Search Results (20,075)

Background/Objectives: Fibromyalgia (FM) syndrome is characterised by constant and pervasive musculoskeletal pain and may be comorbid with obesity. Glucagon Peptide-1 Receptor Agonists (GLP-1RAs) are relatively new pharmacotherapies developed for the treatment of type 2 diabetes mellitus (T2DM) and have been repurposed for the treatment of obesity. In addition to their well-established impact on glucose balance, new evidence indicates that GLP-1RAs may have anti-inflammatory properties beyond glycaemic regulation. The use of GLP-1RAs has been proposed to modulate the central pain pathways in patients with FM; however, few studies have directly evaluated their effects on central pain. Hence, the purpose of this study is to review the relationship between FM and obesity and to explore the potential role of GLP-1RAs in the management of FM. Methods: A literature search was conducted across four databases—PubMed/Medline, Cochrane, Google Scholar, and PEDro—up to May 2025. The literature was sparse, and no formal evaluation process was performed; however, papers were excluded if they failed to address either FM or GLP-1RAs. The key characteristics of each study were extracted and summarised in table form to enable efficient narrative synthesis. Results: Of the 56 included studies, 24 were preclinical reviews, 16 were clinical reviews, 8 examined preclinical animal models, and only 8 focused on human data, limited to retrospective analyses of data and self-reporting. There is some evidence that GLP-1RAs may reduce neuronal excitability, inhibit pain signalling, and decrease inflammation. Conclusions: However, no clinical trials directly evaluating GLP-1RAs in FM were identified, and therefore no conclusions can be drawn regarding clinical efficacy in FM, including in patients with comorbid obesity. Full article

Opioid-induced constipation (OIC) represents a prevalent adverse effect of opioid analgesics, affecting 60–90% of patients and ssignificantly compromising quality of life. This review delineates the multifactorial pathogenesis of OIC. Peripheral μ-opioid receptor (MOR) activation suppresses enteric neuronal excitability, inhibits intestinal motility and secretion, and impairs rectoanal function. Notably, the colon appears to exhibit a distinctive lack of tolerance to opioids. Enteric glial cell activation has been implicated in neuroinflammation, while interstitial cells of Cajal show impaired pacemaker function. Central mechanisms are increasingly recognized to involve the brain–gut axis. Furthermore, opioid-induced barrier disruption, microbiota dysbiosis, and LPS/TLR4-mediated inflammation are proposed to interact and may contribute to a self-reinforcing cycle. Animal models have been instrumental in dissecting these mechanisms. However, they present limitations in reproducibility, clinical phenotype fidelity, and translational validity, particularly regarding microbiome composition and neuroimmune responses. Future research should prioritize the development of standardized, physiologically relevant animal models incorporating multi-omics approaches, and validate mechanism-based therapeutic strategies, including peripherally acting MOR antagonists and microbiota-targeted interventions, for precision management of OIC. Full article

Tau hyperphosphorylation is a hallmark of tauopathies and is closely associated with neurodegeneration. While targeting kinases and phosphatases to suppress tau phosphorylation has become an increasingly attractive therapeutic approach, the functional significance of tau phosphorylation and the potential risks of suppressing this process are not fully understood. Using C. elegans, we introduced non-phosphorylatable tau mutations (hTauAP) to model the suppression of tau phosphorylation. Unexpectedly, we found that hTauAP induced severe neurotoxicity, resulting in behavioural deficits and severe neurite abnormalities. This neurotoxicity is associated with excessive accumulation of hTauAP on microtubules, leading to both neurite developmental defects and adult neurite degeneration. The neurotoxic effects of hTauAP require its microtubule-binding domain (MTB) and are primarily driven by the loss of phosphorylation in the C-terminal region (CTR). Removing either domain reduces microtubule association and suppresses toxicity. Within CTR, suppressing phosphorylation at S396 or S404 is critical for neurotoxicity. These findings highlight the essential role of tau phosphorylation in neuronal function and underscore the potential risks of broadly suppressing tau phosphorylation as a therapeutic strategy. Full article

