Search Results (12,133)

The synuclein family, comprising α-, β-, and γ-synucleins, consists of highly conserved, intrinsically disordered proteins sharing substantial structural homology and exhibiting multifunctional roles in membrane interactions, vesicle trafficking, lipid homeostasis, and cellular signalling. Synucleins are enriched at presynaptic terminals, where they regulate synaptic vesicle dynamics and neurotransmission by contributing to vesicle clustering, trafficking, and the availability of vesicles for release. Aberrant expression, misfolding, and aggregation of synucleins are associated with several human diseases, particularly neurodegenerative disorders and certain cancers, highlighting their biological and clinical relevance. The primary aim of this review was to provide a focused overview of current knowledge regarding the physiological presynaptic functions of synucleins. By concentrating on this relatively underexplored aspect of synuclein biology, we sought to highlight their roles in synaptic transmission and presynaptic regulation, thereby complementing the extensive literature devoted to their pathological significance. Here, the recent findings on the contributions of α-, β-, and γ-synucleins to synaptic vesicle organization, trafficking and neurotransmitter release were summarized, and their emerging roles in maintaining presynaptic homeostasis were discussed. In addition, we consider how disruption of these physiological functions may contribute to synaptic dysfunction and the development of disease. Full article

The cerebellum is traditionally considered a structure responsible for motor control, but it is also involved in auditory perception, vocalization, speech, memory, emotional control, and social cognition. Due to its high intrinsic synaptic plasticity and complex connectivity with other brain regions, it is of potential interest for monitoring adaptive responses under various physiological and pathological conditions to capture global brain dynamics. Nevertheless, the use of electrocerebellography (ECeG) to detect changes in cerebellar electrical activity is limited, and a systematic evaluation of ECeG data to inform future research directions is lacking. This review summarizes recent ECeG research to explore the contribution of this time-honored method to deciphering the cerebellum’s spatial and temporal dynamics in health and disease. ECeG studies from the past three decades examining the slow and fast adaptive responses of the cerebellum in different cerebellar layers during sleep, anesthesia, brain injury, epilepsy, neurodegenerative diseases, and neuropsychiatric disorders are compiled from the PubMed, Scopus, and Google Scholar databases and discussed accordingly. It can be concluded that, despite certain limitations, ECeG is a practical, valuable, and reliable technique for detecting and predicting the complex spatial and temporal features of cerebellar electrical activity. Full article

Background/Objectives: Natural products derived from plants, animals, and microorganisms have long been used as nutritional supplements and are increasingly recognized for their potential role in preventing and managing human diseases. This narrative review aims to summarize current evidence on the therapeutic relevance of natural products as dietary supplements across major disease categories and to highlight their mechanisms of action, clinical efficacy, and safety considerations. Methods: A narrative literature review was conducted using peer-reviewed articles, systematic reviews, and clinical studies focusing on natural products used as nutritional supplements in disease management. Relevant data were analyzed thematically, with emphasis on bioactive compounds, mechanisms of action, and evidence from preclinical and clinical research. Results: Natural products, particularly plant-derived polyphenols, flavonoids, terpenoids, omega-3 fatty acids, and probiotic-derived metabolites, exhibit diverse biological activities, including antioxidant, anti-inflammatory, immunomodulatory, and antimicrobial effects. Evidence suggests potential benefits in cardiovascular diseases, metabolic disorders such as diabetes and obesity, neurodegenerative conditions, certain cancers, gastrointestinal disorders, and infectious diseases. However, clinical efficacy varies depending on compound type, dosage, and formulation. Key limitations include low bioavailability, variability in composition, and insufficient large-scale clinical trials. Safety concerns such as herb–drug interactions and lack of standardization remain significant challenges. Conclusions: Natural products as nutritional supplements represent a promising adjunct strategy in the prevention and management of various human diseases. While preclinical and early clinical evidence is encouraging, stronger clinical validation, improved standardization, and clearer regulatory frameworks are required to fully integrate these agents into evidence-based medical practice. Full article

