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Ecotoxicology and Environmental Safety Jun 2024Hydrogen sulphide (HS) is considered an immunotoxicant, and its presence in the water can influence the mucosal barrier functions of fish. However, there is a...
Hydrogen sulphide (HS) is considered an immunotoxicant, and its presence in the water can influence the mucosal barrier functions of fish. However, there is a significant knowledge gap on how fish mucosa responds to low environmental HS levels. The present study investigated the consequences of prolonged exposure to sub-lethal levels of HS on the mucosal defences of Atlantic salmon (Salmo salar). Fish were continuously exposed to two levels of HS (low: 0.05 µM; and high: 0.12 µM) for 12 days. Unexposed fish served as control. Molecular and histological profiling focused on the changes in the skin, gills and olfactory rosette. In addition, metabolomics and proteomics were performed on the skin and gill mucus. The gene expression profile indicated that the gills and olfactory rosette were more sensitive to HS than the skin. The olfactory rosette showed a dose-dependent response, but not the gills. Genes related to stress responses were triggered at mucosal sites by HS. Moreover, HS elicited strong inflammatory responses, particularly in the gills. All mucosal organs demonstrated the key molecular repertoire for sulphide detoxification, but their temporal and spatial expression was not substantially affected by sub-lethal HS levels. Mucosal barrier integrity was not considerably affected by HS. Mucus metabolomes of the skin and gills were unaffected, but a matrix-dependent response was identified. Comparing the high-concentration group's skin and gills mucus metabolomes identified altered amino acid biosynthesis and metabolism pathways. The skin and gill mucus exhibited distinct proteomic profiles. Enrichment analysis revealed that proteins related to immunity and metabolism were affected in both mucus matrices. The present study expands our knowledge of the defence mechanisms against HS at mucosal sites in Atlantic salmon. The findings offer insights into the health and welfare consequences of sub-lethal HS, which can be incorporated into the risk assessment protocols in salmon land-based farms.
PubMed: 38905940
DOI: 10.1016/j.ecoenv.2024.116617 -
Frontiers in Neural Circuits 2024The olfactory epithelium (OE) is directly exposed to environmental agents entering the nasal cavity, leaving OSNs prone to injury and degeneration. The causes of... (Review)
Review
The olfactory epithelium (OE) is directly exposed to environmental agents entering the nasal cavity, leaving OSNs prone to injury and degeneration. The causes of olfactory dysfunction are diverse and include head trauma, neurodegenerative diseases, and aging, but the main causes are chronic rhinosinusitis (CRS) and viral infections. In CRS and viral infections, reduced airflow due to local inflammation, inflammatory cytokine production, release of degranulated proteins from eosinophils, and cell injury lead to decreased olfactory function. It is well known that injury-induced loss of mature OSNs in the adult OE causes massive regeneration of new OSNs within a few months through the proliferation and differentiation of progenitor basal cells that are subsequently incorporated into olfactory neural circuits. Although normal olfactory function returns after injury in most cases, prolonged olfactory impairment and lack of improvement in olfactory function in some cases poses a major clinical problem. Persistent inflammation or severe injury in the OE results in morphological changes in the OE and respiratory epithelium and decreases the number of mature OSNs, resulting in irreversible loss of olfactory function. In this review, we discuss the histological structure and distribution of the human OE, and the pathogenesis of olfactory dysfunction associated with CRS and viral infection.
Topics: Humans; Olfactory Mucosa; Olfaction Disorders; Olfactory Receptor Neurons; Sinusitis; Rhinitis; Animals
PubMed: 38903957
DOI: 10.3389/fncir.2024.1406218 -
International Journal of Molecular... May 2024The cell surface metalloprotease ADAM17 (a disintegrin and metalloprotease 17) and its binding partners iRhom2 and iRhom1 (inactive Rhomboid-like proteins 1 and 2)...
