Interleukin-19 enhances eosinophil infiltration through upregulation of epithelium-derived RANTES expression via the ERK/NF-κB signalling pathway in patients with eosinophilic CRSwNP.

BACKGROUD: The recurrence rate of chronic rhinosinusitis with nasal polyps (CRSwNP) is positively correlated with eosinophil infiltration. Increased interleukin (IL)-19 and eosinophil chemokine RANTES levels have been reported in patients with CRSwNP. This study aimed to clarify the role of IL-19 in mediating RANTES expression and eosinophilic infiltration in eosinophilic CRSwNP (Eos CRSwNP). METHODS: Nasal tissue samples were obtained from patients with CRSwNP and controls. The expression of IL-19, its receptors, ECP, and RANTES in tissues was investigated. Primary human nasal epithelial cells (HNECs) and nasal polyp tissue blocks were cultured, then stimulated by IL-19; ERK phosphorylation, NF-κB pathway activation, RANTES level, eosinophils migration and infiltration were detected using RT-qPCR, ELISA, western blotting, HE, immunohistochemistry, immunofluorescence staining, confocal microscopy, and transwell migration assay. RESULTS: The expression of IL-19 and its receptors (IL-20R1/IL-20R2), eosinophil cationic protein, and RANTES in nasal tissues from patients with Eos CRSwNP was significantly increased compared to that in non-Eos CRSwNP and control subjects. IL-19 co-localized with RANTES in nasal tissues and significantly elevated RANTES expression in HNECs. IL-19-blocking antibody and siRNA knockdown of IL-20R1 ameliorated the effect of IL-19 on RANTES secretion in HNECs. Moreover, IL-19-induced RANTES upregulation was associated with the activation of the ERK and NF-κB pathways. NF-κB activation was mediated by the ERK pathway in IL-19-treated HNECs, and IL-19 enhanced eosinophil infiltration in nasal polyp tissue blocks. CONCLUSIONS: Our findings indicate that IL-19 promotes RANTES expression via the ERK/NF-κB pathway in HNECs and is implicated in eosinophil infiltration in patients with Eos CRSwNP.

IL-21 induces pyroptosis of Treg cells via Akt-mTOR-NLRP3-caspase 1 axis in eosinophilic chronic rhinosinusitis.

BACKGROUND: Regulatory T (Treg) cells, which prevent inflammation-induced eosinophil infiltration, are deficient in nasal polyps (NPs) in patients with eosinophilic chronic rhinosinusitis (ECRS). It is concomitant with loss of Foxp3 after certain inflammatory stimuli. OBJECTIVE: We sought to determine the inflammatory cytokines involved in inducing the loss of Treg cells in NPs. METHODS: The abundance of cytokines in ECRS patients or mice were tested using ELISA, immunochemistry, immunofluorescence, quantitative reverse transcription PCR (qPCR), and/or flow cytometry. Expression of eosinophil cationic protein (ECP), CD4+ T cells, IL-4, and IL-17A and eosinophils in nasal mucosa of mouse model was investigated by immunochemistry, immunofluorescence, and hematoxylin and eosin staining. The percentage and death of induced Treg (iTreg) cells, source of IL-21 in NPs from ECRS and non-ECRS patients, and abundance of different systemic phenotypes of CD4+ T cells in a mouse model were studied by flow cytometry. Western blot analysis, scanning, and transmission electronic microscopy were used to detect pyroptosis of iTreg cells. RESULTS: IL-21 was highly expressed in nasal mucosa of ECRS patients and mice, causing pyroptosis and preventing development of iTreg cells in vitro. The elevated IL-21 in NPs from ECRS patients was mainly produced by CD3+ T cells, including T follicular helper, T peripheral helper, TH2, and TH17 cells and CD3+CD4- T cells. T peripheral helper cells and CD3+CD4- T cells were the predominant source of IL-21 in NPs from non-ECRS patients. Blocking IL-21/IL-21R signaling significantly reduced the number of eosinophils and CD4+ T cells along with ECP, IL-4, and IL-17A expression in the nasal mucosa of ECRS mice. It also increased Treg cell percentage and systemically decreased TH2 and TH17 ratios. Akt-mTOR inhibition prevented IL-21-induced pyroptosis in human and mouse iTreg cells. CONCLUSION: Elevated IL-21 drives pyroptosis and prevents Treg cell development in ECRS patients. IL-21 induced pyroptosis via activating Akt-mTOR-NLRP3-caspase 1 signaling.

