GLCCI1 reduces collagen deposition and airway hyper-responsiveness in a mouse asthma model through binding with WD repeat domain 45B.

Asthma is a serious public health problem worldwide, without effective therapeutic methods. Our previous study indicated that glucocorticoid-induced transcript 1 gene (GLCCI1) knockout reduces the sensitivity to glucocorticoid in asthmatic mouse. Here, we explored the role and action mechanism of GLCCI1 in asthma development. In ovalbumin-sensitized mice, airway resistance and tissue damage increased, the production of inflammatory cytokines were up-regulated, GLCCI1 expression was reduced and autophagy was activated. Increasing of GLCCI1 inhibited human and mouse airway epithelial cell (AEC) autophagy, while decreasing of GLCCI1 promoted autophagy. Furthermore, we found that GLCCI1 bound with WD repeat domain 45B (WDR45B) and inhibited its expression. Increasing of WDR45B partly reversed the inhibition of GLCCI1 to autophagy-related proteins expression and autophagosome formation in vitro. Increasing of WDR45B in vivo reversed the improvement of GLCCI1 on airway remodelling in asthma and the inhibition to autophagy level in lung tissues. Overall, our data showed that GLCCI1 improved airway remodelling in ovalbumin-sensitized mice through inhibiting autophagy via combination with WDR45B and inhibiting its expression. Our results proved a new idea for asthma treatment.

Transfer of the IL-37b gene elicits anti-tumor responses in mice bearing 4T1 breast cancer.

AIM: IL-37b has shown anti-cancer activities in addition to its anti-inflammatory properties. In this study, we investigated the effects of IL-37b on breast carcinoma growth in mice and to determine the involvement of T cell activation in the effects. METHODS: IL-37b gene was transferred into mouse breast carcinoma cell line 4T1 (4T1-IL37b cells), the expression of secretory IL-37b by the cells was detected, and the effects of IL-37b expression on the cell proliferation in vitro was evaluated. After injection of 4T1 cells or 4T1-IL37b cells into immunocompetent BALB/c mice, immunodeficient BALB/c nude mice and NOD-SCID mice, the tumor growth and survival rate were measured. The proliferation of T cells in vitro was also detected. RESULTS: IL-37b was detected in the supernatants of 4T1-IL37b cells with a concentration of 12.02 ± 0.875 ng/mL. IL-37b expression did not affect 4T1 cell proliferation in vitro. BALB/c mice inoculated with 4T1-IL37b cells showed significant retardation of tumor growth. BALB/c mice inoculated with both 4T1 cells and mitomycin C-treated 4T1-IL37b cells also showed significant retardation of tumor growth. But the anti-cancer activity of IL-37b was abrogated in BALB/c nude mice and NOD-SCID mice inoculated with 4T1-IL37b cells. Recombinant IL-37b slightly promoted CD4(+) T cell proliferation without affecting CD8(+) T cell proliferation. CONCLUSION: IL-37b exerts anti-4T1 breast carcinoma effects in vivo by modulating the tumor microenvironment and influencing T cell activation.

A multicentre, randomised, double-blind, double-dummy, parallel-controlled, phase 3 clinical trial assessing the efficacy and safety of intravenous nemonoxacin malate vs. levofloxacin for community-acquired pneumonia in adult patients.

BACKGROUND: Nemonoxacin malate is a novel non-fluorinated quinolone for oral and intravenous (IV) administration. This phase 3, multicentre, randomised, double-blind, double-dummy, parallel-controlled clinical trial (NCT02205112) evaluated the efficacy and safety of IV nemonoxacin vs. levofloxacin for the treatment of community-acquired pneumonia (CAP) in adult patients. METHODS: Eligible patients were randomised to receive 500 mg nemonoxacin or levofloxacin via IV infusion, once daily for 7-14 days. The primary endpoint was the clinical cure rate at the test-of-cure (TOC) visit in the modified intent-to-treat (mITT) population. Secondary efficacy and safety were also compared between nemonoxacin and levofloxacin. RESULTS: Overall, 525 patients were randomised and treated with nemonoxacin (n = 349) or levofloxacin (n = 176). The clinical cure rate was 91.8% (279/304) for nemonoxacin and 85.7% (138/161) for levofloxacin in the mITT population (P > 0.05). The clinical efficacy of nemonoxacin was non-inferior to levofloxacin for treatment of CAP. Microbiological success rate with nemonoxacin was 88.8% (95/107) and with levofloxacin was 87.8% (43/49) (P > 0.05) at the TOC visit in the bacteriological mITT population. The incidence of drug-related adverse events (AEs) was 37.1% in the nemonoxacin group and 22.2% in the levofloxacin group. These AEs were mostly local reactions at the infusion site, nausea, elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST), and QT interval prolongation. The nemonoxacin-related AEs were mostly mild and resolved after discontinuation of nemonoxacin. CONCLUSIONS: Nemonoxacin 500 mg IV once daily for 7-14 days is effective and safe and non-inferior to levofloxacin for treating CAP in adult patients.

