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Ischemic stroke (IS) induces profound dysregulation of the neuro-molecular innate immune-vascular network, yet the molecular immune states and regulatory mechanisms of key cellular subpopulations remain insufficiently defined. Although traditional Chinese medicine (TCM) exhibits multi-target immunomodulatory potential, its cell-type and cell-state-specific actions within the ischemic brain microenvironment at single-cell resolution remain unclear. Single-cell RNA sequencing was used to construct a cellular atlas of the ischemic mouse brain, followed by integrative bioinformatic analyses to characterize innate immune-related neural cell subpopulations and their regulatory networks. Network pharmacology and molecular docking were applied to identify salidroside (SAL), a major active compound of Rhodiola, and predict its potential molecular targets. In vivo experiments were performed to validate cellular and molecular changes associated with SAL treatment. In a mouse model of IS, ischemic injury induced pronounced imbalances across multiple immune and glial cell subpopulations. A transcriptionally defined Notch1+ Hes5+ astrocyte (ASC), enriched for progenitor-like and reparative gene signatures, was markedly reduced after ischemic injury, whereas reactive SerpinA3N+ ASC and pro-inflammatory Sell+ microglia (MG) were expanded. Additionally, alterations were observed in immune-regulatory cell populations, including Cxcl12+ endothelial cells (ECs) and Gpr34+ Ptgs1+ MG. In vivo validation showed that SAL treatment was associated with modulation of Notch1/Hes5 signaling in ASC, reduced reactive ASC features, and partial normalization of ECs alterations, accompanied by changes consistent with attenuated neuroimmune activation. These effects coincided with altered intercellular communication, particularly involving NOTCH signaling. This study provides single-cell-level insights into innate immune microenvironment remodeling following IS and identifies a Notch1+ Hes5+ ASC subpopulation with transcriptional features associated with reparative-related programs and responsiveness to SAL. The findings suggest that SAL-associated neuroprotection was accompanied by modulation of ASC states and immune-glial communication, highlighting the potential of SAL-associated immunoregulatory effects at the single-cell level in IS.

Vascular dementia (VaD), a major contributor to cognitive decline, arises primarily from impaired regulation of cerebral circulation. Pterostilbene (PTE), a natural stilbene, exhibits potent neuroprotective properties, including antioxidative, anti-apoptotic, and cognition-enhancing effects; however, the molecular basis of its protective action in VaD remains poorly defined. Here, we integrated network pharmacology with in-vitro and in-vivo validation to delineate the mechanistic underpinnings of PTE. An ischemic injury model was established in SH-SY5Y cells using oxygen-glucose deprivation/reoxygenation (OGD/R), while VaD was induced in rats by bilateral common carotid artery occlusion. Cognitive function was assessed by behavioural paradigms, and neuronal integrity, vascular architecture, mitochondrial function, respiratory complex activities, and synaptic plasticity via the cAMP/PKA/CREB signalling cascade were evaluated using histological, biochemical, and molecular assays. Network pharmacology identified the cAMP pathway as a principal mediator of PTE activity. In ischemia injured SH-SY5Y cells, PTE improved viability, reduced oxidative stress, stabilized mitochondrial membrane potential, and elevated ATP production. In VaD rats, PTE enhanced spatial learning and memory, preserved cortical and hippocampal structures, and promoted mitochondrial health, evidenced by upregulation of PGC-1α and TFAM, restoration of respiratory complex activities, and preservation of mitochondrial ultrastructure. PTE also increased expression of synaptic proteins (PSD95, Synaptophysin). Consistently across both models, PTE activated the cAMP/PKA/CREB signalling axis. Collectively, these findings demonstrate that PTE mitigates ischemia-induced cognitive impairment by reversing mitochondrial dysfunction while sustaining synaptic plasticity through cAMP/PKA/CREB activation, highlighting its translational potential as a therapeutic candidate for VaD.