Interleukin-19 upregulates fibronectin and collagen I expression via the NF-κB-Smad2/3 pathway in fibroblasts of patients with chronic rhinosinusitis.

BACKGROUND: Tissue remodeling is a prominent characteristic of chronic rhinosinusitis (CRS). Excess deposition of fibronectin (FN) and collagen (Col) I by fibroblasts is crucial for the pathologic tissue remodeling in CRS without nasal polyps (CRSsNP). Increased interleukin (IL)-19 level in patients with CRS had been demonstrated in our previous studies. Here, we aimed to evaluate the role of IL-19 in mediating FN and Col I expression in CRS. METHODS: Nasal mucosal tissue samples were collected from patients with CRS with nasal polyps (CRSwNP), CRSsNP, and controls. The expression of IL-19, vimentin, FN, and Col I were detected using immunohistochemistry and immunofluorescence. Primary human nasal fibroblasts were treated with IL-19, then the activation of Smad2/3, NF-κB and relevant pathways, and the expression of FN and Col I were measured. RESULTS: Expression levels of vimentin, FN, and Col I were significantly increased in nasal tissues from patients with CRSsNP compared with CRSwNP and control subjects. Moreover, IL-19 co-localized with FN and Col Ι in nasal tissues. IL-19-treated fibroblasts had increased production of FN and Col I, which was associated with the activated Smad2/3 and NF-κB pathways. Moreover, Smad2/3 activation was mediated by the NF-κB pathway in IL-19-treated fibroblasts. CONCLUSIONS: IL-19 promotes FN and Col I production via the activated NF-κB-Smad2/3 pathway in fibroblasts, leading to fibrosis and collagen deposition in patients with CRS.

IL-17A mediates pyroptosis via the ERK pathway and contributes to steroid resistance in CRSwNP.

BACKGROUND: Pyroptosis is closely related to inflammation. However, the molecular mechanisms and pathologic contributions of pyroptotic epithelial cell are not yet fully understood. OBJECTIVE: This study aimed to explore the function and molecular mechanisms of IL-17A on human nasal epithelial cell (hNEC) pyroptosis. METHODS: The expression of pyroptosis-related biomarkers and IL-17A was assessed in sinonasal mucosa from control individuals, patients with chronic rhinosinusitis without nasal polyps, and patients with chronic rhinosinusitis with nasal polyps (CRSwNP) by using quantitative RT-PCR. Their localization was analyzed via immunohistochemistry and immunofluorescence. The ultrastructural characteristics of IL-17A-induced pyroptosis in hNECs were visualized by using electron microscopy. IL-17A functional assays were performed on hNECs and airway epithelial cell lines. Cytokine levels were quantified via ELISA. The signaling pathways involved in IL-17A-induced pyroptosis were studied via unbiased RNA sequencing and Western blotting. RESULTS: The expression of IL-17A and the pyroptotic biomarkers NOD-like receptor family, pyrin domain containing 3 (NLRP3), caspase-1, gasdermin D, and IL-1ß was increased in nasal mucosa from patients with CRSwNP compared with in those with chronic rhinosinusitis without nasal polyps and the control subjects. IL-17A was positively correlated and colocalized with the pyroptotic biomarkers. IL-17A treatment induced pyroptosis in the hNECs and cell lines analyzed, primarily through the extracellular signal-regulated kinase (ERK)-NLRP3/caspase-1 signaling pathway, and increased IL-1ß and IL-18 secretion in hNECs. Moreover, IL-17A-induced pyroptosis contributed to steroid resistance by affecting glucocorticoid receptor-α and glucocorticoid receptor-ß expression, and the inhibition of pyroptotic proteins partially abolished IL-17A-induced steroid resistance in hNECs. CONCLUSION: Elevated IL-17A level promotes pyroptosis in hNECs through the ERK-NLRP3/caspase-1 signaling pathway and contributes to glucocorticoid resistance by affecting glucocorticoid receptor homeostasis in patients with CRSwNP.