Microtubule-associated proteins (MAPs) are key regulators of microtubule architecture and dynamics, orchestrating microtubule stability, post-translational modification, and spatial organization across diverse cellular contexts. Through these activities, MAPs govern essential processes including cell division, intracellular transport, signaling, and differentiation. This review synthesizes current insights into how MAPs regulate a diverse range of cellular processes, including maintenance of structural integrity, centriole assembly, cell division, the dynamic transition between centrosomal and ciliary states, and neuronal growth and connectivity. We discuss advances from structural biology, proteomics, and cell imaging that are redefining the molecular landscape of centriole and cilia regulation, and we highlight emerging themes linking MAP dysfunction to human disease, including cancer, ciliopathies, and neurodegenerative disorders. By integrating these diverse perspectives, the review outlines a unifying framework for understanding how MAPs orchestrate microtubule function and identifies key challenges and opportunities for future research. Full article

Aberrant self-assembly of ataxin-3 (ATX3) into amyloid aggregates is a key pathological event in spinocerebellar ataxia type 3 (SCA3). Bioactive nutraceutical compounds, particularly polyphenols, have emerged as promising candidates for targeting protein aggregation and cellular stress responses associated with neurodegenerative disorders. Here, we investigated cinnamon bud extract as a natural source of neuroprotective molecules, focusing on its total extract (Etot) and two bioactive fractions: a polyphenol-enriched fraction (Fr. B) and a cinnamaldehyde-rich fraction (Fr. C). By integrating biochemical and biophysical techniques, we demonstrate that cinnamon-derived compounds modulate ATX3 aggregation by reducing the formation of β-sheet-rich amyloid assemblies and promoting the generation of SDS-resistant, soluble, structurally distinct, non-fibrillar species. NMR profiling identified flavonoids, cinnamaldehyde, and cinnamic acid as key ATX3-interacting molecules, supporting their contribution to the anti-amyloidogenic activity of the extract. Moreover, in a Caenorhabditis elegans SCA3 model, Etot and Fr. B improved locomotor defects and enhanced resistance to oxidative and thermal stress, indicating broader cytoprotective effects beyond direct aggregation modulation. Overall, these findings highlight cinnamon bud extract, particularly its polyphenol-rich fraction, as a promising nutraceutical source of bioactive compounds with potential neuroprotective properties and provide a basis for further investigation of nutraceutical strategies targeting polyglutamine-related neurodegenerative diseases. Full article

Objectives: Thiocarbohydrazones represent an important class of Schiff base derivatives with versatile chemical and biological properties. Methods: Herein, we present a combined in silico spectroscopic and molecular docking investigation of N′-benzylidenehydrazinecarbothiohydrazide (1). Results: Conformational docking studies were conducted against cathepsin B, acetylcholinesterase, HER2, protein kinase C, and protein kinase A. The compound displayed favorable binding affinities and key interactions within the catalytic sites of all targets, with the strongest predicted binding observed for acetylcholinesterase. Notably, all conformers exhibited higher affinity for protein kinase C than the reference inhibitor balanol, and hydroxylation led to an approximately 10% enhancement in docking performance. Density functional theory (DFT) calculations were employed to analyze vibrational properties, and IR and Raman spectra were computed to elucidate structural features and conformational behavior. Conclusions: The integrated spectroscopic and docking analyses provide mechanistic insights into ligand–target interactions and support rational drug design. These findings identify thiocarbohydrazone derivatives as promising multi-target candidates for the development of enzyme inhibitors relevant to neurodegenerative, oncological, and inflammatory diseases. Full article

