Changgui Wu

Curcumin promotes apoptosis in A549/DDP multidrug-resistant human lung adenocarcinoma cells through an miRNA signaling pathway

Curcumin extracted from the rhizomes of Curcuma longa L. has been shown to have inhibitory effects on cancers through its anti-proliferative and pro-apoptotic activities. Emerging evidence demonstrates that curcumin can overcome drug resistance to classical chemotherapies. Thus, the mechanisms underlying the anti-tumor activities of curcumin require further study. In our study, we first demonstrated that curcumin had anti-cancer effects on A549/DDP multidrug-resistant human lung adenocarcinoma cells. Further studies showed that curcumin altered miRNA expression; in particular, significantly downregulated the expression of miR-186 * in A549/DDP. In addition, transfection of cells with a miR-186 * inhibitor promoted A549/DDP apoptosis, and overexpression of miR-186 * significantly inhibited curcumin-induced apoptosis in A549/DDP cells. These observations suggest that miR-186 * may serve as a potential gene therapy target for refractory lung cancer that is sensitive to curcumin.

DW MRI at 3.0 T versus FDG PET/CT for detection of malignant pulmonary tumors.

Emerging evidence suggests that diffusion‐weighted magnetic resonance imaging (DW MRI) could be useful for tumor detection with N and M staging of lung cancer in place of fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT). DW MRI at 3.0 T and FDG PET/CT were performed before therapy in 113 patients with pulmonary nodules. Mean apparent diffusion coefficient (ADC), maximal standardized uptake value (SUVmax) and Ki‐67 scores were assessed. Quantitatively, specificity and accuracy of ADC (91.7 and 92.9%, respectively) were significantly higher than those of SUVmax (66.7 and 77.9% respectively, p < 0.05), although sensitivity was not significantly different between them (93.5 and 83.1%, p > 0.05). Qualitatively, sensitivity, specificity and accuracy of DW MRI (96.1, 83.3 and 92.0%, respectively) were also not significantly different from that of FDG PET/CT (88.3, 83.3 and 86.7%, respectively, p > 0.05). Significant negative correlation was found between Ki‐67 score and ADC (r = −0.66, p < 0.05), ADC and SUVmax (r = −0.37, p < 0.05), but not between Ki‐67 score and SUVmax (r = −0.11, p > 0.05). In conclusion, quantitative and qualitative assessments for detection of malignant pulmonary tumors with DW MRI at 3.0 T are superior to those with FDG PET/CT. Furthermore, ADC could predict the malignancy of lung cancer.

Inhibition of non-small cell lung cancer cell proliferation and tumor growth by vector-based small interfering RNAs targeting HER2/neu

Amplification and over-expression of HER2/neu oncogene is found in diverse types of human cancers, and is closely related to tumor occurrence, metastasis, angiogenesis and chemotherapy resistance. Therapeutic agents targeting HER2/neu have been intensively addressed over the past decades. In non-small cell lung cancers (NSCLCs), the prevalence of HER2/neu activation, its role in prognosis, and its possible implications as a therapeutic target, are still to be elucidated. Here we show that the abundant or moderate over-expression of HER2/neu could be detected in both pulmonary adenocarcinoma and pulmonary large cell carcinoma cell lines. Stable knockdown of HER2/neu expression in the NSCLC cell line SPC-A-1 was achieved by vector-based small interfering RNAs (siRNAs), which consequently caused significant decrease in cell proliferation and clone forming efficiency, as well as cell cycle arrest at G(1) phase. Compared with the parental NSCLC cells, HER2/neu knockdown cells exhibited attenuated capacities in developing tumors in nude mice, and the growth tumors xenografts derived from these cells were dramatically regressed. These data provided direct evidence that HER2/neu signaling is essential for tumorigenicity of NSCLC cells, and suggested that siRNAs targeted to HER2/neu may provide a novel therapeutic strategy in the treatment of NSCLC, especially when combined with traditional therapeutics or via development of vector-based siRNAs of multiple targets that synergistically contribute to carcinogenesis, e.g. EGFR and HER2/neu.

