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1.
Rom J Morphol Embryol ; 63(2): 413-419, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36374146

RESUMO

Currently, allergic rhinitis (AR) is the most common allergic disease worldwide. AR is defined as immunoglobulin E (IgE)-mediated chronic inflammatory disease of the upper airways. It characterizes by symptoms like nasal obstruction, rhinorrhea, nasal itching, and sneezing. The immune system and genetic susceptibility in the interaction with the environment lead to the development of AR. Many cytokines, chemokines and cells maintain allergic inflammation. Studies show that 10% to 30% of the adult population are affected, and that prevalence rates are increasing world widely. AR, nasal polyps (NP), as well as chronic rhinosinusitis (CRS) are all associated with eosinophilic infiltration and large quantities of mast cells (MCs) within the mucosa. The diagnosis and management of chronic sinonasal diseases involves the analysis of eosinophilic infiltration, MCs, and their markers eosinophilic cationic protein (ECP) and tryptase. Regarding nasal cancer, nasal allergies were found to exhibit a dual function: immune surveillance may help in the defense against malignant cells, but an opposite effect is observed in tissues with chronic stimulation and inflammation. In the present paper, we studied a group of 70 patients diagnosed with AR and NP, rhinosinusitis or nasal cancer, admitted to the Ear, Nose & Throat (ENT) Clinic of the Emergency City Hospital, Timisoara, Romania, between January 2016 and December 2020, and we identified 37 (53%) patients diagnosed with AR and NP, 25 (36%) patients diagnosed with AR and rhinosinusitis, and eight (11%) patients diagnosed with AR and nasal cancer. The average age of the patients was 53 years old. Every patient included in the study was histopathologically and immunohistochemically diagnosed.


Assuntos
Pólipos Nasais , Neoplasias Nasais , Rinite Alérgica , Sinusite , Humanos , Adulto , Pessoa de Meia-Idade , Pólipos Nasais/complicações , Pólipos Nasais/patologia , Neoplasias Nasais/patologia , Sinusite/complicações , Sinusite/patologia , Rinite Alérgica/complicações , Rinite Alérgica/metabolismo , Doença Crônica , Inflamação/patologia , Mucosa Nasal/patologia
2.
Sci Rep ; 12(1): 16164, 2022 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-36171394

RESUMO

Deviated nasal septum (DNS) is suggested to be associated with nonspecific inflammation of the nasal mucosa. The authors hypothesized septoplasty may reduce nasal mucosal inflammation, therefore the authors aimed to measure various inflammatory biomarkers in the nasal secretion following septoplasty. Prospectively, 17 patients undergoing elective septoplasty were included. Symptomatic changes after septoplasty were evaluated with Sino-nasal Outcome Test (SNOT-22) and Nasal obstruction symptom evaluation (NOSE) scores. Using acoustic rhinometry, changes of the nasal airway volume were measured. Nasal secretion was collected within 2 weeks and 3 months before and after septoplasty, respectively. The inflammatory biomarker high-mobility group box 1 (HMGB1) and vasoactive intestinal peptide (VIP), and inflammatory cytokines including tumor necrosis factor α (TNF α), interferon γ (IFN-γ), interleukin-4 (IL-4), eotaxin-1, and regulated upon activation, normal T cell expressed and presumably secreted (RANTES) were quantified in the nasal secretion by enzyme-linked immunosorbent assays or multiplex bead array assays. The patients' mean age was 30.5 ± 6.8 (ranging from 19 to 43), consisting of 15 male and 2 female patients. The median SNOT-22 and NOSE scores changed from 54 to 14 and 78 to 15, respectively, both showing a significant decrease. In acoustic rhinometry, nasal cavity volume of convex side significantly increased after septoplasty, whereas significant discrepancy of nasal airway volume between concave and convex sides became insignificant. No significant difference was noted both before and after septoplasty between the concave and convex sides in all seven biomarkers. The HMGB1, RANTES, IL-4, and TNF-α concentrations following septoplasty showed significant decrease in 34 nasal cavities of 17 patients (all p < 0.05). However, when the 17 concave and 17 convex sides were analyzed separately, the significant reduction in four biomarkers were only significant in the concave sides (all p < 0.05), but not significantly reduced in convex sides. Septoplasty may have benefited not only in normalizing the nasal airflow and symptom improvement, but also in nonspecific inflammation attenuation in the nasal airway.


