Aluminium, an omnipresent environmental pollutant, has been recognized for its neurotoxic effects, particularly its ability to promote neuronal death. More research evidence links aluminium exposure to death through molecular mechanisms. This review delves into the mechanisms underlying aluminium-induced neurotoxicity, including programmed cell death pathways such as apoptosis, necroptosis, autophagy, ferroptosis, and pyroptosis. Aluminium exposure leads to disruption of oxidative homeostasis and induction of endoplasmic reticulum stress, mitochondrial dysfunction and DNA damage, which in turn trigger different cell death pathways. Substantial changes in key signalling pathways, such as the IL-1β/JNK, PI3K/Akt/mTOR, Nrf2/Ho-1, System Xc-/GPX4, and NLRP3 inflammasome activation pathways, were observed. Overall, these intertwined pathways highlight aluminium as a potent modulator of neuronal survival pathways, driving neurodegeneration through multifactorial mechanisms. A thorough understanding of these changes provides a fundamental explanation of the role of aluminium toxicity in the etiology of neurodegenerative diseases and provides a foundation for treatment.

Post-Traumatic Stress Disorder is a complex psychiatric condition characterized by persistent fear, emotional dysregulation, cognitive impairment, hyperarousal, and chronic stress. Although PTSD is typically triggered by exposure to traumatic events, the underlying biological mechanisms contributing to its development and progression remain incompletely understood. Glycation, a non-enzymatic biochemical process leading to the formation of Advanced Glycation End Products (AGEs), has emerged as a potential mechanistic link between chronic stress, neuroinflammation, and stress-related neuropsychiatric disorders, including PTSD. This review explores the role of glycation and deglycation in the pathophysiology of PTSD. It examines how chronic psychological stress contributes to AGE accumulation, neuroinflammation, oxidative damage, and neuronal dysfunction. Additionally, the review discusses diagnostic biomarkers, potential therapeutic targets, dietary and nutritional interventions, and hormonal therapies that may help restore glycation-deglycation balance and improve clinical outcomes in individuals with PTSD. A comprehensive review of the literature was conducted to evaluate the molecular and physiological mechanisms underlying PTSD, with particular emphasis on glycation-related pathways. Studies investigating the roles of AGEs, their receptors, endogenous deglycation systems, dietary factors, and pharmacological interventions were analysed. The review also assessed emerging precision medicine approaches and nutritional strategies aimed at reducing AGE formation and mitigating stress-induced neurobiological alterations. Chronic psychological stress may disrupt the physiological balance between glycation and deglycation, leading to carbonyl stress, excessive AGE formation, mitochondrial dysfunction, oxidative stress, and persistent neuroinflammation. AGEs activate the receptor for advanced glycation end products (RAGE), triggering inflammatory signalling pathways such as NF-κB and promoting neuronal injury. Key molecular targets linking PTSD and glycation include RAGE, hypoxia-inducible factor-1 alpha (HIF-1α), KEAP1/Nrf2 signalling, FKBP5-glucocorticoid receptor pathways, the glyoxalase system (GLO1 and GLO2), and DJ-1/PARK7. Biomarker studies reveal alterations across neuroendocrine, inflammatory, genetic, epigenetic, psychophysiological, and neuroanatomical pathways in PTSD. Nutritional interventions rich in polyphenols, antioxidants, omega-3 fatty acids, probiotics, vitamins, and anti-inflammatory compounds may reduce AGE formation, enhance endogenous deglycation mechanisms, and improve neurobiological resilience. Emerging hormonal therapies, including glucocorticoids, DHEA, allopregnanolone, estrogen, testosterone, oxytocin, vasopressin antagonists, and IGF-1 modulation, may further complement conventional PTSD treatment strategies. Dysregulation of glycation and deglycation pathways represents a promising mechanistic framework for understanding the development and progression of PTSD. Excessive AGE accumulation may contribute to neuroinflammation, oxidative stress, impaired neuroplasticity, and accelerated biological aging observed in affected individuals. Targeting AGE formation and enhancing endogenous deglycation mechanisms through pharmacological, nutritional, and hormonal interventions may offer novel therapeutic opportunities for PTSD and related stress-associated disorders. These findings support the development of personalized treatment approaches aimed at improving long-term outcomes and resilience in individuals with PTSD.

