Maternal oxycodone (oxy) exposure can disrupt placental function and fetal neurodevelopment, but the molecular mechanisms remain unclear. We investigated whether prenatal oxy exposure activates inflammation and stress response pathways in the placenta and fetal brain, and if maternal melatonin supplementation attenuates these effects. Female Sprague-Dawley rats received either saline or oxy via oral gavage for 15 days before mating (10-15mg/kg/day dose escalation) and throughout pregnancy (15mg/kg/day). From gestational day (GD) 12.5, half of the dams received melatonin (10mg/kg/day). On GD 19.5, placental and fetal brain tissues were collected. Changes in expression of markers of oxidative stress, antioxidant defense signaling, inflammation, ER stress, and apoptosis were assessed by western blotting. Data were analyzed by two-way ANOVA with Tukey's post hoc test. Neither oxy exposure nor melatonin treatment increased markers of oxidative stress or antioxidant defenses in the placenta and fetal brain. Oxy exposure increased placental IL-1β expression but did not alter expression of the other inflammatory markers examined. Oxy increased phosphorylation of eIF2α and increased the phospho-eIF2α:eIF2α ratio in the placentas of male fetuses, and fetal brains of both sexes. CHOP expression was increased in the placentas and brains of female, but not male fetuses after oxy exposure. Oxy exposure increased levels of cleaved caspase-3 and cleaved caspase-9 in the fetal brain, but not the placenta; melatonin treatment attenuated the oxy-induced increase in cleaved caspase-9, but not cleaved caspase-3. Prenatal oxy exposure induced a modest inflammatory response in the placenta and activated the integrated stress response and intrinsic apoptotic signaling in the fetal brain. Maternal melatonin supplementation partially mitigated the oxy-induced upregulation of caspase-9 but did not prevent stress signaling in either tissue. These findings demonstrate the presence of sex-specific placental and fetal brain responses to prenatal oxy exposure but suggest that melatonin may not provide complete protection against oxy-induced neurodevelopmental impairment.
This study aimed to systematically elucidate the molecular mechanisms underlying PD-associated brain-gut dysfunction through multi-omics analyses and to evaluate the therapeutic potential of combined Deep Brain Stimulation (DBS) and Brain-Computer Interface (BCI) interventions. Transcriptomic and 16S rRNA datasets from Gene Expression Omnibus (GEO) and Sequence Read Archive (SRA) were integrated and analyzed using DESeq2, limma, Gene Set Enrichment Analysis (GSEA), and PICRUSt2 to identify disrupted pathways and microbial functional features. In the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model, four groups (Normal, MPTP, MPTP + DBS, and MPTP + DBS+BCI) were assessed using behavioral testing, Local Field Potentials (LFP) recordings, molecular assays, and histological analysis. The findings revealed synaptic damage and metabolic pathway disruptions in PD brains, accompanied by reduced abundance of Short-Chain Fatty Acid (SCFA)-producing gut microbes. Combined DBS and BCI markedly improved motor deficits, suppressed aberrant β oscillations, restored gut barrier integrity and microbial homeostasis, and reduced pathological α-synuclein (αSyn) aggregation. Collectively, these results demonstrate that DBS + BCI is associated with improvements across neural, microbial and inflammatory readouts, supporting a correlative brain-gut-immune framework.
Normal brain function involves soluble Aβ peptides that support synaptic activity. However, Aβ peptides are prone to aggregation under abnormal or pathogenic conditions, forming clumps known as oligomers and protofibrils, which subsequently lead to the formation of mature, stable β-sheet rich fibrils. The accumulation of such misfolded amyloid aggregates in the brain is the hallmark of Alzheimer's disease (AD). Recent experimental studies suggested that BMS-984923 successfully blocks the action of Aβ induced toxicity while preserving glutamate signaling via the metabotropic glutamate receptor 5 (mGluR5), which is a key excitatory neurotransmitter in the brain. However, the molecular mechanism by which BMS-984923 interacts with Aβ peptide remains unclear. In this work, we investigated the inhibitory mechanism of BMS-984923 against the Aβ monomeric structures with the help of molecular docking and molecular dynamics (MD) simulations. To elucidate the atomic level interactions, we employed DSSP for performing secondary structure analysis, MM-PBSA, per-residue decomposition and free energy landscape (FEL) analyses. The two representative structures from the apo simulation are further subjected to MD simulation, followed by similar analyses. MD simulation analyses revealed the distinct modes of ligand interaction across the different monomeric forms, accompanied by extensive contacts with residues in the binding region. Therefore, our study, which provides insights for evaluating the efficacy of BMS-984923 to facilitate subsequent binding with the target protein, will offer a framework for the rational design of potential inhibitors against the pathogenic Aβ peptide.