Cluster analysis of clinical phenotypic heterogeneity in obstructive sleep apnea assessed using photoplethysmography.

BACKGROUND: We evaluated heterogeneity in clinical phenotypes among patients with obstructive sleep apnea syndrome (OSAHS) using photoplethysmography (PPG) in cluster analysis. METHODS: All enrolled patients underwent polysomnography (PSG) monitoring while wearing a PPG device. Pulse wave signals were recorded with a modified pulse oximetry probe in the PPG device. The pulse wave-derived cardiac risk composite parameter (CRI) and eight derived signal parameters were used to assess OSAHS phenotype. We defined a high cardiovascular risk OSAHS group (CRI ≥0.5) and low cardiovascular risk OSAHS group (CRI <0.5). K-means clustering was performed for analysis of clinical phenotype heterogeneity in OSAHS by combining the CRI and its derived signals. RESULTS: The OSAHS group had high cardiovascular risk for sex, age, body mass index, systolic and diastolic blood pressure, apnea hypopnea index, and obstructive arousal index and higher risk of developing hypertension, diabetes, and cerebrovascular comorbidities. The low cardiovascular risk OSAHS group had higher blood oxygen levels. Three clinical phenotypes were identified in CRI clustering: 1) typical OSAHS with high risk of hypertension (characterized by middle age, obesity, hypertension with severe OSAHS); 2) older women and mild OSAHS; 3) older men and mild OSAHS. Three subtypes were obtained based on the eight cardiac risk-derived parameters: 1) hypoxia combined with decreased pulse wave amplitude variation; 2) decreased vascular pulse wave amplitude combined with decreased pulse frequency; 3) arrhythmia combined with hypoxia. CONCLUSIONS: Establishing OSAHS clinical phenotypes with the CRI and derived parameters using PPG may help in establishing multi-dimensional assessment of cardiovascular risk in OSAHS.

[Superoxide dismutase gene polymorphisms and functional activity in chronic obstructive pulmonary disease].

OBJECTIVE: To explore the association of genetic polymorphism of superoxide dismutase (SOD) and superoxide dismutase activity in chronic obstructive pulmonary disease. METHODS: A total of 114 patients with COPD (the COPD group) and 80 healthy volunteers (the control group) were enrolled in this study. Peripheral blood was taken and whole blood cell genomic DNA was extracted. The genetic polymorphisms of Mn-SOD (G5774A) and EC-SOD G (-4466)T genes were determined by DNA sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Peripheral blood plasma was collected and the functional activity of SOD was determined by a SOD kit. RESULTS: The distribution of the Mn-SOD genotype frequencies (GG, AG, AA) between the patients [27.2% (31/114), 53.5% (61/114) and 19.3% (22/114)] and the controls [46.3% (37/80), 37.5% (30/80) and 16.2% (13/80)] were significantly different (χ(2) = 7.681, P < 0.05). The A allele gene frequencies of the patients (46.1%, 105/228) were significant higher than those of the controls (35.0%, 56/160), and subjects with the A allele gene of Mn-SOD were more likely to have COPD [OR = 1.585, 95%CI (1.045 - 2.404), P < 0.05]. The AA and AG genotypes of Mn-SOD were correlated with the most severe COPD (χ(2) = 12.345, P < 0.01). The distribution of the EC-SOD genotype frequencies (GG, GT, TT) was 76.3% (87/114), 22.8% (26/114), 0.9% (1/114) in the patients and 71.3% (57/80), 28.7% (23/80), 0% (0/80) in the controls. The allele gene frequencies of the EC-SOD (G, T) were 87.7% (200/228), 12.3% (28/228) in the patients and 85.6% (137/160), 14.4% (23/160) in the controls. There were no significant differences in the distribution of the different genotypes or allele gene frequencies between the patients and the controls in the EC-SOD genes (χ(2) = 0.631, P > 0.05; χ(2) = 0.36, P > 0.05). The SOD activity of COPD patients [(84 ± 17) kU/L] was significant lower than that of the healthy controls [(109 ± 15) kU/L]. CONCLUSIONS: Mn-SOD (G5774A) genetic polymorphism is related to the development of COPD. The Mn-SOD 5774A allele gene may be one of the predisposing genes for COPD. The AA and AG genotypes of Mn-SOD were correlated with the most severy COPD. The decrease of blood plasma SOD activity in COPD patients indicates a dysfunction of the oxidant/antioxidant defense system in the disease.