Assuntos
Proteína HMGB1 , Obstrução Nasal , Adulto , Biomarcadores , Quimiocina CCL11 , Quimiocina CCL5 , Feminino , Humanos , Inflamação/patologia , Interferon gama , Interleucina-4 , Masculino , Mucosa Nasal/patologia , Septo Nasal/cirurgia , Resultado do Tratamento , Fator de Necrose Tumoral alfa , Peptídeo Intestinal Vasoativo , Adulto Jovem
4.
Artigo em Inglês | MEDLINE | ID: mdl-35742518

RESUMO

Although extensive research has shown the pathological effect of fine and ultrafine airborne particles, clear evidence of association of environmental exposure to them and inflammatory changes in human nasal mucosa is missing. Meanwhile, pathogenesis of chronic rhinosinusitis, despite being a disease with high prevalence in the population, is still unclear. The increasing evidence of the pro-inflammatory properties of these particles raises the question of their possible role in chronic rhinosinusitis. The presented study focused on detection of microsized anorganic particles and clusters of nanosized anorganic particles in the nasal mucosa of patients with chronic rhinosinusitis by Raman microspectroscopy and comparison of their composition to histologic findings. The results were compared to the findings in mucosa obtained from cadavers with no history of chronic rhinosinusitis. Solid particles were found in 90% of tissue samples in the group with chronic rhinosinusitis, showing histologic signs of inflammation in 95%, while in the control group, the particles were found in 20% of samples, with normal histologic findings in all of them. The main detected compounds were graphite, TiO2, amorphous carbon, calcite, ankerite and iron compounds. The results are in accordance with the premise that exogenous airborne particles interact with the nasal mucosa and possibly deposit in it in cases where the epithelial barrier is compromised in chronic rhinosinusitis.


Assuntos
Rinite , Sinusite , Doença Crônica , Humanos , Mucosa Nasal/patologia
5.
J Immunol Res ; 2022: 7783481, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35755169

RESUMO

To identify the effect of long noncoding RNA (lncRNA) FR215775 in regulating CD4+ T cells on murine models of allergic rhinitis (AR), the expression of lncRNA FR215775 in primary Th2 cells was detected through qRT-PCR. After knocking down the expression of lncRNA FR215775 via Sh-FR215775-Ads, Cell Counting Kit-8, cytometric bead array, and fluorescence-activated cell sorting were performed to determine its functions in vitro. Moreover, lncRNA FR215775-silencing or nonsilencing cells were injected intravenously into AR mice. Then, hematoxylin and eosin, Alcian blue-periodic acid Schiff, and toluidine blue staining were performed, and the levels of IL-2, IL-4, IL-5, IL-6, IL-10, IL-17A, IFN-γ, and TNF in the AR mice were also determined. We found that the expression of lncRNA FR215775 was specifically higher in the murine primary Th2 cells. After the knockdown of lncRNA FR215775, the proliferation of CD4+ T cells was inhibited, and the expressions of IL-4 and IL-5 in the cell culture supernatant were significantly decreased (P < 0.001), along with the percentage of Th2 cells (P < 0.05). The lncRNA FR215775-silencing AR group showed less serious allergic symptoms and a low level of ovalbumin-specific immunoglobulin E (P < 0.01). Meanwhile, the eosinophilia inflammation, goblet cell hyperplasia, and mast cell inflammation in the nasal mucosa all decreased, which indicated attenuated allergic inflammation in the lncRNA FR215775-silencing AR group. In addition, the Th2-related cytokines IL-4 and IL-5 were downregulated in the serum and nasal lavage fluid of this group (P < 0.01). In conclusion, lncRNA FR215775 may play a vital role in the function and differentiation of Th2 cells, which may encourage allergic inflammation. These results may provide significant insights into AR pathogenesis and offer new treatment targets for alleviating AR.


