Yucheng Yang

Impaired Balance of Th17/Treg in Patients with Nasal Polyposis

Nasal polyposis (NP) is a chronic inflammatory disease of the nasal cavity and sinuses that is regulated by T lymphocyte subsets. Imbalance of Th17/Treg has been considered critical in the development of inflammation and atopic reactions. To assess whether the balance of Th17/Treg is disrupted in patients with NP, we evaluated the distribution of Th17 and Treg cells among peripheral blood mononuclear cells (PBMCs) in atopic patients with NP, non‐atopic patients with NP and controls. We then determined mRNA levels of RORc and Foxp3 and protein levels of IL‐17, TGF‐β and IL‐10 in polyp tissue among the three groups. Finally, we investigated the correlation between Th17‐, Treg‐ and Th1‐, Th2‐related cytokines (INF‐γ, IL‐4, IL‐5). The results demonstrated that both atopic and non‐atopic patients with NP revealed significantly increased Th17 proportion and decreased Treg proportion in PBMCs, as well as significantly increased RORc and IL‐17 levels and decreased Foxp3 and TGF‐β levels in polyp tissue. Furthermore, these differences were significant between atopic and non‐atopic groups. The frequency of Treg in PBMCs was found to be negatively correlated with Th1 and Th2 cytokines in polyps. These results indicated that an impaired balance of Th17/Treg existed in patients with NP and was more severe in atopic patients, suggesting that the imbalance of Treg/Th17 may play an important role in the development of NP and that atopy may aggravate NP by promoting the imbalance of Th17/Treg.

Transforming growth factor‐beta 1 pathways in inflammatory airway diseases

Transforming growth factor‐beta 1 (TGF‐β1) has been reported being involved in the remodeling and immunosuppression processes of inflammatory airway diseases; understanding the regulation of TGF‐β1 is therefore a key to unravel the pathomechanisms of these diseases. This review briefly summarizes the current knowledge on the influencing factors for driving TGF‐β1 and its regulatory pathways in inflammatory airway diseases and discusses possible therapeutic approaches to TGF‐β1 control. The factors include smoking and oxidative stress, prostaglandins (PGs), leukotrienes (LTs), bradykinin (BK), and microRNAs (miRs). Based on the summary, new innovative treatment strategies may be developed for inflammatory airway diseases with an impaired expression of TGF‐β1.

Differential expression and release of activin A and follistatin in chronic rhinosinusitis with and without nasal polyps

Background Chronic rhinosinusitis with (CRSwNP) and without nasal polyps (CRSsNP) should be regarded as distinct clinical entities based on differential inflammatory mediator and remodeling profiles. Activin A, a member of the TGF-β superfamily, plays an important role in inflammation and remodeling in the lower airways, although its expression and release in the upper airways remain undescribed. Objective To investigate the expression of activin A and its inhibitor follistatin in nasal tissue samples from CRSsNP and CRSwNP patients, and to monitor the spontaneous release of these molecules in a human mucosal model. Methods Protein levels were determined using ELISA for activin A, follistatin, TGF-β1 and indicator proteins (IL-5, ECP, IFNγ) in 13 CRSsNP, 23 CRSwNP, and 10 control samples. The spontaneous release rate and the release ratios of activin A, follistatin and TGF-β1 were determined in 9 CRSsNP and 7 CRSwNP tissue fragments cultured ex-vivo. The induction of activin A and TGF-β1 by one another was studied in 7 CRSsNP tissue fragments cultured ex-vivo. Results Significantly higher concentrations of activin A, follistatin, TGF-β1, and IFNγ were observed in CRSsNP compared with CRSwNP samples, whereas the concentrations of IL-5 and ECP were significantly lower. Follistatin was positively and linearly correlated with activin A in CRSsNP and CRSwNP. Activin A, follistatin and TGF-β1 were all spontaneously released by the samples, although the relative ratios released by tissue fragments from CRSsNP and CRSwNP samples were significantly different, with a higher follistatin/activin A-ratio and a follistatin/TGFß1-ratio (with less overall TGF-β1) in CRSwNP than in CRSsNP. Furthermore, TGF-β1 enhanced activin A secretion in CRSsNP tissue fragments cultured ex-vivo. Conclusion The differences in tissue concentrations and spontaneous release rates for activin A and follistatin in different CRS samples support the hypothesis that CRSsNP and CRSwNP are two distinct disease entities with respect to remodeling patterns.

