Search Results (1,046)

Buds are continuously renewed sensory organs in which development, adult maintenance, and repair share overlapping molecular circuitry. During embryogenesis, WNT/β-catenin signaling promotes taste placode formation and placodal Shh expression, while SHH refines papilla spacing and restricts neighboring papilla formation. SOX2 functions as a taste-competence and progenitor maintenance factor. In adults, LGR5/LGR6–RSPO–WNT signaling sustains progenitor activity, and gustatory neurons are an important source of RSPO2; available genetic evidence is consistent with a neuron-derived contribution to the LGR5/LGR6 niche, and AAV-Cre-mediated neuron-specific ablation of Rspo2 in the petrosal ganglion led to near-complete loss of circumvallate taste buds. HH signaling from epithelial and neuronal sources further supports SOX2-dependent progenitor homeostasis. Lineage allocation is governed by transcriptional programs that include POU2F3/SKN-1a for sweet, umami, and bitter type II taste receptor cells, and ASCL1 with posterior-field NKX2-2 for type III presynaptic/sour cells. After denervation or irradiation, regeneration depends primarily on LGR5⁺/KRT14⁺ progenitors and may be supplemented, in specific injury contexts, by plasticity of a subset of K8-lineage taste receptor cells that acquire KRT14/SOX2/PCNA progenitor-like features. Key unresolved questions include the direct chromatin targets of taste lineage regulators (which remain to be defined by ChIP-seq in native taste progenitors), the identity of the type I cell selector, the contribution of dedifferentiation across injury models, and the degree to which mouse-derived networks are conserved in human taste biology. Full article

Background: Olfactory dysfunction is a pathology associated with viral infections, toxic damage, aging, and neurodegenerative diseases. Damage to the olfactory epithelium impairs olfactory function and related neurological behaviors. This study evaluated the restorative effects of Scutellaria baicalensis Georgi (SBG) extract and baicalein in a methimazole-induced olfactory dysfunction model. Methods: Olfactory epithelial damage was induced in mice with methimazole, followed by treatment with SBG extract or baicalein. Olfactory and neurobehavioral functions were assessed using odor-finding, novel object recognition (NOR), Morris water maze (MWM), open field (OFT), and elevated plus maze tests (EPM). Histological, immunohistochemical, and in vitro analyses were performed to evaluate epithelial regeneration, mature olfactory sensory neurons (OSNs) expressing olfactory marker protein (OMP), and proliferative activity. Results: Methimazole induced severe olfactory epithelial damage, impairing olfactory behavior and reducing learning and memory. Treatment with SBG extract and baicalein significantly improved olfactory and cognitive functions. Histological and immunohistochemical analyses confirmed restoration of epithelial structure and olfactory neurons. In vitro, SBG extract increased epithelial cell density and modulated proliferative activity. Conclusions: SBG extract and baicalein promote recovery of olfactory function and improve neurobehavioral outcomes, indicating their potential as therapies for olfactory dysfunction. Full article

Eosinophilic chronic rhinosinusitis (eCRS) is an upper respiratory condition frequently associated with olfactory dysfunction (OD). Despite its high prevalence, the mechanisms underlying OD remain poorly understood. Several eCRS models have been described, but their olfactory phenotypes are poorly characterized. In this study, we compared two of the most frequently used mouse models of eCRS in order to standardize in vivo research on eCRS-related OD. Male and female mice were challenged with ovalbumin (OVA) combined with Staphylococcus aureus enterotoxin B (SEB) over a 13-week protocol or with OVA combined with Aspergillus oryzae protease (AP) for 6 or 12 weeks. Olfactory function was assessed using the buried food test and habituation/dishabituation test. After sacrifice, the integrity and inflammation of the olfactory epithelium were assessed on coronal skull sections by (immuno)histology, including sex as a biological variable. Both models exhibited impaired olfactory function, reduced olfactory epithelium surface area and thickness, and eosinophil infiltration of the olfactory mucosa. The OVA-AP model showed additional presence of neutrophils in the olfactory mucosa, suggesting a mixed inflammatory response. No functional or histological difference was detected between male and female mice, except for epithelial thickness in OVA-SEB control mice. Overall, both murine models are suitable for mechanistic studies of OD in eCRS, with the AP-12-week model displaying the most pronounced inflammation. Full article