Effects of Smoking on ACE2 Expression Pattern: Risk and Severity of SARS-CoV-2 Infection.

BACKGROUND: Respiratory epithelium expressing angiotensin-converting enzyme 2 (ACE2) is the entry for novel coronavirus (SARS-CoV-2), pathogen of the COVID-19 pneumonia outbreak, although a few recent studies have found different ACE2 expression in lung tissue of smokers. The effect of smoking on ACE2 expression and COVID-19 is still not clear. So, we did this research to determine the effect of smoking on ACE2 expression pattern and its relationship with the risk and severity of COVID-19. METHODS: The clinical data of COVID-19 patients with smoking and non-smoking were analyzed, and ACE2 expression of respiratory and digestive mucosa epithelia from smoker and non-smoker patients or healthy subjects were detected by immunohistochemical (IHC) staining. RESULTS: Of all 295 laboratory-confirmed COVID-19 patients, only 24 (8.1%) were current smokers with moderate smoking or above, which accounted for 54.2% of severe cases with higher mortality than non-smokers (8.3% vs. 0.4%, p = 0.018). Data analysis showed the proportion of smokers in COVID-19 patients was lower than that in general population of China (Z = 11.65, P < 0.001). IHC staining showed ACE2 expression in respiratory and digestive epithelia of smokers were generally downregulated. CONCLUSIONS: The proportion of smokers in COVID-19 patients was lower, which may be explained by ACE2 downregulation in respiratory mucosa epithelia. However, smoking COVID-19 patients accounted for a higher proportion in severe cases and higher mortality than for non-smoking COVID-19 patients, which needs to be noted.

Type 2 inflammation suppression by T-regulatory cells attenuates the eosinophil recruitment in mucosa of chronic sinusitis.

Type 2 inflammation and eosinophilic infiltration are prominent pathologic features of chronic rhinosinusitis with nasal polyps (CRSwNP). The purpose of the present study was to determine the roles of Tregs in controlling type 2 inflammation and inhibiting eosinophilic infiltration in CRSwNP. A total of 134 nasal polyps, 67 ostiomeatal complex from chronic rhinosinusitis (CRS) and 62 normal nasal tissues from controls were collected to study the enumeration and function of Tregs cells and the expressions of cytokine profiles via immunofluorescence staining, flow cytometry, qRT-PCR, ELISA, and/or H&E staining. The effects of Tregs on type2 and type3 inflammations were determined in an eosinophilic chronic sinusitis (ECRS) mice model. It was confirmed that the CRSwNP displayed the features of Th2 and Th17 cells-mediated inflammation, accompanying by an increased level of eosinophilic infiltration and the eosinophil cationic protein (ECP), with a decreased frequency of Treg cells. Furthermore, the percentages of CD4+CD25+CD127lowTreg and CD4+CD25+Foxp3+Treg were only decreased in the polyps of CRSwNP but not in the paired peripheral blood. The CRSwNP possessed the decreased Nrp1+Tregs, Helios+Treg, and low TGF-ß and interleukin (IL)-10 expressions in Tregs. The ECRS mice showed similar inflammatory characteristics to CRSwNP patients. The adoptive transfer of CD4+CD25+Foxp3+ Treg cells significantly decreased the inflammatory cytokines, eosinophilic chemotactic factors in the mucosa of the ECRS mice without alteration of the immune balance in the peripheral blood and spleen. In conclusion, CRSwNP showed high type 2 and type3 inflammation and defective Tregs. The induced regulatory T cell (iTreg) may correct the imbalance between immune tolerance and effect via limiting the eosinophil recruitment of mucosa in CRSwNP.

Interleukin-17A Expression Correlated with the Prognosis of Chronic Rhinosinusitis with Nasal Polyps and the Anti-Interleukin-17A Effect in a Murine Nasal Polyps Model.