The cell surface metalloprotease ADAM17 (a disintegrin and metalloprotease 17) and its binding partners iRhom2 and iRhom1 (inactive Rhomboid-like proteins 1 and 2) modulate cell-cell interactions by mediating the release of membrane proteins such as TNFα (Tumor necrosis factor α) and EGFR (Epidermal growth factor receptor) ligands from the cell surface. Most cell types express both iRhoms, though myeloid cells exclusively express iRhom2, and iRhom1 is the main iRhom in the mouse brain. Here, we report that iRhom2 is uniquely expressed in olfactory sensory neurons (OSNs), highly specialized cells expressing one olfactory receptor (OR) from a repertoire of more than a thousand OR genes in mice. mice had no evident morphological defects in the olfactory epithelium (OE), yet RNAseq analysis revealed differential expression of a small subset of ORs. Notably, while the majority of ORs remain unaffected in OE, OSNs expressing ORs that are enriched in OE showed fewer gene expression changes upon odor environmental changes than the majority of OSNs. Moreover, we discovered an inverse correlation between the expression of iRhom2 compared to OSN activity genes and that odor exposure negatively regulates iRhom2 expression. Given that ORs are specialized G-protein coupled receptors (GPCRs) and many GPCRs activate iRhom2/ADAM17, we investigated if ORs could activate iRhom2/ADAM17. Activation of an olfactory receptor that is ectopically expressed in keratinocytes (OR2AT4) by its agonist Sandalore leads to ERK1/2 phosphorylation, likely via an iRhom2/ADAM17-dependent pathway. Taken together, these findings point to a mechanism by which odor stimulation of OSNs activates iRhom2/ADAM17 catalytic activity, resulting in downstream transcriptional changes to the OR repertoire and activity genes, and driving a negative feedback loop to downregulate iRhom2 expression.
Topics: Animals; Receptors, Odorant; Mice; Olfactory Receptor Neurons; Smell; ADAM17 Protein; Mice, Knockout; Carrier Proteins; Olfactory Mucosa; Gene Expression Regulation; Membrane Proteins; Mice, Inbred C57BL; Humans
PubMed: 38892263
DOI: 10.3390/ijms25116079 -
Journal of Otolaryngology - Head & Neck... 2024Mesenchymal stem cells (MSCs) have the capability of providing ongoing paracrine support to degenerating tissues. Since MSCs can be extracted from a broad range of...
IMPORTANCE
Mesenchymal stem cells (MSCs) have the capability of providing ongoing paracrine support to degenerating tissues. Since MSCs can be extracted from a broad range of tissues, their specific surface marker profiles and growth factor secretions can be different. We hypothesized that MSCs derived from different sources might also have different neuroprotective potential.
OBJECTIVE
In this study, we extracted MSCs from rodent olfactory mucosa and compared their neuroprotective effects on auditory hair cell survival with MSCs extracted from rodent adipose tissue.
METHODS
Organ of Corti explants were dissected from 41 cochlea and incubated with olfactory mesenchymal stem cells (OMSCs) and adipose mesenchymal stem cells (AMSCs). After 72 hours, Corti explants were fixed, stained, and hair cells counted. Growth factor concentrations were determined in the supernatant and cell lysate using Enzyme-Linked Immunosorbent Assay (ELISA).
RESULTS
Co-culturing of organ of Corti explants with OMSCs resulted in a significant increase in inner and outer hair cell stereocilia survival, compared to control. Comparisons between both stem cell lines, showed that co-culturing with OMSCs resulted in superior inner and outer hair cell stereocilia survival rates over co-culturing with AMSCs. Assessment of growth factor secretions revealed that the OMSCs secrete significant amounts of insulin-like growth factor 1 (IGF-1). Co-culturing OMSCs with organ of Corti explants resulted in a 10-fold increase in IGF-1 level compared to control, and their secretion was 2 to 3 times higher compared to the AMSCs.
CONCLUSIONS
This study has shown that OMSCs may mitigate auditory hair cell stereocilia degeneration. Their neuroprotective effects may, at least partially, be ascribed to their enhanced IGF-1 secretory abilities compared to AMSCs.
Topics: Animals; Insulin-Like Growth Factor I; Mesenchymal Stem Cells; Rats; Hair Cells, Auditory; Olfactory Mucosa; Enzyme-Linked Immunosorbent Assay; Coculture Techniques; Cell Survival; Cells, Cultured; Adipose Tissue; Mesenchymal Stem Cell Transplantation
PubMed: 38888945
DOI: 10.1177/19160216241258431 -
Science Advances Jun 2024Olfaction is essential for complex social behavior in insects. To discriminate complex social cues, ants evolved an expanded number of () genes. Mutations in the...
Olfaction is essential for complex social behavior in insects. To discriminate complex social cues, ants evolved an expanded number of () genes. Mutations in the obligate odorant co-receptor gene lead to the loss of ~80% of the antennal lobe glomeruli in the jumping ant . However, the cellular mechanism remains unclear. Here, we demonstrate massive apoptosis of odorant receptor neurons (ORNs) in the mid to late stages of pupal development, possibly due to ER stress in the absence of Orco. Further bulk and single-nucleus transcriptome analysis shows that, although most -expressing ORNs die in mutants, a small proportion of them survive: They express () genes that form IR complexes. In addition, we found that some genes are expressed in mechanosensory neurons and nonneuronal cells, possibly due to leaky regulation from nearby non- genes. Our findings provide a comprehensive overview of ORN development and expression in .
