Search Results (1,335)

Background: Appetite regulation is governed by a complex neuroendocrine network that integrates peripheral peptide signals with hypothalamic and brainstem circuits to coordinate energy intake and maintain energy homeostasis. Disruption of these pathways contributes to obesity and other disorders characterised by dysregulated feeding behaviour. Objective: To map and synthesise the current evidence on the role of appetite-regulating peptide hormones and central neural pathways in appetite control, obesity pathophysiology, and emerging therapeutic approaches. Methods: A scoping review of the literature was conducted to identify and synthesise evidence relating to the physiological and pathological mechanisms of appetite regulation. The review examined the actions of key peptide hormones, including ghrelin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), leptin, and insulin, their interactions within the gut–brain axis, and their effects on central appetite-regulating circuits. Results The evidence highlights the central role of the arcuate nucleus in integrating peripheral hormonal signals with neural pathways controlling feeding behaviour. Appetite regulation is mediated by the balance between orexigenic neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons and anorexigenic pro-opiomelanocortin/cocaine- and amphetamine-regulated transcript (POMC/CART) neurons, with further modulation by the paraventricular, lateral, and ventromedial hypothalamic nuclei. The literature identifies hormone resistance, impaired satiety signalling, and altered neuroendocrine feedback as major contributors to obesity. Evidence on therapeutic interventions demonstrates the potential of GLP-1 receptor agonists, including liraglutide and semaglutide, and the dual incretin agonist tirzepatide, while also highlighting challenges related to treatment durability, adverse effects, and weight regain following discontinuation. Conclusions: Current evidence demonstrates that appetite regulation involves highly interconnected peripheral and central signalling pathways. The reviewed literature supports the development of multi-target and precision-based therapeutic strategies for obesity and identifies important areas for future research, including mechanisms of treatment resistance, long-term efficacy, and inter-individual variability in neuroendocrine responses. Full article

Background: Selecting the most efficient and specific adeno-associated virus (AAV) capsids for gene delivery to the nervous system via minimally invasive routes is critical to gene therapy advancement. While AAV9, rAAV2-retro, AAV-PHP.eB, and AAV-MacpnS1 have demonstrated significant central nervous system (CNS) transduction ability after systemic delivery, their tropism, efficiency, and safety profiles in a developmentally relevant model have yet to be systematically compared. This study comparatively evaluated four capsids after intravenous administration in neonatal C57BL/6 mice. Methods: Transgene expression was quantitatively assessed across multiple CNS regions, as well as in the heart and liver. Associated biochemical indicators of hepatic stress were also evaluated. Results: The resulting transduction profiles were distinct and capsid-specific. Both AAV9 and AAV-MacpnS1 induced widespread CNS transduction and robust peripheral organ expression. However, AAV-MacpnS1-neuronal tropism in the thalamus was superior, and it was also associated with the most prominent biochemical indicators of hepatic stress. In contrast, rAAV2-retro was remarkably specific to the medulla and spinal motor neurons, demonstrating a valuable safety profile. AAV-PHP.eB achieved broad cellular transduction in the spinal cord, but it was the least specific towards cholinergic motor neurons. Furthermore, transduction in DRG neurons using AAV9 and AAV-MacpnS1 was efficient, but that using rAAV2-retro or AAV-PHP.eB was not. Conclusions: These findings provide an “atlas-like” comparative framework that clearly outlines the strengths and limitations of each vector. They also offer valuable guidance on selecting the most suitable AAV capsid for fundamental neuroscience applications and for developing targeted gene therapies, particularly for neurodevelopmental and motor neuron disorders, where intravenous administration in the early stages of life is a promising strategy. Full article