Assuntos
RNA Longo não Codificante , Rinite Alérgica , Células Th2 , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/patologia , Interleucina-4/genética , Interleucina-4/farmacologia , Interleucina-5/genética , Interleucina-5/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Mucosa Nasal/patologia , Ovalbumina , RNA Longo não Codificante/genética , RNA Longo não Codificante/imunologia , Rinite Alérgica/genética , Rinite Alérgica/imunologia , Células Th2/imunologia , Células Th2/patologia
6.
STAR Protoc ; 3(2): 101419, 2022 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-35664255

RESUMO

Here, we present a standardized protocol for isolation, maintenance, and polarization of the respiratory epithelial primary cells from patient samples acquired from nasal brushing, polyp specimens, or lung explants. This protocol generates a clearly defined polarized layer of epithelial cells on filters, with a good number of ciliated cells and a thin layer of mucus. We detail the steps for samples prepared from patients with cystic fibrosis as well as from subjects without cystic fibrosis.


Assuntos
Fibrose Cística , Pólipos , Fibrose Cística/patologia , Células Epiteliais/patologia , Humanos , Pulmão , Muco , Mucosa Nasal/patologia , Pólipos/patologia
7.
Cells ; 11(7)2022 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-35406717

RESUMO

Despite over half a century of research, respiratory syncytial virus (RSV)-induced bronchiolitis remains a major cause of hospitalisation in infancy, while vaccines and specific therapies still await development. Our understanding of mucosal immune responses to RSV continues to evolve, but recent studies again highlight the role of Type-2 immune responses in RSV disease and hint at the possibility that it dampens Type-1 antiviral immunity. Other immunoregulatory pathways implicated in RSV disease highlight the importance of focussing on localised mucosal responses in the respiratory mucosa, as befits a virus that is essentially confined to the ciliated respiratory epithelium. In this review, we discuss studies of mucosal immune cell infiltration and production of inflammatory mediators in RSV bronchiolitis and relate these studies to observations from peripheral blood. We also discuss the advantages and limitations of studying the nasal mucosa in a disease that is most severe in the lower airway. A fresh focus on studies of RSV pathogenesis in the airway mucosa is set to revolutionise our understanding of this common and important infection.


Assuntos
Bronquiolite , Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Humanos , Imunidade nas Mucosas , Mucosa Nasal/patologia
8.
Rhinology ; 60(2): 118-127, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35379996

RESUMO

BACKGROUND: Changes in the nasal function following total laryngectomy resulted in histopathological alterations of the nasal mucosa. We aimed to evaluate the long-term histopathological changes and the mucociliary clearance (MCC) of the nasal mucosa after total laryngectomy. METHODS: We performed a histological examination of inferior turbinate biopsy, and saccharine test to assess the MCC time for patients who were candidates for total laryngectomy before the procedure, 6-12 months after surgery, and at least two years postoperatively. RESULTS: Seventy-five patients scheduled for total laryngectomy were initially enrolled in our study. We excluded patients who received postoperative radiotherapy or were lost during the follow-up period. Eventually, 63 and 54 patients were available for assessment 6-12 months after surgery and at least two years postoperatively, respectively. Except for ciliary and goblet cell destruction, which were significantly reduced 6-12 months postoperatively, there were no statistically significant differences in the histopathological findings of the nasal mucosa before surgery and 6-12 months postoperatively. After two years, the histopathological alterations of the nasal mucosa were statistically more evident than those before surgery and 6-12 months postoperatively; the most common histopathological findings were mononuclear cell infiltration and stromal fibrosis. The mean MCC time preoperatively was 12.56 minutes that statistically significantly decreased to 11.81 minutes 6-12 months after surgery; then, it significantly increased to 20.98 minutes at least two years postoperatively. CONCLUSIONS: After total laryngectomy, the nasal mucosa showed histopathological alterations and early enhancement of the MCC, which was later impaired due to nasal mucosal atrophy and the saprophytic infection.


