Search Results (5,930)

Alzheimer’s disease (AD) is a neurodegenerative disorder, whereas myasthenia gravis (MG) is an autoimmune neuromuscular disease. Despite their distinct clinical manifestations, both disorders involve immune dysregulation and cholinergic dysfunction, and epidemiological evidence for an association remains inconclusive. Here, we investigated the genetic architecture underlying the AD–MG relationship using large-scale European-ancestry genome-wide association study (GWAS) data, including early- and late-onset MG, within a multi-resolution analytical framework. Genome-wide analyses indicated modest polygenic overlap between AD and MG, supported by nominally significant and directionally consistent correlations across datasets, SNPeffect concordance in the primary GWAS, and robust gene-level overlap. Evidence for genome-wide correlation was weaker and non-significant across AD-MG subtypes. Local genetic correlation analyses revealed that shared AD-MG signals were largely locus-specific and heterogeneous, with regions showing both concordant and discordant effects, particularly across MG subtypes. Subtype-specific analyses indicated broader and more heterogeneous overlap for AD–late-onset MG, including both major histocompatibility complex (MHC) and non-MHC loci, whereas AD–early-onset MG showed more restricted patterns largely confined to the MHC. Cross-trait meta-analysis and colocalisation further refined these findings, identifying a limited number of loci with evidence of shared AD-MG association, while most regions were consistent with distinct causal variants. A chromosome 16 locus showed the most consistent shared cross-trait AD-MG signal across multiple analytical frameworks. Mendelian randomisation analyses provided no evidence of a causal effect of AD liability on MG and yielded only suggestive, and inconclusive evidence for the reverse direction. Gene-level and expression-informed analyses prioritised immune-related genes, as well as regulators of transcription, chromatin organisation, and synaptic processes, without implying concordant causal variants across traits. Tissue and pathway analyses suggested shared immune involvement, with differential emphasis on innate immune processes in AD and adaptive immune pathways in MG. Notably, heterogeneity of effects within the MHC and across loci suggests that overlap reflects a complex, context-dependent architecture rather than a uniform immune-driven signal. Overall, our findings indicate that the AD–MG relationship is characterised by modest genome-wide polygenic overlap, substantial locus-specific heterogeneity, and partial convergence on immune-related genetic architecture, rather than a uniformly shared mechanism. Full article

Neuroscience is a rapidly advancing field; however, a comprehensive understanding of brain function at the molecular, cellular, and systems levels remains incomplete. Neurological and psychiatric disorders represent a major global health burden, highlighting the need for improved diagnostic and therapeutic strategies. Cerebrospinal fluid (CSF) is one of the most informative biofluids for investigating central nervous system (CNS) pathology due to its close biochemical relationship with brain tissue. Recent advances in neurometabolomics, defined as the comprehensive analysis of small-molecule metabolites in CSF, have been driven by the development of highly sensitive and informative mass spectrometry-based techniques. These approaches enable the identification of disease-associated metabolic signatures. This review summarizes current chromatography–mass spectrometry-based methods used in both untargeted and targeted CSF metabolomics, with particular emphasis on their analytical performance, reproducibility, and limitations. Special attention is given to method standardization and validation, as well as to the identification of reliable metabolic biomarkers for the diagnosis and monitoring of neurological disorders, including neurodegenerative, psychiatric, oncological, and neuroinflammatory diseases. Full article