Walking is not merely locomotion but a window into the nervous system, integrating cortical, subcortical, cerebellar, spinal, and peripheral networks into a unified motor behavior. Across neurological diseases—including Parkinson’s disease, atypical parkinsonism, cerebellar ataxias, stroke, multiple sclerosis, neuropathies, neuromuscular disorders, and functional gait syndromes—gait disturbances are among the most disabling clinical features, contributing to falls, loss of independence, institutionalization, and premature mortality. Traditional bedside observation remains indispensable, but it lacks the sensitivity and reproducibility needed to capture subtle, episodic, or prodromal abnormalities. Over the past decade, advances in wearable sensors, marker-based and markerless motion capture, pressure-sensitive walkways, force plates, artificial intelligence, and machine learning have positioned digital mobility outcomes as promising, ecologically valid biomarkers of neurological function. These measures can support differential diagnosis, provide prognostic information on falls and survival, and serve as sensitive endpoints in therapeutic trials. They may also detect early abnormalities, such as increased stride-to-stride variability or prolonged double-support time, before overt clinical deterioration becomes evident. Clinical applications are increasingly evident across disorders, including distinguishing Parkinson’s disease from atypical parkinsonism, quantifying treatment response in normal-pressure hydrocephalus, tracking progression in ataxia and multiple sclerosis, predicting functional decline in motor neuron disease, and guiding rehabilitation after stroke. Integration with neuroimaging, electrophysiology, and molecular biomarkers is beginning to reveal the circuits underlying variability, instability, and freezing, positioning gait as a systems-level marker of neural integrity. Nevertheless, methodological heterogeneity, limited disease-specific validation, insufficient longitudinal data, and lack of consensus on clinically meaningful parameters continue to constrain translation. Cognitive, affective, and environmental influences also remain insufficiently represented in digital frameworks, while equity, accessibility, algorithmic bias, and privacy require careful ethical governance. Reconceptualizing gait as a “sixth vital sign” reframes mobility as a multidimensional biomarker of neural and systemic health. With harmonized protocols, robust validation, multimodal integration, and appropriate ethical frameworks, gait analysis could become a cornerstone of precision neurology. Full article

Orthodontic pain, a fundamental biological response to mechanically induced tooth movement, is primarily associated with sterile inflammation and neurogenic processes within the periodontal ligament (PDL). Although photobiomodulation therapy (PBMT) has been widely investigated as a nonpharmacological approach for pain attenuation, its mechanisms of action remain incompletely understood, and current interpretations are often limited to peripheral anti-inflammatory effects. This review re-examines the biological basis of orthodontic pain by integrating evidence derived predominantly from in vitro and in vivo experimental studies. Particular emphasis is placed on neurogenic inflammation, neuropeptide regulation, and neuron–glia interactions along the trigeminal nociceptive pathway. PBMT can reduce periodontal inflammatory/neuropeptide-related markers and pain-related behaviors in selected models; however, evidence for direct central neuron–glia modulation remains largely marker-based and parameter-dependent. Direct functional validation of trigeminal circuit modulation (e.g., electrophysiological recordings or calcium imaging) remains limited in orthodontic pain models; thus, the proposed neuroimmune mechanisms should be interpreted as testable hypotheses for future work. By synthesizing mechanistic insights across multiple biological levels, this review proposes a broader framework for understanding PBMT-mediated pain modulation extending beyond conventional peripheral models. These perspectives may help clarify inconsistencies in the reported outcomes and provide a rationale for future hypothesis-driven experimental and translational research. Full article

Background: Spinal Muscular Atrophy (SMA) is a neurodegenerative disease caused by reduced survival motor neuron (SMN) protein levels due to SMN1 gene mutations. The natural history of SMA has dramatically changed since innovative therapies were approved; among them, Risdiplam (an oral molecule) increases the peripheral levels of SMN by modifying the pre-mRNA slicing of the paralogous SMN2 that also codes for the protein. Methods: We performed longitudinal RNA sequencing on peripheral blood samples from 16 adult SMA patients (types II and III) before and after 12 months of Risdiplam treatment to assess transcriptomic changes. Results: During Risdiplam treatment, increased SMN2 transcript levels were observed, which was coherent with the clinical condition of the investigated SMA cohort. Upregulated mitochondria genes or pseudogenes (i.e., MT-ATP8 and MTND1P11) and downregulated autophagy-related pathways were also found. Baseline differences in gene expression between SMA type II and type III involved neurodegenerative (i.e., MS4A3, C4BPA, and NEILS3) and immune-related (B2M) genes. Conclusions: These findings support Risdiplam’s systemic impact in adult SMA subjects and reveal molecular distinctions between SMA phenotypes (types II and III), which may be of some relevance for future clinical and therapeutic strategies. Full article