Vitamin K acts as a critical regulator across diverse biological systems, contributing significantly to skeletal integrity, cardiovascular functions, metabolic homeostasis, and immune defenses. Experimental studies increasingly suggest that it also plays an important role in the nervous system, supporting neuronal growth, differentiation, and survival. Its antioxidant, anti-inflammatory, and antiapoptotic effects, along with its capacity to act as an alternative electron carrier in mitochondria, further indicate potential neuroprotective properties. This narrative review synthesizes evidence from recent cell and animal studies, mechanistic research on sphingolipid metabolism, and observational data evaluating vitamin K status and cognitive outcomes. Findings from populations receiving long-term vitamin K antagonist therapy were reviewed to highlight potential clinical implications. Regulation of sphingolipid pathways by vitamin K appears to support neuronal proliferation and resilience, while adequate vitamin K levels have been associated with better cognitive performance. Conversely, prolonged exposure to vitamin K antagonists has been linked to impairments in visual memory and verbal fluency, as well as reductions in brain volume. Evidence also indicates that vitamin K is essential for the synthesis and maintenance of myelin and neuronal membrane components, and for activating vitamin K-dependent proteins that preserve neuronal integrity. Beyond its established role in coagulation, emerging preclinical and observational evidence suggests that vitamin K may possess neuroprotective potential through molecular, structural, and antioxidant mechanisms. The observed association between vitamin K antagonist therapy and cognitive decline in older adults highlights the need for comprehensive clinical studies to clarify causality, determine therapeutic relevance, and better define the role of vitamin K in brain health.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder increasingly associated with cognitive impairment and neurodegeneration. Peripheral metabolic dysfunction, particularly insulin resistance and glycation stress, represents a critical link between diabetes and brain pathology. This study investigated the relationship between metabolic alterations and cognitive frailty using a murine T2DM model induced by a high-fat diet (HFD) combined with low-dose streptozotocin (STZ). Male C57BL/6J mice were longitudinally followed from adulthood to senescence and subjected to HFD alone or HFD plus STZ. Metabolic parameters, including fasting glycemia, oral glucose tolerance, insulin resistance (HOMA-IR), glycated albumin (GA), and methylglyoxal (MGO), were assessed over time. Cognitive function was evaluated using spontaneous behavioral tests of recognition memory (Novel Object Recognition, Object Location, and Y-maze), integrated into a cognitive frailty index. Post-mortem histological and immunohistochemical analyses were performed on pancreatic and hippocampal tissues. While HFD alone induced mild alterations, HFD/STZ mice developed a stable diabetic phenotype with severe hyperglycemia, pancreatic β-cell damage, elevated HOMA-IR, and increased GA and MGO levels. Notably, HFD/STZ mice exhibited a marked decline in recognition memory, affecting both knowledge and remembering components. At the central level, diabetic mice showed hippocampal cytoarchitectural alterations, increased tau hyperphosphorylation, and amyloid accumulation. Crucially, both insulin resistance and glycation stress (GA) directly correlated with recognition memory deficits. These findings demonstrate that peripheral metabolic dysfunction, i.e. insulin resistance and advanced glycation, directly correlates with hippocampal pathology and cognitive decline, supporting the translational relevance of the HFD/STZ model for diabetes-related cognitive frailty.