Assuntos
Laringectomia , Mucosa Nasal , Humanos , Depuração Mucociliar , Mucosa Nasal/patologia , Estudos Prospectivos , Conchas Nasais
9.
Immunobiology ; 227(3): 152215, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35468553

RESUMO

BACKGROUND: Corticosteroid resistance (CR) is a serious disadvantage in treating many chronic inflammatory conditions. Eosinophils are the main inflammation cells in allergic reactions. Environmental pollution, such as PM2.5, is associated with the pathogenesis of allergic disorders. The objective of this study is to elucidate the mechanism by which the exposure to PM2.5 confers eosinophil CR status. METHODS: Patients with allergic rhinitis were recruited and assigned to corticosteroid sensitive (CS) and CR groups. Eosinophils were purified from nasal lavage fluids collected from patients with allergic rhinitis. A murine AR mouse model was developed with dust mite allergens and PM2.5 as the sensitization reagents. RESULTS: CR status was detected in about 60% eosinophil collected in patients with AR. Upon exposure to eosinophil activators, CS eosinophils released a large quantity of mediators, which was suppressed by the presence of steroids in the culture. CR eosinophils demonstrated resistance to steroidal therapy. RAS activation levels in eosinophils were higher in CR eosinophils than in CS eosinophils. Higher expression of the Son of sevenless-1 (Sos1) was detected in CR eosinophils, which formed a complex with RAS and glucocorticoidreceptor-α in CR eosinophils to prevent the binding between steroids and glucocorticoidreceptor-α. The presence of an Sos1 inhibitor dissociated glucocorticoid receptor-α from RAS/Sos1 complex, that restored the sensitivity to steroids in eosinophils. Administering the Sos1 inhibitor effectively attenuated the experimental allergic rhinitis. CONCLUSIONS: CR status was detected in approximately 1/3 eosinophils sampled from patients with allergic rhinitis. Sos1 was instrumental in the development and perseverance of CR in eosinophils. Sos1 inhibition restored sensitivity to steroids in CR eosinophils, which effectively reduced experimental allergic rhinitis.


Assuntos
Eosinófilos , Rinite Alérgica , Corticosteroides/farmacologia , Corticosteroides/uso terapêutico , Animais , Eosinófilos/metabolismo , Humanos , Licenciamento , Camundongos , Mucosa Nasal/patologia , Núcleo Familiar , Material Particulado , Rinite Alérgica/tratamento farmacológico
10.
J Clin Lab Anal ; 36(4): e24316, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35285093

RESUMO

BACKGROUND: Studies have shown the promising prospects of rosmarinic acid (RosA) for the prevention and treatment of allergic diseases. OBJECTIVE: The aim of this study was to investigate the effects of RosA on inflammatory reaction in rat models of allergic rhinitis (AR) after PM2.5 exposure. METHODS: Allergic rhinitis rat models were established by ovalbumin sensitization, and PM2.5 was applied at a concentration of 1000 µg/m3 , 3 h a day for 30 consecutive days. RosA was administered via intraperitoneal injection (20 mg/kg/d) for seven consecutive days. Allergic nasal symptoms were recorded. The expressions of interleukin (IL)-4, IL-13, interferon (INF)-γ, and OVA-sIgE were determined by ELISA. Histopathological changes in nasal mucosa were observed by HE staining. mRNA expressions of T-bet and GATA-3 in nasal mucosa were detected by RT-PCR. NF-κBp65 in cell nuclei and IκBα in cytoplasm were analyzed by Western blot. RESULTS: PM2.5 exposure worsened allergic nasal symptoms in AR rats, while RosA ameliorated these symptoms. Histopathologically, AR rats exhibited disorganized nasal mucosal epithelium, cell exfoliation, eosinophilic infiltration of lamina propria, gland swelling, and submucosal vascular congestion, which were aggravated by PM2.5 exposure and alleviated by RosA. RosA decreased the expressions of IL-4, IL-13, and increased the level of IFN-γ in PM2.5-exposed AR rats. After RosA intervention, the expressions of GATA-3 mRNA and NF-κBp65 in PM2.5-exposed AR rats were significantly reduced, while those of T-bet mRNA and IκBα were markedly increased. CONCLUSION: Rosmarinic acid may alleviate symptoms of AR rat models exposed to PM2.5 through the modulation of the NF-κB pathway and Th1/Th2 balance.