Background: Long-term diabetes mellitus may precipitate severe complications, including cognitive dysfunction. Existing research has shown that diabetic cognitive impairment (DCI) in rats is characterized by memory deterioration and a disordered arrangement of hippocampal cells. The Shichangpu–Xiyangshen herb pair (SX) effectively improved the pathological changes induced by DCI. However, the role of SX in regulating the physiological and behavioral responses to DCI remains unclear. Methods: We sought to determine the small-molecule metabolites of cerebrospinal fluid (CSF) and delineate the pathways to elucidate the potential mechanism of the effect of SX in the treatment of DCI by metabolomics strategies, focusing on key mechanisms. Behavioral assessments were conducted on DCI rats and the rats treated with SX, as well as an evaluation of neuronal morphology in the hippocampal region. Metabolomics was used to analyze biomarkers in cerebrospinal fluid at different time points during the development of DCI, to uncover the underlying core mechanisms of DCI, and to investigate the regulatory effects of SX on these core mechanisms. The mechanisms of SX on DCI were investigated using quantitative reverse transcription polymerase chain reaction, immunohistochemistry, Western blot, and ELISA. Results: The Morris water maze (MWM) and social interaction test results revealed that SX administration effectively counteracted cognitive impairments in rats with DCI while simultaneously diminishing pathological damage in the CA1, CA3, and DG hippocampal regions. Further analysis showed that SX restored the significantly reduced levels of IL-8, ROX, and TNF-α, and reduced Aβ plaque formation (as indicated by APP and BACE1 protein expression). Simultaneously, SX markedly ameliorated arachidonic acid metabolic disorders in DCI, including significant reductions in arachidonic acid (AA), PGE2, and LTB4 and reduced expression of COX-2 (PTGS2) and 5-LOX (ALOX-5). Conclusions: Our findings indicate that SX effectively counteracted cognitive impairment in rats with DCI by inhibiting AA metabolism through both cyclooxygenase and lipoxygenase pathways, thereby minimizing neuronal damage. Full article

Mitochondria are increasingly recognized as multifunctional organelles that integrate metabolic, redox, immune, and cell fate signaling, thereby maintaining cellular and tissue homeostasis under physiological conditions. Beyond their classical role in ATP production, mitochondria act as central regulatory hubs coordinating adaptive responses to metabolic demands and environmental stress. These functions are sustained through tightly regulated quality control mechanisms, including mitochondrial biogenesis, dynamic fusion–fission remodeling, redox signaling, and selective removal of damaged organelles via mitophagy. Disruption of these processes compromises cellular resilience and contributes to disease initiation and progression. This review summarizes and critically evaluates current evidence on mitochondrial function in health and its dysregulation in pathological conditions, with a particular focus on rheumatoid arthritis (RA), ischemic stroke (IS), and autism spectrum disorder (ASD). Despite their distinct clinical manifestations, these disorders share convergent mitochondrial abnormalities, including metabolic reprogramming toward glycolysis, excessive or persistent reactive oxygen species production, impaired mitophagy, mitochondrial DNA-driven innate immune activation, and hypoxia-related stress. In RA, mitochondrial dysfunction sustains chronic inflammation and joint destruction; in IS, acute mitochondrial failure and reperfusion-associated oxidative stress drive neuronal injury; and in ASD, mitochondrial metabolic inflexibility and defective quality control contribute to chronic low-grade inflammation and neurodevelopmental vulnerability. A variety of methods for the assessment of mitochondrial function are available to study these pathological conditions. Collectively, these findings position mitochondrial dysfunction as a unifying pathogenic mechanism linking inflammatory, neurodegenerative, and neurodevelopmental processes. Targeting mitochondrial metabolism, redox balance, and quality control pathways therefore represents a promising cross-disease therapeutic strategy. Full article

Prion diseases are fatal neurodegenerative disorders that affect humans and animals, caused by the conformational conversion of the normal cellular prion protein (PrP^C) into its misfolded, infectious isoform PrP^Sc. Recently, camel prion disease (CPrD) was identified in dromedary camels (Camelus dromedarius) in Algeria. Due to the potential implications for animal and human health, as well as the possible socio-economic impact in Mediterranean regions where camels play a pivotal role as a source of food, in-depth characterization of camel prions is important to increase our understanding of camel prion disease. We developed a neuronal cell line model for studying the molecular features of camel prion infection. We genetically edited mouse neuronal CAD5 cells to generate CAD5 PrP knockout (KO) cells. We then used lentiviral transduction to generate CAD5 cells expressing camel PrP (CAD5-camel-PrP). Following infection of these cells with a CPrD-positive camel brain homogenate, we observed PrP^Sc signals at various passages, as indicated by immunoblotting analysis. RT-QuIC (Real-Time Quaking-Induced Conversion) assays further supported these findings, demonstrating transient prion conversion activity in the CPrD-infected CAD5-camel-PrP cells. Taken together, our data describe the first neuronal cell line permissive to camel prion infection, a novel in vitro tool for mechanistic studies of camel prion disease. Full article