Neuronal differentiation into specific subtypes is crucial for nervous system development and function, guided by neurotrophic factors. γ-Enolase, a neuron-specific glycolytic enzyme, exhibits neurotrophic-like properties and supports neuronal differentiation; however, its role in specific neuronal subtypes remains unknown. Here, we investigate the role of γ-enolase in differentiation dopaminergic-, cholinergic-, and adrenergic-like neuronal cells. Our results demonstrate that γ-enolase expression is significantly upregulated in differentiated cells, with the highest expression observed in cholinergic-like neurons. Full-length γ-enolase, compared to its truncated form, promoted enhanced neurite outgrowth and increased β-tubulin, a cytoskeletal marker. Conversely, silencing endogenous γ-enolase significantly reduced neurite length, confirming its essential role in driving neuronal morphological maturation. Furthermore, a γ-enolase-derived peptide corresponding to the active C-terminus of γ-enolase significantly promoted neurite outgrowth and increased β-tubulin expression, particularly in cholinergic-like neuronal cells. Notably, γ-enolase activity is regulated by cathepsin X, a lysosomal peptidase that cleaves γ-enolase at its C-terminus, reducing its neurotrophic effects. Confocal microscopy revealed increased co-localization of γ-enolase and cathepsin X in differentiated neuronal cells, emphasizing their interaction in cholinergic-like neurons. Inhibiting cathepsin X preserved active γ-enolase, promoted neuronal differentiation, and altered cytoskeletal marker expression. These findings suggest an important role for γ-enolase in cholinergic-like neuronal cells and propose cathepsin X as a regulatory modulator of γ-enolase activity, suggesting novel therapeutic strategies for neuroregeneration.

Peripheral nerve injury significantly impacts patients' quality of life, with poor nerve regeneration and insufficient functional recovery being urgent challenges. Even with early medical and surgical interventions, desired outcomes are often not achieved. Our research focuses on effective surgical and rehabilitation strategies, as well as the development of innovative technologies. Peripheral nerve injury repair is analyzed from three main perspectives: first, improving intrinsic axonal growth capacity, which involves signaling pathways and the regulation of neuromodulatory factors; second, enhancing the injury repair environment, where Schwann cells (SCs) and macrophages play key roles in reducing inhibitory factors, and regulating the immune microenvironment is crucial; and third, ensuring the successful and correct reconnection of the repaired nerve to the innervated tissue, preventing distal tissue degeneration and scar formation. This review explores concepts related to peripheral nerve injury (PNI) and the associated anatomical changes, offering a schematic representation of the various types of nerve damage. We review studies conducted in experimental models of peripheral nerve injury treatment, discussing existing treatment methods-such as surgical interventions, drug-based therapies, and other approaches-and highlight new PNI treatments, particularly for critical lesions, aimed at overcoming existing limitations and achieving better clinical outcomes.

Ferroptosis, an iron-dependent form of regulated cell death, has been increasingly linked to neurodegeneration in Parkinson's disease (PD). The lipid-peroxidizing enzyme 5-lipoxygenase (5-LOX) contributes to ferroptotic stress, while montelukast, a leukotriene receptor antagonist widely used for asthma, indirectly interferes with this pathway. Here, we investigated whether montelukast protects against dopaminergic injury in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mice were evaluated for behavioral deficits and underwent histological and biochemical analyses to assess iron burden, oxidative stress, ferroptosis markers, and neuroinflammation. Montelukast administration alleviated MPTP-induced motor dysfunction, preserved tyrosine hydroxylase-positive neurons, and reduced α-synuclein accumulation. Treatment also decreased iron deposition and malondialdehyde production while restoring glutathione and superoxide dismutase activity. At the molecular level, montelukast upregulated xCT/GPX4 while downregulating ACSL4/5-LOX, indicating suppression of ferroptosis. Moreover, montelukast attenuated microglial activation and pro-inflammatory cytokine expression. Collectively, our results suggest that prophylactic administration of montelukast mitigates dopaminergic neurodegeneration by modulating markers of ferroptosis and inflammatory signaling. These findings indicate the GPX4/ACSL4/5-LOX axis as a potential neuroprotective target for PD.

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The cerebral adenosinergic system is involved in sleep-wake regulation and presumably represents a neuro-molecular correlate of homeostatic sleep pressure. For acute sleep deprivation, it has been shown that increased cerebral A1 adenosine receptor (A1AR) availability was related to impairments in cognitive performance. The present study examined A1AR availability in response to chronic sleep restriction and recovery. To quantify A1AR availability we used [18F]CPFPX positron emission tomography in 21 volunteers after 5 nights with 5-h sleep opportunities followed by 8 h recovery sleep. Data were compared to a control group of 15 volunteers who slept 8 h each night. In addition, polysomnography, cognitive performance, and alertness were recorded. Chronic sleep restriction did not increase the A1AR availability. Slow wave sleep (SWS) and EEG slow-wave-activity (SWA) in the first 5 h of sleep did not differ from baseline, but SWA in the last 3 h of sleep was increased and cognitive performance and alertness were impaired. While SWA returned to baseline in the last 3 h of recovery sleep, performance and alertness remained impaired. The results indicate that chronic sleep loss likely induces parallel upregulations of extracellular adenosine and A1AR resulting in no net gain in receptor availability. The results contrast with findings from acute sleep deprivation in which we found impaired performance and increased A1AR availability that were restored to rested levels after recovery sleep. The findings reveal fundamental differences in the mechanisms through which acute and chronic sleep loss affect adenosinergic regulation and cognitive performance.