Notch signaling regulates col1α1 and col1α2 expression in airway fibroblasts

Subepithelial fibrosis is one of the common pathological features of asthmatic airway remodeling. During subepithelial fibrosis, type I collagen becomes the most abundant extracellular protein component. Studies have shown that Notch signaling participates in the progression of fibrosis; however, whether Notch signaling is involved in regulating type I collagen expression in airway fibroblasts remains unclear. The aim of the present study was to examine whether Notch signaling can regulate type I collagen expression in airway fibroblasts and to explore the underlying molecular mechanisms. Here, the expression of Notch signaling components was examined in mouse L929 cells and human MRC-5 cells. After upregulating or downregulating Notch signaling in these cell lines, col1α1 and col1α2 expression was examined. Using gene reporter assays, site-directed mutagenesis, and ChIP assays, the role of Hes1 binding sites in both the mouse and human COL1A1 and COL1A2 promoters was investigated. This study revealed that Notch signaling-related molecules (including Notch1, Hes1, and others) are expressed in L929 and MRC-5 cells and that Notch signaling regulates the expression of col1α1 and col1α2 in both cell lines. Additionally, over-expression of the Notch intracellular domain resulted in activation of the COL1A1 and COL1A2 promoters, and site-directed mutagenesis reporter assays revealed that Hes1 proteins might augment both mouse and human COL1A1 and COL1A2 promoter activity. Furthermore, ChIP assays confirmed that Hes1 binds to the COL1A1 and COL1A2 promoters in both L929 and MRC-5 cells. Therefore, it is reasonable to assume that Notch signaling can directly upregulate COL1A1 and COL1A2 promoter activity through a Hes1-dependent mechanism, which could serve as a possible target for pharmacotherapy of airway subepithelial fibrosis.

Rapidly Progressive Diffuse Cystic Lesions as a Radiological Hallmark of Lung Adenocarcinoma

CASE PRESENTATION A 39-year-old nonsmoking man presented to us with complaints of progressive hoarseness and nonproductive cough. Laboratory examinations revealed elevated serum carcino-embryonic antigen (15.49 ng/ml) and cancer antigen125 (40.01 U/ml). Chest computed tomography (CT) 1 month earlier showed a 25 20 mm central located mass in the left upper lobe and diffused cystic lesions in bilateral lungs (Figure 1). Repeated chest CT scan in our institution showed increased size of the mass at 35 30 mm and rapidly enlarged, widespread, disseminated thin-walled cystic lesions in bilateral lungs (Figure 2). Bronchoscopy revealed an endobronchial whitish lesion in the left apicoposterior segment bronchus but was otherwise normal. Histologic and immunohistochemical examination of the mass and blind-aspirated lung specimen established the diagnosis of adenocarcinoma. The cancer cells were poorly differentiated with a positive reaction to carcino-embryonic antigen, thyroid transcription factor 1, and cytokeratin 7 staining. Positron emission tomography revealed heterogeneous uptake of the mass, cystic lesion, and mediastinal lymph nodes, suggesting intrapulmonary metastasis. His clinical stage was T1N2M1 stage IV and epidermal growth factor receptor mutation test was negative. He underwent cisplatin/gemcitabine chemotherapy for four cycles. The next 3 months follow-up documented significant improvement and the patient was alive and stable. This report highlights that lung adenocarcinoma might present as multiple cystic lesions on rare occasions.1 It is essential to maintain a high index of suspicion for adenocarcinoma in patients with mediastinal mass and diffused thinwalled cystic lesions as observed in our case.

Der p2 recombinant bacille Calmette‐Guerin priming of bone marrow‐derived dendritic cells suppresses Der p2‐induced T helper17 function in a mouse model of asthma

Previous studies have demonstrated that our recombinant bacille Calmette‐Guerin (rBCG), which expresses Der p2 in house dust mite (Der p2 rBCG) suppresses asthmatic airway inflammation by regulating the phenotype and function of dendritic cells (DC) and reprogramming T helper (Th) 0 cell differentiation into different T cell (Th1/Th2/Treg) subtypes. However, the exact role of Der p2 rBCG in reprogramming Th17 differentiation and the relevant mechanisms are not known. The aim of this study was to examine whether Der p2 rBCG‐mediated inhibition of allergic airway inflammation is mediated by regulating Th17 differentiation in a murine asthma model.

Bronchoscopic Lung Volume Reduction For Pulmonary Emphysema: Preliminary Experience With Endobronchial Occluder

OBJECTIVE: To describe the self-expanding endobronchial occluder, as utilized in bronchoscopic lung volume reduction, with a 36 month follow-up procedure. METHODS: Twenty-three subjects with severe emphysema were recruited and underwent flexible bronchoscopic placement of self-expanding endobronchial occluders. Outcomes were assessed at 1 week, 1-month, 3-, 6-, 12-, 24-, and 36-month intervals. Feasibility, safety, and efficacy were analyzed by means of pulmonary function testing, 6-min walk test, dyspnea score, BODE (body mass index, air-flow obstruction, dyspnea, and exercise capacity) index, and St Georges Respiratory Questionnaire. RESULTS: Fifty-eight self-expanding endobronchial occluders were implanted into 23 lobes previously selected. No displacement was found during the follow-up. Five subjects experienced postoperative complications of cough, and 6 subjects had lobar pneumonia, which were not located in any of the blocked segments. The FEV1 in 18 subjects was improved by > 15%, compared with baselines (P < .001), and the mean first efficacy time and maximal efficacy time were 5.65 ± 1.51 months and 6.35 ± 3.08 months, respectively. No significant changes were observed in FVC or the ratio of residual volume to TLC. The 6-min walk distance, dyspnea score, and St Georges Respiratory Questionnaire total score were improved in 22 subjects over a 24-month period, and a minority of subjects continued to improve through to the end of the study. Mean baseline BODE index had improved during follow-up, but not at the studys conclusion. CONCLUSIONS: This preliminary study demonstrates early significant improvements in pulmonary function, 6-min walk distance, dyspnea score, BODE index, and quality of life after placement of the self-expanding endobronchial occluder in bronchoscopic lung volume reduction. Its placement also proved both easy and safe. However, the initial improvements were maintained long-term for only a minority of subjects.