OBJECTIVE: To investigate the expression of interleukin-17A (IL-17A) in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and to analyze its effect on prognosis and to explore the role and mechanism of anti-IL-17A effect in vivo by establishing a murine nasal polyps (NP) model. METHODS: Patients with CRSwNP who underwent endoscopic sinus surgery and matched control subjects were collected. We investigated IL-17A expression in human NP tissues using immunohistochemistry and analyzed their clinical features, including Lund-Mackay computed tomography scoring (LMCS) before surgery, Lund-Kennedy endoscopic scoring (LKES) before surgery (LKES B), LKES 6 months after surgery (LKES A), and reduction of LKES (LKES R). Then, after establishing the murine NP model to detect the expression and correlation of IL-17A and matrix metalloproteinase-9 (MMP-9) in nasal tissue, we studied nasal lavage fluid and serum by PCR and enzyme-linked immunosorbent assay in vivo. Anti-IL-17A treatment was administered in the murine NP model to confirm the function of IL-17A during the pathogenic processes. RESULTS: IL-17A expression was upregulated in NP tissues from patients with CRSwNP compared with control subjects (p < 0.001). The number of IL-17A+ cells was significantly negatively correlated with LKES R in patients with CRSwNP (p < 0.01). However, there was no significant correlation between IL-17A and LMCS or LKES B (all p < 0.05). Further, IL-17A and MMP-9 were more abundant in nasal mucosa of the murine NP model compared with that of control mice (all p < 0.05), and severe polypoid lesions were apparently observed in murine NP models. Anti-IL-17A treatment downregulated the mRNA and protein expression of MMP-9 in nasal mucosa and reduced the number of polypoid lesions in the murine NP model (all p < 0.05). CONCLUSION: Our results suggest that IL-17A plays a crucial role and may affect the prognosis of CRSwNP. Anti-IL-17A treatment may reduce the formation of polypoid lesions through inhibition of MMP-9 expression.

γδT cells contribute to type 2 inflammatory profiles in eosinophilic chronic rhinosinusitis with nasal polyps.

Eosinophilic chronic rhinosinusitis with nasal polyps (ECRS) is a condition linked with type 2 inflammation, poor treatment outcomes, and high recurrence tendency. Although γδT cells have been reported to induce type 2 immune responses and eosinophilic infiltration in several diseases, their role in ECRS has not been fully explored. We aimed to evaluate the association of γδT cells with the type 2 inflammatory profiles in ECRS. Nasal tissue samples obtained from patients with chronic rhinosinusitis with nasal polyps (CRSwNP) (51 eosinophilic and 48 non-eosinophilic), 50 patients with chronic rhinosinusitis without nasal polyps (CRSsNP), and 58 control subjects were examined for γδT cells, inflammatory markers and eosinophils using HE, RT-qPCR, ELISA, immunofluorescence, and flow cytometry. In parallel, studies were also conducted in an ECRS murine model induced by anti-γδT cells neutralizing antibody administration. γδT cells expression was significantly increased in tissues from patients with ECRS compared with non-ECRS, CRSsNP and control subjects. Moreover, inflammatory markers including type 2 proinflammatory cytokines (IL-4, IL-5, IL-13), GATA3, eosinophil cationic protein (ECP), and eotaxin levels were also increased in nasal tissues of patients with ECRS, and Vγ1+ γδT cells mRNA expression was positively correlated with type 2 cytokines, GATA3, and ECP. In the ECRS murine model, anti-Vγ1+ γδT antibody treatment reduced the infiltration of eosinophils and expression of type 2 cytokines, GATA3, and ECP in nasal mucosae. In conclusion, the results of the present study suggest that γδT cells play a crucial role in the type 2 inflammatory profiles and nasal tissue eosinophilic infiltration in patients with ECRS.

Budesonide nasal irrigation improved Lund-Kennedy endoscopic score of chronic rhinosinusitis patients after endoscopic sinus surgery.