Glucocorticoid induced transcript 1 represses airway remodeling of asthmatic mouse via inhibiting IL-13/periostin/TGF-ß1 signaling.

Asthma is characterized by airway remodeling. Glucocorticoid induced transcript 1 (GLCCI1) was reported to be associated with the development of asthma, while its exact mechanism is still not clear. In our study, ovalbumin (OVA) combined with aluminum hydroxide were used to establish asthmatic mouse model. ELISA assay was fulfilled to ensure the concentration of inflammatory factors in both bronchoalveolar lavage fluid and serum. The pathological changes and collagen deposition in lung tissues were analyzed using H&E staining and Masson staining, respectively. The expression of proteins was measured using western blot, and the expression of GLCCI1 mRNA was ensured by qRT-PCR. Here, we demonstrated that OVA-induced inflammation, lung structural remodeling and collagen deposition in asthmatic mice was notably improved by hydroprednisone treatment or GLCCI1 overexpressing. The expression of GLCCI1 was decreased, while IL-13, periostin and TGF-ß1 were increased in the lung tissue of asthmatic mice. Importantly, upregulation of GLCCI1 suppressed the expression of IL-13, periostin and TGF-ß1, phosphorylation of Smad2 and Smad3, and extracellular matrix (ECM) deposition-related proteins expression. IL-13-induced upregulation of periostin and TGF-ß1 expression, phosphorylation of Smad2 and Smad3, and ECM deposition in airway epithelial cells (AECs) was repressed by GLCCI1 increasing. Furthermore, our results showed that overexpression of GLCCI1 repressed the effect of IL-13 on AECs via inhibiting periostin expression. Overall, our data revealed that GLCCI1 limited the airway remodeling in mice with asthma through inhibiting IL-13/periostin/TGF-ß1 signaling pathway. Our data provided a novel target for asthma treatment.

miR-126a-3p targets HIF-1α and alleviates obstructive sleep apnea syndrome with hypertension.

The obstructive sleep apnea syndrome (OSAS) is a common sleep-related breathing disorder and an important cause of refractory hypertension. MicroRNAs (miRNAs) are involved in the development of hypertension, but their role in OSAS with hypertension (OSAS-hypertension) has been little studied. Evidence indicates that miR-126a-3p expression is lower in patients with OSAS-hypertension compared with the patients with OSAS alone. However, its role in the pathogenesis of OSAS-hypertension remains unclear. Therefore, this study aims to investigate the role of miR-126a-3p in OSAS-hypertension and to determine whether HIF-1α is involved in this process. Sprague Dawley rats were exposed to chronic intermittent hypoxia (CIH) for 8 weeks to induce OSAS-hypertension. Rat aortic smooth muscle cells (A7r5) were cultured under hypoxia as an in vitro model. Our results showed that rats exposed to 8 week CIH exhibited decreased miR-126a-3p and increased HIF-1α expression. Furthermore, administration of recombinant adeno-associated virus expressing miR-126a-3p (rAAV-miR-126a) counteracted the CIH-induced systolic blood pressure upregulation, oxidase stress, inflammation, and heart and abdominal aorta vascular remodeling. Moreover, the mechanism was associated with its targeted suppression of HIF-1α. These findings suggest that miR-126a-3p might be a novel potential therapeutic target for the treatment of OSAS-hypertension.

A randomized, double-blind, multicenter Phase II study comparing the efficacy and safety of oral nemonoxacin with oral levofloxacin in the treatment of community-acquired pneumonia.