Assuntos
Interleucina-13 , Rinite Alérgica , Animais , Cinamatos , Citocinas/genética , Citocinas/metabolismo , Depsídeos , Humanos , Interferon gama/metabolismo , Interleucina-13/genética , Interleucina-13/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Material Particulado/metabolismo , Material Particulado/toxicidade , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Rinite Alérgica/induzido quimicamente , Rinite Alérgica/tratamento farmacológico
11.
Am J Dermatopathol ; 44(6): 424-432, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35315370

RESUMO

ABSTRACT: Primary sinonasal mucosal melanoma (SNMM) is an aggressive tumor with high metastatic potential and poor outcomes. Presenting symptoms are nonspecific, and the nasal cavity is the most common site of origin followed by the maxillary and ethmoid sinuses. Histopathologically, SNMMs are pleomorphic and predominantly composed of epithelioid cell type. Identifying these tumors requires a high index of suspicion for melanoma and the use of a panel of immunohistochemical markers when typical histopathological features are missing. Not infrequently, these tumors are undifferentiated and/or amelanotic. Currently, SNMM falls into 2 different staging systems proposed by the American Joint Committee on Cancer, one for carcinoma of the nasal cavity and sinuses and the other for head and neck melanoma. Although therapeutic standards do not exist, surgical resection with adjuvant radiotherapy and/or systemic therapy may offer the best outcome. Lymphadenectomy including possible parotidectomy and neck dissection should be considered in patients with regional lymph node metastasis. However, the role of elective lymph node dissection is controversial. Genetic profiling has identified a number of recurrent gene mutations that may prove useful in providing targets for novel, emerging biological treatments. In this article, we provide an update on clinicopathological features, staging, molecular discoveries, and treatment options for SNMM.


Assuntos
Melanoma , Neoplasias dos Seios Paranasais , Humanos , Melanoma/diagnóstico , Melanoma/genética , Melanoma/terapia , Mucosa Nasal/patologia , Mucosa Nasal/cirurgia , Neoplasias dos Seios Paranasais/patologia , Neoplasias dos Seios Paranasais/terapia , Radioterapia Adjuvante
12.
J Immunoassay Immunochem ; 43(4): 403-419, 2022 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-35147059

RESUMO

Sinonasal polyps are benign projections of edematous nasal mucosa lined by respiratory epithelium. Langerhans cells (LCs) belonging to the dendritic cell family located in respiratory epithelium are involved in antigen presentation and maintenance of local immunological homeostasis. This study aims to elucidate the morphology and distribution of CD1a positive LCs in normal nasal mucosa and compare the same with polypoid nasal mucosa by immunohistochemistry. Normal nasal mucosa (n = 20) was obtained from patients who underwent septoplasty for deviated nasal septum. Polypoid nasal mucosa (n = 22) was obtained from patients with chronic rhinosinusitis (CRS) or allergic fungal rhinosinusitis who underwent excision of nasal polyps. The tissues obtained were processed for immunohistochemistry and stained with CD1a-EP80 Rabbit monoclonal antibody. In the tissues studied, CD1a positive LCs were observed in both the epithelium and lamina propria. Different morphological subtypes of LCs were noted in the epithelium. The cells were distributed adjacent to walls of subepithelial capillaries and cysts. The median number of CD1a positive LCs was significantly higher in polypoid category (13.5 per mm2) as compared with normal nasal mucosa (2.5per mm2) (p = .001). Presence of CD1a positive LCs in polypoid nasal mucosa hints at a critical immunological role in the etiopathogenesis of nasal polyps.