PURPOSE: Budesonide improves the prognosis of chronic rhinosinusitis (CRS). However, few reports have examined whether its use for nasal irrigation, compared to normal saline, improves the prognosis of patients after endoscopic sinus surgery (ESS). We compared the effects of nasal irrigation with budesonide and normal saline in CRS patients after ESS. METHODS: Sixty CRS patients who had undergone ESS were randomly divided into an experimental group (30 patients), which used budesonide nasal irrigation, and a control group (30 patients), which used normal saline nasal irrigation. All patients received regular follow-up evaluations and were assessed via questionnaires, including the Lund-Kennedy endoscopic score (LKES), the symptom visual analog scale (VAS), the 22-item Sino-Nasal Outcome Test (SNOT-22), the Short-Form 36-Item Questionnaire (SF-36), the Self-Rating Anxiety Scale (SAS), the Self-Rating Depression Scale (SDS) and a side effects scale. RESULTS: Scores of polyposis, mucosal edema, secretions and total score of LKES; VAS scores of nasal blockage, hyposmia and rhinorrhea; and SNOT-22 results in both groups were significantly improved 3 months after ESS. Scores of polyposis, mucosal edema, secretions and scarring and total score of LKES in experimental group were significantly better than in control group 3 months after ESS. No significant differences were observed in SF-36, SAS or SDS before or 3 months after ESS within or between the two groups. The side effects of the two groups were not significantly different. CONCLUSIONS: Nasal irrigation improved the prognosis of CRS patients after ESS. Budesonide nasal irrigation had a better effect than normal saline nasal irrigation.

Image decomposition fusion method based on sparse representation and neural network.

For noisy images, in most existing sparse representation-based models, fusion and denoising proceed simultaneously using the coefficients of a universal dictionary. This paper proposes an image fusion method based on a cartoon + texture dictionary pair combined with a deep neural network combination (DNNC). In our model, denoising and fusion are carried out alternately. The proposed method is divided into three main steps: denoising + fusion + network denoising. More specifically, (1) denoise the source images using external/internal methods separately; (2) fuse these preliminary denoised results with external/internal cartoon and texture dictionary pair to obtain the external cartoon + texture sparse representation result (E-CTSR) and internal cartoon + texture sparse representation result (I-CTSR); and (3) combine E-CTSR and I-CTSR using DNNC (EI-CTSR) to obtain the final result. Experimental results demonstrate that EI-CTSR outperforms not only the stand-alone E-CTSR and I-CTSR methods but also state-of-the-art methods such as sparse representation (SR) and adaptive sparse representation (ASR) for isomorphic images, and E-CTSR outperforms SR and ASR for heterogeneous multi-mode images.

A Retrospective Analysis of γδ T Cell Expression in Chronic Rhinosinusitis and Its Association with Recurrence of Nasal Polyps.

BACKGROUND/AIMS: To examine whether γδ T cell is expressed in the nasal mucosa of chronic rhinosinusitis (CRS) patients and its potential association with recurrence of nasal polyps. METHODS: Thirty-six patients with CRS with nasal polyps (CRSwNP) and 25 patients with CRS without nasal polyps (CRSsNP) were recruited. Twenty-six patients with other nasal diseases served as controls. The CRSwNP group was divided into the eosinophilic CRSwNP and noneosinophilic CRSwNP groups. The expression of γδ T cells was detected by immunohistochemistry. The expression of each subtype of γδ T cells was detected by using qRT-PCR. All patients underwent nasal endoscopy, and postoperative follow-up lasted over 12 months. CRS patients were evaluated by preoperative VAS scores of symptoms and nasal endoscopy Lund-Kennedy scores. RESULTS: The expression of γδ T cells in the CRSwNP groups was stronger than in the CRSsNP and the control group (p < 0.05, p < 0.05). The expression of Vγ1+γδ T cells in the eosinophilic CRSwNP group was higher than that in the CRSsNP group and the control group (p < 0.05, p < 0.05). The expression of γδ T cells was associated with high rate of recurrence, tissue eosinophil infiltration, worse symptom score of nasal obstruction, and higher Lund-Kennedy score (all p < 0.05). CONCLUSIONS: Increased expression of γδ T cells in CRSwNP may be associated with recurrence of nasal polyps.

Targeting Rad50 sensitizes human nasopharyngeal carcinoma cells to radiotherapy.

