TET2 deficiency promotes anxiety and depression-like behaviors by activating NLRP3/IL-1ß pathway in microglia of allergic rhinitis mice.

BACKGROUND: Anxiety and depression-like behaviors in allergic rhinitis (AR) are attracting attention, while the precise mechanism has not been clearly elucidated. Recent evidence shows that neuroinflammation in anterior cingulate cortex (ACC) may be the core of these neuropsychiatric symptoms in AR. Here, we investigated the molecular link between the anxiety and depression-like behaviors and neuroinflammation in ACC. METHODS: Mice were sensitized and challenged with ovalbumin (OVA) to induce AR. Nasal inflammation levels were assessed by H&E staining and PAS staining. Anxiety and depression-like behaviors were evaluated by behavioral experiments including open field test, forced swimming test, and sucrose preference test. Neuronal impairment was characterized via Nissl staining and 18FDG-PET. The role of ten-eleven translocation 2 (TET2) in AR-related anxiety and depression was assessed by Tet2-/- mice. In addition, the murine BV2 microglial cell line was utilized to explore the molecular mechanisms by which TET2 mediates neuroinflammation. The levels of TET2, NLRP3 and their downstream molecules were detected by immunohistochemistry, Western blot, Dot blot and ELISA. The effects of metformin on depression-like behaviors in AR mice were also evaluated. RESULTS: AR mice showed significant anxiety and depression-like behaviors, which associated with the activation of ACC. Loss of TET2 activated the NLRP3/IL-1ß pathway of microglia in AR mice, further accelerating the anxiety and depression-like behaviors. In addition, knockdown of TET2 activated the NLRP3/IL-1ß pathway in BV2 cells. Metformin improved the neuropsychiatric symptoms of AR mice by reducing the activation of NLRP3/IL-1ß pathway after upregulating TET2. CONCLUSION: TET2 deficiency activates the NLRP3/IL-1ß pathway of microglia in the ACC, promoting the pathological process of anxiety and depression-like behavior in AR. Metformin could be effective in treating neuroinflammation by regulating microglia via TET2 up-regulation, indicating that metformin is a potential way to treat anxiety and depression-like behaviors in AR.

Metformin Improves Comorbid Depressive Symptoms in Mice with Allergic Rhinitis by Reducing Olfactory Bulb Damage.

Allergic rhinitis (AR) is a widespread disease that is frequently comorbid with depression. However, the mechanisms and treatments for depression in AR remain underexplored. Metformin, a widely used antidiabetic drug, has shown antidepressant effects. The aim of this study was to explore the effects and potential mechanisms of metformin on depression-like behaviors in an AR mouse model. In the present study, mice were sensitized and challenged with ovalbumin (OVA) to induce AR. Results showed that mice with AR exhibited significant depression-like behavior which was attenuated by metformin. In addition, the levels of expression of synaptic plasticity markers (anti-microtubule-associated protein 2, synaptophysin, postsynaptic density protein 95), neurogenesis markers (doublecortin and Ki-67), and brain-derived neurotrophic factor were decreased in the olfactory bulb (OB) of mice with AR, while metformin ameliorated all these alterations and reduced apoptosis in the OB of these mice. Furthermore, it enhanced the phosphorylation of AMP-activated kinase (AMPK) and the levels of ten-eleven translocation 2 (TET2) and 5-hydroxymethylcytosine in the OB. In conclusion, our findings suggest that metformin might be a viable strategy for treating AR-related depression, possibly by modulating neuroplasticity, neurogenesis, apoptosis, and BDNF signaling in the OB via the AMPK/TET2 pathway.

Global characteristics and trends of presbycusis research from 2002 to 2021: a bibliometric study.