Assuntos
Pólipos Nasais , Sinusite , Doença Crônica , Células Dendríticas , Humanos , Imuno-Histoquímica , Mucosa Nasal/patologia , Pólipos Nasais/patologia , Pólipos Nasais/cirurgia , Sinusite/patologia
14.
Nature ; 603(7902): 706-714, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35104837

RESUMO

The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and has multiple mutations in its spike protein2. Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron's evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralization. Importantly, the antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared with Delta. The differences in replication were mapped to the entry efficiency of the virus on the basis of spike-pseudotyped virus assays. The defect in entry of Omicron pseudotyped virus to specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and deletion of TMPRSS2 affected Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently uses the cellular protease TMPRSS2, which promotes cell entry through plasma membrane fusion, with greater dependency on cell entry through the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to use TMPRSS2, syncytium formation by the Omicron spike was substantially impaired compared with the Delta spike. The less efficient spike cleavage of Omicron at S1/S2 is associated with a shift in cellular tropism away from TMPRSS2-expressing cells, with implications for altered pathogenesis.


Assuntos
COVID-19/patologia , COVID-19/virologia , Fusão de Membrana , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Serina Endopeptidases/metabolismo , Internalização do Vírus , Adulto , Idoso , Idoso de 80 Anos ou mais , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , Vacinas contra COVID-19/imunologia , Linhagem Celular , Membrana Celular/metabolismo , Membrana Celular/virologia , Chlorocebus aethiops , Convalescença , Feminino , Humanos , Soros Imunes/imunologia , Intestinos/patologia , Intestinos/virologia , Pulmão/patologia , Pulmão/virologia , Masculino , Pessoa de Meia-Idade , Mutação , Mucosa Nasal/patologia , Mucosa Nasal/virologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Técnicas de Cultura de Tecidos , Virulência , Replicação Viral
15.
Eur Rev Med Pharmacol Sci ; 26(1): 198-203, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35048995

RESUMO

OBJECTIVE: We have previously shown that the intranasal administration of dantrolene ameliorated cognitive dysfunction in the 5XFAD mouse model of Alzheimer's disease. This study examines the morphology of the nasal mucosa after 10 months of intranasal dantrolene in 5XFAD mice. MATERIALS AND METHODS: 5XFAD mice were either treated with intranasal dantrolene (5 mg/kg, 3 times/wk) from 2 months to 12 months of age or given no treatment at all. The mice were euthanatized at 12 months of age and the snouts were processed for histological examination. The morphology of the nasal mucosa was assessed and compared between the two groups. RESULTS: There were no significant differences in the thickness of the olfactory epithelium or the proportion of the thickness of the glandular layer to the wall of mucosa and submucosa in the nasal passages. CONCLUSIONS: Long-term intranasal administration of dantrolene did not significantly change the nasal mucosa morphology in 5XFAD mice.


Assuntos
Doença de Alzheimer , Dantroleno , Administração Intranasal , Doença de Alzheimer/patologia , Animais , Dantroleno/farmacologia , Dantroleno/uso terapêutico , Camundongos , Mucosa Nasal/patologia , Mucosa Olfatória/patologia
16.
Am J Hum Genet ; 109(2): 253-269, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-35065708