Brain energetics rely on a distributed partnership among cell types and fuel sources. Beyond astrocytic glycogen, the brain has limited conventional energy reserves. Emerging evidence broadens this view by positioning myelin and oligodendrocytes as active stabilizers of metabolic homeostasis. They align substrate delivery with demand and directly sustain axonal ATP production. This review highlights current understanding that myelin lipid stores function as a conditional metabolic buffer that can be mobilized when glycolytic supply wanes. Firstly, we outline the protective repertoire of myelin (e.g., adaptive myelination, antioxidant defense, and metabolic coupling) and then summarize myelin lipid metabolism, spanning de novo synthesis and β-oxidation. We next demonstrate disease contexts marked by energetic failure. Specifically, Alzheimer’s disease exhibits a chronic metabolic downshift, whereas ischemic stroke produces an acute collapse of energy production. Both states may recruit the proposed buffer. However, leveraging lipid-derived fuels is not without risk. Reactive oxygen species, acidosis, and iron handling must be tightly regulated to avoid collateral injury. Finally, we highlight methodological priorities that can resolve mechanism in vivo, including white matter-resolved fluxomics, myelin specific imaging paired with proteo-lipidomics, and lineage-restricted perturbations of β-oxidation and autophagy. On the translational front, we propose stage specific strategies. In summary, defining when and how to mobilize and supplement myelin lipid reserves could transform a conceptual buffer into a practical lever for disease modification in hypometabolic brain disorders.

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Chronic cerebral hypoperfusion (CCH) is a key pathological hallmark observable in multiple subtypes of cerebral small vessel disease (CSVD). This condition causes both structural and functional changes within the brain's vascular system, and is particularly damaging to brain microvascular endothelial cells (BMECs). The exact molecular mechanisms underlying BMEC impairment in CCH remain insufficiently defined despite their clinical importance. Emerging evidence indicates that disturbances in intracellular lipid metabolism might contribute substantially to promoting endothelial inflammation and functional deficits. This study aims to investigate whether aberrant lipid metabolism contributes to endothelial inflammation and tight junction (TJ) dysfunction in BMECs under the condition of CCH, and to assess the therapeutic potential of intervention with simvastatin. A rat model of chronic CSVD was created via permanent bilateral ligation of the common carotid arteries (2VO) in animal subjects. Samples of cortical microvasculature were collected at predefined intervals for transcriptome profiling. Assessments of lipid metabolism, inflammation-related factors, and TJ protein levels were conducted in both in vivo and after induction of hypoxia and administration of simvastatin. At 14d post-2VO, mRNA expression of TJ proteins including occludin (Ocln), claudin-5 (Cldn5), and zonula occludens-1 (Zo-1) was significantly downregulated in BMECs compared to sham controls. Simultaneously, there was a notable buildup of lipid droplets, rise in cholesterol levels, and upregulation of pro-inflammatory indicators including VCAM1, TNF-α, and ICAM1. Simvastatin administration effectively reduced lipid buildup, suppressed inflammation, and restored TJ integrity. Dysregulated lipid metabolism and heightened inflammatory responses contribute to TJ disruption in BMECs with CCH. Simvastatin therapy mitigates lipid accumulation, dampens inflammation, and improves TJ function in BMECs with CCH.

Tay-Sachs disease is a severe neurodegenerative disorder caused by mutations in the HEXA gene, which encodes the α-subunit of the β-hexosaminidase A (HexA) enzyme. HexA deficiency leads to abnormal GM2 accumulation, eventually causing cell death and neurodegeneration. A double-knockout mouse model lacking both Hexa and Neu3 genes (Hexa-/-Neu3-/-, DKO) exhibits neuropathological and clinical features similar to those of the disease, including neuroinflammation. B4Galnt1 (ß-1,4-N-acetyl-galactosaminyltransferase 1) is involved in lipid biosynthesis in mice. We hypothesized that creating a triple knockout model (Hexa-/-Neu3-/-B4Galnt1-/-, TKO) could prevent excessive GM2 ganglioside accumulation and reduce disease symptoms. Molecular biology and immunohistochemistry analyses showed that GM2 ganglioside accumulation was halted in TKO mice. Preventing GM2 ganglioside accumulation alleviated neuroinflammation and neuronal death, extending lifespan by more than 18 months. Our findings suggest that knocking out B4Galnt1 to block GM2 ganglioside accumulation may reverse disease symptoms in the DKO mouse model, indicating a promising, safe target for substrate-reduction therapy via siRNA silencing. The online version contains supplementary material available at 10.1007/s12017-026-08916-x.