BACKGROUND: The Mre11-Rad50-Nbs1 (MRN) complex is well known for its crucial role in initiating DNA double strand breaks (DSBs) repair pathways to resistant irradiation (IR) injury and thus facilitating radioresistance which severely reduces radiocurability of nasopharyngeal cancer (NPC). Targeting native cellular MRN function would sensitize NPC cells to IR. METHODS: A recombinant adenovirus containing a mutant Rad50 gene (Ad-RAD50) expressing Rad50 zinc hook domain but lacking the ATPase domain and the Mre11 interaction domain was constructed to disrupt native cellular MRN functions. The effects of Ad-RAD50 on the MRN functions were assessed in NPC cells lines using western blot, co-immunoprecipitation and confocal microscopy analyses. The increased radiosensitivity of transient Ad-RAD50 to IR was examined in NPC cells, including MTT assay, colony formation. The molecular mechanisms of radiosensitization were confirmed by neutral comet assay and western bolts. Nude mice subcutaneous injection, tumor growth curve and TUNEL assay were used to evaluate tumor regression and apoptosis in vivo. RESULTS: Rad50 is remarkably upregulated in NPC cells after IR, implying the critical role of Rad50 in MRN functions. The transient expression of this mutant Rad50 decreased the levels of native cellular Rad50, Mre11 and Nbs1, weakened the interactions among these proteins, abrogated the G2/M arrest induced by DSBs and reduced the DNA repair ability in NPC cells. A combination of IR and mutant RAD50 therapy produced significant tumor cytotoxicity in vitro, with a corresponding increase in DNA damage, prevented proliferation and cell viability. Furthermore, Ad-RAD50 sensitized NPC cells to IR by causing dramatic tumor regression and inducing apoptosis in vivo. CONCLUSION: Our findings define a novel therapeutic approach to NPC radiosensitization via targeted native cellular Rad50 disruption.

Effectiveness of HPV 16 viral load and the E2/E6 ratio for the prediction of cervical cancer risk among Chinese women.

The effectiveness of the E2/E6 ratio, the state of viral genome integration and the viral load of human papillomavirus 16 (HPV 16) in predicting the risk of cervical cancer among Chinese women was investigated. Quantitative PCRs for the E2/E6 ratio and the viral load were performed on 85 cervical cancer samples and 55 HPV 16 positive healthy controls. The integrated form of the viral genome was found in 10.9% control samples and in 26.4% cervical cancer samples (P = 0.02). The majority of the cervical cancer (63.2%) and control samples (60%) were mixed forms. The E2/E6 ratio was associated with a high risk of cervical cancer (OR = 7.29, P = 9.55E-6). The integrated form (OR = 6.54, P = 0.005) and mixed form (OR = 2.93, P = 0.042) increased the risk of cervical cancer. The mean viral load in cervical cancer samples (37,371 ± 227,135) was higher than that in the controls (4,619 ± 27,079; P = 0.011). Additionally, the viral load increased along with the cervical cancer progression from the International Federation of Gynecology and Obstetrics (FIGO) stage I (12,337 ± 25,604) to stage II (67,453 ± 319,821). Compared with the state of viral genome integration (area under the receiver operating characteristic curve (AUC) = 0.743) or the viral load (AUC = 0.694), the E2/E6 ratio improved the effectiveness of the risk prediction of cervical cancer (AUC = 0.777), with the sensitivity (specificity) 81.2% (71.7%). The state of viral genome integration and the viral load of HPV 16 were important factors for the risk prediction of cervical cancer among Chinese women, and the E2/E6 ratio had a better cervical cancer risk prediction with age adjustment.

Distribution of genital wart human papillomavirus genotypes in China: a multi-center study.

Although it is understood that low-risk human papillomavirus (HPV) genotypes are associated with genital warts, there have been very few published studies reporting the genotype-specific prevalence of HPV among Chinese population. The aim of the study was to assess the prevalence of HPV genotypes in genital warts across China, and thus to evaluate the potential benefit of a quadrivalent HPV vaccine in this population. The tissue samples of a total of 1,005 genital warts cases were collected from seven geographical regions of China. HPV genotypes were analyzed using the general primer PCR and sequence-based typing method. Prevalence differences between sexes, geographical regions and age groups were assessed. The overall prevalence of HPV DNA in genital warts patients was 88.7% (891/1,005). Low-risk genotypes predominated, with a prevalence of 78.1% (785/1,005). The most prevalent genotypes were HPV-6 (41.3%), HPV-11 (37.6%) and HPV-16 (10.4%). Among HPV positive patients, single infections were more frequent (866/891, 97.2%) than co-infections (25/891, 2.8%). Both the overall prevalence of HPV DNA and that of HPV-6/-11/-16 (positive for any of the three types) decreased with age (P-trend = 0.010 and P-trend = 0.025, respectively). The prevalence of HPV-6/-11 (positive for either HPV type) and HPV-16 varied by geographic region (P = 0.003 and P ≤ 0.001, respectively). The prevalence of HPV-16 in female patients between urban and rural areas showed a marginally significant difference (P = 0.05). In sum, the results provide strong evidence that, in China, the most prevalent HPV genotypes in genital warts are HPV-6, HPV-11 and HPV-16. This indicates that a quadrivalent HPV vaccine may decrease the incidence of genital warts in the future.