MicroRNA expression profile of mature dendritic cell in chronic rhinosinusitis

ObjectiveChronic rhinosinusitis (CRS), which includes CRS without nasal polyposis (CRSsNP) and with nasal polyposis (CRSwNP), shows imbalance of helper T cells (Th) and regulatory T cells (Treg). The balance of Th and Treg cells is orchestrated by dendritic cells (DCs). Recent studies show functions of DCs can be regulated by microRNAs (miRNAs or miRs). This study is aimed to investigate miRNAs expression profiles of peripheral blood DCs in CRS.MethodsPeripheral blood samples of 30 patients with CRS and 7 patients with nasal septum deviation alone were collected. CD14+ monocytes were isolated from these samples and differentiated into dendritic cells (DCs). Small RNAs were extracted from mature DCs and reversely transcribed into cDNA by Mir-XTM miRNA First-Strand synthesis method. MiRNA microarrays were used for miRNA expression analysis. Microarray results were validated by real-time PCR performed on five top list target genes.ResultsMiRNA microarrays showed that DCs from different types of patients have different sets of differential expressed miRNAs when comparing with Controls; they also share 31 commonly changed miRNAs among all three groups of CRS patients. Of these 31 miRNAs, 5 miRNAs were up-regulated and 25 miRNAs were down-regulated in all three types of CRS, while MiR-1290 was down-regulated in CRSsNP but up-regulated in both atopic CRSwNP and non-atopic CRSwNP.ConclusionsBy comparing miRNA gene expression patterns in 3 types of CRS patients, we have been able to identify candidate miRNAs that might mediate the core pathogenesis of CRS through regulating dendritic cells. These miRNAs could serve as potential therapeutic targets for CRS.

Allergen induced Th17 response in the peripheral blood mononuclear cells (PBMCs) of patients with nasal polyposis

BACKGROUND Nasal polyposis (NP) is a chronic inflammatory disease of the nasal cavity and sinuses. Th17 cells have been considered to play roles in allergic airway diseases and various chronic inflammatory disorders. AIM OF THE STUDY This study aimed to investigate the population and function of peripheral Th17 cells in response to house dust mite extracts (HDM) allergen in NP patients, and evaluate the possible correlation between Th17 cells and atopy, to explore the role of atopy in the pathogenesis of NP. METHODS Peripheral blood mononuclear cells (PBMCs) obtained from atopic NP patients, non-atopic NP patients, and controls were stimulated by phytohemagglutinin (PHA) or HDM plus PHA. The resulting frequency of Th17 cells was detected by flow cytometry and the expression of RORc was measured by real-time PCR. Then the concentrations of IL-17A, INF-γ, IL-4 and IL-5 in the supernatants were assayed by specific ELISAs. RESULTS The population and function of Th17 cells in allergen stimulated PBMCs were significantly higher in atopic NP patients. In addition, in atopic group, HDM+PHA stimulation induced significant increase of Th17 population and IL-17A production versus those in PHA stimulated ones. However, the frequency of Th17 cells was not correlated with Th1, Th2 cytokine productions. CONCLUSION Th17 immunity is involved in the systemic immune responses to allergen in atopic NP and atopy may aggravate NP by stimulating the increase of Th17 population and IL-17A production. The mechanism of Th17 cells response to allergen may be regulated differently from the regulation of Th1 and Th2 immunity in NP.

Knockdown of NFBD1/MDC1 enhances chemosensitivity to cisplatin or 5-fluorouracil in nasopharyngeal carcinoma CNE1 cells

Abstract Nasopharyngeal carcinoma (NPC) is a rare but highly invasive cancer that is prevalent among people of southern Chinese ancestry in southern China and Southeast Asia. Radiotherapy and cisplatin (CDDP)-based chemotherapy are the main treatment options. Unfortunately, disease response to concurrent chemoradiotherapy varies among patients with NPC, and many cases are resistant to CDDP and radiotherapy. NFBD1 functions in cell cycle checkpoint activation and DNA repair following DNA damage. In this study, we identified the NFBD1 as a tractable molecular target to chemosensitize NPC cells. NFBD1 expression in NPC CNE1 cell lines was depleted using lentivirus-mediated short hairpin RNA, and the elevated sensitivity of these NFBD1-inhibited NPC cells to therapeutic reagent CDDP and 5-fluorouracil (5-FU) was evaluated using MTS assays. Flow cytometry analysis also showed that NFBD1 knockdown led to an obvious induction of apoptosis in CDDP- or 5-FU-treated CNE1 cells. Furthermore, we implicated the involvement of NFBD1 in Rad51 and DNA-PKcs foci formation following CDDP or 5-FU chemotherapy. In conclusion, NFBD1 knockdown improves the chemosensitivity of NPC cells by inhibiting cell growth and promoting apoptosis through the impairment of DNA damage repair, suggesting NFBD1 as a novel therapeutic target for NPC.