Both postmenopausal estrogen decline and chronic unpredictable mild stress (CUMS) contribute to the onset and progression of brain dysfunctions in women. Genistein, a phytoestrogen predominantly found in soy and soy products, may reverse brain dysfunctions. Therefore, the current study focused on determining the effect of GEN in the modulation of brain dysfunction by using the Ovariectomized (OVX)-CUMS rat model. To induce postmenopausal brain dysfunction, female SD rats were bilaterally OVX and then exposed to CUMS for a total of 28 days. Various basic physiological and neurobehavioral parameters were performed. Oxidative stress was measured in the brain. Brain inflammation (TNF-α, IL-6, & NF-kB/p65), apoptotic (Bax) and anti-apoptotic (Bcl-2) markers were analyzed using RT-PCR and/or ELISA. Decreased estrogen levels and CUMS both combinedly cause a reduction in serum estradiol levels, downregulation of ER-α and ER-β genes, and enhancement of oxidative stress, neuroinflammation, and apoptosis. Collectively, all these factors were responsible for the development of neuronal dysfunctions. GEN at doses of 10 & 20-mg/kg significantly and dose dependently restores serum estradiol levels and ER-β gene expression. With this, genistein also reduces oxidative stress, apoptosis, and neuroinflammation in the brain of OVX-CUMS rats. Thus, GEN (10 & 20-mg/kg) dose-dependently restores the estrogen deficiency and chronic stress-induced brain dysfunction.

The Presenilins are multi-pass transmembrane proteins that form part of the multi-protein gamma secretase complex. The hydrolytic activity of the gamma secretase complex is responsible for the cleavage of a wide range of substrates, including the amyloid precursor protein (APP) - a proteolytic event that is the final step in the production of the amyloid beta peptide, a protein fragment deposited in the brains of individuals with Alzheimer's disease (AD). Both PSEN1 and PSEN2, the genes encoding the Presenilins, are mutated in familial AD, generating intense interest in the activity and function of these proteins. Despite this attention, the post-translational modification and regulation of the Presenilins is poorly understood. In order to address this gap in our knowledge, a bioinformatic approach was taken to examine the extant evidence for Presenilin phosphorylation. Derived from the Phosphosite repository, these data reveal divergent patterns of phosphorylation across Presenilin 1 and 2, highlighting distinct regulatory pathways that have implications for our understanding of the biology of these proteins, gamma secretase, and drug discovery targeting this complex.

Neurodegenerative diseases impose a substantial and growing global burden, affecting millions worldwide and leading to high medical, social, and economic costs. These are characterized by progressive neuronal dysfunction and loss, leading to cognitive, motor, and behavioral impairments. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease are driven by intertwined mechanisms of oxidative stress, neuroinflammation, protein aggregation, and neuronal apoptosis. Activation of the TLR-2/NF-κB axis promotes neuroinflammation and pyroptotic cell death through excessive production of pro-inflammatory cytokines, contributing to neuronal damage. Dysregulation of the TLR-2/Akt/mTOR pathway impairs autophagy, leading to defective clearance and accumulation of α-synuclein, a central event in synucleinopathies. Moreover, compromised Nrf2-mediated antioxidant signaling weakens cellular redox homeostasis and anti-apoptotic defenses, thereby linking redox imbalance to caspase-dependent neuronal apoptosis. Given the complex and multifactorial nature of neurodegenerative diseases, there is a pressing need for multitarget agents. Phloretin is a natural dihydrochalcone predominantly found in apples, pears, and strawberries. It exhibits broad pharmacological activities, including antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective effects, making it a promising multitarget phytochemical for neurodegenerative conditions. Phloretin mediates its neuroprotective properties through the modulation of several mediators, including Aβ, TLR-2, NF-κB, COX, iNOS, PPARγ, Nrf2, beclin-1, Bax, Bcl-2, caspases, PI3K/Akt, mTOR, pro-inflammatory cytokines, and antioxidant enzymes, among others. Despite compelling preclinical evidence, critical gaps remain regarding phloretin's effects on inflammasome initiation, ER stress responses, mitophagy, neurotrophic signaling, and, importantly, its clinical safety and efficacy, underscoring the need for integrated mechanistic studies and well-designed clinical trials.