Diabetic neuropathy (DN) is a multifactorial complication of diabetes mellitus driven by chronic hyperglycemia, insulin resistance, and disturbed metabolic homeostasis, leading to progressive injury of both the peripheral and central nervous systems. This study investigated whether L-serine supplementation could attenuate DN through dose-dependent metabolic and neuroprotective mechanisms in a high-fat diet (HFD) plus streptozotocin (STZ)-induced diabetic rat model. Male Wistar rats (n = 8 per group) were allocated to five groups: normal control (NC), diabetic control (DC), pioglitazone (PIO; 1.5 mg/kg/day), low-dose L-serine (S1; 200 mg/kg/day), and high-dose L-serine (S2; 400 mg/kg/day). After 60 days of oral gavage, behavioural testing, glucose and insulin profiling, HOMA-IR calculation, brain histopathology, nerve growth factor (NGF) immunohistochemistry, and LC–MS/MS-based proteomic analysis of cerebral tissue were performed. Diabetic rats exhibited marked hyperglycaemia (355.33 ± 4.72 mg/dL), hyperinsulinaemia, severe insulin resistance (HOMA-IR 16.8 ± 3.2; a 14-fold increase), impaired thermal nociception, motor dysfunction, and pronounced neuronal degeneration. L-serine supplementation significantly improved metabolic status: S1 reduced HOMA-IR by 77.4% and S2 by 87.5% relative to diabetic controls (p < 0.001). High-dose L-serine produced greater improvements in thermal sensitivity, motor coordination (rotarod latency 26.67 ± 1.52 s vs. 16.1 ± 0.85 s in DC; p < 0.05), and NGF expression (8.6-fold increase vs. DC). Histopathology confirmed attenuation of neuronal injury and gliosis in both treatment groups. Exploratory, group-level proteomic profiling identified dose-specific molecular signatures: S1 was predominantly associated with carbohydrate, lipid, and biosynthetic pathways, whereas S2 was associated with synaptic, neurotransmission-related, and proteostasis pathways. Within the constraints of an exploratory design—group-level pooled proteomics, analysis of cerebral rather than peripheral-nerve tissue, and only two doses—these findings indicate that L-serine attenuates the metabolic and behavioural features of experimental diabetic neuropathy and generates the testable hypothesis of dose-dependent neuro-metabolic remodelling. The proteomic signatures are hypothesis-generating and require orthogonal validation before any mechanistic or translational inference can be drawn. Full article