Equine asthma is a chronic inflammatory disease of the lower respiratory tract, primarily associated with inhalation of organic dust, microbial particles and environmental aeroantigens. Although the inflammatory and immunological mechanisms underlying equine asthma have been extensively investigated, the potential contribution of neuroimmune pathways remains poorly understood. In humans and rodent models, asthma is increasingly recognised as a disorder involving complex bidirectional interactions between the nervous and immune systems. Sensory nerve activation, neuropeptide release, autonomic dysregulation and neuronal remodelling contribute to bronchoconstriction, airway hyperresponsiveness, mucus hypersecretion and chronic airway remodelling. This review summarises current knowledge of the neuroimmune mechanisms involved in asthma, with particular emphasis on comparative aspects across humans, rodents and horses. Literature searches were conducted using the PubMed database, focusing on studies investigating neurogenic inflammation, airway innervation, neuropeptides, transient receptor potential channels and neuronal remodelling in asthma and chronic airway disease. Existing equine evidence indicates the presence of substance P- and calcitonin gene-related peptide-immunoreactive nerve fibres in the equine airways, increased neurokinin-mediated bronchoconstriction in severe equine asthma, and enhanced airway innervation in affected horses. However, compared with human and rodent studies, horse-specific data remain extremely limited. Current evidence suggests that neuroimmune pathways are unlikely to be the primary initiating mechanism of equine asthma, but may act as important modulators of chronic airway dysfunction and disease progression. The marked scarcity of equine studies investigating neuroimmune signalling represents a major knowledge gap and highlights an important direction for future research in equine respiratory medicine. 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

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

Visceral pain is a central feature of chronic gastrointestinal disorders, yet the epithelial sensory mechanisms that shape afferent input before it enters pain-relevant neural pathways remain insufficiently integrated into current models. This review advances the concept that the intestinal epithelium is not only a barrier or endocrine interface, but also an active neuroepithelial regulatory layer positioned upstream of visceral sensory signaling. Neuropod-cell studies established that specialized epithelial cells can communicate rapidly with vagal neurons and preserve luminal stimulus identity through transmitter-selective coding. Enterochromaffin cells extend this framework as polymodal epithelial sensory transducers that detect chemical, microbial, neurohumoral, and mechanical cues, convert them into serotonergic afferent signaling, and can causally amplify visceral hypersensitivity in experimental models. Complementing these amplifying pathways, GUCY2C^high (guanylate cyclase C-enriched) neuropod-like epithelial cells reveal a pain-restraining mechanism that regulates dorsal root ganglion excitability and preserves linaclotide-responsive suppression of nociceptive output in preclinical systems. Together, these findings support an integrative model in which epithelial sensory circuits may act as filters of biological meaning, amplifiers of afferent gain, and brakes on aberrant nociceptive escalation. This framework does not replace neural, immune, or central mechanisms of visceral pain, but adds an upstream epithelial tier that may shape pain vulnerability, persistence, or treatment responsiveness in selected contexts. Defining the cellular logic, molecular mediators, and human relevance of these circuits will be essential for advancing neuroepithelial pain biology toward disease-relevant and therapeutic applications. Full article

The calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide belonging to the calcitonin family, discovered as a product of alternative splicing of the calcitonin gene. CGRP has emerged as a pleiotropic signaling molecule with widespread distribution in the central and peripheral nervous systems, particularly within primary sensory neurons. This narrative review synthesizes current knowledge on the CGRP system, integrating recent advances in its molecular structure, gene organization, and post-translational processing with high-resolution structural insights into its heterodimeric receptor complex (CLR-RAMP1) obtained through cryo-electron microscopy. We also include long-term safety data on anti-CGRP monoclonal antibodies, emerging cardiovascular risk signals, and novel therapeutic applications in vestibular migraine and pediatric populations. The intracellular signaling cascades activated by CGRP, including the canonical cAMP-PKA pathway, MAP kinase activation, and context-dependent calcium signaling, are discussed in relation to its diverse physiological functions. These encompass vasodilation, nociception modulation, neurogenic inflammation, gastrointestinal motility, bone metabolism, tissue regeneration, and energy homeostasis. The central role of CGRP in migraine pathophysiology is examined to understand the development of targeted therapies. The current pharmacological landscape is reviewed, including the evolution of small-molecule CGRP receptor antagonists (gepants) through three generations and the four approved monoclonal antibodies targeting CGRP or its receptor, with comparative analysis of their efficacy, safety profiles, and clinical positioning. Beyond migraine, emerging and predominantly preclinical roles of the CGRP system are discussed in chronic pain, osteoarthritis, cardiovascular diseases, sepsis, cancer (particularly bone metastases and tumor microenvironment immunomodulation), and neurodegenerative disorders such as Alzheimer’s disease. In these areas, the available evidence remains heterogeneous and, in most cases, is not yet sufficient to support clinical translation. Finally, future directions are discussed, including the development of stable CGRP analogs, allosteric modulators, and the potential expansion of therapeutic applications into oncology, intensive care medicine, and neuroprotection. Full article