Vascular pulsations are increasingly recognized as key contributors to cerebral perfusion and brain clearance mechanisms, with alterations linked to aging and neurodegenerative diseases. However, capturing fast physiological dynamics in preclinical models remains technically challenging due to high cardiac frequencies and small brain size. Here, we investigated the feasibility of zero echo time (ZTE) functional MRI (fMRI) to capture cardiac- and respiration-related pulsations across multiple temporal scales in the rat brain under isoflurane anesthesia. We used retrospective binning to assess cardiac- and respiration-related pulsations. Cardiovascular state was modulated with medetomidine, and functional connectivity analyses were performed to evaluate slower neural dynamics. ZTE fMRI robustly detected physiological pulsations across the brain, achieving effective temporal resolution of 8 ms, with the strongest signals observed in large arteries, consistent with an inflow‑based contrast mechanism. Cardiac pulsation amplitudes increased significantly under combined medetomidine-isoflurane anesthesia, whereas respiration‑related pulsations remained stable. Functional connectivity decreased under combined anesthesia, confirming ZTE fMRI sensitivity to slower neural dynamics. ZTE fMRI enables simultaneous assessment of cerebrovascular pulsatility and functional connectivity, providing a powerful tool for studying physiological brain dynamics in vivo.
Nutrition is increasingly recognized as a central determinant of brain health across the lifespan. Beyond their classical roles as energetic substrates, dietary components and their bioactive metabolites may act as signaling molecules capable of reshaping neuronal and glial phenotypes through integrated metabolic, epigenetic, and immunological mechanisms. Emerging evidence positions nutritional inputs as dynamic regulators of synaptic integrity, cellular bioenergetics, neurotransmission, neuroimmune interactions, and blood-brain barrier function. These effects occur across multiple temporal and spatial scales, from acute modulation of neuronal excitability to long-term reprogramming of gene expression and chromatin landscapes. This mini-review integrates current molecular neuroscience perspectives to propose a systems-level framework in which nutritional signals act across interconnected regulatory layers linking peripheral metabolism with central nervous system homeostasis. We examine nutrient-sensing pathways that preserve proteostasis and synaptic resilience, as well as metabolic and membrane-associated processes that govern neuronal excitability, network stability, and mitochondrial quality control. Furthermore, we discuss how dietary modulation may influence glial activation states, neuroinflammatory cascades, and epigenetic remodeling, and how gut-derived metabolites contribute to these processes. Understanding nutrition as an active signaling network rather than a passive support system may offer novel opportunities for preventive and therapeutic intervention in neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease, as well as in age-associated cognitive decline. We propose that targeted nutritional modulation represents a tractable strategy to reprogram brain aging trajectories toward enhanced resilience, functional plasticity, and long-term cognitive health.