Diabetic neuropathy is typically diagnosed with distal sensory and nerve conduction abnormalities. These symptoms may reflect earlier disturbances of axonal maintenance. This review examines axonal transport and cytoskeletal failure as convergent cellular mechanisms of diabetic axonopathy. Long peripheral axons are particularly vulnerable to damage because their integrity depends on continuous communication between the neuronal soma and distal terminals. This process involves the continuous renewal of cytoskeletal and functional proteins and the involvement of organelles such as mitochondria. Diabetes in experimental models disrupts this system at several levels. It slows cargo transport. The supply of neurofilaments, tubulin and retrograde signaling is reduced, and regenerative growth after injury is weakened. Carbonyl stress and AGEs cause modifications of neural proteins, the extracellular matrix, vascular barriers, and the excitability of sensory neurons. RAGE ligands, including AGEs and the proteins HMGB1 and S100, link the diabetic tissue environment to redox and inflammatory signaling. This occurs in neural and glial compartments, as well as in vascular tissue and the immune system. RAGE interacts with DIAPH1 to activate GTPase signaling and remodel the cytoskeleton. The RAGE–DIAPH1 interaction provides a plausible route from diabetic ligand accumulation to cytoskeletal remodeling. These observations provide a mechanistic context for axonal transport, although not all represent direct measurements of cargo movement. Direct evidence for transport impairment comes mainly from experimental studies showing altered slow cytoskeletal transport, impaired retrograde signaling, and weakened regenerative responses. This work highlights the possibility of developing therapies that go beyond symptomatic relief. Verifying the effectiveness of interventions in protecting axonal transport and nerve fiber integrity in diabetic neuropathy may be therapeutically beneficial. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder traditionally defined by dopaminergic neuronal loss and Lewy body pathology; however, increasing evidence indicates that metabolic dysfunction contributes to both motor and non-motor manifestations of disease. While metabolomics studies in PD have largely focused on peripheral biofluids or subcortical brain regions, metabolic remodeling within cortical regions critical for cognition remains poorly characterized. Here, we applied LC-MS/MS-based untargeted metabolomics to post-mortem frontal cortex tissue from PD and neurologically normal control donors, with statistical models adjusted for age, sex, and post-mortem interval. A total of 893 metabolites were quantified, of which 234 exhibited significant differential abundance following false discovery rate correction. Pathway enrichment and network-based integration revealed coordinated metabolic remodeling characterized by predicted inhibition of β-alanine metabolism and pantothenate-dependent coenzyme A biosynthesis alongside activation of amino acid, vitamin B-dependent, cofactor-related, redox-associated, oxidative stress, and inflammatory pathways. Recurrent alterations in pantothenic acid, β-alanine-related intermediates, arginine- and histidine-derived metabolites, lumichrome, and vitamin B₆-associated species may reflect cortical metabolic perturbations associated with mitochondrial bioenergetic vulnerability and oxidative stress. Together, these findings indicate selective metabolic vulnerability in the PD frontal cortex rather than diffuse metabolic collapse. Full article

As the primary peripheral relay station for vibrissal tactile information, the trigeminal ganglion (TG) features heterogeneous three-dimensional (3D) cytoarchitecture that eludes full characterization using conventional two-dimensional methodologies. A high-resolution 3D imaging and reconstruction pipeline is thus required to unveil TG structural organization and define the spatial framework of target-related sensory neurons. Herein, we established a fluorescence micro-optical sectioning tomography (fMOST)-based workflow for 3D cytoarchitectural mapping of TG anatomy and validated its utility for profiling the distributions of TG neurons innervating vibrissae via single-axon tracing. fMOST imaging coupled with propidium iodide (PI) staining was applied to acquire whole-head anatomical data encompassing the vibrissae and the TG at cellular resolution. Based on clearly resolved cellular morphology and the spatial distribution of neuronal somata, we delineated the soma distribution of TG neurons and revealed a spatially heterogeneous 3D organization pattern, from which we operationally defined two anatomically distinct subdomains: the neuronal soma-rich region (NSRR) and the fiber-rich region (FRR). Furthermore, with retrograde viral/genetic labeling combined with neuronal tracing, TG neurons innervating the C2, D3, and δ vibrissae were observed in both NSRR and FRR, showing partially overlapping yet spatially biased distributions consistent with previous population-level observations of vibrissa-row-dependent topography. Notably, TG neurons innervating the δ vibrissa occupied a comparatively broader spatial extent along the anteroposterior plane in our dataset. Overall, this study facilitates an in-depth mechanistic and anatomical understanding of TG cytoarchitectural organization and underlying functional mechanisms. Full article