Neurological disorders, including stroke, Parkinson's disease (PD), and Alzheimer's disease (AD), are among the most prevalent and debilitating neuropathological conditions, affecting over 50 million people globally. Effective prevention and treatment strategies require a comprehensive understanding of reliable and disease-specific biomarkers. Such insights can enhance diagnostic precision, enable early detection, and support the development of targeted therapeutic approaches. In this review, we focus on exosome-derived proteins and small non-coding RNAs as promising non-invasive biomarkers for stroke, PD, and AD, given the accessibility and stability of exosomes in biological fluids. Furthermore, we examine their potential diagnostic and therapeutic relevance, emphasizing their functional roles, specificity, and sensitivity. Finally, we discuss current limitations, emerging challenges, and future research directions to guide the advancement of exosome-based biomarker discovery and clinical translation in neurological disorders. However, we emphasize that the comparative effectiveness of exosomal microRNAs (miRNAs) versus protein biomarkers requires direct validation in future head‑to‑head cohort studies.

Hepatic encephalopathy (HE) represents a severe neuropsychiatric manifestation secondary to advanced hepatic dysfunction, predominantly driven by hyperammonaemia and associated neuroinflammatory processes. Although lactulose remains a mainstay in the clinical management of HE due to its ammonia-lowering properties, its limited efficacy in attenuating neuroinflammation necessitates the use of adjunctive therapeutic strategies. Previously, we identified berberine, a plant-derived isoquinoline alkaloid, as an anti-HE agent via the reduction of neuroinflammation and NLRP3 inflammasome activation. Therefore, in the present study, we investigated the potential beneficial effects of co-administering berberine and lactulose in a rat model of thioacetamide (TAA)-induced hepatic encephalopathy. HE was induced via intraperitoneal injections of TAA (200 mg/kg) on alternate days for one week. Animals received oral pre-treatment with lactulose (8 mL/kg) alone or in combination with berberine (100 mg/kg) for 14 consecutive days. Comprehensive behavioural assessments were conducted alongside biochemical quantification of systemic ammonia, hepatic transaminases (ALT, AST), and oxidative stress markers (MDA, GSH) in both hepatic and cerebral tissues. Histopathological evaluations of the liver and brain further corroborated the biochemical findings. Notably, combination therapy significantly ameliorated cognitive deficits, reduced systemic ammonia burden, normalised liver and brain enzyme profiles, and markedly attenuated central neuroinflammatory signalling, as evidenced by reduced hippocampal NF-κB activation and GFAP immunoreactivity, in addition to suppressing hepatic NF-κB expression, surpassing the effects observed with monotherapy. Histological analyses revealed reduced neuronal degeneration and hepatic architectural disruption. These findings underscore the therapeutic potential of berberine-lactulose co-treatment in mitigating both hepatic and neuroinflammatory pathologies associated with HE, offering a promising adjunctive strategy for improving neurocognitive outcomes in liver failure.

Neurodegenerative diseases are characterized by impairment of neuronal functions and neuronal loss. Huntington's disease is one of the neurodegenerative diseases caused by the formation of mutant Huntingtin protein aggregates in the brain. The other pathological reasons behind this disease are oxidative stress, mitochondrial dysfunction, and excitotoxicity, which lead to impairment of motor, cognitive, and psychiatric functions. The vitamins are considered an essential part of a healthy diet, as they tend to increase the nutritional value of the diet. Insufficient intake of macro- and micronutrients can deteriorate human health, which may lead to malnutrition. Nowadays, these vitamins are also considered molecules to manage neurodegenerative disease with the intention of a dual response, along with nourishment. In vivo research reflects the antioxidant potential of vitamins and also functions as an integral part of various metabolic processes of the body that play a vital role in the pathology of Huntington's disease. Despite several neuroprotective properties, current research on vitamins remains limited. The review focuses on evidences exploring the functional significance of vitamins in maintaining neuronal and brain health and their possible impact on the symptoms and pathogenesis of Huntington's disease. It also highlights how the vitamins' potential is at stake to reach the clinical perspective, along with different strategies to overcome their limitations using novel drug delivery and biomarker-based approaches.

