neurological symptoms and syringomyelia, whereas others with extensive descent remain asymptomatic. Emerging evidence from neuroimaging, developmental biology and human genetics indicates that CM1 is not a single anatomical entity but a spectrum of disorders resulting from disruptions in coordinated growth and homeostasis across the cerebellum, posterior fossa, craniocervical junction, cerebrospinal fluid and neurovascular systems. CM1 may be best understood as a disorder of disrupted developmental scaling, in which the tightly regulated relationships between cerebellar growth and cranial accommodation are altered within a dynamic neurovascular and cerebrospinal fluid environment. In this context, tonsillar herniation is a geometric consequence rather than the primary disease process. This Primer synthesizes current knowledge on the epidemiology, mechanisms, diagnosis and management of CM1 across the lifespan. We highlight advances in neuroimaging, genomics and phenomics that support a shift from anatomy-based definitions towards an integrated genomic-phenomic classification.