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) and the accumulation of tau in the brain, which triggers robust innate immune responses. Growing evidence indicates that neuroinflammation contributes to AD progression by overactivating microglia through the release of cytokines and chemokines. In general, chemokines can disrupt neuronal communication and promote blood–brain barrier permeability. Peripheral immune cells are mobilized into the brain by a gradient of chemokines. These processes link peripheral immune responses with substantial T-cell infiltration into the CNS parenchyma, leptomeninges and cerebrospinal fluid of both AD mice and AD patients. This finding underscores the relevance of the adaptive immune system, particularly T and B cells, in AD neuropathology. T-cell infiltration into the brain can influence amyloid clearance through chemokine signalling. However, chemokines play a critical role in AD by either promoting or suppressing disease progression. The infiltration of peripheral T and B cells into the brain parenchyma can exacerbate neuronal loss, yet it may also exert neuroprotective effects. Despite the presence of CD4⁺ and CD8⁺ T cells in postmortem brains of AD patients, debate continues about their role in AD brains, in terms of whether they are protective or detrimental. Understanding the complex role of chemokines in controlling innate and adaptive immune responses by modulating neuron–glia interactions (involving astrocytes and microglia) may provide novel therapeutic approaches for AD. Targeting chemokine signalling or treating with drugs that can prevent the recruitment of immune cells may be promising strategies for treating AD neuropathology. Therapies that prevent the overactivation of T cells in the brain could lead to protective strategies against AD. In fact, regulatory T cells (Tregs) could delay the onset of cognitive symptoms, because they suppress inflammation and slow the accumulation of Aβ plaques and p-Tau in the brain. Complementary strategies, such as photobiomodulation, nanoparticle, and T-cell-based approaches, could mitigate AD progression in patients. Full article

α-synuclein (α-syn) aggregation in dopaminergic neurons is a central event in Parkinson’s disease (PD) pathogenesis. Immunotherapeutic strategies targeting α-syn, including passive and active approaches, aim to inhibit aggregation, propagation, and toxicity of pathological species while promoting their clearance via immune mechanisms. This review summarizes α-syn directed immunotherapies evaluated in in silico, in vitro, and in vivo models, as well as early phase clinical trials, focusing on how epitope selection and antibody formats influence efficacy, safety, and target engagement. Data on monoclonal antibody, peptide, and protein-based vaccines, and structure-guided immunogens were analyzed, integrating behavioral, neuropathological, proteomic, and structural outcomes alongside biomarker development for α-syn species in cerebrospinal fluid and peripheral compartments. Clinical evidence indicates that several candidates induce sustained anti-α-syn antibody responses with acceptable safety profiles and signs of pharmacodynamic engagement, including reductions in free or oligomeric α-syn. However, consistent long-term clinical benefits remain unproven, highlighting the gap between preclinical success and disease modification in humans. Advances in structural biology and proteomics support rational epitope selection and improved immunogen design, reinforcing α-syn-targeted immunotherapy as a promising yet experimental strategy for PD, and highlighting the need for mechanistically oriented, biomarker-driven clinical trials initiated in well-characterized prodromal and early-stage cohorts. Full article

We previously demonstrated that botulinum neurotoxin A (BoNT-A) exerts bilateral antinociceptive effects, involving trans-synaptic transport at the level of the lumbar spinal cord. However, the potential distribution of the toxin to supraspinal sites has not yet been investigated. In the present study, we examined the distribution of cleaved SNAP-25 (cl-SNAP-25), a marker of BoNT-A activity, in the rat brain following peripheral unilateral BoNT-A administration. Brain tissues from rats treated with BoNT-A (7 U/kg, into the hind paw) were analyzed using immunofluorescent tyramide signal amplification to detect cl-SNAP-25. To assess the contribution of trans-synaptic transport, a BoNT-A-neutralizing antitoxin (2 IU) was administered intrathecally 24 h after BoNT-A injection. Signal intensity was evaluated using a semi-quantitative immunohistochemical scoring method based on cl-SNAP-25-positive nerve fibers. Bilateral cl-SNAP-25 immunoreactivity was observed in multiple supraspinal regions, most prominently within the trigeminal complex and the facial and gracile nuclei. Signal intensity was significantly reduced by intrathecal antitoxin, indicating that trans-synaptic transport contributes to central BoNT-A distribution. Peripherally administered BoNT-A reaches distant supraspinal regions, possibly via neuronal retrograde and trans-synaptic transport. Further studies are warranted to clarify exact pathways and alternative distribution routes, determine the functional relevance of central BoNT-A presence, and assess its clinical implications. Full article