Atopic dermatitis (AD) is a chronic inflammatory skin disease driven by immune dysregulation and epidermal barrier dysfunction, in which eosinophils act as key effector cells contributing to tissue damage and persistent inflammation. This comprehensive review elucidates the multifaceted contributions of eosinophils to the progression of AD. Driven by key type 2 cytokines (notably IL-4, IL-5, and IL-13) and specific chemokines, eosinophils infiltrate lesional skin and undergo IgE-mediated degranulation. The subsequent release of cytotoxic granule proteins, including major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN), and eosinophil peroxidase (EPX), directly induces keratinocyte apoptosis, exacerbates tissue remodeling, and sustains the local inflammatory cascade. Furthermore, we explore the intricate crosstalk between eosinophils and sensory neurons, which, alongside cytokines like IL-31, profoundly aggravates chronic pruritus. Consequently, modulating eosinophil activation and recruitment has emerged as a vital therapeutic approach. We systematically evaluate current and emerging pharmacological interventions, ranging from conventional topical corticosteroids to advanced targeted therapies. Particular emphasis is placed on the mechanistic impact of novel biologics and small-molecule Janus kinase (JAK) inhibitors, demonstrating how they attenuate eosinophilic inflammation. By identifying current gaps in this field, this review provides valuable insights for future research and clinical practice in the field of AD. Full article

Multiple Sclerosis (MS) is a chronic, immune-mediated disorder of the central nervous system characterized by leukocyte infiltration, inflammation, demyelination, and progressive neurodegeneration. Susceptibility to MS is influenced by genetic factors, including variants within the human leukocyte antigen (HLA) region, (notably HLA-DR15), and multiple single nucleotide polymorphisms that modulate T cell function and immune regulation. Clinically, early manifestations such as visual disturbances, sensory deficits, fatigue, and impaired coordination often precede more advanced features, including cognitive decline and bladder or bowel dysfunction. Although experimental and genetic models of neuroinflammation have facilitated the development of therapies that reduce relapse rates and slow disease progression, the underlying pathological mechanisms remain incompletely understood. Emerging evidence points to the importance of cytoskeletal organization and membrane-associated signaling platforms in maintaining neuronal and immune cell function. Disruption of these systems may contribute to demyelination and neuroinflammatory cascades. Within this context, a systems biology perspective is particularly valuable, as it emphasizes the integration of multiple, interdependent pathways rather than isolated mechanisms. Caveolin-1 (Cav-1), an integral membrane protein of caveolae, has gained attention as a potential central regulator due to its role in coordinating signaling processes across diverse cellular compartments. In this review, we examine the potential genetic and functional contributions of Cav-1 to MS pathophysiology, with a focus on its involvement in oxidative stress, inflammation, blood–brain barrier integrity, and autophagy. By framing these processes as components of an interconnected network, we highlight Cav-1 as a context-dependent modulator that may influence both disease progression and severity. However, despite its mechanistic relevance, the translational potential of Cav-1 remains uncertain, and further studies are required to clarify its precise role and evaluate its suitability as a therapeutic target in MS. Full article

Dental pain due to dentine hypersensitivity or pulpitis is characterized by short or lasting episodes of pain triggered by normally innocuous stimuli originating from exposed dentine. Both represent the most frequent pain of the orofacial region. Transient receptor potential (TRP) superfamily of ion channels participates in the detection of different modalities of sensibility in the mammalian sensory teeth system, i.e., trigeminal neurons and odontoblasts. In particular, some members of the melastatin family (TRPM) serve as molecular thermal sensors, and temperature is one of the most potent stimuli in triggering dentine hypersensitivity. Here we review and update the information about the distribution of TRPM channels in the trigeminal ganglion and dental pulp cells, especially odontoblasts, in humans and animal models. In addition to the well-known sensory roles of TRPM, other functions such as the development and mineralization of teeth are considered. Full article

