Search Results (2,279)

Chronic pain and sleep disturbances are frequently associated and profoundly affect the quality of life, creating intertwined physical, emotional, and social challenges. This narrative review synthesizes current evidence on the molecular mechanisms and pharmacological influences underlying this bidirectional relationship. Elevated pro-inflammatory cytokines (IL-1β, IL-6, IL-10, TNF-α), neurodegenerative markers (tau, β-amyloid 42), metabolic hormones, and fasting glucose have been consistently associated with both objective and subjective sleep impairments in chronic pain conditions. Pharmacological agents such as melatonin and opioids exhibit heterogeneous effects on neurophysiological pathways, reflecting differences in mechanisms of action and their modulation of biological processes. Rather than offering therapeutic recommendations, this review aims to clarify how these mediators and drugs shape the complex interplay between pain and sleep. Overall, the evidence suggests that persistent dysregulation of inflammatory, neurodegenerative, and metabolic pathways may drive the reciprocal and detrimental interaction between chronic pain and sleep disturbances, highlighting opportunities for targeted research and integrated clinical strategies. Full article

Neuroinflammation is a defining feature of many neurological disorders, including neurodegenerative diseases, traumatic brain injury, and demyelinating conditions. Glial cells play a central role in this process by initiating, modulating, and resolving inflammatory responses in the CNS. This review examines the diverse roles of glial cells in neuroinflammation, focusing on their molecular and cellular interactions, context-dependent activation states, and phenotypic plasticity. It discusses how microglial activation can result in both neuroprotective and neurotoxic effects, while astrocytes contribute to immune regulation, blood–brain barrier integrity, and neuronal survival. The review also highlights interactions between glial cells and peripheral immune components, which may exert synergistic or antagonistic effects. Finally, it outlines emerging preclinical and clinical strategies targeting glial pathways to modulate several neuroinflammatory outcomes, emphasizing that a detailed understanding of glial dynamics is essential for developing effective CNS therapies. Full article

Astrocytes are critical for maintaining brain homeostasis through metabolic support, neurotransmitter regulation, and blood–brain barrier integrity. In the aging brain and neurodegenerative conditions, astrocytes undergo functional and morphological changes that culminate in a state of cellular senescence. Astrocytic senescence—characterized by irreversible cell-cycle arrest and a pro-inflammatory senescence-associated secretory phenotype (SASP)—is emerging as a key contributor of chronic neuroinflammation and synaptic dysfunction in aging. This review examines the molecular mechanisms underlying astrocyte senescence, highlighting how persistent DNA damage responses (DDR), oxidative stress, and mitochondrial dysfunction disrupt essential astrocytic functions (e.g., glutamate uptake, K⁺ buffering, and metabolic coupling with neurons). These senescent changes in astrocytes lead to impaired synaptic plasticity and contribute to age-related cognitive decline. Collectively, astrocytic senescence represents a pivotal and targetable mechanism in age-related neurodegeneration, and therapeutic strategies aimed at eliminating senescent cells or modulating the SASP hold promise for restoring synaptic function and promoting healthy brain aging. Full article

Activation of microglia and resulting neuroinflammation are central processes that significantly contribute to neurodegenerative disease progression. Treatments capable of attenuating neuroinflammation are therefore an urgent medical need. Vitis vinifera L., cultivated since ancient times for its fruits, is known for its antioxidant and anti-inflammatory activities. However, polyphenols, the main bioactive molecules in V. vinifera extracts, exhibit considerable variability due to numerous hard-to-control factors, which complicates the production of standardized extracts with consistent biological activity. To address this issue, plant cell culture biotechnology was used to produce a highly standardized V. vinifera phytocomplex (VP), and its anti-neuroinflammatory profile was investigated in LPS-stimulated microglial cells, an in vitro model of neuroinflammation. VP reduced the LPS-induced pro-inflammatory phenotype, improved cell viability and cell number, attenuated NF-κB activation and ERK1/2 phosphorylation, and increased SIRT1 levels. To overcome VP’s poor water solubility, water-soluble cellulose nanocrystal (CNC)-based formulations were developed and tested. VP-CNC formulations markedly reduced the BV2 pro-inflammatory phenotype and increased cell viability under both basal and LPS-stimulated conditions. The nanoformulations also decreased pERK1/2 levels and increased SIRT1 expression, exhibiting biological activities comparable to VP alone. V. vinifera phytocomplex derived from plant cell cultures represents an innovative and standardized product with promising anti-neuroinflammatory properties. Full article