SARS-CoV-2 infection is associated with not only acute respiratory symptoms but is also characterized by strong neurotropism which may contribute to the development of the multisystem post-COVID syndrome (PASC). Patients frequently report chronic neurocognitive disorders such as brain fog, significant attention deficits and increased susceptibility to epileptiform discharges. The aim of this review is to systematize the knowledge regarding deviations in quantitative electroencephalography (QEEG) recordings in convalescents and to evaluate the utility of this method as an objective biomarker. This work constitutes a comprehensive literature review integrating the latest data on neuroinflammation, blood-brain barrier damage and changes in cortical oscillatory dynamics induced by the infection. The literature analysis indicates that the virus may induce a pathological excitation and inhibition imbalance (E/I imbalance) in neuronal networks. In QEEG studies this manifests as excessive activity of slow bands (Theta, Delta), a deficit of rhythms responsible for attention and sensorimotor integration (SMR) and a pathologically elevated Theta to Beta ratio (TBR). In conclusion, QEEG can serve as an objective and highly sensitive tool supporting the diagnosis and stratification of patients with neurocognitive complications of Long COVID. The integration of precise electrophysiological phenotyping with targeted behavioral neuromodulation (e.g., EEG-Biofeedback) fits into the paradigm of personalized medicine and offers a prospective strategy for mitigating long-term neurological burdens. Full article

The retina is a complex sensory neural tissue composed of six major types of neurons and one type of glial cell. The cell fate specification of retinal cells is tightly governed by intrinsic factors and extrinsic microenvironmental cues. Among the key regulators directing retinal cell fate differentiation is a group of bHLH family transcription factors (TFs). Our previous work demonstrated that the bHLH TF Ngn3 exhibits robust potential to induce retinogenesis in both distantly related fibroblasts in vitro and late retinal progenitor cells (RPCs) in vivo. However, the underlying molecular mechanisms remain largely elusive. In this study, we combined immunohistological examination and RNA-seq and ATAC-seq analyses to investigate the cellular and molecular mechanisms governing Ngn3-driven retinogenesis in late RPCs. Our results revealed that Ngn3 overexpression promotes premature cell cycle exit in late RPCs and remodels their transcriptomic and epigenomic landscape towards a state favoring rod photoreceptor and RGC differentiation. Furthermore, cross-comparison with Ngn3-overexpressing fibroblasts in vitro revealed cell-type-specific mechanisms underlying Ngn3-mediated neuronal fate reprogramming. These findings advance our understanding of Ngn family-mediated retinal cell fate regulation and provide a mechanistic framework for optimizing Ngn3-based retinal regeneration strategies for the treatment of retinal degeneration diseases. Full article

Background: Neuroinflammation is recognized as a key contributor to Parkinson’s disease (PD), but the relationships between inflammatory signaling, immune-state alterations, and cell-type-specific transcriptional programs remain unclear. Methods: Public transcriptomic datasets, including GSE20141 (discovery cohort) and the substantia nigra subset of GSE114517 (external validation cohort), were analyzed. Genes identified by exploratory differential-expression screening in the discovery cohort were intersected with predefined inflammation- and chemokine-related gene sets to define a candidate space for downstream prioritization. Protein–protein interaction, Gene Ontology, KEGG, and immune-signature analyses were performed, followed by machine learning-based feature prioritization using Elastic Net, support vector machine-recursive feature elimination, and random forest. Prioritized candidates were further evaluated by cross-platform validation, single-nucleus transcriptomic mapping, and a hypothesis-generating in silico perturbation analysis in PD astrocytes. Results: Seventeen genes were retained at the intersection of PD-related differentially expressed genes and inflammation-/chemokine-associated gene sets. These candidates formed a response module enriched in mitochondrial organization, oxidative phosphorylation, and mitophagy pathways. Immune-signature analysis suggested an altered transcriptome-derived immune landscape in PD, with changes in NK cell-related signatures and significant correlations between immune-state scores and the candidate genes. Machine learning-based prioritization yielded five shared candidates, of which only CCL2 and PAK6 showed same-direction support with nominal significance in the external validation cohort. Single-nucleus transcriptomic analysis localized CCL2 predominantly to astrocytes, whereas PAK6 was more strongly associated with neuronal populations, particularly OTX2-positive ventral midbrain neurons. In silico perturbation analysis further predicted that CCL2 suppression in PD astrocytes may be associated with translational- and ribosome-related regulatory programs. Conclusions: CCL2 and PAK6 emerged as prioritized candidate biomarkers associated with PD-related inflammatory and chemokine-linked transcriptional alterations in the substantia nigra. More broadly, this study provides a multi-layered framework for candidate prioritization, cross-platform validation, and cell-type-level contextualization in PD neuroinflammation. Because the study is computational and the perturbation analysis is predictive, orthogonal experimental validation will be required to determine whether CCL2 and PAK6 are biomarkers of disease-associated transcriptional states, functional contributors to PD pathogenesis, or both. Full article