BACKGROUND AND OBJECTIVE: Age-related hearing loss, also termed presbycusis, is the most prevalent sensory impairment in older adults. Presbycusis research has considerably advanced over the past few decades, however, comprehensive and objective reports on the current state of presbycusis research are lacking. We used bibliometric methods to objectively analyzed the progress of presbycusis research over the past 20 years and to identify the research hotspots and emerging trends in this field. METHODS: Eligible literature metadata published between 2002 and 2021 were obtained from the Web of Science Core Collection on September 1, 2022. Bibliometric tools including CiteSpace, VOSviewer, Bibliometrix R Package, Microsoft Excel 2019, and an online bibliometric platform were used to conduct bibliometric and visualized analyses. RESULTS: A total of 1,693 publications related to presbycusis were retrieved. The number of publications increased continuously from 2002 to 2021, and the USA occupied the lead position in the field, with the highest research output. The most productive and influential institution, author, and journal were the University of California, Frisina DR of the University of South Florida, and Hearing Research, respectively. Co-citation cluster and trend topics analyses revealed that "cochlear synaptopathy", "oxidative stress", and "dementia" were the predominant foci of presbycusis research. Burst detection of keywords indicated that "auditory cortex" and "Alzheimer's disease" were the newly-emerged aspects. CONCLUSION: During the past two decades, presbycusis research has been flourishing. The current research foci are "cochlear synaptopathy", "oxidative stress", and "dementia". "Auditory cortex" and "Alzheimer's disease" may be potential future directions in this field. This bibliometric analysis represents the first quantitative overview of presbycusis research, thus providing valuable references and insights for scholars, medical practitioners, and policymakers concerned with this field.

Mapping the knowledge structure and emerging trends of efferocytosis research: a bibliometric analysis.

BACKGROUND: Efferocytosis refers to the physiological clearance process of apoptotic cells by specialized and non-phagocytes and it is essential in human health and disease. However, there is a lack of comprehensive and objective reports on the current status of efferocytosis research. Here, we visually analyzed the hotspots and trending issues of efferocytosis research with bibliometric analysis. METHODS: Relevant publications were obtained from the Web of Science Core Collection on February 18, 2022. We performed bibliometric and visual analysis using CiteSpace, VOSviewer, Microsoft Excel 2019, and the online Bibliometric platform. RESULTS: A total of 1007 publications on efferocytosis were retrieved. The number of efferocytosis studies increased rapidly from 2006 to 2021. The country that published the most efferocytosis related articles was the USA and the most productive institutions were Harvard University and Brigham and Women's Hospital. The most prolific and influential author was I. Tabas of Columbia University. Frontiers in Immunology published the most research papers on efferocytosis, the while Journal of Immunology had the highest co-citation frequency. The high-frequency keywords were "efferocytosis", "inflammation", "apoptotic cells", "macrophages", and "apoptosis". The analysis of keywords with the strongest citation bursts identified "cell" and "resolution" as emerging hotspots. CONCLUSION: Our results demonstrated that efferocytosis research increased steadily within the past decade. Current efferocytosis studies focus on three main aspects: mechanisms, basic biology, and potential role in disease. The research trends included the cellular players of the efferocytosis process and the role of efferocytosis in inflammation resolution. This bibliometric analysis presented a comprehensive overview of efferocytosis research and provided valuable references and ideas for scholars interested in this field.

Development, Validation and Comparison of Artificial Neural Network and Logistic Regression Models Predicting Eosinophilic Chronic Rhinosinusitis With Nasal Polyps.