Neurofibrillary tangles composed of hyperphosphorylated tau are a defining pathological hallmark of Alzheimer's disease (AD); however, the pathways and mechanisms associated with the transition from physiological tau to tangle pathology remain unclear. Here, we integrate laser microdissection of post-mortem, fixed human AD brain tissue labelled with an antibody recognizing tangle-associated phospho-tau (AT8) with mass spectrometry-based proteomics, applied to individual neurons and to small neuronal pools. This approach identified ∼2,000 and ∼5,000 proteins, respectively, and enabled direct detection of disease-associated tau phosphorylation sites without prior enrichment. A layered analysis of the proteome of tangle-positive and tangle-negative neurons revealed heterogeneous disease-associated states. Pseudotime analysis, combined with an AI-driven analytical framework, indicates that neurons do not segregate into discrete classes but instead organize along a continuum of proteomic changes that correlate with tau abundance. This organization enabled the construction of a trajectory of pathological neuronal responses that can be resolved within an individual brain. Early stages of this trajectory are characterized by coordinated remodeling of proteostasis networks, including reduced proteasome component abundance and increased lysosomal acidification machinery, followed by disruption of synaptic pathways. Notably, despite extensive proteomic remodeling, neurons bearing tangles show little evidence of activated cell-death programs, suggesting prolonged molecular adaptation rather than acute degeneration. Together, these findings establish a framework for single-cell-resolved proteome analysis of human brain disease in situ and define a continuum of neuronal states underlying tau pathogenesis, revealing early vulnerabilities and adaptive responses during AD progression.
Somatic variants are a prominent cause of epilepsy-associated cortical malformations, but about half of patients undergoing genetic testing have no finding due partly to limitations in variant detection. Most studies have focused on single-nucleotide variants or small indels that are accessible to short-read sequencing technologies, but somatic structural variants are also emerging as important contributors despite their unique detection challenges. Optical genome mapping (OGM) is a promising methodology for the detection of structural variants, but requires high quality, high molecular weight DNA from clinical specimens. Here we successfully optimize a protocol for OGM of surgically-resected patient brain tissue which yields ∼450x effective coverage - suitable for detecting somatic variants at low allele fractions. We apply this approach to brain specimens from four patients with epilepsy. OGM identifies large and complex mosaic structural variants ranging from 7-40% variant allele fraction, most of which are not captured by short-read exome sequencing of the same specimen. In one patient with a known germline DEPDC5 variant, OGM reveals a somatic variant - a 13.2kb deletion in DEPDC5 at approximately 20% VAF - consistent with the established two-hit model in DEPDC5-associated lesional epilepsies. By resolving the breakpoints in PacBio HiFi sequencing data, we identify a mechanism for this somatic deletion, mediated by recombination of two Alu elements flanking the region. Our findings demonstrate that OGM is a robust and complementary tool for detecting somatic structural variation in human brain tissue, with potential to improve diagnostic yield and refine genotype-phenotype correlations in neurological disorders.
Molecular mechanisms in frontotemporal dementia (FTD) and Alzheimer's disease (AD) are obscure. FTD can result from loss-of-function progranulin mutations, although pathogenetic consequences are uncertain. Progranulin insufficiency also increases human AD risk, and progranulin treatment improves mouse AD. Furthermore, AD and FTD risks are abetted by obesity/diabetes-induced hyperinsulinemia and hyperactivation of brain insulin signaling, and progranulin deficiency activates insulin signaling in fat and liver. Here, we found progranulin deletion in mouse brain increased activation of IRS-1 and activities of downstream PKC-λ/ι, NF-κB and mTOR, but diminished IRS-2 and Akt. Similarly, in microglial cells, progranulin deletion increased, and progranulin treatment diminished, activation of IRS-1, PKC-λ/ι, NF-κB, and mTOR. These progranulin-related changes in IRS-1 activation were due to JNK-mediated phosphorylation of inhibitory serine-302/307 residues in IRS-1. Progranulin deficiency in brain selectively activates an IRS-1-dependent insulin signaling pathway, and the resultant increases in inflammation and impaired autophagy/lysosomal function may augment progranulin deficiency-related neuropathology.