Garrya flavescens S. Wats. (GF) has been traditionally used to treat gastrointestinal spasms, yet its bioactivity within the central nervous system remains unexplored. This study aimed to characterize the bioactive constituents of GF and evaluate its anti-inflammatory and metabolic regulatory effects in lipopolysaccharide-activated microglia. Phytochemical profiling using LC-HRMS and HPLC identified rutin as a primary bioactive component, present at an exceptionally high concentration (9309 μg/g). In BV-2 microglial and RAW 264.7 cells, GF treatment significantly suppressed the expression of pro-inflammatory cytokines and mediators in a dose-dependent manner. Mechanistic studies revealed that GF specifically modulated the ERK signaling pathway. Furthermore, Seahorse XF analysis demonstrated that GF restored mitochondrial homeostasis by reducing basal respiration and proton leak while significantly enhancing spare respiratory capacity. Finally, conditioned medium from GF-treated microglia improved the viability of N2A neuronal cells. These findings highlight GF as a potent botanical source with significant neuroprotective potential, offering a promising candidate for functional food or nutraceutical applications targeting neuroinflammatory disorders. Full article

Background: Magnesium regulates neuronal excitability, NMDA receptor activity, and cerebrovascular tone. Dysmagnesemia is common in patients with acute brain injury (>65%), yet large randomized trials of magnesium neuroprotection have been neutral despite strong physiological rationale and consistent observational associations with outcomes. A key limitation may be diagnostic misclassification: the total serum magnesium poorly reflects the biologically active ionized fraction and may misclassify magnesium status in 20–85% of ICU patients during critical illness. Purpose: This narrative review synthesizes current evidence on magnesium physiology, measurement limitations, and clinical implications in neurocritical care. Overview: We discuss the mechanisms of magnesium depletion, outline the conceptual “two-hit” model (chronic deficiency plus acute ICU losses), and highlight the potential value of ionized magnesium for improved patient evaluation. Emerging syndrome-specific data suggest that magnesium disturbances are associated with prognostic signals. Improved phenotyping may help explain prior trial neutrality and support stratified approaches to magnesium monitoring and repletion. Future studies should evaluate magnesium-guided strategies and phenotype-driven trials to clarify the therapeutic role of magnesium in neurocritical care. Full article

Background and Objectives: The pathogenesis of liver steatosis is associated with obesity and systemic inflammation, particularly in subjects with body mass index (BMI) above 40 kg/m² and altered serum levels of tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10). Recent evidence suggests that disruption of the blood–brain barrier (BBB) may be associated with the development of steatosis, although limited data are available in humans. Thus, we assessed serum levels of neuron-specific enolase (NSE), transglutaminase 2 (TGM2), and glial fibrillary acidic protein (GFAP) as indirect markers of BBB dysfunction and examined their associations with steatosis severity, TNF-α and IL-10 in patients with morbid obesity. Materials and Methods: We biopsied the liver during bariatric surgery to assess steatosis by histology and serum markers by ELISA. Results: Most study subjects were women aged 38.7 ± 9.9 years with an average BMI of 42.3 ± 7.9 kg/m² and a steatosis prevalence of 78.9%. After grading steatosis as none (n = 8), mild (n = 17), moderate (n = 8), or severe (n = 5), we found no differences in sex, age, BMI, comorbidities, or laboratory variables, including liver enzymes. One-way ANOVA showed that serum IL-10 was 4-fold less in severe steatosis than in mild steatosis (p = 0.038), whereas TNF-α levels increased twice in severe steatosis compared to no steatosis (p = 0.029). NSE and GFAP serum levels, but not TGM2, increased proportionally to steatosis stage, showing differences between severe steatosis and no steatosis (p = 0.012 and p = 0.0002, respectively). Pearson correlation coefficients showed that NSE and GFAP were significantly associated with TNF-α (r = 0.600 and r = 0.402, respectively), but not with IL-10. Conclusions: Steatosis severity is significantly associated with markers of BBB disruption and systemic inflammation in patients with morbid obesity, suggesting a link between the BBB and liver steatosis. Full article