Ischemic stroke is an acute cerebrovascular disease with high disability and morbidity. However, therapeutic approaches are restricted by a narrow time window for reperfusion. Astilbin has various pharmacological activities and good therapeutic potential against ischemic stroke and neurodegenerative diseases. Nevertheless, Astilbin’s mechanism of action remains unclear. Here, we used an integrated strategy that includes network pharmacology, omics validation, and functional verification. Potential targets of Astilbin were predicted using SwissTargetPrediction and PharmMapper, and cross-analyzed with IS-related genes from multiple databases. GO/KEGG enrichment analyses showed that Astilbin synergistically regulates stroke-associated pathways (e.g., MAPK, AGE-RAGE). Combined transcriptomic and metabolomic assays confirmed that Astilbin ameliorates OGD/R-induced oxidative stress and metabolic disorders by modulating the MAPK and ferroptosis pathways. Molecular docking and dynamics simulations revealed that Astilbin has high affinity for core targets (ERK1/2, CREB, p90RSK, MMP9) and binds stably to MMP9. Using an OGD/R-injured neuronal-like PC12 cell line, in vitro assays confirmed that Astilbin alleviates oxidative stress, calcium overload, lipid peroxidation, and intracellular iron levels, while also modulating apoptosis- and inflammation-related genes. Overall, this study has established a comprehensive pharmacological framework for the use of Astilbin against IS, clarified its multi-target, multi-pathway neuroprotective mechanisms of action, and provided evidence for its potential in the treatment of IS. Full article

Background: Neuroinflammation is a key contributor to the progression of several neurodegenerative disorders, including Alzheimer’s disease, stroke, and small vessel disease. Emerging evidence highlights the role of circulating microRNAs (miRNAs) as non-invasive biomarkers of neuroinflammation and neuronal injury. miR-106a-5p, a member of the miR-17~92 cluster, is known to regulate inflammation, apoptosis, and vascular function. While typically studied in plasma or cerebrospinal fluid, gastric juice miRNAs represent a novel and underexplored source for biomarker discovery within the gut–brain axis. This exploratory study aimed to investigate the association between gastric juice miR-106a-5p expression and markers of neuroinflammation, including C-reactive protein (CRP), lactate dehydrogenase (LDH), and imaging-based evidence of neurodegeneration. Methods: A prospective, observational study was conducted on 38 participants (22 with neurodegenerative pathology and 16 healthy controls). Gastric juice samples were analyzed for miR-106a-5p using RT-qPCR, normalized to U6 snRNA. ΔCt values were used to determine relative expression. Statistical analyses included t-tests/Wilcoxon tests, ROC curve analysis, and correlation testing, with significance set at p < 0.05. Results: Patients with neurodegenerative changes exhibited significantly lower gastric miR-106a-5p expression compared to controls (p = 0.044). Elevated CRP and LDH levels were associated with higher ΔCt values (indicating lower expression), with p-values of 0.019 and 0.023, respectively. ROC analysis showed moderate diagnostic accuracy (AUC = 0.701) for miR-106a in identifying neurodegenerative status. miR-106a levels also correlated inversely with carotid intima-media thickness and brain MRI abnormalities, also reduced gastric miR-106a-5p expression is associated with systemic inflammation and neuroimaging evidence of neurodegeneration. Conclusions: While causality cannot be inferred, these findings suggest that gastric miR-106a may serve as a promising non-invasive biomarker within the gut–brain axis framework. Further longitudinal and mechanistic studies are warranted to validate its clinical utility and explore its potential role in monitoring neuroinflammatory conditions. Full article

Neurodegenerative diseases (NDs) pose a significant health burden globally, and this burden is increasing with an ageing population. Despite this challenge, restorative treatments for NDs remain elusive. In these conditions, the brain is vulnerable to oxidative stress and inflammation due to a deficiency or reduction in antioxidative enzymes. Oxidative stress and inflammation damage neuronal cells, leading to neurodegeneration. Various studies have explored the neuroprotective effects of flavonoids in different in vitro and animal models, primarily due to their antioxidative and anti-inflammatory properties. Crude extracts and active metabolites of Semecarpus anacardium L. have shown potential in reversing dysregulated oxidative stress and neuroinflammation. S. anacardium L. extract (SAE) and its phytocomponents, such as butein, anacardic acid, and amentoflavone, have been experimentally demonstrated to modulate oxidative stress and neuroinflammation through coordinated activation of Nrf2-mediated antioxidant pathways and suppression of NF-ĸB-driven inflammatory signaling. At a molecular level, flavonoids from SAE induce the expression of p38 MAPK and Nrf2, as well as antioxidant enzymes. Furthermore, inflammatory genes such as NF-ĸB, MAPK, AP-1, iNOS, and COX-2 are suppressed following treatment with SAE. NF-ĸB inhibition leads to neuroprotection via inhibiting the function of caspase-3 and apoptosis. Overall, this review discusses the protective role of SAE and its phytocomponents in mitigating neuronal oxidative stress, inflammation, and degeneration. Furthermore, this review highlights the translational potential of SAE and its phytocomponents as complementary therapeutic candidates for neurodegenerative disorders. However, variability in extract composition and limited pharmacokinetic characterization remain key barriers to clinical translation. Full article