The ZFP36 family proteins (TTP, ZFP36L1, and ZFP36L2) are RNA-binding proteins that function as key post-transcriptional regulators of gene expression. They bind AU-rich elements (AREs) in target mRNA 3′UTRs, recruit the CCR4-NOT deadenylation complex to trigger mRNA decay, and maintain homeostasis in immunity, barrier function, and stem cell fate. Rather than acting on single targets, all family members share a conserved mRNA destabilization mechanism, with outcomes determined by member-specific expression, kinase-mediated regulation, and cell-type-dependent target availability. Dysregulation of this network stabilizes mRNAs encoding pro-inflammatory cytokines, immune checkpoints, and oncogenes, driving pathogenesis of inflammation, autoimmunity, cancer, cardiovascular and neurodegenerative diseases. Individual family members exert context-dependent and sometimes opposing effects, so their net function depends on the specific cellular and disease context. Therapeutic strategies targeting ZFP36 activity, including phosphatase agonism and epigenetic modulation, have shown promising preclinical results, but clinical translation remains early. This review summarizes the molecular regulatory networks of the ZFP36 family and their physiological and pathological roles, emphasizing the mechanistic principles that unify family-member function and the contextual factors that diversify it, to provide a foundation for future therapeutic development. Full article

Neurodegenerative diseases like Alzheimer’s disease (AD) and Parkinson’s disease (PD) are regarded as systemic illnesses, mainly characterized by long-term neuroinflammation, metabolic dysregulation and barrier dysfunction. All these factors interact through the gut–immune–brain axis. The Mediterranean diet, rich in plant-based foods, olive oil, and fish, has been consistently associated with slower cognitive decline and reduced risk of neurodegeneration in observational studies and some clinical trials. This review provides a systems-level synthesis that distinguishes itself from previous narratives by integrating disease-specific mechanistic frameworks with multi-omics-guided precision nutrition strategies. We summarize recent evidence showing that this dietary pattern can remodel gut microbiota composition and enhance the production of bioactive metabolites such as short-chain fatty acids (SCFAs). These metabolites are associated with improved intestinal barrier integrity, reduced systemic inflammation, and potential modulation of brain functions. Within the central nervous system, diet-related metabolites have been linked to reduced neuroinflammation via modulation of microglial and astrocytic states. They have been linked to protection of mitochondrial function, maintenance of proteostasis, and preservation of blood–brain barrier (BBB) integrity. In AD and PD patients, adherence to this diet is associated with favorable changes in pathological hallmarks, including amyloid-beta (Aβ), tau, and α-synuclein accumulation. Nowadays, multi-omics tools, including single-cell transcriptomics, spatial transcriptomics and microbiome analysis, are widely used in this field, which helps researchers explore these complicated effects more deeply. Importantly, individual responses to the diet vary considerably due to differences in genetic background, gut microbial composition, and metabolic phenotypes, which underscore the need to move from generalized dietary guidelines toward personalized precision nutrition. The Mediterranean diet is not only a dietary pattern but also an effective way to modulate neuro-immune and metabolic networks. However, current evidence remains largely observational, and we critically discuss the need for more randomized controlled trials (RCTs) and standardized multi-omics data analysis frameworks. To sum up, the Mediterranean diet plays a neuroprotective role via the gut–immune–brain axis, and multi-omics techniques promote the development of precision nutrition. More trials and improved multi-omics systems are required to apply these research results in clinical practice. Full article