The microglia, first identified by Pío del Río-Hortega, are resident macrophages in the CNS that aid in immune monitoring, synaptic remodeling, and tissue repair. Microglial biology’s dual functions in maintaining homeostasis and contributing to neurodegeneration are examined in this review, with a focus on neurodegenerative disease treatment targets. Methods: We reviewed microglial research using single-cell transcriptomics, molecular genetics, and neuroimmunology to analyze heterogeneity and activation states beyond the M1/M2 paradigm. Results: Microglia maintains homeostasis through phagocytosis, trophic factor production, and synaptic pruning. They acquire activated morphologies in pathological conditions, releasing proinflammatory cytokines and reactive oxygen species via NF-κB, MAPK, and NLRP3 signaling. Single-cell investigations show TREM2 and APOE-expressing disease-associated microglia (DAM) in neurodegenerative lesions. Microglial senescence, mitochondrial failure, and chronic inflammation result from Nrf2/Keap1 redox pathway malfunction in ageing. Microglial interactions with astrocytes via IL-1α, TNF-α, and C1q result in neurotoxic or neuroprotective A2 astrocytes, demonstrating linked glial responses. Microglial inflammatory or reparative responses are influenced by epigenetic and metabolic reprogramming, such as regulation of PGC-1α, SIRT1, and glycolytic flux. Microglia are essential to neuroprotection and neurodegeneration. TREM2 agonists, NLRP3 inhibitors, and epigenetic modulators can treat chronic neuroinflammation and restore CNS homeostasis in neurodegenerative illnesses by targeting microglial signaling pathways. Full article

Background/Objectives: Citicoline, also known as CDP-choline, is a nootropic agent currently used in the treatment of glaucoma and is undergoing evaluation as a first-line therapy in a multi-center, international, phase III, randomized clinical trial involving citicoline eyedrops (ClinicalTrials.gov ID: NCT05710198). Numerous clinical and preclinical studies have linked the neuroenhancement and neuroprotective effects of citicoline to its role as a metabolic precursor for structural and functional components of cell membranes (such as phosphatidylcholine and sphingomyelin) and for neurotransmitters (e.g., acetylcholine and dopamine). However, compelling evidence suggests that the molecular mechanisms underlying its cytoprotective activity involve additional as-yet uncharacterized pharmacological actions. Methods: To further elucidate its pharmacology, we investigated the effect of two cytoprotective doses of citicoline (0.1 mM and 1 mM) on the global proteome of neuroblastoma cells using an unbiased shotgun proteomics approach. Results: With over 4000 unique proteins identified and quantified per experimental condition, the proteomics analysis revealed that citicoline, after 6 h of stimulation, induces a profound and robust remodeling of the intracellular proteome compared to untreated cells. Importantly, this effect was observed to significantly diminish by 18 h of stimulation, highlighting its transient nature (data are available via ProteomeXchange with identifier PXD061053). The clustering and rationalization of proteins upregulated by citicoline treatment identified the enrichment of key pathways for mRNA splicing, protein translation, proteostasis balance through the ubiquitin proteasome system (UPS), and mitochondrial metabolism. Conclusions: These proteomics findings introduce previously uncharacterized biological effects of citicoline and foster the working hypothesis that this drug may exert its cytoprotective activity through molecular mechanisms linked to the hormesis principle. These data further support the rationale for its clinical application in neurodegenerative processes and human disorders characterized by proteotoxicity. Full article