The brain undergoes profound molecular and structural changes during the aging process, resulting in the development of neurodegeneration, cognitive impairment, and increased vulnerability to chronic diseases. At the cellular level, brain aging is characterized by oxidative damage, genomic instability, and chronic low-grade inflammation known as inflammaging. Central to this process is Sirtuin 1 (SIRT1), a NAD+-dependent class III histone deacetylase, known for its regulatory role in chromatin remodeling, oxidative stress responses, mitochondrial biogenesis, and neuroplasticity. Recent research has identified SIRT1 as a molecular target capable of reversing or attenuating several hallmarks of aging, particularly within the central nervous system (CNS). This narrative review critically evaluates the emerging evidence surrounding the geroprotective effects of SIRT1 activators, which exert dual actions, senomorphic and senolytic, via modulation of signaling pathways, thereby reducing neuronal senescence, enhancing autophagy, and mitigating inflammatory responses. The discussion also addresses the region-specific role of SIRT1 across the brain, particularly in the hippocampus and hypothalamus, which are essential for memory, energy homeostasis, and resilience to stress. Additionally, this review explores how SIRT1 depletion during aging contributes to the development of synaptic dysfunction, impaired cognitive function, and susceptibility to neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). The therapeutic potential of SIRT1 activators is supported by preclinical and early clinical studies, suggesting their value in preventing or delaying brain aging. Thus, SIRT1 could be a promising pharmacological target for age-associated brain disorders, warranting more robust translational studies to validate these findings in humans.

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Scrub typhus, caused by the obligate intracellular bacterium Orientia tsutsugamushi(O. tsutsugamushi), is an acute febrile illness. While neurological complications are known, hearing loss is an uncommon manifestation, and coinfection with Epstein-Barr virus(EBV) presents unique diagnostic and pathophysiological challenges. A 58-year-old woman presented with a 5-day history of high fever, severe headache, and constitutional symptoms. She reported transient, fluctuating bilateral hearing loss. Examination revealed characteristic eschars on her legs. Laboratory findings indicated hepatic impairment and systemic inflammation. Metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid detected O. tsutsugamushi and EBV. EBV serology profile (VCA-IgG+, VCA-IgM-, EBNA-IgG+) suggested viral reactivation. The patient failed to respond to initial beta-lactam antibiotic therapy but showed rapid and complete resolution of symptoms, including hearing loss, after initiation of doxycycline. At the 1-month and 3-month follow-up, audiological assessment confirmed normal hearing. This case highlights a rare presentation of scrub typhus with EBV coinfection involving fluctuating hearing loss. The dramatic response to doxycycline suggests this auditory symptom may be a reversible, immune-mediated complication of O. tsutsugamushi infection. Physicians should be aware of this potential manifestation in endemic areas. The immunological interplay between these pathogens warrants further investigation.

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Down syndrome (DS) represents one of the most common genetic disorders attributable to a partial or complete trisomy of chromosome 21 that affects about 1 in 700 individuals at birth. The diagnosis of Alzheimer's Disease (AD)-correlated cognitive decline in this population requires new approaches and new biomarkers that comprehensively assess health status and early cognitive decline. In this observational study, we explored for the first time the relation of IL-18, a cytokine member of IL-1 family involved in both innate and acquired immune responses, with DS associated cognitive decline. We observed that plasma total IL-18, in subjects with DS over 35 with and without AD-related cognitive decline, and plasma concentrations of its binding protein in subjects with DS (19-35 years) were correlated with lower plasma concentrations of Transforming Growth Factor (TGF-β1), which are linked to an increased rate of cognitive decline in adults with DS. In addition, we found a significant association between low baseline concentrations of Free IL-18, the active form of the cytokine, and an increased rate of cognitive decline at 12 months, calculated as delta of the Test for Severe Impairment (dTSI), in individuals with DS (19-35 years). Finally, we demonstrated a reduction of Free IL-18/TNF-α ratio, considered as a new possible double biomarker, in both young and older adult DS subjects without AD-related cognitive decline (area under the receiver operating curve (AUC) was 0.82 and 0.71, respectively), suggesting the advantage of the composite biomarkers in the discrimination of patients from healthy people over single biomarkers.