PURPOSE: Chronic rhinosinusitis with nasal polyps (CRSwNP) can be classified into eosinophilic CRSwNP (eCRSwNP) and non-eosinophilic CRSwNP (non-eCRSwNP) by tissue biopsy, which is difficult to perform preoperatively. Clinical biomarkers have predictive value for the classification of CRSwNP. We aimed to evaluate the application of artificial neural network (ANN) modeling in distinguishing different endotypes of CRSwNP based on clinical biomarkers. METHODS: Clinical parameters were collected from 109 CRSwNP patients, and their predictive ability was analyzed. ANN and logistic regression (LR) models were developed in the training group (72 patients) and further tested in the test group (37 patients). The output variable was the diagnosis of eCRSwNP, defined as tissue eosinophil count > 10 per high-power field. The receiver operating characteristics curve was used to assess model performance. RESULTS: A total of 15 clinical features from 60 healthy controls, 60 eCRSwNP and 49 non-eCRSwNP were selected as candidate predictors. Nasal nitric oxide levels, peripheral eosinophil absolute count, total immunoglobulin E, and ratio of bilateral computed tomography scores for the ethmoid sinus and maxillary sinus were identified as important features for modeling. Two ANN models based on 4 and 15 clinical features were developed to predict eCRSwNP, which showed better performance, with the area under the receiver operator characteristics significantly higher than those from the respective LR models (0.976 vs. 0.902, P = 0.048; 0.970 vs. 0.845, P = 0.011). All ANN models had better fits than single variable prediction models (all P < 0.05), and ANN model 1 had the best predictive performance among all models. CONCLUSIONS: Machine learning models assist clinicians in predicting endotypes of nasal polyps before invasive detection. The ANN model has the potential to predict eCRSwNP with high sensitivity and specificity, and is superior to the LR model. ANNs are valuable for optimizing personalized patient management.

Knowledge mapping of the links between the microbiota and allergic diseases: A bibliometric analysis (2002-2021).

Background: In recent decades, dramatic changes in modern environmental exposures and lifestyles have resulted in a steep rise in the prevalence of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis and food allergies. Evidence is mounting that the microbiota plays a crucial role in allergic disorder development and evolution. Therefore, a better understanding of allergic diseases within the context of the microbiota is urgently needed. This work aimed to comprehensively outline general characteristics, research hotspots, evolution routes, and emerging trends in this area. Methods: Relevant publications from January 2002 to December 2021 were obtained from the Web of Science Core Collection on 5 August 2022. Bibliometric and visual analyses were performed using CiteSpace; VOSviewer; an online bibliometric platform; and Microsoft Excel 2019. Results: In total, 2535 documents met the requirements. The annual number of publications has shown rapid growth in the last two decades. The USA, University of California System, and Isolauri E of the University of Turku were the most productive and influential country, institution, and author, respectively. The Journal of Allergy and Clinical Immunology was the most prolific and most cocited journal. High-frequency keywords included "gut microbiota", "asthma", "atopic dermatitis", "children", and "probiotics". Recent studies have focused on "atopic dermatitis", "skin", "asthma", and "probiotics", according to the cocitation analysis of references. Burst detection analysis of keywords showed that "community", "skin microbiome", "microbiome", "Staphylococcus aureus", and "chain fatty acid" were emerging research frontiers, which currently have ongoing bursts. Conclusion: In the last 20 years, studies of the microbiota in allergic diseases have been flourishing, and the themes have been increasing in depth. These findings provide valuable references on the current research hotspots and gaps and development trends in the link between the microbiota and allergic diseases.

Online public attention toward allergic rhinitis in Wuhan, China: Infodemiology study using Baidu index and meteorological data.

Background: With the popularization of the Internet and medical knowledge, more and more people are learning about allergic rhinitis (AR) on the Internet. Objective: This study aims to analyze the epidemiological characteristics and online public attention to AR in Wuhan, China, utilizing the most popular search engine in mainland China and meteorological data of Wuhan. Methods: To study the Internet attention and epidemiological characteristics of AR in Wuhan, the search volume (SV) of "Allergic Rhinitis" in Mandarin and AR-related search terms from 1 January 2014 through 31 December 2021 were recorded. For user interest, the search and demand data were collected and analyzed. Results: The yearly average Baidu SV of AR in both Wuhan and China increased year by year but began to decline gradually after the COVID-19 pandemic. Baidu SV of AR in Wuhan exhibited significant seasonal variation, with the first peak was from March to May and the second peak occurring between September and October. Correlation analysis revealed a moderate positive correlation between the monthly average SV of "Allergic Rhinitis" and "Mites" and "Mites + Pollen Allergy" in Wuhan, a weak positive correlation between the monthly average SV of "Allergic Rhinitis" and "Pollen Allergy," and a positive correlation between monthly SV of "Allergic Rhinitis" and the meteorological index of pollen allergy (MIPA). Conclusion: The attention given to the topic on the internet, as measured by the search volume, was reflective of the situation in Wuhan, China. It has the potential to predict the epidemiological characteristics of AR and help medical professionals more effectively plan seasonal AR health education.