Pathogenic variants in the PAK1 gene are linked to neurodevelopmental and neurodegenerative disorders by disrupting neuronal signaling and function. Despite increasing recognition, the mechanisms underlying these conditions remain incompletely understood, limiting therapeutic options. Here, we report a novel de novo PAK1 variant, c.396C>A (p.Asn132Lys), in a 5-year-old girl with Intellectual Developmental Disorder with Macrocephaly, Seizures, and Speech Delay (IDDMSSD). The patient presented with mild intellectual disability, delayed speech, macrocephaly, hypotonia, gait ataxia, autism-like behaviors, and focal epileptiform activity. Trio exome sequencing confirmed the variant as likely pathogenic, absent in her parents and population databases. This finding expands the phenotypic spectrum of PAK1-related disorders and underscores the critical role of the autoinhibitory domain in neurodevelopment. In addition, we performed a comprehensive literature review of PAK1 variants affecting both the autoregulatory and kinase domains, summarizing associated clinical features and pathogenic mechanisms. Our study highlights the importance of identifying PAK1 pathogenic variants for accurate diagnosis, refined genotype-phenotype correlations, and the development of potential targeted therapeutic strategies. By integrating novel case data with existing literature, this work advances understanding of PAK1-related neurodevelopmental disorders and supports the application of genetic analysis in rare pediatric NDD cases. Full article

Melanin pigments are ubiquitous biopolymers across diverse life forms and play multifaceted roles in cellular defense and environmental adaptation. The specialized neuromelanin in human brains accumulates mainly within catecholaminergic neurons of the substantia nigra and locus coeruleus, serving as a crucial modulator of brain homeostasis, metal detoxification, and oxidative stress responses. The intricate processes of human melanogenesis, encompassing both cutaneous and neuronal forms, are governed by complex genetic networks. Concurrently, melanin in fungi (synthesized through distinct genetic pathways) confers remarkable resistance to environmental stressors, including ionizing radiation. Recent advancements in omics technologies—including transcriptomics, proteomics, metabolomics, and epigenomics—have profoundly enhanced our understanding of neuromelanin’s molecular environment in health, aging, and neurodegenerative conditions such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and other neurological disorders. This article reviews the genetic underpinnings of human melanogenesis and fungal melanogenesis, explores the convergent and divergent evolutionary pressures driving their functions, and synthesizes the rapidly accumulating omics data to elucidate neuromelanin’s critical, and often dual, role in human brain pathology. Moreover, we discuss the intriguing parallels between neuromelanin and fungal melanin, highlighting radioprotection and its potential implications for neuroprotection and astrobiology, with a special emphasis on the need to investigate neuromelanin’s potential for radioprotection in light of fungal melanin’s remarkable protective properties. Full article

The autophagy–lysosome system is a master regulator of cellular homeostasis, integrating quality control, metabolism, and cell fate through the selective degradation of cytoplasmic components. Disruption of either autophagic flux or lysosomal function compromises this degradative pathway and leads to diverse pathological conditions. Emerging evidence identifies the autophagy–lysosome network as a central signaling hub that connects metabolic balance to disease progression, particularly in neurodegenerative disorders and cancer. Although cancer and neurodegenerative diseases exhibit seemingly opposite outcomes—uncontrolled proliferation versus progressive neuronal loss—both share common mechanistic foundations within the autophagy–lysosome axis. Here, we synthesize recent advances on the roles of autophagy and lysosomal mechanisms in neurodegenerative diseases and cancer, especially on how defects in lysosomal acidification, membrane integrity, and autophagosome–lysosome fusion contribute to toxic protein accumulation and organelle damage in Alzheimer’s and Parkinson’s diseases, while the same machinery is repurposed by tumor cells to sustain anabolic growth, stress tolerance, and therapy resistance. We also highlight emerging lysosome-centered therapeutic approaches, including small molecules that induce lysosomal membrane permeabilization, nanomedicine-based pH correction, and next-generation protein degradation technologies. Finally, we discuss the major challenges and future opportunities for translating these mechanistic insights into clinical interventions. Full article