Aluminum chloride (AlCl3) is widely used to model Alzheimer's-related neurotoxicity and cognitive decline. Hesperidin, a citrus flavanone with antioxidant and anti-inflammatory properties, has unclear neuroprotective mechanisms against aluminum-induced neurodegeneration. This study investigated hesperidin's neuroprotective effects against AlCl3-induced cognitive impairment in mice, focusing on ERK/MAPK signaling, tau expression, neuroinflammation, and microglial activation. Mice received AlCl3 (100 mg/kg) daily for four weeks, hesperidin (100 mg/kg), both, or vehicle, with hesperidin administered during weeks 3 and 4 in the co-treated group. Cognitive function was assessed using the Morris water maze and Y-maze tests. TNF-α and IL-1β were quantified in brain tissue. IBA1-positive microglial density, ERK immunoreactivity, and tau expression were evaluated immunohistochemically in the hippocampal CA3 region and the prefrontal cortex. AlCl3 impaired spatial and working memory, elevated pro-inflammatory cytokines, increased microglial activation, and upregulated ERK and tau immunoexpression in both regions. Hesperidin co-treatment significantly rescued cognitive deficits, attenuated neuroinflammation, reduced microglial reactivity, modulated ERK signaling, and decreased tau overexpression. These findings demonstrate that hesperidin protects against AlCl3-induced neurodegeneration by concurrently modulating neuroinflammatory and kinase-dependent pathways, supporting its therapeutic potential in aluminum-related tauopathies.

Peripheral nerve injury-induced persistent pain hypersensitivity cannot be fully explained by increased neuronal excitability alone. Rather, it is increasingly recognized as a pathological tissue state characterized by sustained glial activation, immune signaling, and synaptic remodeling within the spinal cord. In this context, metabolic remodeling of the spinal cord has emerged as a potentially important feature of neuropathic pain. However, the metabolic patterns associated with this state, and their relationship to underlying molecular programs, remain incompletely defined. Here, we performed GC-MS-based untargeted metabolomic profiling of the spinal cord dorsal horn on day 7 after spinal nerve transection (SNT). To provide orthogonal validation, we integrated pathway-analysis results from four independent spinal cord RNA-sequencing datasets derived from distinct neuropathic pain models and further conducted qPCR-based validation. Metabolic profiling revealed a clear separation between SNT and sham samples, marked by broad depletion of the free fatty acid pool and features consistent with an immunometabolic shift. Consistently, analyses across RNA-sequencing datasets and qPCR validation demonstrated upregulation of immune and inflammatory programs, together with downregulation of fatty acid metabolism and cholesterol homeostasis. Collectively, these findings suggest that persistent neuropathic pain should be interpreted not simply as a consequence of neuronal and immune signaling, but also through the metabolic tissue environment that supports and sustains this pathological state.

Ischemic stroke (IS) is a detrimental neurological disorder with limited clinical therapeutic options. The Astragalus-Safflower herb pair (AS) shows therapeutic effects against IS, but its mechanism remains unclear. Herein, this study combined cerebral untargeted metabolomics, mitochondrial ultrastructural observation and 16 S rDNA gut microbiota profiling to systematically explore its neuroprotective mechanism. This study aimed to evaluate the efficacy of AS in alleviating IS, and investigate its mechanism of action. Rat models of middle cerebral artery occlusion (MCAO) were established using the intraluminal filament method. Behavioral tests confirmed that AS significantly improved neurological deficits and motor function. Untargeted metabolomics revealed that AS reversed nine IS-related energy metabolites in brain tissue. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment indicated involvement of nicotinamide metabolism and the TCA cycle. Molecular studies demonstrated that AS regulated mitochondrial energy metabolism via the AMPK/Sirt1/PGC-1α axis. Additionally, 16 S rDNA sequencing showed that AS restructured gut microbiota composition. Correlation analysis suggested a gut-brain axis mechanism linking microbial changes to cerebral energy metabolism. In conclusion, AS exerts neuroprotection against IS by activating the AMPK/Sirt1/PGC-1α pathway, thereby enhancing TCA cycle activity and maintaining energy homeostasis. Concurrently, AS reshapes the gut microbiota, contributing to its effects via the gut-brain axis. Taken together, this integrated multi-omics study systematically clarifies the multi-target pharmacological characteristics of AS. These findings provide a novel multi-target mechanistic basis for the clinical application of AS in the treatment of IS and enrich the understanding of its synergistic neuroprotective mechanism.