IL-17A facilitates type 2 inflammation in a modified eosinophilic chronic rhinosinusitis mouse model.

BACKGROUND: Eosinophilic chronic rhinosinusitis (ECRS) is predominantly characterized by nasal type 2 inflammation. The pathogenesis of this condition is complex. High levels of IL-17A are associated with eosinophil infiltration in some inflammatory diseases and contribute to the severity and insensitivity of corticosteroid therapy for chronic rhinosinusitis. METHODS: In the first experiment, we constructed a modified ECRS mouse model using four groups of mice: phosphate-buffered saline (PBS)-sensitized and nasal instillation (control); PBS-sensitized and Staphylococcus aureus enterotoxin B (SEB) nasal instillation after nasal tamponade (SEB group); ovalbumin (OVA)-sensitized and nasal instillation (OVA group); and OVA-sensitized combined with OVA and SEB nasal instillation after nasal tamponade (OVA + SEB group). In the second experiment, we examined the role of IL-17A by dividing the mice into four groups: control group; ECRS group; ECRS + anti-IL-17A group; and ECRS + IL-17A group. The latter two groups received intraperitoneal injections of anti-IL-17A antibody or IL-17A, respectively. RESULTS: We constructed a modified ECRS mouse model (OVA + SEB group), where the IL-17A levels were upregulated in the nasal sinus of ECRS mice and the IL-17A levels were significantly correlated with eosinophil infiltration. We further demonstrated that IL-17A induced type 2 inflammation and eosinophil infiltration in the ECRS group of mice. In contrast, IL-17A neutralization attenuated type 2 inflammatory cytokine secretion and eosinophil infiltration. CONCLUSION: OVA sensitization and unilateral nasal tamponade, combined with SEB and OVA alternate nasal instillation (OVA + SEB group), could be used to construct a more typical ECRS mouse model in which IL-17A enhanced the expression of type 2 cytokines and eosinophil infiltration.

Nondestructive Testing Based Compressive Bearing Capacity Prediction Method for Damaged Wood Components of Ancient Timber Buildings.

In this research, a wave-drag modulus nondestructive testing method was proposed to predict the compressive bearing capacity of damaged wood components. Using an ancient Chinese building as a case study, internal and external inspections were performed to obtain defect data and related tree species information. Using the same tree species, wave-drag modulus and scale tests were carried out to predict the residual bearing capacity when there was damage in the form of internal cavities or edge material reduction and to compare the damage and loss experimental data. The results show that the internal defect combination model established by two nondestructive testing methods (stress wave and impedance meter) based on the weight distribution can accurately determine the internal damage condition of wood components. There was a significant correlation between wave-drag modulus and compressive strength along the wood grains. The measured values of wood components with different defects were consistent with the theoretical values predicted by the wave-drag modulus, which can effectively improve the prediction of residual bearing capacity. In addition, it was determined that edge material reduction is more destructive to a wood component than the presence of an interior cavity. Thus, the wave-drag modulus can quickly locate vulnerable sections and provide a relevant basis for judging the material condition of wood components in ancient buildings.

IL-19 induced by IL-13/IL-17A in the nasal epithelium of patients with chronic rhinosinusitis upregulates MMP-9 expression via ERK/NF-κB signaling pathway.