TrkB promotes laryngeal cancer metastasis via activation PI3K/AKT pathway

Objectives The aim of our study was to investigate the role of TrkB pathway in tumor occurrence and development for in order to provide theoretical basis to laryngeal cancer therapy. Materials and methods Biological characteristics of the cells were studied by migration tests and colony forming assay. Gene and protein expression analysis was performed by RT-PCR or western blot. in vivo experiments were conducted in syngeneic BALB/c mice. Results Significant changes in protein and gene expression, including higher expression level of TrkB, were found in cells and laryngeal cancer specimens. we demonstrated that TrkB activates AKT via c-Src, leading to increased proliferation. Also, TrkB induced EMT via increased expression of EMT related transcription factors such as Twist-1 and Twist-2. Conclusion Our data indicate TrkB are overexpressed in laryngeal cancer, and TrkB signaling is involved in tumorigenicity of laryngeal cancer. These observations suggest that TrkB is a promising target for future intervention strategies to prevent tumor metastasis, EMT program in laryngeal cancer. What is already known about this subject? • Cancer of the larynx is one of the most common types of head and neck cancer. • The survival rate of advanced laryngeal cancer is only 30 to 40%. • The tropomyosin-related kinase B receptor (TrkB), together with TrkA and TrkC, are neurotrophin receptors regulating the proliferation and differentiation of neuronal cells. What are the new findings? • TrkB are overexpressed in laryngeal cancer. • TrkB signaling is involved in tumorigenicity of laryngeal cancer. • TrkB acts as a key regulator of the PI3K/AKT signal pathway-mediated tumor metastasis. How might these results change the focus of research or clinical practice? • These observations suggest that TrkB is a promising target for future intervention strategies to prevent tumor metastasis, EMT program in laryngeal cancer. Our study provides molecular insight into the tumor metastasis and has important implications in elucidating oncogenic processes.

Influence of Chitosan-Based Dressing on Prevention of Synechia and Wound Healing after Endoscopic Sinus Surgery: A Meta-Analysis

Introduction Endoscopic sinus surgery (ESS) has had many complications, e.g., synechia formation. This meta-analysis investigated the effect of a novel chitosan-based dressing on prevention of synechia and wound healing after ESS. Methods We systematically searched various medical literature data bases and included the randomized controlled trials (RCT) regarding the effect of novel chitosan-based dressing on ESS. The study outcomes included synechia, granulations, hemostasis, crusting scores, and infection. Results Six RCTs, which involved 337 patients, were included in the meta-analysis. Compared with control intervention after ESS, chitosan-based gel dressing substantially inhibited synechia (risk ratio [RR] 0.28 [95% confidence interval {CI}, 0.15–0.54]; p = 0.0001), improved granulations (RR 1.47 [95% CI, 1.07–2.03]; p = 0.02), and hemostasis (RR 1.47 [95% CI, 1.07–2.03]; p = 0.02) but demonstrated no effect on crusting scores (standard mean difference -0.41 [95% CI, -1.06 to 0.23]; p = 0.21) and infection (RR 0.88 [95% CI, 0.51–1.52]; p = 0.64). Conclusion Compared with control intervention, chitosan-based dressing was associated with significantly reduced synechia and with increased granulations and hemostasis but showed no influence on crusting and infection after ESS.

Differential Expression of the Aryl Hydrocarbon Receptor and Transforming Growth Factor Beta 1 in Chronic Rhinosinusitis with Nasal Polyps with Allergic Rhinitis

Objective: This study aimed to determine the aryl hydrocarbon receptor (AhR) and transforming growth factor beta 1 (TGF-β1) expression levels in chronic rhinosinusitis (CRS) and their possible correlation with allergic state and tissue remodeling. Methods: Patients were enrolled and divided into the following groups: CRS without nasal polyps (NP) without allergic rhinitis (AR) (CRSsNPsAR; n = 20), CRS with NP with AR (CRSwNPwAR; n = 20), CRS with NP without AR (CRSwNPsAR; n = 20), and controls (n = 15). Tissue samples were analyzed by Masson trichrome staining for collagen, while the location and expression of AhR and TGF-β1 were analyzed by immunohistochemistry, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and Western blotting. Results: The collagen amounts as well as AhR and TGF-β1 mRNA and protein expression levels were significantly increased in the CRSsNPsAR group compared with the CRSwNP (CRSwNPsAR and CRSwNPwAR) samples (p < 0.01). However, higher collagen amounts (p < 0.05) and higher TGF-β1 (p < 0.05) but lower AhR expression levels (p < 0.05) were detected in the CRSwNPwAR versus the CRSwNPsAR patients. Both AhR and TGF-β1 expression were positively correlated with the collagen level in CRS samples (p < 0.01). Conclusions: Elevated AhR expression may be involved in the progression of tissue remodeling in CRSsNPsAR similar to TGF-β1 expression. Conversely, lower AhR expression may be involved in allergic reactions in CRSwNPwAR.