RESUMO

Mucus obstruction is a central feature in the cystic fibrosis (CF) airways. A genome-wide association study (GWAS) of lung disease by the CF Gene Modifier Consortium (CFGMC) identified a significant locus containing two mucin genes, MUC20 and MUC4. Expression quantitative trait locus (eQTL) analysis using human nasal epithelia (HNE) from 94 CF-affected Canadians in the CFGMC demonstrated MUC4 eQTLs that mirrored the lung association pattern in the region, suggesting that MUC4 expression may mediate CF lung disease. Complications arose, however, with colocalization testing using existing methods: the locus is complex and the associated SNPs span a 0.2 Mb region with high linkage disequilibrium (LD) and evidence of allelic heterogeneity. We previously developed the Simple Sum (SS), a powerful colocalization test in regions with allelic heterogeneity, but SS assumed eQTLs to be present to achieve type I error control. Here we propose a two-stage SS (SS2) colocalization test that avoids a priori eQTL assumptions, accounts for multiple hypothesis testing and the composite null hypothesis, and enables meta-analysis. We compare SS2 to published approaches through simulation and demonstrate type I error control for all settings with the greatest power in the presence of high LD and allelic heterogeneity. Applying SS2 to the MUC20/MUC4 CF lung disease locus with eQTLs from CF HNE revealed significant colocalization with MUC4 (p = 1.31 × 10-5) rather than with MUC20. The SS2 is a powerful method to inform the responsible gene(s) at a locus and guide future functional studies. SS2 has been implemented in the application LocusFocus.


Assuntos
Sistemas de Transporte de Aminoácidos/genética , Fibrose Cística/genética , Modelos Estatísticos , Mucina-4/genética , Mucinas/genética , Locos de Características Quantitativas , Alelos , Sistemas de Transporte de Aminoácidos/metabolismo , Fibrose Cística/metabolismo , Fibrose Cística/patologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Heterogeneidade Genética , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Pulmão/metabolismo , Pulmão/patologia , Mucina-4/metabolismo , Mucinas/metabolismo , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Polimorfismo de Nucleotídeo Único
17.
Int Immunopharmacol ; 104: 108509, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34998035

RESUMO

The present study aims to investigate the effects of CCR3 gene knockout in bone marrow cells (CCR3-KO) on the mouse model of combined allergic rhinitis and asthma syndrome (CARAS). It was found that CCR3-KO significantly reduced eosinophil (EOS) migration into the nasal (NALF) and bronchoalveolar (BALF) cavities of mice, and decreased Th2 cytokines (such as, IL-4, IL-5 and IL-13) levels in nasal mucosa and lung tissues. In addition, histological analysis showed that the damage degree of nasal mucosa structure in ovalbumin (OVA) modulated CCR3-KO mice was significantly less than that in OVA modulated Wild type (WT) mice, with reduced inflammatory cell infiltration and nasal mucus secretion. The infiltration of inflammatory cells in lung tissue was significantly reduced, and the proliferation of lung smooth muscle layer and extracellular matrix (ECM) production were decreased. Symptom analysis showed that CCR3-KO can reduced allergic rhinitis (AR) signals as nose scratching and sneezing. It was also found CCR3-KO reduce OVA-induced weight loss. The results showed that CCR3-KO could reduce the symptoms of allergic inflammation in CARAS mice by reducing airway inflammatory cell infiltration and down-regulating the expression of Th2 cytokines, and CCR3 gene could be used as a target gene for the treatment of CARAS.


Assuntos
Asma/genética , Receptores CCR3/genética , Rinite Alérgica/genética , Alérgenos/imunologia , Animais , Asma/metabolismo , Asma/patologia , Células da Medula Óssea , Líquido da Lavagem Broncoalveolar/citologia , Citocinas/genética , Eosinófilos/imunologia , Imunoglobulina E/sangue , Pulmão/metabolismo , Pulmão/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Líquido da Lavagem Nasal/citologia , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Ovalbumina/imunologia , Receptores CCR3/metabolismo , Rinite Alérgica/metabolismo , Rinite Alérgica/patologia , Síndrome , Células Th2
19.
Int Arch Allergy Immunol ; 183(2): 235-245, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34537772