Alzheimer’s disease (AD) is a neurodegenerative disorder defined not only by amyloid-β plaques and tau pathology but also by several interacting processes that drive disease progression. These include neuroinflammation, neuronal cell death, synaptic dysfunction, blood–brain barrier (BBB) breakdown, and myelin and axonal damage. Together, they lead to neuronal loss and cognitive decline. In this review, we present a cell-centered framework linking these processes with key molecular markers. Neuroinflammation is driven by activated microglia and astrocytes and is associated with markers such as Iba1, CD68, GFAP, and C3, along with cytokines including IL-1β and TNF-α. Neuronal cell death occurs through apoptosis, ferroptosis, pyroptosis, and necroptosis, with markers such as caspase-3, GPX4, GSDMD, and MLKL. Synaptic dysfunction is reflected by reduced synaptic proteins, including synaptophysin and PSD-95. BBB breakdown increases permeability and reduces clearance of toxic molecules. Myelin and axonal damage, associated with MBP and NfL, disrupt neural connectivity. These processes are dynamically interconnected and may contribute differently across disease stages. This integrated cell-centered and systems-level framework provides insight into AD progression while highlighting potential biomarkers and therapeutic targets for diagnosis, disease monitoring, and therapeutic intervention. Full article

Background/Objectives: Parkinson’s disease (PD) is a major neurodegenerative disorder with no cure. The goal is to develop an active immunotherapy targeting aggregated alpha synuclein (aSyn), the root cause of PD. TRB-001 is the lead candidate of a novel class of vaccines. It is a peptide/protein conjugate coupled to sugar residues, which is used to target and activate antigen-presenting cells, and addresses aSyn. Methods: A 33-year-old male, diagnosed with PD seven years previously, with a Hoehn & Yahr stage of 1, taking Levodopa/Benserazide (100/25 mg, 6× per day), Rotigotine (8 mg) and Rasagiline (1 mg), amounting to a Levodopa equivalent daily dose (LEDD) of 940 mg, also complicated by impulse control disorder, requested experimental therapy. He received a total of four TRB-001 administrations (weeks 0, 4, 8 and 34) following informed consent. The workup included safety, immunological and clinical parameters. Results: Vaccinations were well tolerated. They induced a high-titer aSyn-specific antibody (Ab) response. Titer increase was associated with a reduction in aSyn plasma levels, suggesting target engagement. The Ab titer and the reduction in aSyn plasma levels were both long-lived. The boost elicited a recall-type Ab titer increase and triggered avidity maturation (factor 7.8). Abs demonstrated a high degree of selectivity for aggregated aSyn (factor 30). Moreover, they were found to preferentially react with tissue from PD brain lysates. The Movement Disorder Society-Sponsored Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) score for the patient remained essentially stable throughout the observation period of 53 weeks. At the time of the boost, the symptomatic PD therapy was simplified to Levodopa/Carbidopa/Entacapone 100/25/200 mg four times a day, amounting to an LEDD of 532 mg. This put an end to the symptoms of the impulse control disorder. Conclusions: Results obtained suggest that this new class of vaccines may yield Ab responses comparable in magnitude and target avidity to the therapeutic setting of monoclonal Abs. TRB-001 is currently being translated to a randomized, placebo-controlled Phase 1B study. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, which has recently been found to be closely associated with neuroinflammation. As an anti-inflammatory drug, triptolide (TP), a natural diterpenoid from Tripterygium wilfordii, was selected in the current study for treating PS19 (tau^P301S transgenic) mice, tauopathy AD mice. In addition, we have previously found that TP had the ability to reduce the level of cholesterol. However, the roles and mechanisms of TP in the above processes are not clear. To this end, we found that elevated cholesterol in serum and brain tissues upregulated the expression of apolipoprotein E (APOE) and sialic acid-binding Ig-like lectin 3 (CD33), leading to the activation of SH2-containing protein tyrosine phosphatase 1 (SHP-1). The activation of SHP-1 inhibits the signaling pathways of Janus kinase 1 (JAK1) and signal transducer and activator of transcription 6 (STAT6), which results in inhibition of the M2 polarization of microglia, which exacerbates neuroinflammation and cognitive decline in high-cholesterol diet (HCD)-fed mice. Conversely, TP treatment significantly inhibited the hepatic sterol regulatory element-binding protein 2 (SREBP2)/3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) pathway, which reduced the cholesterol levels in the serum and brain. By depressing the levels of cholesterol, the axis of CD33 and SHP-1 was suppressed, which resulted in restoration of the activity of JAK1 and STAT6 pathways, leading to the transition of microglia from the M1 to the M2 phenotype. Of note, these observations demonstrate that TP alleviates the cognitive impairment of PS19 mice via depressing neuroinflammation. Altogether, our results revealed the mechanisms of TP in treating AD via CD33/SHP-1/JAK1/STAT6 pathways in a cholesterol-dependent manner. Full article

Neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), arise from highly interconnected molecular and cellular abnormalities that progressively lead to neuronal dysfunction, synaptic failure, and cell death. This review provides a unified framework to understand the interrelated molecular mechanisms driving these diseases, with a focus on identifying key disease-specific intervention nodes. Core contributors include oxidative stress, mitochondrial dysfunction, protein aggregation, neuroinflammation, and emerging roles of peroxisomal dysfunction in redox imbalance, lipid dysregulation, and inflammatory amplification. Single-target therapies often show limited efficacy due to the complex, interconnected nature of these pathways. In contrast, polypharmacology, which targets multiple disease-relevant mechanisms simultaneously, offers a more promising therapeutic strategy. This review critically examines how pathway crosstalk drives neurodegenerative progression, with particular emphasis on mitochondrial–ROS–inflammatory signaling, aggregation–proteostasis failure, synaptic–neuroimmune dysfunction, and gut–brain communication. It evaluates various multi-node intervention strategies, including multi-target-directed ligands (MTDLs), molecular hybrids, natural products, drug repurposing, and nanocarrier-based delivery systems. Advances in network pharmacology, artificial intelligence (AI), bioinformatics, and multi-omics have enhanced the identification of actionable therapeutic nodes, candidate compounds, and brain-targeted delivery platforms. Notably, the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome and cyclic GMP–AMP synthase (cGAS)—stimulator of interferon genes (STING) pathways—play distinct roles in neuroinflammation, amplifying neuronal damage by releasing inflammatory cytokines and inducing mitochondrial dysfunction. However, successful translation into clinical practice remains constrained by challenges such as blood–brain barrier penetration, patient heterogeneity, and biomarker limitations. The review advocates for a shift towards mechanism-informed, patient-stratified polypharmacological strategies to better address the network pathology of neurodegeneration, despite significant translational hurdles. Full article