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra. Oxidative stress, neuroinflammation, and α-synuclein aggregation are central pathological features of PD. Zanthoxylum piperitum DC, commonly known as Korean pepper or chopi, is a traditional dietary spice in Eastern Asia and has been reported to possess antioxidant and anti-inflammatory properties. This study investigated the neuroprotective and motor function–enhancing effects of distilled extract of Z. piperitum (deZP) in 1-Methyl-4-phenylpyridinium (MPP⁺)-treated Caenorhabditis elegans and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse models of PD. Methods: In the C. elegans model, dopaminergic neurotoxicity was induced by MPP⁺, and deZP was tested at 0.25, 0.5, and 1% (v/v) to evaluate neuronal preservation through GFP-labeled dopaminergic neurons and α-synuclein expression. Concurrently, in the MPTP-induced mouse model, deZP was administered intranasally at a fixed dose of 20 μL/mouse, equivalent to 5 mg/mouse. Motor function was assessed using the rota-rod test, pole test, and grip strength test, while dopaminergic neuronal survival was evaluated by tyrosine hydroxylase (TH) immunostaining. Results: In MPP⁺-treated C. elegans, deZP significantly restored green fluorescent protein (GFP) fluorescence in dopaminergic neurons and reduced α-synuclein expression, with the most pronounced effects observed at 1% (v/v). In the MPTP-induced mouse model, deZP at this fixed intranasal dose significantly improved motor performance and preserved TH-positive neurons in the substantia nigra. Conclusions: These findings suggest that deZP may represent a promising preclinical candidate for further investigation in PD-related neurodegeneration. Full article

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder and a leading cause of dementia worldwide, yet effective disease-modifying therapies remain elusive. Rodent models have been indispensable for elucidating key pathological mechanisms, including amyloid-beta (Aβ) deposition, tau pathology, neuroinflammation, and synaptic dysfunction. However, despite decades of preclinical success, the translation of therapeutic findings from rodent studies to clinical efficacy in humans has been largely unsuccessful, highlighting critical limitations in current modelling approaches. This narrative review provides a comprehensive and critical evaluation of rodent models of AD, encompassing transgenic, chemically induced, metabolic, inflammatory, and lesion-based paradigms. Rather than presenting these models in isolation, we propose a systems-level framework that categorizes them based on their ability to recapitulate distinct domains of AD pathology, including genetic, environmental, and systemic contributors. By synthesising existing research, highlighting critical gaps, and proposing a tiered minimum-criteria framework for the development of next-generation models, we offer a definitive operational roadmap instead of merely a list of deficiencies. We highlight that most existing models predominantly reflect familial and reductionist aspects of the disease, while failing to capture the complexity of sporadic AD, aging processes, vascular dysfunction, and whole-body interactions. Importantly, we emphasize emerging dimensions that are underrepresented in current rodent models, including glymphatic dysfunction, cerebral small vessel disease, and the microbiota–gut–brain axis, all of which play crucial roles in AD pathogenesis. We further discuss how integrating these factors into next-generation models may improve translational relevance and therapeutic predictability. By synthesizing current evidence and identifying key gaps, we provide a strategic roadmap for the development of more physiologically relevant and translationally robust rodent models. Advancing toward integrative, systems-based approaches will be essential for bridging the persistent gap between preclinical discoveries and clinical success in AD. Full article

The glymphatic system is a brain-wide clearance pathway that facilitates the removal of interstitial solutes, including amyloid-β, and plays a critical role in maintaining brain homeostasis. Impairments in glymphatic transport have been implicated in aging and neurodegenerative diseases, including Alzheimer’s disease. While glymphatic activity is most pronounced during sleep, emerging evidence suggests that specific patterns of neural activity, including gamma-frequency oscillations entrained by sensory stimulation, can modulate glymphatic transport even during wakefulness. Preclinical studies further indicate that 40 Hz sensory stimulation, delivered via light, sound, or multisensory paradigms, can induce gamma oscillations, reduce pathological protein accumulation, and enhance cognitive performance in animal models of Alzheimer’s disease. Early clinical investigations similarly suggest that gamma-frequency sensory stimulation may improve blood-based biomarkers, neuroimaging measures, and cognitive outcomes in patients with Alzheimer’s disease. To translate gamma-frequency stimulation into broadly applicable preventive or therapeutic strategies, approaches must be both effective and tolerable for long-term use. Conventional auditory gamma stimulation can be perceived as acoustically rough or monotonous, reducing listener comfort and limiting acceptability for prolonged use in broader populations. User-friendly auditory formats, such as “gamma music” and the more recently introduced “immersive gamma music”, have been proposed as potentially useful approaches for delivering gamma-frequency stimulation while improving listening comfort and facilitating sustained use. Collectively, gamma-frequency sensory stimulation represents a promising approach to support healthy brain aging and mitigate neurodegenerative processes, particularly when implemented via user-friendly auditory formats that facilitate repeated and long-term use. While these findings are encouraging, further research is needed to validate these approaches and determine their clinical relevance. Full article