Efficacy and tolerability of moxifloxacin in patients with respiratory tract infections treated in general practice: Results of a post-marketing surveillance study.

AbstractObjective: This study aimed to assess the efficacy, safety and tolerability of oral moxifloxacin in patients with respiratory tract infections (RTIs) treated by attending physicians in routine clinical practice in China. Methods: This was an open-label, prospective, uncontrolled, post-marketing surveillance study that was undertaken between November 2002 and July 2003. Altogether, 855 patients with RTIs were treated with moxifloxacin. Data were collected by 257 physicians throughout China. Symptoms of RTI (fever, cough, purulent sputum, dyspnoea, thoracic pain, nasal obstruction, nasal secretion and headache), together with auscultatory findings, were assessed at baseline and at follow-up visits, and classified as ‘absent’, ‘mild’ or ‘severe’ by the attending physician. Results: Moxifloxacin produced significant improvements in 70.7% of patients after only 3 days of treatment. In 91.7% of patients, symptoms were improved after 5 days of treatment; 76.1% of patients recovered after 7 days and 84.7% recovered after 10 days of treatment. The mean ± SD time until recovery was 5.1 ± 2.6 days. Assessment of treatment efficacy by the physicians was ‘good’ or ‘very good’ for 89.2% of patients. In 87.3% of cases, physicians rated patients’ acceptance of therapy with moxifloxacin as ‘good’ or ‘very good’. The tolerability of moxifloxacin therapy was rated as ‘good’ or ‘very good’ for 88.8% of patients. Very few adverse events (4.1% of patients) were reported with moxifloxacin; most of them involved mild CNS disorders and gastrointestinal disturbances. Conclusions: Moxifloxacin was shown to be an effective and well tolerated treatment for this group of patients with RTIs and was highly rated by both physicians and patients because of rapid symptom improvement and good tolerability.

Notch signaling pathway regulates the growth and the expression of inflammatory cytokines in mouse basophils

Basophils (BAs) are the least common granulocytes of all leukocytes, but they play an important role in orchestrating of chronic allergic inflammation. The Notch signaling pathway is a highly conserved pathway that influences cell lineage decisions and differentiation during various stages of development. However, the relationship between Notch signaling and BA remains to be elucidate. Here, we report that several Notch signaling molecules were found to be expressed in BAs. γ-secretase inhibitor (GSI) treatment increase BAs apoptosis, and suppress BAs proliferation. Furthermore, GSI reduced BAs in the S phase, with a concomitant accumulation in G1 and G2 phases. In addition, GSI also significantly down-regulated mRNA levels of cytokines IL-4, IL-6 and IL-13 induced by A23187, and this effect was dependent on MAPK pathway. Finally, IL-6 inhibition was specifically associated with ERK and IL-13 with JNK. Therefore, Notch signaling regulates BA biological function, at least partially via the modulation of MAPK.

Association of the glucocorticoid receptor D641V variant with steroid-resistant asthma: a case-control study.

Objectives Several mutations of the glucocorticoid receptor (GR) gene cause malfunction of the protein, resulting in steroid resistance. In diseases other than asthma, the GR variants I559N, D641V, and V729I have been linked to steroid resistance. The aim of this study was to evaluate the link of these GR variants in steroid-resistant (SR) asthma in the Chinese Han population. Methods GR polymorphisms were determined in 64 SR asthma patients, 217 steroid-sensitive (SS) asthma patients and 221 healthy control (CTR) individuals. The analysis of the GR variants was performed using PCR-sequence specific primers according to the European Molecular Biology Laboratory database (NC_000005.8). In addition, ligand binding and serum cortisol levels were determined. Results Compared with SS asthma patients and CTRs, a significant lower frequency of the GR D641V variant AA genotype (P=0.003, 0.014, respectively) and the A allele (P=0.001, 0.009, respectively) was found in SR asthma patients. Furthermore, the equilibrium dissociation constant (Kd) of GR ligand binding in SR asthma patients with the GR D641V variant AA genotype was significantly lower compared with the AT or the TT genotype carriers (P=0.006, 0.016, respectively). There was no significant difference between the I559N and V729I GR variants on comparing SR asthma patients with SS asthma patients or CTRs. Conclusion This study suggests that the D641V variant of the GR is probably associated with SR asthma in the Chinese Han population.