Background: Rotenone is a widely used environmental pesticide, and epidemiological studies suggest that exposure is associated with an increased risk of Parkinson’s disease (PD); however, the molecular toxicological basis of this association remains incompletely defined. Ferroptosis is an iron-dependent, lipid peroxidation-driven form of regulated cell death that is relevant to PD and other neurodegenerative disorders. In this study, we provide disease-contextual functional evidence linking ferroptosis to rotenone-induced PD-like neurotoxicity. Methods: We combined network toxicology, human PD substantia nigra transcriptomic analysis using GSE7621, and SH-SY5Y cell-based validation. Rotenone-associated targets were predicted and analyzed for ferroptosis-related enrichment, PD transcriptomic signatures were used for disease-contextual candidate prioritization, and selected findings were validated using qPCR, CCK-8, Western blotting, C11-BODIPY lipid peroxidation staining, and transmission electron microscopy. Results: By further integrating a human PD substantia nigra transcriptomic dataset (GSE7621), we prioritized an 11-gene, PD-contextualized ferroptosis-associated candidate module (LIPF, FAM170A, MCHR1, IL17A, MYB, GFAP, ARMC3, GKN1, GATA3, IL17F, and TEKT1). In SH-SY5Y cells, rotenone exposure consistently upregulated this candidate transcriptional module, and this induction was broadly attenuated by the ferroptosis inhibitor ferrostatin-1 (Fer-1). In parallel, orthogonal functional assays supported an iron- and lipid peroxidation-driven injury state under rotenone exposure that was suppressible by ferroptosis inhibition and iron chelation. Finally, we further performed an exploratory drug–gene association screen to prioritize clinically available candidates, and a limited qPCR check suggested that several selected compounds partially attenuated representative hub-gene induction under rotenone exposure. Conclusions: Collectively, these findings provide disease-contextual and experimentally supported evidence linking rotenone exposure to ferroptosis-associated neurotoxicity, and identify a ferroptosis-responsive transcriptional module for future hypothesis-driven mechanistic investigation. Full article

Retinal neurovascular unit (RNVU) dysfunction underlies major blinding and neurodegenerative conditions including glaucoma, diabetic retinopathy (DR), age-related macular degeneration (AMD), retinal ischemia–reperfusion (RIR) injury, and Alzheimer’s disease (AD)-associated retinopathy. Within the RNVU, calcium ions coordinate neurotransmission, glial activation, vascular tone, and blood–retinal barrier maintenance, and calcium dysregulation is emerging as a unifying pathogenic hub across these conditions. Although upstream triggers differ, including mechanical stress in glaucoma, hyperglycemia in DR, oxidative damage in AMD, ischemic energy failure in RIR, and amyloid-β–driven endoplasmic reticulum stress in AD, all converge on disruption of intracellular calcium homeostasis, producing shared downstream consequences including excitotoxic injury of retinal ganglion cells (RGCs), Müller cell reactive gliosis, and pericyte hypercontraction. Broad-spectrum calcium channel blockade has shown limited clinical success, underscoring the need for cell-type-specific and pathway-selective approaches. This review therefore catalogs key interventional nodes, including transient receptor potential (TRP) channel antagonists, T-type calcium channel inhibitors, calcium/calmodulin-dependent protein kinase II (CaMKII) suppressors, and mitochondrial permeability transition pore (mPTP) inhibitors, and discusses how precision targeting of these pathways may restore RNVU homeostasis and open a therapeutic window into central nervous system (CNS) degenerative disorders. Full article

Apitherapy is a complementary therapeutic approach based on the use of bee-derived products, particularly bee venom (BV), also known as apitoxin. Bee venom is a complex mixture of biologically active compounds, including peptides, enzymes, and biogenic amines, that exhibit diverse pharmacological activities. Major bioactive constituents such as melittin, apamin, adolapin, and phospholipase A2 have attracted increasing scientific interest due to their anti-inflammatory, antioxidant, antimicrobial, analgesic, and immunomodulatory properties. This review provides a comprehensive overview of the biological effects and therapeutic potential of bee venom in the management of chronic diseases, particularly diabetes, cancer, and neurological disorders. Evidence from experimental and clinical studies suggests that BV and its components can modulate multiple molecular pathways associated with oxidative stress, inflammation, apoptosis, and immune responses. These mechanisms contribute to potential benefits in glycemic control, tumor suppression, neuroprotection, and pain management. Additionally, bee venom has been investigated for its capacity to influence signaling pathways involved in cellular proliferation and survival, highlighting its potential as a complementary strategy in the treatment of complex diseases such as neurodegenerative disorders, including Parkinson’s and Alzheimer’s diseases. Despite these promising therapeutic effects, the clinical use of BV remains limited due to safety concerns, particularly the risk of allergic reactions, systemic toxicity, and anaphylaxis. Recent advances in drug delivery systems and nanotechnology may help improve the safety and efficacy of BV-based therapies by enabling targeted delivery and controlled dosing. Overall, bee venom represents a promising source of bioactive compounds with potential applications in translational and integrative medicine; however, further well-designed clinical trials and mechanistic studies are necessary to establish its safety, efficacy, and long-term therapeutic value. Full article