SARS-CoV-2 infection leads to extrapulmonary complications in multiple organs, including the brain, both in the short-term and long-term. The neurological manifestation of SARS-CoV-2 infection ranges from benign signs like loss of smell and loss of taste to severe complications like encephalitis, stroke, and exacerbation of Alzheimer’s disease (AD) progression. Pericytes are mural cells of the brain vasculature that help maintain the blood–brain barrier (BBB), regulate cerebral blood flow (CBF), modulate neuroinflammation, and clear toxic materials, including amyloid beta. Pericytes express ACE2, the receptor for SARS-CoV-2, and therefore may be targeted by either direct virus infection or virus-induced inflammatory cytokines induced by the virus in the brain. To further study the effects of SARS-CoV-2 on pericytes and BBB integrity, the long-term effects of SARS-CoV-2 infection on brain pericytes, inflammation, and other neuropathological complications were analyzed in mice. K18 (human ACE2 transgenic) mice were infected with 10³ PFU of SARS-CoV-2 (delta strain), and the brains were analyzed at 6, 14, and 30 days post-infection (dpi). A significant reduction in the weight of infected mice was observed by 6 dpi. Viral nucleocapsid protein and infectious SARS-CoV-2 were observed in the brains of all mice by 6 dpi, and in some mice by 14 dpi, but not at 30 dpi. This observation suggests viral neurotropism with subsequent clearance at later timepoints. Despite virus clearance, the levels of inflammatory mediators, including TNF-α and IFN-γ were significantly elevated up to 30 dpi. We also observed a significant reduction in the level of brain pericytes by 14 dpi up to 30 dpi. Importantly, an increase was observed in the level of Friend Leukemia Integration 1 (FLI-1), a transcription factor known to promote pericyte cell death, from 14 dpi up to 30 dpi. The level of amyloid beta 1–42 was elevated in the brain of infected mice at 6 dpi, and this was maintained up to 30 dpi, and there was a decrease in neuronal density from 14 to 30 dpi. Furthermore, we observed an increased expression of Alzheimer’s disease (AD)-associated genes like PSEN1, BACE1, and APP. Furthermore, there was increased activation of several neurodegenerative pathways, including “G alpha (z) signaling pathway”, “Apelin muscle signaling pathway”, and “G beta-gamma (Gβγ) signaling”, in the brains of infected mice compared to control mice. Collectively, the observed neuropathology and unique molecular markers of neurodegenerative disease progression provide a novel mechanism by which COVID-19 may promote dementia/AD by contributing to pericyte loss and BBB dysfunction during infection. Full article

The kynurenine pathway (KP) constitutes the primary route of tryptophan catabolism, generating a spectrum of neuroactive metabolites that profoundly influence central nervous system function. Dysregulation of the KP is increasingly recognized as a critical pathogenic mechanism underlying diverse neuropathological conditions. This review critically evaluates the most widely cited mammalian cellular models currently utilized to delineate the causal role of KP alterations in neurological disease. Specifically, this article examines primary cell cultures, immortalized and tumor-derived cell lines, stem cell-derived systems, and ex vivo organotypic brain slices and tissues, highlighting their distinct methodological advantages, translational limitations, and specific enzymatic profiles. Across the described cellular systems, a recurring mechanistic theme emerges: quinolinic acid-driven mitochondrial dysfunction, oxidative stress, and NAD+ depletion converge in neurodegenerative conditions such as Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Conversely, kynurenic acid exhibits disorder-dependent—and at times opposing—roles, attenuating dopaminergic neurotoxicity in Parkinson’s disease models while contributing to synaptic pruning deficits in schizophrenia models. Furthermore, cellular models demonstrate that IDO1/TDO induction and downstream metabolite shifts are frequently cell type- and species-dependent, complicating direct extrapolation to human pathology. Because no single experimental system achieves complete physiological fidelity, elucidating the complex dynamics of the KP and identifying novel therapeutic targets requires the integration of data across complementary platforms. Full article