Circular RNA (circRNA)-based nucleic acid therapeutics exhibits distinct pharmacological advantages including sustained therapeutic effects from single-dose administration, but the molecular basis governing this persistence remains mechanistically unresolved. Using single-cell RNA sequencing (scRNA-seq), methylated RNA immunoprecipitation sequencing (MeRIP-seq), and genetic animal models, we demonstrated that a single dose of exogenous circSCMH1 sustained elevated endogenous circSCMH1 levels in the peri-infarct region. This persistence stems from a self-sustaining loop initiated by exogenous circSCMH1, as confirmed by experiments with a modified circSCMH1 variant (ΔcircSCMH1), which distinguishes endogenous from exogenous sources. Mechanistically, microglial overexpression of the m6A demethylase FTO enhances circSCMH1 biogenesis by suppressing m6A methylation, with YTHDC1 identified as the primary m6A reader protein facilitating this process. Furthermore, YTHDC1 collaborates with Exportin-4 to mediate m6A-dependent nuclear export of circSCMH1, a step critical for its therapeutic efficacy. In Exportin-4-deficient mice, impaired nuclear export abolishes the sustained brain repair induced by circSCMH1, as evidenced by diminished sensorimotor recovery in behavioural tests. These findings elucidate how a single dose of circSCMH1 improves brain repair through a self-sustaining loop that leverages endogenous circRNA biogenesis machinery. Unlike traditional therapies requiring repeated dosing, this approach achieves prolonged therapeutic efficacy, offering substantial translational advantages for stroke treatment.
Exercise can regulate the physiological functions of the body by inducing the secretion of myokines, which are bioactive factors mainly secreted by muscle cells. This review classifies myokines based on their functional characteristics, including metabolic regulation (such as myostatin, interleukin-6), neuroregulation (brain-derived neurotrophic factor), cell proliferation/differentiation regulation (myogenic proteins), immune regulation (tumor necrosis factor- alpha), and factors involved in angiogenesis and extracellular matrix remodeling (such as connective tissue growth factor).Cancer, as a consuming disease, often accompanies muscle atrophy and depletion in its advanced stage, thereby affecting the normal secretion of myokines. Increasing research evidence indicates that myokines play a dual regulatory role in the occurrence and development of cancer. Some myokines (such as interleukin-6, tumor necrosis factor- alpha) have environment-dependent functions and can exhibit pro-cancer or anti-cancer effects depending on the microenvironment; while factors such as myostatin show stable anti-tumor potential by regulating key molecular pathways such as the PI3K/AKT pathway, epithelial-mesenchymal transition, and HIF-1α. It is worth noting that muscle cell factors can indirectly influence the disease outcome of cancer by regulating key cells and structures in the tumor microenvironment (such as tumor-associated macrophages, regulatory T cells, and cancer-associated fibroblasts), as well as by participating in the angiogenesis process. At the clinical application level, muscle cell factors are expected to become potential biomarkers for cancer diagnosis and prognosis assessment (such as elevated irisin levels in patients with renal cancer and elevated interleukin-6 levels in patients with bile duct cancer). They also have great potential as therapeutic targets. For example, MSTN inhibitors can effectively alleviate cancer cachexia symptoms, and the combination of anti-interleukin-6 treatment with immune checkpoint blockade therapy can produce a significant synergistic therapeutic effect. This review systematically summarizes the latest research progress on the molecular interaction mechanisms mediated by myokines in cancer, emphasizing their potential for translational applications in precision oncology. Myokines not only regulate the physiological functions of the musculoskeletal system, but also have a close association with the occurrence and development of cancer. The intrinsic connection between myokines and muscle atrophy as well as cancer-related cachexia still requires further in-depth exploration. As emerging biomarkers, myokines can be combined with various diagnostic and therapeutic techniques, which is expected to further improve the survival rate of cancer patients, protect muscle function, and also provide new research ideas for exploring the interrelationship between muscles and cancer and the pathogenesis of related muscle diseases.
Spatially resolved single-cell technologies enable profiling of cells in situ , yet computational approaches that jointly discover multicellular spatial patterns and characterize their molecular programs remain limited. Here we introduce SpatialQuery, a framework that can both identify cellular motifs, i.e. recurrent multicellular co-localization patterns, and perform molecular analyses focused on the motifs. It uncovers genes modulated by spatial contexts through differential expression analysis, and detects coordinated expression changes through covariation analysis. SpatialQuery can identify functional tissue units, and goes beyond pairwise analyses to characterize multicellular interactions. Applications to both spatial transcriptomics and proteomics data uncover cross-germ-layer signaling in gut tube patterning, disease-specific fibrotic and immunosuppressive niches in kidney and colon, and regional determinants of motif-associated transcriptional programs in a mouse brain atlas. SpatialQuery is available as a Python package, and we demonstrate how its light computational footprint enables integration into web-based cell atlas portals for interactive visualization and exploration.