Sensorineural hearing loss (SNHL) can result from genetic mutations, excessive noise exposure, ototoxic drugs, and aging. Glutamate excitotoxicity is one of the underlying mechanisms of SNHL. However, the specific roles of different glutamate receptor subtypes in normal signaling and excitotoxic damage remain unclear. Addressing these questions requires relevant experimental models. This review compares existing protocols for the isolation and cultivation of primary spiral ganglion cells. It also evaluates the utility of this model for studying glutamatergic transmission and glutamate-induced excitotoxicity. A literature search was conducted in PubMed, Scopus, Google Scholar, and Web of Science. We identified 16 relevant English-language articles published since 1990, when the model was first used to study glutamatergic signaling. Our analysis reveals significant heterogeneity in spiral ganglion cell isolation protocols and culture conditions. We highlight major differences in glutamate concentrations and exposure times used to model excitotoxicity. The most significant limitation of this model is the loss of the native microenvironment of auditory neurons, including their dendritic and axonal contacts. Nevertheless, primary spiral ganglion cells serve as a suitable in vitro model for investigating auditory neuron function and pathology. The number of neurons and neurite length serve as reliable indicators of otoprotective effects under conditions of glutamate excitotoxicity. Based on an analysis of the key stages of primary SGC culture establishment, this study proposes approaches to overcome limitations and improve the practice of using this model. A better understanding of the function of glutamate receptors of SGNs and the mechanisms behind glutamate excitotoxicity could help us to develop new treatments for SNHL. This review serves as a practical guide for researchers implementing or optimizing primary SGC cultures. Full article

Neuronal activity and cerebral blood flow are tightly coupled to support the high metabolic demands of the brain. Disruption of neurovascular coupling is a defining feature of many neurodegenerative disorders such as Alzheimer’s disease, stroke, small vessel disease, Parkinson’s disease, and aging. Progress in understanding the mechanisms underlying neurovascular coupling requires experimental approaches that can simultaneously measure neuronal activity and vascular dynamics with high spatial and temporal resolution, while also enabling targeted perturbations of the system. Here, we present a methodological framework that combines chronic electrophysiological recordings with two-photon imaging of cerebral blood flow and optogenetic manipulation of the vasculature in vivo. Using a chronically implanted flexible electrode array, we obtain measurements of the single- and multi-unit spiking activity, as well as local field potentials. Concurrently, two-photon microscopy enables high-resolution measurements of vessel diameter and blood flow within individual vascular segments. In addition, optogenetic control of vascular smooth muscle cells allows for rapid and reversible manipulation of the vessel diameter through the same cranial window while simultaneously recording the neural and vascular activity. We provide detailed protocols for surgical implantation, data acquisition, and analysis, and discuss experimental considerations and limitations. This combined platform offers a powerful tool for mechanistic studies of neurovascular coupling and its dysfunction in disease models. Full article

Nanogrooves provide instructive cues to cells in culture. Several nanofabrication techniques have been developed to create biomimetic substrates, advancing our understanding of cell adhesion. Their integration into nervous system models highlights the critical role of the extracellular matrix (ECM) in developing functional tissue constructs for in vitro platforms such as Brain-on-Chip (BoC) and Nervous System-on-Chip (NoC). This study presents a nanofabrication approach that integrates photolithography and microtransfer molding (μTM) to pattern nanogrooves using photocurable polymer NOA81 onto microelectrode array (MEA) plates. The resulting nanogrooves exhibited a pattern periodicity of 976 nm and a ridge width of 232 nm, as confirmed by scanning electron microscopy and atomic force microscopy. We assessed the biocompatibility and functional impact of these modified substrates using human induced pluripotent stem cell (hiPSC)-derived neuronal cultures. Neurons cultured on nanogroove-modified MEAs exhibited aligned neural processes due to the anisotropic surface features and expressed vivid spiking behavior and higher burst frequency compared to randomly cultured neuronal networks. In conclusion, the proposed fabrication technique integrates nanogrooves with commercial MEAs using a combination of microtransfer molding and photolithography, resulting in modified culture substrates that enhance spike activity and network organization, aiding in the development of more in vivo-like neural models. Full article