Topics: Animals; Olfactory Receptor Neurons; Ants; Receptors, Odorant; Apoptosis; Mutation; Cell Survival; Insect Proteins; Gene Expression Profiling; Transcriptome
PubMed: 38848359
DOI: 10.1126/sciadv.adk9000 -
ENeuro Jun 2024Viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), use respiratory epithelial cells as an entry point for infection. Within the nasal cavity,...
Viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), use respiratory epithelial cells as an entry point for infection. Within the nasal cavity, the olfactory epithelium (OE) is particularly sensitive to infections which may lead to olfactory dysfunction. In patients suffering from coronavirus disease 2019, deficits in olfaction have been characterized as a distinctive symptom. Here, we used the K18hACE2 mice to study the spread of SARS-CoV-2 infection and inflammation in the olfactory system (OS) after 7 d of infection. In the OE, we found that SARS-CoV-2 selectively targeted the supporting/sustentacular cells (SCs) and macrophages from the lamina propria. In the brain, SARS-CoV-2 infected some microglial cells in the olfactory bulb (OB), and there was a widespread infection of projection neurons in the OB, piriform cortex (PC), and tubular striatum (TuS). Inflammation, indicated by both elevated numbers and morphologically activated IBA1 cells (monocyte/macrophage lineages), was preferentially increased in the OE septum, while it was homogeneously distributed throughout the layers of the OB, PC, and TuS. Myelinated OS axonal tracts, the lateral olfactory tract, and the anterior commissure, exhibited decreased levels of 2',3'-cyclic-nucleotide 3'-phosphodiesterase, indicative of myelin defects. Collectively, our work supports the hypothesis that SARS-CoV-2 infected SC and macrophages in the OE and, centrally, microglia and subpopulations of OS neurons. The observed inflammation throughout the OS areas and central myelin defects may account for the long-lasting olfactory deficit.
Topics: Animals; COVID-19; Mice; Olfactory Mucosa; Olfactory Bulb; SARS-CoV-2; Myelin Sheath; Microglia; Mice, Transgenic; Angiotensin-Converting Enzyme 2; Olfaction Disorders; Disease Models, Animal; Male; Inflammation; Macrophages; Female
PubMed: 38834299
DOI: 10.1523/ENEURO.0106-24.2024 -
Cancer Cell Jun 2024The olfactory epithelium undergoes neuronal regeneration from basal stem cells and is susceptible to olfactory neuroblastoma (ONB), a rare tumor of unclear origins....
The olfactory epithelium undergoes neuronal regeneration from basal stem cells and is susceptible to olfactory neuroblastoma (ONB), a rare tumor of unclear origins. Employing alterations in Rb1/Trp53/Myc (RPM), we establish a genetically engineered mouse model of high-grade metastatic ONB exhibiting a NEUROD1 immature neuronal phenotype. We demonstrate that globose basal cells (GBCs) are a permissive cell of origin for ONB and that ONBs exhibit cell fate heterogeneity that mimics normal GBC developmental trajectories. ASCL1 loss in RPM ONB leads to emergence of non-neuronal histopathologies, including a POU2F3 microvillar-like state. Similar to small-cell lung cancer (SCLC), mouse and human ONBs exhibit mutually exclusive NEUROD1 and POU2F3-like states, an immune-cold tumor microenvironment, intratumoral cell fate heterogeneity comprising neuronal and non-neuronal lineages, and cell fate plasticity-evidenced by barcode-based lineage tracing and single-cell transcriptomics. Collectively, our findings highlight conserved similarities between ONB and neuroendocrine tumors with significant implications for ONB classification and treatment.
Topics: Animals; Mice; Small Cell Lung Carcinoma; Humans; Esthesioneuroblastoma, Olfactory; Cell Lineage; Lung Neoplasms; Basic Helix-Loop-Helix Transcription Factors; Tumor Microenvironment; Nose Neoplasms; Olfactory Mucosa; Disease Models, Animal; Tumor Suppressor Protein p53
PubMed: 38788720
DOI: 10.1016/j.ccell.2024.05.003 -
Current Issues in Molecular Biology May 2024Type I interferon signaling (IFN-I) perturbations are major drivers of COVID-19. Dysregulated IFN-I in the brain, however, has been linked to both reduced cognitive...