Downregulation of deubiquitinating enzyme USP25 promotes the development of allergic rhinitis by enhancing TSLP signaling in the nasal epithelium.

Ubiquitin­specific peptidase 25 (USP25) is a key deubiquitylase belonging to the USP superfamily that is primarily involved in inflammation and the immune response. Thymic stromal lymphopoietin (TSLP) is an epithelial­derived cytokine that is regarded as the master switch that initiates and maintains the type 2 immune response in allergic rhinitis (AR). However, the molecular mechanisms by which USP25 regulates TSLP signaling in the nasal epithelium in AR remain unclear. The present study assessed the protein expression levels of USP25 in the nasal epithelium of patients with AR. Moreover, USP25 knockout (KO) and wild­type (WT) mice were treated with ovalbumin (OVA) to establish a model of AR. The results of western blotting and immunohistochemistry in the present study demonstrated that the protein expression levels of USP25 were significantly decreased in the nasal mucosa of patients with AR and AR mice, whereas the protein expression levels of TSLP were significantly increased. Allergic inflammation was more severe in USP25 KO mice compared with WT mice exposed to OVA, as demonstrated by increased nose scratching and sneezing, increased eosinophil infiltration, goblet cell hyperplasia and enhanced T helper type 2 (Th2) cytokine production. The results of in vitro experiments demonstrated that silencing or overexpression of USP25 decreased or increased TNF receptor­associated factor 3 (TRAF3) protein expression levels, respectively, in human nasal epithelial cells, whereas TSLP protein expression levels were negatively associated with the expression of USP25 and TRAF3. In summary, USP25 downregulation enhanced TSLP signaling in the nasal mucosal epithelium via decreased TRAF3 expression, thereby exacerbating inflammation in AR. Therefore, USP25 may act as a novel therapeutic target in AR.

Activation of NLRP3 inflammasome contributes to the inflammatory response to allergic rhinitis via macrophage pyroptosis.

OBJECTIVE: Allergic rhinitis (AR) is a heterogeneous disease and its pathogenesis is still unclear. Growing clinical evidence has thrown light on the key role of NOD-like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation of allergic disease. However, the effect of NLRP3 activation in macrophages for AR has not been elucidated. This study aims to investigate the role of NLRP3 in ovalbumin (OVA)-stimulated bone marrow-derived macrophages (BMDMs) and to confirm the impact of macrophage pyroptosis in allergic rhinitis. METHODS: Nasal inflammation levels were assessed by H&E and dual immunofluorescence staining. BMDMs were cultured and were stimulated with OVA in the presence or absence of MCC950 to further investigate the effect of NLRP3 activation in macrophages. The cell lysates and supernatants were harvested to measure NLRP3 and downstream molecules, as well as cell rupture, and IL-1ß production. Besides, an OVA-exposed AR mouse model was developed, and the histopathology in nasal mucosa, and the relationship between macrophage pyroptosis and local inflammation were detected. The inhibitory role of MCC950 was also evaluated. RESULTS: The present results uncovered that the number of macrophages and NLRP3 expression were increased in the nasal mucosa of AR subjects, and upregulation of macrophage pyroptosis contributed to local allergic inflammation. In addition, the OVA challenge induced NLRP3 inflammasome activation in BMDMs, as evidenced by enhanced expressions of NLRP3-ASC-caspase-1 inflammasome, gasdermin D, production of IL-1ß, and increased macrophage lysis. Furthermore, inhibition of NLRP3 inflammasome attenuated nasal inflammation, accompanied by a reduced number of inflammatory cells and lower levels of IL-1ß and OVA-specific IgE. CONCLUSIONS: Our results indicate that NLRP3 inflammasome played an important role in allergic airway inflammation by activating macrophage's pyroptotic cell death and releasing inflammatory mediators to local tissues. Inhibition of NLRP3 inflammasome-mediated pyroptosis could be a promising therapeutic strategy for ameliorating inflammatory responses in allergic rhinitis.