Majoon-e-Boolis (MB), a traditional Unani formulation, has been used for neurological conditions; however, its molecular mechanism remains largely unexplored. The current study was designed to explore the novel mechanistic insights between antioxidant activity, anti-inflammatory effects, dopaminergic support and anti-aggregation properties of the formulation for modulating the pathogenesis of Alzheimer's Disease (AD). Behavioral deficits were studied via Novel Object Recognition, Elevated Plus Maze and Open Field Test. In addition, the study looked at the immunohistochemistry of superoxide dismutase 2, tumor necrosis factor-alpha, tyrosine hydroxylase and α-synuclein (α-Syn) against Aβ1-42-induced AD model. Additionally, histopathological alterations were also performed against the AD model. The observed findings demonstrated that MB treatment in Aβ1-42-induced AD in rat models significantly improved their cognitive impairments and alleviated anti-anxiety behaviour with enhanced locomotor activity. Moreover, MB induced significant reduction in oxidative stress and neuroinflammation with enhanced dopaminergic neuronal activity. GC-MS analysis of MB revealed the presence of bioactive phytochemicals such as thiophene, guanidinopropionic acid, 5-hydroxymethylfurfural etc. The findings underscore the potential of MB as a promising therapeutic agent in mitigating the multifaceted pathology of Aβ1-42-induced AD in a rat model by exerting its neuroprotective effects, cognition restoration and overall maintenance of neuronal architecture through a combination of antioxidant, anti-inflammatory and anti-aggregation mechanisms, making it a multifaceted therapeutic candidate for AD.

Dysregulated lipid metabolism and neuroinflammation are increasingly recognized as interacting contributors to Alzheimer's disease (AD), but the cell-type-specific genetic links between fatty acid metabolism and AD remain incompletely defined. This study aimed to identify fatty acid metabolism-related genes associated with AD risk and to characterize their relevance to perivascular macrophage (PVM) states. Single-cell RNA-sequencing data from GSE160936 and bulk transcriptomic data from GSE270454 were integrated to evaluate cell-type-specific fatty acid metabolism activity in AD and control samples.The primary data sources, fatty acid metabolism gene set, AUCell scoring strategy, CellChat workflow, GSEA resources, and MR software settings were specified to improve reproducibility. PVMs were further analyzed for differential expression, ligand-receptor communication, pathway enrichment, transcription factor regulation, and pseudotime-associated transcriptional changes. Cis-eQTL-based two-sample Mendelian randomization was performed using eQTLGen exposure data and AD GWAS summary statistics, followed by sensitivity analyses, reverse MR, and Bayesian colocalization.The analyses were interpreted across three distinct evidence levels: cell-type-resolved transcriptional association, systemic genetic expression prioritization, and tissue-level protein expression. Nominal MR findings were interpreted alongside multiple-testing considerations and colocalization support.Candidate protein expression was examined in hippocampal tissue from APP/PS1 and wild-type mice by Western blotting. Single-cell analysis identified eight major cell populations and showed increased fatty acid metabolism activity in PVMs from AD samples. Mendelian randomization prioritized ten fatty acid metabolism-related genes associated with AD risk, among which ACSL1, EPM2AIP1, MALT1, and RASGRP3 showed strong colocalization support (PP.H4 > 0.9). Pathway analyses linked these genes to lipid metabolic regulation, inflammatory signaling, phagocytosis, and mitochondrial/peroxisomal fatty acid metabolism. Co-expression analysis suggested associations between MALT1 and fatty acid oxidation-related genes, including ACADM and ACOX1. Western blotting in whole hippocampal lysates from APP/PS1 mice provided exploratory tissue-level protein evidence, showing increased ACSL1 and MALT1 and decreased RASGRP3 expression; these findings should not be interpreted as confirmatory PVM-specific validation. This integrative analysis prioritizes ACSL1, EPM2AIP1, MALT1, and RASGRP3 as candidate genes connecting fatty acid metabolic dysregulation with AD-associated neuroinflammatory processes. Because the genetic instruments were blood-derived and the protein assays used whole hippocampal lysates, the findings should be interpreted as candidate-gene prioritization and hypothesis generation rather than proof of direct PVM-specific causality.Accordingly, the study supports a prioritized candidate framework for future functional testing, not validated therapeutic targets or direct causal proof.