At present, there is still a lack of effective treatments to slow the progression of Parkinson’s disease. Naturally derived active substances, valued for their safety and multi-target potential, have become an important direction in anti-PD drug development, with marine organisms representing a valuable source of bioactive peptides. This study aimed to isolate and identify anti-PD peptides from Rapana venosa protein hydrolysates. Through bioactivity-guided screening combined with an MPTP-induced zebrafish PD model, three novel active peptides—KSTELLI, FLVKLPMFM, and SDSLSEILIS—were successfully identified. The study showed that these peptides significantly alleviated dopaminergic neuron loss, improved the cerebral vascular system, restored motor and sensory function, and alleviated oxidative stress. Molecular docking confirmed their stable binding to key PD targets (DDC, α-synuclein, and MAO-B). Further transcriptomic and gene expression analyses revealed that their neuroprotective effects involve the regulation of pathways related to metabolism, oxidative stress, inflammation, and apoptosis, with the three peptides exhibiting distinct mechanistic emphases. The research demonstrates that these marine-derived peptides exert neuroprotective effects through a synergistic multi-target mechanism, laying a foundation for the development of novel lead compounds against Parkinson’s disease. Full article

Background/Objectives: Vagus nerve stimulation (VNS) has evolved from a laboratory experiment to a standard of care in several neurological disorders like epilepsy, depression and stroke rehabilitation at present. Methods: We reviewed the published literature relevant to its origins in animal models leading to various clinical applications. Results: Bailey and Bremer published their observations following VNS in animals while further studies established its utility in some forms of epilepsy. Subsequent observations in epilepsy patients treated with VNS revealed the unequivocal improvement in psychological and behavioral disorders. Consequently, VNS received approval for its application in resistant depression disorders. Multiple studies revealed changes due to neuronal plasticity following VNS that could result in the significant clinical recovery of motor function in chronic ischemic stroke patients. Chronic incomplete cervical spinal cord injury, head injury and peripheral nerve injury deficits are also being studied for recovery patterns. Transcutaneous approaches and closed-loop stimulation are showing encouraging results that may facilitate the extension of the application of neuromodulation using VNS. Conclusions: For the recovery of motor function following paralysis in stroke patients or cervical spinal cord injuries, the timing of the stimulation after physical activity during rehabilitation has been identified as a key factor. In addition to the timing of the stimulation, the titration of the parameters is also being studied to obtain optimized recovery in cases of motor, sensory, or sphincter deficits. Full article

Mitochondrial proteostasis in neurons relies on the coordinated expression, targeting, and import of a predominantly nuclear-encoded proteome to meet high metabolic demands. Here, we identify the RNA-binding protein cold shock domain containing E1 (CSDE1) as a TOM20-associated factor linked to mitochondrial protein-encoding mRNAs in sensory neurons. CSDE1 immunoprecipitation followed by sequencing from naïve dorsal root ganglion tissue revealed association with nuclear-encoded mitochondrial mRNAs enriched for inner membrane/matrix and oxidative phosphorylation pathways. A subset of CSDE1 localized to mitochondria and associated with the outer mitochondrial membrane import receptor TOM20 via its N-terminal region in an RNA-independent manner. In cultured sensory neurons, CSDE1 depletion reduced the mitochondrial-fraction abundance of representative nuclear-encoded electron transport chain mRNAs and decreased the abundance of selected mitochondrial proteins in the mitochondrial fraction. CSDE1 depletion reduced TMRM-positive mitochondrial puncta density along sensory neurites, without significantly increasing MitoSOX-detectable mitochondrial superoxide signals under either basal or oxidative challenge conditions. These findings identify CSDE1 as a TOM20-associated RNA-binding protein linked to mitochondrial protein-encoding transcripts in sensory neurons and support a model in which CSDE1 contributes to mitochondria-associated post-transcriptional regulation. Full article

Peripheral nerve ischemia–reperfusion injury is considered to contribute to sensory disturbances that impair quality of life in patients with diabetic neuropathy and chemotherapy-induced neuropathy. However, the spinal mechanisms underlying these disturbances remain unclear, partly due to the lack of established animal models and evaluation systems. In the present study, we used a rat hindlimb ischemia–reperfusion model and in vivo extracellular recording to examine bidirectional changes in neuronal activity in the spinal dorsal horn. Ischemia was induced by tightly binding the rat ankle with a rubber band, followed by reperfusion. Behavioral analysis showed a significant increase in hindlimb licking behavior after reperfusion, indicating the development of sensory disturbance-like responses. Extracellular recordings from superficial dorsal horn neurons showed diverse patterns of spontaneous firing and responses to mechanical stimulation, with both hypersensitive and desensitized responses. Furthermore, mRNA expression levels of immediate early genes (Egr1, Egr3, and Fos) were upregulated in the spinal cord after reperfusion. These results suggest that this ischemia–reperfusion model reproduces complex neuronal responses relevant to peripheral neuropathy and provides a useful evaluation system for evaluating both increased and decreased neural activity. This approach may contribute to elucidating the mechanisms of sensory disturbances and to the development of new treatments for neuropathic conditions. Full article