Heterologous expression of pediocin/papA in Bacillus subtilis.

Listeria monocytogenes is a food-borne pathogen. Pediocin is a group IIα bacteriocin with anti-listeria activity that is naturally produced by Pediococcus acidilactic and Lactobacillus plantarum. The pedA/papA gene encodes pediocin/plantaricin. In native hosts, the expression and secretion of active PedA/PapA protein rely on the accessory protein PedC/PapC and ABC transporter PedD/PapD on the same operon. The excretion machines were also necessary for pediocin protein expression in heterologous hosts of E. coli, Lactobacillus lactis, and Corynebacterium glutamicum. In this study, two vectors carrying the codon sequence of the mature PapA peptide were constructed, one with and one without a His tag. Both fragments were inserted into the plasmid pHT43 and transformed into Bacillus subtilis WB800N. The strains were induced with IPTG to secrete the fused proteins PA1 and PA2. Supernatants from both recombinant strains can inhibit Listeria monocytogenes ATCC54003 directly. The fused protein possesses inhibition activity as a whole dispense with removal of the leading peptide. This is the first report of active pediocin/PapA expression without the assistance of PedCD/PapCD in heterogeneous hosts. In addition, the PA1 protein can be purified by nickel-nitrilotriacetic acid (Ni-NTA) metal affinity chromatography.

The hMeDIP-Seq identified INPP4A as a novel biomarker for eosinophilic chronic rhinosinusitis with nasal polyps.

Background: Eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) is an endotype of chronic rhinosinusitis with nasal polyps characterized by more severe symptoms, a stronger association with asthma and a greater recurrence risk. It is unknown whether DNA hydroxymethylation could influence ECRSwNP. Methods: Hydroxymethylated DNA immunoprecipitation sequencing was carried out in three distinct groups (control, ECRSwNP and NECRSwNP). Additional qRT-PCR, immunohistochemistry and analysis of the receiver operating characteristic curve were performed. Results: Between ECRSwNP and NECRSwNP, 26 genes exhibited differential DNA hydroxymethylation. Consistent with their hydroxymethylation level, GNAL, INPP4A and IRF4 expression levels were significantly different between ECRSwNP and the other two groups. The receiver operating characteristic curve revealed that INPP4A mRNA has a high predictive accuracy for ECRSwNP. Conclusion: DNA hydroxymethylation regulates the expression of multiple genes in ECRSwNP. INPP4A mRNA was markedly decreased in ECRSwNP polyps and can predict ECRSwNP.

A novel approach for audible acoustic quick response codes.

Compared to image-based quick response (QR) codes, acoustic QR codes have some advantages. However, an acoustic QR scanner cannot recognize an acoustic QR code at a distance of more than two meters from an acoustic QR announcer. To this end, we propose a new sort of acoustic QR code, called an audible acoustic QR code (AAQRC), which employs humanly audible sound to carry users' information directly. First, a user's string of characters is translated into a string of pitches. Then, the related algorithms convert the string of pitches into a playable audio file. As a result, an AAQRC is generated, consisting of the audio itself. AAQRC recognition is the opposite process of AAQRC generation. Compared with the existing approach for acoustic QR codes, the new method can recognize acoustic QR codes at a longer distance, even if there are obstacles between the AAQRC announcer and AAQRC scanner.

Synthesis of Single-Layer Two-Dimensional Metal-Organic Frameworks M3 (HAT)2 (M=Ni, Fe, Co, HAT=1,4,5,8,9,12-hexaazatriphenylene) Using an On-Surface Reaction.