BACKGROUND/PURPOSE: To compare the clinical efficacy and safety of nemonoxacin with levofloxacin in treating community-acquired pneumonia (CAP) in a Phase II clinical trial. METHODS: One hundred ninety-two patients with CAP were randomized to receive oral nemonoxacin (500 mg or 750 mg) or levofloxacin (500 mg) once daily for 7-10 days. Clinical and bacteriological responses were determined at the test of cure (TOC) visit in the full analysis set (FAS). RESULTS: The clinical cure rate of nemonoxacin (500 mg), nemonoxacin (750 mg), and levofloxacin (500 mg) was 93.3%, 87.3%, and 88.5%, respectively, in the FAS (n = 168), and 93.0%, 93.9%, and 88.9%, respectively in the per protocol set (n = 152). At the TOC visit, nemonoxacin at 500 mg and 750 mg was proven to be noninferior to levofloxacin at 500 mg in the FAS in terms of clinical efficacy. The overall bacteriological success rate was 83.3% in both nemonoxacin groups and 80.0% in the levofloxacin 500 mg group in the bacteriological FAS. The comprehensive efficacy rate was comparable among the three groups (87.5% for the nemonoxacin 500 mg group, 93.8% for the nemonoxacin 750 mg group, and 81.3% for the levofloxacin 500 mg group). Most drug-related adverse events were mild and transient, mainly gastrointestinal symptoms such as nausea and vomiting, transient neutropenia, and elevated liver enzymes. No drug-related serious adverse events occurred. CONCLUSION: Either 500 mg or 750 mg of oral nemonoxacin taken once daily for 7-10 days demonstrated high clinical and bacteriological success rates in Chinese adult patients with CAP. Nemonoxacin at 500 mg once daily for 7-10 days is recommended for future Phase III clinical trials. ClinicalTrials.gov identifier: NCT01537250.

NRSN2 promotes non-small cell lung cancer cell growth through PI3K/Akt/mTOR pathway.

Neurensin-2 (NRSN2), a small neural membrane protein which localized in small vesicles in neural cells. Recent report suggested that Neurensin-2 might play a suppressive role in tumor. While the biological functions and molecular mechanisms in cancer progression remain unknown. We retrieved Oncomine Database and found that NRSN2 is commonly highly expressed in non-small cell lung cancer (NSCLC). We examined the levels of NRSN2 in 18 pairs of NSCLC and adjacent tissues and found that NRSN2 was overexpressed in malignant tissues. Both loss and gain of function experiments in NSCLC cell lines suggest that NRSN2 promotes cell growth, but no effects in cell invasion. Further investigation show that NRSN2 could affect phosphatidylinositol 3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling. Taken together, our findings suggest that NRSN2 promotes non-small cell lung cancer cell growth through PI3K/Akt/mTOR pathway.

Adoptive transfer of induced-Treg cells effectively attenuates murine airway allergic inflammation.

Both nature and induced regulatory T (Treg) lymphocytes are potent regulators of autoimmune and allergic disorders. Defects in endogenous Treg cells have been reported in patients with allergic asthma, suggesting that disrupted Treg cell-mediated immunological regulation may play an important role in airway allergic inflammation. In order to determine whether adoptive transfer of induced Treg cells generated in vitro can be used as an effective therapeutic approach to suppress airway allergic inflammation, exogenously induced Treg cells were infused into ovalbumin-sensitized mice prior to or during intranasal ovalbumin challenge. The results showed that adoptive transfer of induced Treg cells prior to allergen challenge markedly reduced airway hyperresponsiveness, eosinophil recruitment, mucus hyper-production, airway remodeling, and IgE levels. This effect was associated with increase of Treg cells (CD4(+)FoxP3(+)) and decrease of dendritic cells in the draining lymph nodes, and with reduction of Th1, Th2, and Th17 cell response as compared to the controls. Moreover, adoptive transfer of induced Treg cells during allergen challenge also effectively attenuate airway inflammation and improve airway function, which are comparable to those by natural Treg cell infusion. Therefore, adoptive transfer of in vitro induced Treg cells may be a promising therapeutic approach to prevent and treat severe asthma.

Lengthy diagnostic challenge in a rare case of pulmonary veno-occlusive disease: case report and review of the literature.

Pulmonary veno-occlusive disease (PVOD) is a rare and usually survival poor disorder. We report a patient with a long history of progressive dyspnea of over 8 years, who with a diagnosis of chronic cor pulmonale confirmed elsewhere, was ultimately diagnosed as PVOD via histological analysis of a lung biopsy. After treatment with combined bosentan, diuretics and digoxin, his symptoms and function improved. This case highlights that PVOD is an under-recognised and often misdiagnosed disease, especially in its chronic form. Understanding its pathogenesis, its poor response to medical therapy and its dismal prognosis remain challenges for the treatment of PVOD.