Traumatic brain injury (TBI) induces complex molecular and neuroendocrine alterations that extend beyond the site of injury. The hypothalamic–pituitary–adrenal (HPA) axis, a hierarchically organized neuroendocrine system composed of the hypothalamus, pituitary gland, and adrenal glands, plays a central role in coordinating stress and metabolic homeostasis. Despite its critical importance, the temporal transcriptional mechanisms underlying HPA axis dysregulation following TBI remain poorly understood, particularly in relation to coordinated neuronal injury and regeneration processes. This study aimed to investigate the time-dependent transcriptional dynamics of genes associated with neuronal injury and regeneration within the HPA axis following experimental TBI. Moderate-to-severe TBI was induced in Sprague–Dawley rats using a controlled cortical impact (CCI) model. Animals were allocated into sham, acute (24 h), and chronic (30 days) groups. Transcript profiles of 24 HPA axis- and neuroregeneration-related genes were analyzed in hypothalamic, pituitary, and adrenal tissues using quantitative real-time PCR, with normalization to a housekeeping gene and statistical evaluation of differential expression across time points. TBI induced distinct, tissue-specific, and time-dependent transcriptional alterations across the HPA axis. In the acute phase, stress-response genes showed divergent regulation between central and peripheral tissues, whereas the chronic phase was characterized by transcriptional reorganization involving neurotrophic, metabolic, and neuroendocrine pathways. Key regulators such as Hif1a, Rad18, Avp, Gata3, and OxtR exhibited significant and region-specific expression changes. These findings demonstrate that TBI triggers coordinated yet heterogeneous transcriptional responses within the HPA axis, linking central injury to systemic endocrine adaptation. This study provides novel insight into the molecular basis of neuroendocrine dysfunction and recovery after TBI and identifies candidate targets for future therapeutic strategies. Full article

Osteoarthritis (OA) and major depressive disorder (MDD) share inflammatory and oxidative stress pathways, but the role of programmed cell death (PCD) in their comorbidity remains unclear. This study used independent OA synovial and MDD peripheral blood transcriptomic datasets—not a unified comorbid discovery cohort—to identify candidate PCD-related molecular signatures commonly dysregulated in both conditions. Transcriptomic data from OA synovium and MDD brain tissues were obtained from GEO (six training [three OA synovial and three MDD peripheral-blood], seven validation, and two single-cell RNA-seq datasets). Differentially expressed genes (DEGs) were identified, and PCD-related DEGs were screened. Machine learning (LASSO, SVM-RFE, Random Forest) was used to identify hub PCD-DEGs from the OA training set. WGCNA identified MDD-associated modules for comorbidity-gene selection. Functional enrichment, immune infiltration, scRNA-seq localization, and clinical validation (qRT-PCR/WB) were performed. From the OA cohort, four hub PCD-DEGs (CDKN1A, CX3CR1, INHBB, RHOB) showed moderate diagnostic value for OA (nomogram AUC = 0.82). Eight candidate genes (VAMP8, PDK4, P2RX4, ITM2C, IL10RA, HSP90AA1, CTSO, CRIP1) were commonly dysregulated across both OA and MDD datasets. Immune infiltration revealed upregulated B memory cells, plasma cells, Tregs, and neutrophils in OA, and neutrophils in MDD. scRNA-seq localized CDKN1A/RHOB to OA synovial cells and HSP90AA1/ITM2C to MDD neurons. Enrichment analyses highlighted TNF signaling, apoptosis, and stress responses in both diseases. An independent OA–MDD clinical cohort confirmed differential expression of CDKN1A, RHOB, ITM2C, and HSP90AA1. This study identifies four PCD-related hub genes associated with OA and eight candidate comorbidity genes showing common dysregulation across OA and MDD datasets and in an independent clinical cohort. These findings generate hypotheses about shared inflammatory pathways linking OA and MDD. As these associations derive from independent disease-specific cohorts rather than a true comorbid discovery cohort, they represent candidate signatures requiring functional validation rather than established mechanisms. Full article