1,4,5,8,9,12-Hexaazatriphenylene (HAT) is one of the smallest polyheterocyclic aromatic building blocks for forming conjugated metal-organic frameworks (cMOFs). However, the strong inter-molecular steric hindrance impedes the growth of HAT-based cMOFs. Here we employ on-surface synthesis to grow single-layer two-dimensional cMOFs of M3 (HAT)2 (M=Ni, Fe, Co). Using scanning tunnelling microscopy and density-functional theory (DFT) analysis, we resolve that the frameworks comprise a hexagonal lattice of HAT molecules and a Kagome lattice of metal atoms. The DFT analysis indicates that Ni, Co and Fe carry a magnetic moment of 1.1, 2.5, and 3.7 µB, respectively. We anticipate that the small π-conjugated core of HAT and strong bidentate chelating coordination give rise to appealing electronic and magnetic properties.

Dual-band polarization-insensitive toroidal dipole quasi-bound states in the continuum in a permittivity-asymmetric all-dielectric meta-surface.

Ultra-high quality (Q) factor resonances derived from the bound states in the continuum (BICs) have drawn much attention in optics and photonics. Especially in meta-surfaces, they can enable ultrasensitive sensors, spectral filtering, and lasers because of their enhanced light-matter interactions and rare superiority of scalability. In this paper, we propose a permittivity-asymmetric all-dielectric meta-surface, comprising high-index cuboid tetramer clusters with symmetric structural parameters and configuring periodically on a glass substrate. Simulation results offer dual-band quasi-BICs with high Q values of 4447 and 11391, respectively. Multipolar decomposition in cartesian and electromagnetic distributions are engaged to analyze the physical mechanism of dual quasi-BIC modes, which reveals that they are both governed by magnetic quadrupole (MQ) and in-plane toroidal dipole (TD). The polarization-insensitive and scalable characteristics are also investigated. Additionally, we appraise the sensing performances of the proposed structure. As an example, our work supports an uncommon route to design dual-band polarization-insensitive TD quasi-BICs resonators and facilitates their applications in optic and photonics, such as low-threshold lasers and sensing.

Characterization of global research hotspots and trends on ten-eleven translocation 2: visualization and bibliometric analysis.

BACKGROUND AND OBJECTIVE: Ten-eleven translocation-2 (TET2) is member of the methylcytosine dioxygenase family and plays important roles in a variety of physiological and pathological processes; however, no bibliometric analysis has been performed to methodically evaluate the scientific research on TET2. Therefore, the aim of this study was to conduct a visual and scientometric analysis of TET2 research and to explore its current landscape, future direction, and research frontiers. METHODS: Publications related to TET2 research were retrieved from the Web of Science Core Collection (WoSCC) from 2009 to 2021. Excel, CiteSpace, and VOSviewer were utilized to perform the bibliometric visualization analysis. RESULTS: A total of 2384 articles were retrieved. The number of publications on TET2 has been steadily increasing from 2009 to 2021. The USA is the top contributor to the topic, with the largest number of publications. Harvard University and the Institut National de la Santé et de la Recherche Médicale were the leading institutions, while Levine RL of Memorial Sloan-Kettering Cancer Center is the most prolific and influential author. In TET2-related publications, the high-frequency keywords were: "tet2", "DNA methylation", "5-hrdroxymethylcytosine", "5-methylcytosine", "mutations", and "acute myeloid-leukemia". Based on keyword bursts, the emerging TET2 research hotspots include "inflammation", "gene expression", "landscape", and "clonal hematopoiesis". CONCLUSION: Research on TET2 is constantly growing and evolving during the last decade. Here, we provide an objective and comprehensive analysis of the global status, research hotspots, and potential trends in the field of TET2 research by using a bibliometric approach. These results will assist researchers in mastering the knowledge structure and guiding the future research directions of TET2.

Activation of Dopamine D2 Receptor Alleviates Neuroinflammation in a Mouse Model of Allergic Rhinitis With Olfactory Dysfunction.