Alzheimer’s disease (AD) is a progressive, multifactorial neurodegenerative disorder ranking first as cause of dementia in the elderly. It is characterized by the progressive deterioration of the central nervous system, leading to impaired cognitive function and reduced ability to perform daily activities. Pathological hallmarks of AD include the accumulation of β-amyloid plaques and neurofibrillary tangles which ultimately cause neuronal death and synaptic loss. The vast majority of AD cases are sporadic, with aging representing the primary non-modifiable risk factor contributing to disease susceptibility and progression. However, several factors encompassing genetic predisposition, systemic inflammation, chronic diseases, infections, traumatic brain injury, lifestyle factors, and environmental exposures may affect AD onset. This work aims to describe and discuss the main molecular pathways involved in AD pathophysiology and to examine how these mechanisms cross-interact in promoting neurodegeneration and disease progression. Full article

Electroencephalography (EEG) has emerged as a promising non-invasive tool for the diagnosis of neurodegenerative disorders, and artificial intelligence (AI) has shown significant potential in this domain, as demonstrated by recent studies. However, strong inter-subject variability remains a major challenge, limiting the ability of AI-based models to learn disease-specific features that generalize across individuals, thereby hindering the development of clinically deployable subject-independent systems. In this work, we propose a cross-subject, AI-based EEG classification framework to distinguish between Alzheimer’s disease (AD), Creutzfeldt–Jakob disease (CJD), and healthy control subjects using clinical EEG data collected from a local hospital. A lightweight hybrid deep learning model is developed, combining a two-layer one-dimensional convolutional neural network with a two-layer Transformer encoder to capture both local temporal patterns and long-range dependencies in EEG signals. The proposed model achieves an average classification accuracy of $97\%$, representing a $3\%$ improvement over a baseline model evaluated on a cohort of 36 subjects. To assess deployment feasibility in real-time clinical settings, the trained model is implemented and evaluated on an edge-AI platform (NVIDIA Jetson AGX Orin), demonstrating energy efficiency for the inference with a compact model footprint. These results indicate that the proposed approach provides an accurate, efficient, and practically deployable solution for subject-independent EEG-based classification of neurological disorders. Full article

Background/Objectives: Glutathione (GSH) is a fundamental tripeptide essential for maintaining cellular redox homeostasis, detoxification, and immune regulation. While GSH is synthesized endogenously, its levels typically decline with age, potentially increasing susceptibility to oxidative stress-related conditions. This review aims to discuss the benefits of GSH for the body and clarify the distinctions between dietary intake, endogenous synthesis, and supplementation as strategies for maintaining optimal GSH levels. Results: All studies show that GSH is a powerful antioxidant that plays a crucial role in maintaining various physiological processes in the body. It offers several benefits, primarily through its antioxidant properties and involvement in detoxification and immune regulation. This effect has potential implications for various health conditions associated with oxidative stress and inflammation, including neurodegenerative diseases, cardiovascular diseases, and metabolic disorders. Whether through diet or supplementation, ensuring adequate GSH levels can have profound benefits on longevity, immunity, and overall well-being. There are many foods known to contain GSH, and there are also many GSH supplements available on the market, but precursor-based supplements and compounds that activate GSH synthesis pathways show stronger and more consistent increases in human GSH. A diet rich in protein (for amino acids) and phytochemical-dense plants can support this, while targeted precursors (e.g., glycine, γ-glutamylcysteine) and Nrf2-activating foods or agents provide the most robust increases shown so far. Such supplementation can be beneficial, and it is most effective when combined with a diet rich in sulfur-containing foods and other nutrients that support GSH synthesis. Full article