Most, if not all, cellular processes, exemplified by neuroexocytosis, rely on the precise interplay of specific molecules in both space and time. Super-resolution microscopy allows visualization of single-molecule trajectories far below the diffraction limit of visible light, which opens up possibilities for precise spatiotemporal analysis of these cellular processes. While a range of tools have been developed for assessing the spatial distribution of molecules in fixed cell data, the increasing sophistication of single particle tracking (spt) in live cells requires new approaches for spatiotemporal analysis, which can shed light on the nanoscale dynamics of molecular interaction and clustering. In this chapter, we will discuss a recently developed suite of novel tools-NAnoscale SpatioTemporal Indexing Clustering (NASTIC), which uses the overlap of molecular trajectory bounding boxes to establish interaction in space and time, and will describe a workflow to allow the user to use NASTIC to derive spatiotemporal metrics from their own super-resolved live cell trajectory data.
Macrophage-colony stimulating factor (M-CSF) plays a crucial role in the proliferation and differentiation of the monocyte-macrophage lineage across vertebrates. In this study, we identified and characterized two CSF1 paralogues and their corresponding receptor genes in the intestine of the goldfish (Carassius auratus), showing sequence homology with known teleost species. Immunohistochemical analysis confirmed the presence of CSF, its receptor CSF-R1, and bone morphogenetic protein 2 (BMP2) in intestinal macrophages. These macrophages were localized within mucosal, submucosal, and muscularis layers, suggesting distinct functional subtypes. Quantitative PCR analysis revealed differential gene expression patterns, with csf1a, csf1b, and csf1ra highly expressed in the brain, while csf1rb transcripts were predominant in the intestine. Immunophenotypic characterization using CD14 and CD86 markers further demonstrated macrophage heterogeneity. Additionally, BMP2-expressing macrophages were observed in the muscularis externa, implying a potential role in neuromuscular regulation. These findings provide novel insights into the molecular and immunohistochemical profiles of goldfish intestinal macrophages, highlighting their potential role in immune responses and gut homeostasis.
Many cancers, including glioblastoma (GBM), show a male-biased incidence and associated worse outcomes1. The mechanisms that underlie this sex difference remain unclear but may involve an immune response2 that is partly driven by sex hormones such as androgens. Such hormones are thought to suppress antitumour T cell immunity and to promote tumour progression3,4. However, here we report a previously unreported tumour-suppressive role for androgens in brain tumours. Using mouse models, we demonstrate that androgen loss via castration accelerates intracranial tumour growth, whereas the opposite effect (delayed tumour growth) is observed in extracranial tumours. Similar effects were observed in male patients with GBM, in whom testosterone treatment significantly reduced the risk of death. In male mice with GBM tumours, castration-induced systemic T cell dysfunction driven by increased levels of serum glucocorticoids, which act on myeloid cells to promote an immunosuppressive tumour microenvironment. Mechanistically, hyperactivation of the hypothalamus-pituitary-adrenal axis in castrated mice with GBM is driven by increased neuroinflammatory signalling through IL-1β and TNF. Spatial transcriptomic analysis further revealed that androgen loss enhances inflammasome activation in microglia, which promotes this neuroinflammatory state. Together, our findings demonstrate that brain tumours drive distinct neuroinflammatory and neuroendocrine pathways in the androgen-deprived setting and highlight organ-specific regulation of antitumour immunity.