PURPOSE: Allergic rhinitis (AR) is a common otolaryngology disease and one of the clinical causes of olfactory dysfunction (OD). The olfactory bulb serves as a transfer station for olfactory information transmission, and alleviating its neuroinflammation may be expected to improve AR-induced OD. Recent studies have suggested that the dopamine D2 receptor acts as a key target in regulating immune functions and neuroinflammatory reaction. However, the effect of dopamine D2 receptor on AR-induced neuroinflammation is still unknown. METHODS: An AR mouse model with OD induced by ovalbumin were constructed. The buried food pellet test was to evaluate the olfactory function of the mice. Immunofluorescence staining, hematoxylin and eosin staining, enzyme-linked immunosorbent assay and western blotting were also used to investigate the molecular mechanisms underlying the anti-inflammatory effects of the dopamine D2 receptor in AR-induced OD. RESULTS: We found that AR-induced OD has a relationship with inflammatory responses in the olfactory bulb. Nasal administration of quinpirole (Quin, a dopamine D2 receptor agonist, 3 mg/kg) improved olfactory function in mice, inhibited the expression of toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signalings and the levels of tumor necrosis factor-α, interleukin (IL)-1ß and IL-6 in the olfactory bulb. In vitro, Quin (20 µmol/L) inhibited the release of TLR4/NF-κB signalings-dependent inflammatory cytokines in cultured microglia. CONCLUSIONS: Activation of the dopamine D2 receptor inhibits the release of inflammatory cytokines through TLR4/NF-κB signaling in the olfactory bulb microglia, and protects olfactory function.

Changes in Resting-State Spontaneous Brain Activity in Patients With Allergic Rhinitis: A Pilot Neuroimaging Study.

BACKGROUND: Allergic rhinitis (AR) is an inflammatory disorder of the nose caused by immunoglobulin E (IgE)-mediated immune response to allergens. Apart from the typical symptoms of sneezing, itching, rhinorrhea, and nasal congestion, behavioral complications were also reported to be associated with the progression of AR, such as cognitive deficits, mood changes, memory decline, attention deficiency, poor school performance, anxiety, and depression. Recent human studies have suggested that alterations in brain function caused by allergen exposure may precipitate high levels of anxiety and emotional reactivity in asthma patients. But until now, there is no direct evidence of the relationship between brain activity and allergic rhinitis. METHODS: Resting-state functional magnetic resonance imaging (rs-fMRI) was used to excavate whether there remain functional changes of brain activity in AR patients. We measured the amplitude of low-frequency fluctuation (ALFF) and the z conversion of ALFF (zALFF) in 20 patients with AR and 20 age- and sex-matched healthy controls (HCs) using the rs-fMRI data. RESULTS: Compared with healthy controls, AR patients exhibited lower ALFF values in the precuneus (PCUN) and higher ALFF values in the anterior cingulate cortex (ACC). The ALFF values of these features were significantly correlated with the visual analog scale (VAS) scores, the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores, the subscales of RQLQ, and specific IgE, partly. CONCLUSION: We found changes in resting-state spontaneous brain activity in AR patients with hypoactivity in the PCUN and hyperactivity of the ACC. The brain-related symptoms of AR might be another potential clinical intervention target for improving the life quality of AR patients. Further attention to brain activity is essential for a deeper understanding of AR.

The role and mechanism of ß-arrestin2 in signal transduction.

ß-arrestin2 is a ubiquitously expressed scaffold protein localized on the cytoplasm and plasma membrane. It was originally found to bind to GPCRs, uncoupling G proteins and receptors' binding and inhibiting the signal transduction of the GPCRs. Further investigations have revealed that ß-arrestin2 not only mediates the desensitization of GPCRs but also serves as a multifunctional scaffold to mediate receptor internalization, kinase activation, and regulation of various signaling pathways, such as TLR4/NF-κB, MAPK, Wnt, TGF-ß, and AMPK/mTOR pathways. ß-arrestin2 regulates cell invasion, migration, autophagy, angiogenesis, and anti-inflammatory effects by regulating various signaling pathways, which play a vital role in many physiological and pathological processes. This paper reviews the structure and function of ß-arrestin2, the regulation of ß-arrestin2 based signaling pathways. The role and mechanism of ß-arrestin2 signaling have been delineated in sufficient detail. The prospect of regulating the expression and activity of ß-arrestin2 in multisystem diseases holds substantial therapeutic promise.