BACKGROUND: Tissue remodeling is a crucial characteristic of chronic rhinosinusitis (CRS). Imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) is crucial for the pathologic tissue remodeling in CRS. Elevation of interleukin (IL)-19 or MMP-9 levels in patients with CRS had been proven in previous studies. Here, we aimed to investigate the role of IL-19 in mediating MMP-9 expression in CRS. METHODS: Nasal tissue samples were collected from 45 individuals having chronic rhinosinusitis with nasal polyps (CRSwNP), 24 CRS without nasal polyps (CRSsNP), and 17 controls. Expression of IL-19, its receptors (IL-20R1/IL-20R2), and MMP-9 were investigated using RT-qPCR and Immunofluorescence (IF). Human nasal epithelial cells (HNECs) were stimulated by IL-19; ERK phosphorylation, nuclear factor-κB (NF-κB) pathway activation, and MMP-9 level were detected by RT-qPCR, enzyme-linked immunosorbent assay, western blot, and IF. We also explored the effect of type1/2/3 cytokines on IL-19 production by RT-qPCR, and western blot. RESULTS: Expression levels of IL-19, its receptors (IL-20R1/IL-20R2), and MMP-9 were increased in nasal tissues from individuals with CRSwNP compared to those with CRSsNP as well as the controls. IL-19 significantly elevated the production of MMP-9 in HNECs. Furthermore, IL-19 could activate the ERK and NF-κB pathways, accompanied by increased MMP-9 production in HNECs. Conversely, both ERK and NF-κB inhibitors significantly attenuated the role of IL-19 in MMP-9 production. siRNA knockdown of IL-20R1 suppressed ERK and NF-κB pathway activation, thereby decreasing MMP-9 expression. IL-13 and IL-17A were found to stimulate IL-19 production in HNECs. CONCLUSION: IL-19, promoted by IL-13 and IL-17A, contributes to the upregulation of secretion of the tissue remodeling factor MMP-9 in patients with CRS.

Tetrandrine sensitizes nasopharyngeal carcinoma cells to irradiation by inducing autophagy and inhibiting MEK/ERK pathway.

Radioresistance was the main reason for local recurrence and metastasis of nasopharyngeal carcinoma. Tetrandrine is reported as an antitumor drug via inducing cell cycle arrest and apoptosis. In this study, the radiosensitization effects of maximum noncytotoxic doses of tetrandrine in nasopharyngeal carcinoma were analyzed both in vitro and in vivo, using MTT assay, western blot, TUNEL, and HE staining. It was found that the maximum dose of tetrandrine inhibited the phosphorylation of ERK and MEK induced by irradiation, and significantly enhanced irradiation-induced cell growth inhibition in nasopharyngeal carcinoma cells CNE1, CNE2, and C666-1. The ERK activator and overexpression of ERK reversed the radiosensitization effect of tetrandrine. About 50 mg/kg of tetrandrine which was used as the maximum noncytotoxic dose of tetrandrine in vivo, enhanced the radiosensitivity of the xenograft tumor and increased the apoptosis rate of the xenograft tumor cells caused by irradiation, while did not raise the side effect of the treatment. Moreover, tetrandrine increased autophagy in nasopharyngeal carcinoma cells. These results suggested that the maximum noncytotoxic dose of tetrandrine sensitized nasopharyngeal carcinoma to irradiation by inhibiting MEK/ERK pathway and inducing autophagy.

Histological and computed tomographic characteristics of the sinonasal structure of BALB/c mice.

Mice models were used to study the pathogenesis of mice and human diseases. Although some mice models of allergic rhinitis and rhinosinusitis have been reported, no detailed anatomic, histological and computed tomographic comparative data of the normal murine sinus are available in the literature for new researchers to establish mice models. The purpose of this study was to clarify the histological and computed tomographic characteristics of the normal nasal sinus in BALB/c mice. Fifteen sinonasal specimens were collected. Five mice were subjected to micro-computed tomography imaging, and then dissected to observe its anatomic landmarks, and 10 mice were subjected to haematoxylin and eosin staining. Important anatomic landmarks were clearly demonstrated, including the ethmoturbinates, nasoturbinal, maxilloturbinate, ethmoid sinus, maxillary sinus, nasopharyngeal duct, nasolacrimal duct and vomeronasal organ. Full and typical sinonasal landmarks can be visualized by gross anatomy, micro-computed tomography imaging and haematoxylin and eosin staining, which will be useful for establishing the mouse models of nasal disease.