Loss-of-function variants in the human phenylalanine hydroxylase (PAH) gene are the most common genetic causal factors for Phenylketonuria (PKU). Currently, a broad spectrum of variations is recognized in the human PAH gene. However, the molecular function and clinical significance of some novel PAH variants remain unclear. Here, we report on five PKU-affected families carrying three novel PAH variants, including one missense variant (PAH: c.271C>A (p.Leu91Met)) and two deletions (PAH: c.206_208delCTT (p.Ser70del) and PAH: c.541_544delGAGG (p.Glu181Lysfs*13)). These variations constitute different compound heterozygous genotypes with other known pathogenic variants such as PAH: c.721C>T (p.Arg241Cys), PAH: c.168+5G>C, and PAH: c.1238G>C (p.Arg413Pro), which probably led to the patients' PKU etiopathology. qRT-PCR and immunoblotting showed that the protein levels of PAH (S70del) and PAH (E181Kfs*13) were significantly reduced compared with the wild-type control, although their transcript levels were not. Also, the enzyme activity of PAH (S70del) and PAH (E181Kfs*13) mutants was significantly decreased relative to the wild type (P < 0.001). PAH: c.271C>A (p.Leu91Met) had no significant effect on PAH mRNA and protein levels or enzyme activity. Collectively, our data demonstrate that the two deletions PAH: c.206_208delCTT and PAH: c.541_544delGAGG are clinically significant for pathogenicity. Our findings are anticipated to contribute to the advancement of prenatal diagnosis, population-based carrier screening, and genetic counseling for individuals affected by PKU, and is expected to help reduce the incidence of PKU and ameliorate the associated disease burden. See also the graphical abstract(Fig. 1).
Extracellular vesicles (EVs) circulate in biofluids and carry tissue-specific molecular cargo, offering significant potential for the discovery of minimally invasive biomarkers. However, translation in neurodegenerative diseases has been hindered by the lack of validated neuronal EV surface markers that enable selective isolation from plasma. We hypothesized that proteomic profiling of EVs released from human induced pluripotent stem cell (hiPSC)-derived neurons would identify 1. robust Alzheimer's disease (AD)-associated signatures that reflect disease pathogenesis, and 2. surface-accessible neuronal markers capable of enriching disease-relevant cargo. Neurons differentiated from AD patients and age-matched cognitively normal (CN) individuals were used to isolate EVs, which were characterized and analyzed by LC-MS proteomics in both total and membrane-enriched fractions. Proteomic profiling identified numerous dysregulated proteins, with a subset validated across independent AD datasets. We identified CNTNAP2 and STX1B as neuronal, brain-enriched EV surface proteins accessible for selective capture and confirmed their presence in EVs from post-mortem human brain, supporting them as bona fide brain-derived EV markers. Immuno-isolation of plasma EVs showed that CNTNAP2-positive EVs had a robust AD-associated increase in phosphorylated tau, identifying CNTNAP2 as a highly discriminative brain-derived EV marker and supporting its potential for blood-based AD diagnostics.
The slow, age-related development of Alzheimer's disease (AD) and inaccessibility of early-stage brain tissue necessitates model studies to understand its origins and progression. Non-human primate models can provide a platform for linking molecular changes to translatable phenotypes. Here, we assess fibroblast lines derived from marmosets with engineered variants in the PSEN1 gene. Fibroblast cultures were obtained from 10 animals and assayed using a NanoString AD gene expression panel and label-free proteomics. We compared mutant expression changes to human AD signatures in human iPSC-derived neurons and postmortem brains to assess disease relevance. Gene products involved in amyloid-beta interaction and regulation were differentially expressed, providing evidence for the functional relevance of the engineered fibroblasts. Both gene and protein expression changes in the undifferentiated fibroblasts correlated with human iPSCs from AD donors reprogrammed into neuronal lineages, as well as postmortem brains derived from case-control cohorts. Altered expression profiles were noted based on marmoset donor sex and mutation status, highlighting underlying sex-specific biology relevant to Alzheimer's disease. These findings demonstrate that disease-relevant pathways and processes are altered in fibroblasts from mutant marmosets, emphasize the complementarity of transcriptomic and proteomic profiling in AD, and provide a roadmap for more advanced molecular studies of AD in aging marmosets and marmoset-derived cell models.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by nigrostriatal degeneration. While the role of glial cells in PD is increasingly recognized, the coordinated multicellular responses driving PD within the dorsal striatum remain poorly understood. By integrating single-nucleus RNA sequencing of 56 donors with targeted spatial transcriptomics, we disentangle regional from PD-related molecular programs across astrocytes, microglia and oligodendroglia. We identify PD-associated glial subpopulations organized into two distinct multicellular programs: one inflammatory and one UPR-associated, where each patient is dominated by one of these programs. Notably, these programs partition the molecular changes typically associated with PD into two specific, non-overlapping signatures. Multi-region analysis revealed these signatures are globally enriched across the sampled areas and Lewy body disease stages, from brainstem-predominant to neocortical, demonstrating that PD is characterized by mutually exclusive, brain-wide glial multicellular states. Our findings redefine glial alterations in PD as systemic and multicellular, providing a framework for patient stratification and the development of targeted, state-specific therapeutic interventions.