TAK-242 ameliorates olfactory dysfunction in a mouse model of allergic rhinitis by inhibiting neuroinflammation in the olfactory bulb.

OBJECTIVE: Olfactory dysfunction (OD) is a common symptom of allergic rhinitis (AR) that can seriously affect patient quality of life; however, the associated pathogenesis remains unclear. This study aimed to explore the relationship between OD and damage of the olfactory bulb (OB) in allergic rhinitis (AR). The therapeutic potential of TAK-242, a selective TLR4 inhibitor, was evaluated for OD. METHOD: An AR mouse model was established with ovalbumin (OVA) to test the olfactory function of AR mice using the buried food pellet test (BFPT). Mice with OD were intraperitoneally injected with TAK-242 or 1% DMSO (vehicle). Immunohistochemistry was used to detect microglia and astrocyte activation in the OB. TUNNEL staining was performed to detect apoptosis in the OB. Proteins in the TLR4 signaling pathway were detected by Western blot. The level of proinflammatory factor mRNA in the OB was determined by RT-PCR. RESULT: Neuroinflammation was observed in the OB of the OD group, as evidenced by glial cell activation and increased proinflammatory factor expression. The number of apoptotic cells was significantly increased in the OB of the OD group. The expression of TLR4, MyD88, and p-NF-κBp65 was significantly up-regulated in the OB of the OD group. TAK-242 treatment significantly reduced the level of IL-1ß, IL-6, and TNF-α mRNA expression, as well as activation of microglia and astrocytes in the OB tissues. CONCLUSION: TAK-242 improve olfactory function in AR mice mainly by reducing neuroinflammation and apoptosis in the OB, which may be related to blocking the TLR4/MyD88/NF-κB signaling pathway.

miR-31 attenuates murine allergic rhinitis by suppressing interleukin-13-induced nasal epithelial inflammatory responses.

The present study aimed to investigate whether microRNA (miR)­31 exerted therapeutic potential in allergic rhinitis (AR) and to explore its underlying mechanism. Firstly, the expression levels of miR­31 were detected by reverse transcription­quantitative PCR in the nasal mucosa of patients and mice. Subsequently, an ovalbumin (OVA)­induced animal model of AR was constructed. Allergic symptom score, histopathological characteristics, OVA­specific immunoglobulin E (IgE) titers, and T­helper (Th)1 and Th2 cell­related cytokine levels were analyzed in OVA­sensitized mice, miR­31­overexpressing mice, miR­negative control mice and control mice. Furthermore, interleukin (IL)­13­stimulated nasal epithelial cells (NECs) were used to assess the effects of miR­31 on the production of IL­13­induced inflammatory cytokines and mucin 5AC by performing western blotting and ELISA. The expression levels of miR­31 were significantly decreased in the nasal mucosa of the AR group compared with those in the control group. Moreover, upregulation of miR­31 markedly attenuated sneezing and nasal rubbing events, reduced nasal eosinophil infiltration and goblet cell hyperplasia, and decreased the levels of OVA­specific IgE and Th2­related cytokines. In addition, subsequent in vitro experiments showed that upregulation of miR­31 inhibited IL­13 receptor α1 chain expression and signal transducer and activator of transcription 6 phosphorylation in NECs. Furthermore, miR­31 suppressed IL­13­induced expression of thymic stromal lymphopoietin, granulocyte­macrophage colony­stimulating factor, eotaxin and mucin 5AC in NECs. In conclusion, these data revealed that miR­31 could ameliorate AR by suppressing IL­13­induced nasal epithelial inflammatory responses, and thus may serve as a novel therapeutic target for AR.