RESUMO

BACKGROUND: Allergic rhinitis (AR) is regarded as one of the most common allergic disease of nasal mucosa affecting many people worldwide. Long noncoding RNAs are critical modulators affecting AR progression, whereas the pathogenesis of Linc00632 in the development of AR remains unclear. METHODS: T helper cell 2 (Th2) differentiation of CD4+ T cells was measured by flow cytometry. Real-time quantitative PCR assay and Western blot were applied to determine the levels of RNA and proteins, respectively. The interleukin (IL)-4 and IL-13 levels were quantitatively assessed through ELISA. Subcellular fractionation was conducted to detect the cellular localization of Linc00632. RNA immunoprecipitation experiment was employed to validate the interaction relationship between Linc00632 and enhancer of zeste homolog 2 (EZH2). Chromatin immunoprecipitation assay was used for determination of protein-DNA interactions. RESULTS: The expression of Linc00632 was significantly decreased by 4 times in nasal mucosa of AR patients. Human umbilical cord mesenchymal stem cell-derived exosome dramatically inhibited Th2 differentiation, decreased GATA binding protein-3 (GATA-3) protein expressions and IL-4 levels by about 2 times in CD4+ T cells. Knockdown Linc00632 partially reversed the effects of exosomes on Th2 differentiation, IL-4 and IL-13 levels, and GATA-3 expression. Linc00632 overexpression could suppress Th2 differentiation of CD4+ T cells, reduced IL-4 and IL-13 levels, and GATA-3 expressions roughly 2 times. Linc00632 repressed the expression of GATA-3 by interacting with EZH2. GATA-3 overexpression partially reversed the effect of Linc00632 on Th2 differentiation of CD4+ T cells. CONCLUSION: Linc00632 acted as a suppression factor in Th2 differentiation by inhibiting the expression of GATA-3 via interacting with EZH2, which might provide a new insight for understanding the action mechanism of Linc00632 in AR.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/genética , Exossomos/metabolismo , Fator de Transcrição GATA3/genética , Regulação da Expressão Gênica , Células-Tronco Mesenquimais/metabolismo , RNA Longo não Codificante/genética , Células Th2/metabolismo , Biomarcadores , Diferenciação Celular/genética , Citocinas/metabolismo , Suscetibilidade a Doenças , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Fator de Transcrição GATA3/metabolismo , Humanos , Mucosa Nasal/imunologia , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Ligação Proteica , Interferência de RNA , RNA Longo não Codificante/metabolismo , Rinite Alérgica/diagnóstico , Rinite Alérgica/etiologia , Rinite Alérgica/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th2/imunologia
20.
Pigment Cell Melanoma Res ; 35(1): 88-96, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34547192

RESUMO

Mucosal malignant melanoma (MMM) is a rare and aggressive tumor. Despite effective local therapies, tumor recurrence and metastasis remain frequent. The genetics of MMM remain incompletely understood. This study is aimed to identify actionable genetic alterations by next-generation sequencing. Fifteen MMM samples were analyzed by next-generation and Sanger sequencing. Gene copy number alterations were analyzed by MLPA. Mutation status was correlated with pERK, pAKT, and Ki-67 expression and follow-up data. Inactivating mutations and intragenic deletions in neurofibromatosis type-1 (NF1) were identified in 3 and 2 cases, respectively, (in total 5/15, 33%) and activating mutations in NRAS and KRAS (3/15, 20%) cases. Other mutated genes included CDKN2A, APC, ATM, MITF, FGFR1, and FGFR2. BRAF and KIT mutations were not observed. Cases with NF1 alterations tended to have worse overall survival. The mutational status was not associated with pERK, pAKT, or Ki-67 immunostaining. MMM carries frequent gene mutations activating the MAPK pathway, similar to cutaneous melanoma. In contrast, NF1 is the most frequently affected gene. Intragenic NF1 deletions have not been described before and may go undetected by sequencing studies. This finding is clinically relevant as NF1-mutated melanomas have worse survival and could benefit from therapy with immune checkpoint and MEK inhibitors.


Assuntos
Biomarcadores Tumorais/genética , Deleção de Genes , Melanoma/genética , Neurofibromina 1/genética , Neoplasias dos Seios Paranasais/genética , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Melanoma/mortalidade , Melanoma/secundário , Melanoma/terapia , Mucosa Nasal/patologia , Neoplasias dos Seios Paranasais/mortalidade , Neoplasias dos Seios Paranasais/patologia , Neoplasias dos Seios Paranasais/terapia , Fenótipo , Prognóstico
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