Resveratrol (RES), a naturally occurring polyphenolic compound found in grapes, berries, and peanuts, has attracted considerable interest because of its antioxidant, anti-inflammatory, and neuroprotective properties. This narrative review examines the current evidence regarding the potential effects of RES on memory-related processes and neuroinflammatory biomarkers in major neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and cerebral ischemia. Relevant literature was identified through searches of major scientific databases, and studies addressing the molecular mechanisms, experimental outcomes, and therapeutic implications of RES in these conditions were evaluated. The available evidence indicates that RES can modulate several biological pathways associated with neurodegeneration, including oxidative stress, inflammatory signaling, mitochondrial dysfunction, and neuronal survival. Experimental studies suggest that RES may influence key molecular mediators such as pro-inflammatory cytokines, nitric oxide (NO) signaling, and matrix metalloproteinases, which are implicated in neuronal damage and blood-brain barrier disruption. In preclinical models of AD and PD, RES has been associated with improvements in cognitive performance, reduction of neuroinflammatory markers, and attenuation of neuronal loss. Similarly, studies in MS and cerebral ischemia models indicate that RES may modulate immune responses, reduce oxidative damage, and limit ischemia-related neuronal injury. However, most of the current evidence derives from in vitro and animal studies, and clinical data remain limited. Moreover, the low bioavailability of RES and variability in dosing regimens represent important challenges for clinical translation. Therefore, although experimental findings support the potential neuroprotective role of RES, further well-designed clinical studies are required to determine its therapeutic relevance and safety in human neurological disorders. This narrative review was developed through a structured search of PubMed, Scopus, and Web of Science for articles published between 2000 and 2024, focusing on mechanistic, preclinical, and clinical investigations of RES in neurological disorders. This review synthesizes current evidence on the molecular and cellular mechanisms underlying the neuroprotective effects of RES, with particular emphasis on its antioxidant, anti-inflammatory, and immunomodulatory activities. By integrating findings from experimental and clinical research, the review highlights the potential of RES to modulate key pathways involved in neurodegeneration and neuroinflammation. Although further well-designed clinical studies are required to clarify its therapeutic efficacy and translational relevance, the available evidence supports continued investigation of RES as a promising candidate for neuroprotective strategies in neurological disorders.
Magnetic resonance imaging (MRI) has revolutionized diagnostic radiology and medicine over the past five decades1,2. However, clinical applications of MRI are still mainly limited to visual examination of macroscopic tissue pathology3,4. Because diseases, such as tumours, multiple sclerosis (MS) and neurodegenerative disorders, are highly heterogeneous, there is a critical need for a non-invasive imaging technology that can provide quantitative biomarkers for tissue characterization for personalized and precision medicine5. Here we introduce a new approach to MRI data acquisition and processing, called 'multiplexed MRI' (MRx), to achieve high-resolution simultaneous multiparametric mapping of several molecules. We demonstrate that MRx can obtain a large set of quantitative structural, physiological and molecular biomarkers of the whole brain in standard clinical settings. We further demonstrate that these biomarkers could define an effective tissue state index for disease subtyping and lesion characterization in tumours and MS. We anticipate that the new quantitative multiplexed imaging capabilities of MRx would substantially enhance the capability of MRI for diagnosis, monitoring and assessment of therapeutic efficacy of many neurological diseases and potentially transform brain imaging for both research and clinical applications.