Background: The regulation of the synthesis of the nerve growth factor and other neurotrophins is one of the dynamically developing areas of pharmacotherapy of neurological and mental disorders. Despite a large number of studies of various ligands of neurotrophin receptors, only a few have reached clinical application and only for ocular diseases. The aim of this narrative review was to systematize the main progress on neurotrophin-based pharmaceutics; to perform a comparative critical analysis of various therapeutic strategies, elucidate the underlying causes of clinical trial failures, and identify the most promising avenues for future development. Methods: The literature search was conducted in PubMed, Google Scholar, Medline, and EBSCO, and the ClinicalTrials.gov database was used to track current clinical studies, along with the official websites of pharmaceutical companies. The search covered original studies published up to October 2025, with inclusion restricted to articles published in English. Articles describing specific pharmacological compounds that had reached the clinical trial stage were selected. Foundational biological research was referenced to contextually explain the mechanisms of action of the drugs and their therapeutic implications. Results: Recombinant neurotrophins and synthetic molecules, the agonists and antagonists of their receptors, and cell-based gene therapy are promising means for the prevention and rehabilitation of ischemic conditions, as well as the treatment of neuropathic pain and neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Some of these have undergone clinical trials, yet only neurotrophins for ocular diseases have been implemented in clinical practice: recombinant NGF—cenegermin and recombinant CNTF—Revakinagene taroretcel. The success of these eye drugs is likely attributable to their local administration, improved bioavailability, and low ocular immunoresistance. Conclusions: The study identified limitations and future prospects for neurotrophin-based pharmaceuticals. For future clinical trials, attention should be paid to the pharmacogenetic profiles of the patients and the evaluation of the inflammatory status of the disease. Novel plasma biomarkers of the effectiveness are needed as well as TSPO-PET imaging. Drug delivery systems remain insufficient; therefore, efforts should focus on inducing endogenous neurotrophin production and developing highly selective agonists and antagonists of neurotrophin receptors. It is crucial to establish a favorable premorbid background before neurotrophin therapy to minimize immunoresistance. Full article

Background/Objectives: Parkinson’s disease (PD) is an adult-onset neurodegenerative disorder whose pathogenesis is still not completely understood. Several lines of evidence suggest that alterations in epigenetic architecture may contribute to the development of this condition. Here, we present a pilot DNA methylation study from peripheral blood in a cohort of Sicilian PD patients and matched controls. Peripheral tissue analysis has previously been shown to reflect molecular and functional profiles relevant to neurological diseases, supporting their validity as a proxy for studying brain-related epigenetic mechanisms. Methods: We analyzed 20 PD patients and 20 healthy controls (19 males and 21 females overall), matched for sex, with an age range of 60–87 years (mean 72.3 years). Peripheral blood DNA was extracted and processed using the Illumina Infinium MethylationEPIC v2.0 BeadChip, which interrogates over 935,000 CpG sites across the genome, including promoters, enhancers, CpG islands, and other regulatory elements. The assay relies on sodium bisulfite conversion of DNA to detect methylation status at single-base resolution. Results: Epigenome-wide association study (EWAS) data allowed for multiple levels of analysis, including immune cell-type deconvolution, estimation of biological age (epigenetic clocks), quantification of stochastic epigenetic mutations (SEMs) as a measure of epigenomic stability, and differential methylation profiling. Immune cell-type inference revealed an increased but not significant proportion of monocytes in PD patients, consistent with previous reports. In contrast, epigenetic clock analysis did not reveal significant differences in biological age acceleration between cases and controls, partially at odds with earlier studies—likely due to the limited sample size. SEMs burden did not differ significantly between groups. Epivariations reveal genes involved in pathways known to be altered in dopaminergic neuron dysfunction and α-synuclein toxicity. Differential methylation analysis, however, yielded 167 CpG sites, of which 55 were located within genes, corresponding to 54 unique loci. Gene Ontology enrichment analysis highlighted significant overrepresentation of pathways with neurological relevance, including regulation of synapse structure and activity, axonogenesis, neuron migration, and synapse organization. Notably, alterations in KIAA0319, a gene involved in neuronal migration, synaptic formation, and cortical development, have previously been associated with Parkinson’s disease at the gene expression level, while methylation changes in FAM50B have been reported in neurotoxic and cognitive contexts; our data suggest, for the first time, a potential epigenetic involvement of both genes in Parkinson’s disease. Conclusions: This pilot study on a Sicilian population provides further evidence that DNA methylation profiling can yield valuable molecular insights into PD. Despite the small sample size, our results confirm previously reported findings and highlight biological pathways relevant to neuronal structure and function that may contribute to disease pathogenesis. These data support the potential of epigenetic profiling of peripheral blood as a tool to advance the understanding of PD and generate hypotheses for future large-scale studies. Full article