Cadmium (Cd) is a widespread environmental pollutant associated with neurotoxicity, but its underlying mechanisms remain unclear. Disulfidptosis is a regulated cell death driven by disulfide stress under conditions of impaired cellular reducing capacity. This study investigated the potential involvement of disulfidptosis-associated molecular alterations in Cd-induced neurotoxicity. Male Sprague Dawley (SD) rats were exposed to cadmium chloride (Low-Dose Group: CdCl₂: 0.036 mg/kg bw; High-Dose Group: CdCl₂: 3.6 mg/kg bw) by oral gavage for 30 days. Neurobehavioral performance was assessed using the open field test, elevated plus maze, and Morris water maze. Hippocampal ultrastructure, redox-related metabolites, and disulfidptosis-associated genes were analyzed. In addition, bioinformatics analysis was performed by integrating cadmium-related, neurodegenerative disease-related, and disulfidptosis-related genes. The results showed that high-dose Cd exposure impaired locomotor activity, increased anxiety-like behavior, and disrupted spatial learning and memory (p < 0.05), accompanied by mitochondrial damage in hippocampal neurons. Bioinformatics analysis identified seven overlapping genes and enrichment of ferroptosis and oxidative phosphorylation pathways. Biochemically, cadmium exposure significantly increased the NADP⁺/NADPH ratio ([Control: 1.07 ± 0.044] vs. [High-dose: 3.80 ± 0.059], p < 0.05) and decreased the GSH/GSSG ratio ([Control: 2.80 ± 0.059] vs. [High-dose: 1.14 ± 0.091], p < 0.05), indicating severe redox imbalance. At the molecular level, cadmium exposure upregulated SLC7A11 mRNA expression by 1.48 ± 0.12-fold (p < 0.01) and SLC3A2 by 1.91 ± 0.55-fold (p < 0.05), while downregulating NDUFS1 expression to 0.84 ± 0.01-fold of control levels (p < 0.01) in hippocampal tissues. These findings suggest that high-dose Cd exposure induced neurotoxicity is associated with mitochondrial dysfunction, redox imbalance, and disulfidptosis-associated molecular alterations. Full article

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and a leading cause of dementia worldwide, characterized by progressive cognitive decline, memory impairment, and neuronal loss. The pathological hallmarks of AD include extracellular accumulation of amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, chronic neuroinflammation, oxidative stress, mitochondrial dysfunction, and synaptic degeneration. Current symptomatic therapies provide modest clinical benefits, while recently approved amyloid-targeting monoclonal antibodies, such as lecanemab and donanemab, can slow decline in selected early-stage AD patients but do not cure the disease and are associated with safety, access, and cost concerns. This narrative review summarizes mechanistic evidence from in vitro and in vivo studies and distinguishes preclinical promise from validated clinical utility. Phytochemicals, including polyphenols, flavonoids, alkaloids, terpenoids, and carotenoids, demonstrate neuroprotective effects through antioxidant activity, anti-inflammatory modulation, inhibition of amyloid aggregation, regulation of tau phosphorylation, and support of mitochondria and synapses. Evidence from experimental models suggests that several phytochemicals may help slow AD pathology and improve cognitive function, but clinical translation remains limited due to poor bioavailability, inadequate blood–brain barrier (BBB) penetration, and a lack of large-scale clinical trials. This review highlights critical research gaps and emerging strategies to facilitate phytochemical-based preventive and therapeutic approaches in AD. Full article