Type I interferon signaling (IFN-I) perturbations are major drivers of COVID-19. Dysregulated IFN-I in the brain, however, has been linked to both reduced cognitive resilience and neurodegenerative diseases such as Alzheimer's. Previous works from our group have proposed a model where peripheral induction of IFN-I may be relayed to the CNS, even in the absence of fulminant infection. The aim of our study was to identify significantly enriched IFN-I signatures and genes along the transolfactory route, utilizing published datasets of the nasal mucosa and olfactory bulb amygdala transcriptomes of COVID-19 patients. We furthermore sought to identify these IFN-I signature gene networks associated with Alzheimer's disease pathology and risk. Gene expression data involving the nasal epithelium, olfactory bulb, and amygdala of COVID-19 patients and transcriptomic data from Alzheimer's disease patients were scrutinized for enriched Type I interferon pathways. Gene set enrichment analyses and gene-Venn approaches were used to determine genes in IFN-I enriched signatures. The Agora web resource was used to identify genes in IFN-I signatures associated with Alzheimer's disease risk based on its aggregated multi-omic data. For all analyses, false discovery rates (FDR) <0.05 were considered statistically significant. Pathways associated with type I interferon signaling were found in all samples tested. Each type I interferon signature was enriched by IFITM and OAS family genes. A 14-gene signature was associated with COVID-19 CNS and the response to Alzheimer's disease pathology, whereas nine genes were associated with increased risk for Alzheimer's disease based on Agora. Our study provides further support to a type I interferon signaling dysregulation along the extended olfactory network as reconstructed herein, ranging from the nasal epithelium and extending to the amygdala. We furthermore identify the 14 genes implicated in this dysregulated pathway with Alzheimer's disease pathology, among which HLA-C, HLA-B, HLA-A, PSMB8, IFITM3, HLA-E, IFITM1, OAS2, and MX1 as genes with associated conferring increased risk for the latter. Further research into its druggability by IFNb therapeutics may be warranted.
PubMed: 38785545
DOI: 10.3390/cimb46050277 -
Scientific Reports May 2024Most terrestrial mammals have a vomeronasal system to detect specific chemicals. The peripheral organ of this system is a vomeronasal organ (VNO) opening to the incisive...
Most terrestrial mammals have a vomeronasal system to detect specific chemicals. The peripheral organ of this system is a vomeronasal organ (VNO) opening to the incisive duct, and its primary integrative center is an accessory olfactory bulb (AOB). The VNO in seals is thought to be degenerated like whales and manatees, unlike otariids, because of the absence of the AOB. However, olfaction plays pivotal roles in seals, and thus we conducted a detailed morphological evaluation of the vomeronasal system of three harbor seals (Phoca vitulina). The VNO lumen was not found, and the incisive duct did not open into the oral cavity but was recognized as a fossa on the anteroventral side of the nasal cavity. This fossa is rich in mucous glands that secrete acidic mucopolysaccharides, which might originate from the vomeronasal glands. The olfactory bulb consisted only of a main olfactory bulb that received projections from the olfactory mucosa, but an AOB region was not evident. These findings clarified that harbor seals do not have a VNO to detect some chemicals, but the corresponding region is a specialized secretory organ.
Topics: Animals; Vomeronasal Organ; Phoca; Nasal Cavity; Olfactory Bulb; Mucus; Olfactory Mucosa; Male; Smell; Female
PubMed: 38783070
DOI: 10.1038/s41598-024-62711-x -
Science Advances May 2024Neuromorphic sensors, designed to emulate natural sensory systems, hold the promise of revolutionizing data extraction by facilitating rapid and energy-efficient...
Neuromorphic sensors, designed to emulate natural sensory systems, hold the promise of revolutionizing data extraction by facilitating rapid and energy-efficient analysis of extensive datasets. However, a challenge lies in accurately distinguishing specific analytes within mixtures of chemically similar compounds using existing neuromorphic chemical sensors. In this study, we present an artificial olfactory system (AOS), developed through the integration of human olfactory receptors (hORs) and artificial synapses. This AOS is engineered by interfacing an hOR-functionalized extended gate with an organic synaptic device. The AOS generates distinct patterns for odorants and mixtures thereof, at the molecular chain length level, attributed to specific hOR-odorant binding affinities. This approach enables precise pattern recognition via training and inference simulations. These findings establish a foundation for the development of high-performance sensor platforms and artificial sensory systems, which are ideal for applications in wearable and implantable devices.
Topics: Humans; Receptors, Odorant; Odorants; Smell; Synapses; Pattern Recognition, Automated; Olfactory Receptor Neurons; Biosensing Techniques
PubMed: 38781346
DOI: 10.1126/sciadv.adl2882