This study explored how the TLR4-NF-κB-FDX1 cuproptosis axis contributes to type 1 diabetes (T1DM)-related cognitive impairment, seeking to uncover novel intervention targets. Key genes were screened from T1DM datasets via bioinformatics analysis. Primary hippocampal neurons, HBMECs, and a Transwell co-culture BBB model were established under high glucose plus copper overload. Cells received TLR4 inhibitor TAK-242 or FDX1 knockdown. A streptozotocin-induced T1DM mouse model was generated, followed by stereotaxic injection of TLR4-shRNA or FDX1-shRNA adenovirus. Cell viability, cuproptosis markers, BBB permeability, cognitive behaviors, and underlying mechanisms were assessed by CCK-8, ICP-MS, TEER, behavioral tests, Western blot, immunofluorescence, and ChIP-qPCR. FDX1 was markedly upregulated in T1DM and strongly correlated with TLR4/NF-κB. In vitro, high glucose plus copper overload activated the TLR4-NF-κB-FDX1 axis, induced DLAT lipoylation aggregation and cuproptosis, and caused neuronal synaptic injury along with disruption of endothelial tight junctions. Blocking TLR4 or knocking down FDX1 significantly attenuated these damages. In vivo, T1DM mice showed cognitive deficits and BBB disruption, both rescued by TLR4 or FDX1 knockdown. ChIP-qPCR confirmed that NF-κB bound directly to the FDX1 promoter to enhance its transcription. This study demonstrated for the first time that the TLR4-NF-κB-FDX1 cuproptosis axis plays a key pathological role in T1DM-related cognitive impairment, offering a new avenue for targeted therapy.

The complex physiology of Parkinson's disease (PD) and its limited response to conventional therapies make it a challenging condition to manage. Evidence suggests that both environmental and genetic variables play essential roles in the progression of PD. However, the possible interplay between environment and genetics in PD etiology remains mostly unresolved. Brain-derived neurotrophic factor (BDNF) is a neurotrophin widely distributed and intensively investigated in the mammalian brain. BDNF modulates dopaminergic neurotransmission via neuronal differentiation regulation. BDNF communicates with the Tropomyosin receptor kinase B (TrkB) and activates Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) which can subsequently phosphorylate downstream CREB protein at ser133 residue. Research suggests that numerous health advantages, including significant protections for PD, have been linked to olives, a specific component of the Mediterranean diet. OLE is effective in the treatment of a variety of neurological conditions, including PD. Changes in gene expression patterns induced by aberrant histone acetylation can also aid in the causes of PD. Thus, in the context of neurological diseases, comprehending the epigenetic regulation of the neuronal survival gene is thought to be essential. OLE was first administered intraperitoneally as a pretreatment for seven days. Thereafter, OLE was administered one hour after the rotenone injection for 5 weeks. Herein, we have observed the neuroprotective role of OLE in the cellular signalling cascade associated with neuronal survival through the BDNF/ERK/CREB pathway. Subsequently, we examined the effect of OLE on the enrichment of histone acetylation AcH3K9 in the neuro-survival gene promoter region in PD cases. The data suggest that OLE regulates at both cellular and epigenomic levels by promoting the enrichment of acetylated H3K9 on the neuro-survival gene promoter region in the nigrostriatal region of PD mice.