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to the gradual loss of motor control, typically resulting in paralysis and death within 3 to 5 years of diagnosis. ALS shares neuropathological and genetic associations with fronto-temporal dementia (FTD), a neurodegenerative condition primarily impacting cognitive functions. These two conditions are increasingly viewed as manifestations of a single molecular disease process that affects distinct brain systems, impacting motor neuronal pathways in ALS and fronto-cortical functions in FTD. However, this simple dichotomy belies the complexity of these conditions. In particular, patients with primary motor ALS can also experience significant cognitive deficits. Investigating the pathobiological and neurophysiological underpinnings of these impairments is essential for a comprehensive understanding of ALS and may open avenues for targeted therapies to alleviate these debilitating symptoms. Moreover, the biophysical correlates of cognitive deficits in ALS may serve as sensitive biomarkers for evaluating potential therapeutics. In this narrative review, we begin with an overview of the clinical features and genetics of ALS, followed by a review of the associated cognitive deficits that are adjunctive to motor decline. We then highlight neuroimaging studies from our laboratory and the broader literature, using EEG and other modalities that are beginning to uncover systems-level brain disruptions potentially underlying cognitive impairment in motor-dominant ALS. Full article

Metalloproteinases (MPs) are zinc-dependent endopeptidases, including matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs), implicated in various diseases such as cancer, neurodegenerative disorders, and cardiovascular conditions. Among MPs, ADAM-17, also known as tumor necrosis factor-α (TNF-α)-converting enzyme (TACE), plays a crucial role in extracellular matrix remodeling and cytokine release. Dysregulation of ADAM-17 contributes to inflammatory diseases, cancer progression, and immune modulation. While small-molecule inhibitors have been limited by off-target effects and instability, antibody-based approaches offer a more selective strategy. Monoclonal antibodies show promise in blocking ADAM-17 activity, but there are concerns about toxicity due to the lack of selectivity. Enhancing the binding affinity and selectivity of single-chain antibodies requires unraveling the structural details that drive MP targeting. This study uses yeast surface display (YSD) and fluorescence-activated cell sorting (FACS) to engineer single-chain variable fragment (scFv) antibodies with optimized complementarity-determining region 3 of the heavy chain (CDR-H3) conformations. Next-generation sequencing (NGS) was used to identify key residues contributing to high-affinity ADAM-17 binding. These findings offer a framework for designing monoclonal antibodies against ADAM-17 and other MPs, paving the way for novel antibody-based designer scaffolds with applications in developing therapeutics. Full article

Aging is a complex degenerative process characterized by the accumulation of molecular damage and a heightened susceptibility to disease. The oxidative stress theory of aging identifies endogenous reactive oxygen species (ROS) as primary drivers of this cellular deterioration. This review provides a comprehensive analysis of the critical, yet underappreciated, interplay between oxidative stress and the complement system, a powerful effector of innate immunity. We detail the mechanistic pathways through which redox imbalance directly activates complement components and, conversely, how complement activation amplifies oxidative stress, creating a vicious cycle that accelerates tissue damage. A central focus is placed on how this redox–complement axis contributes to the pathophysiology of age-related conditions, including neurodegenerative, cardiovascular, and metabolic diseases. Furthermore, the review explores emerging therapeutic strategies that target this interaction, highlighting the potential of antioxidant and complement-inhibitory approaches to disrupt this cycle and promote healthy aging. By synthesizing current evidence, this work underscores the significance of the redox–complement network as a key mechanistic link in aging and its associated diseases. Full article

Dementia is a neurodegenerative condition marked by progressive cognitive decline, which affects people worldwide. Studies on dementia typically continue over years of uncertainty. Different types of dementia, like Alzheimer’s disease dementia, Lewy body dementia, frontotemporal dementia, and vascular dementia, exhibit different pathological features, yet their downstream inflammatory pathways involve similar inflammatory mediators. As an initial trigger, microglial cells and astrocytes become activated by protein aggregates, mutations, or any other cause, and release pro-inflammatory cytokines, which can lead to synaptic dysfunction, neuronal degeneration, and impaired cognitive function. Neuroinflammation plays a critical role in the pathogenesis of all forms of dementia. Despite their distinct neuropathological features, inflammatory processes may coincide at a point and lead to neuronal degeneration and cognitive decline. Recent advancements in neuroimaging techniques and biomarker discovery revealed potential therapeutic targets that may mitigate neuroinflammation. The primary objective of this review is to explore the underlying mechanisms linking neuroinflammation to various types of dementia. This review focuses on shared and distinct neuroinflammatory mechanisms to unravel significant therapeutic strategies for dementia. Full article