CircRNA0001859, a new diagnostic and prognostic biomarkers for COPD and AECOPD.

BACKGROUND: Dysregulation of circRNAs has been reported to be functionally associated with chronic obstructive pulmonary disease (COPD). The present investigation elucidated the potential role of CircRNA0001859 in regulating chronic obstructive pulmonary disease acute (COPD) and Acute Exacerbation of COPD (AECOPD). METHODS: Mice model of COPD was established to screen and verify the dysregulated expression of CircRNA0001859. Fluorescence in situ hybridization (FISH) and quantitative real-time PCR (qRT-PCR) were carried out to detect the expression of CircRNA0001859. 38 stable COPD patients, 24 AECOPD patients, 57 COPD with lung cancer patients and 28 healthy person with age and sex matched to total patients were used for the present investigation. RESULTS: circRNA0001859 was downregulated in the lung tissue of mice after the three kinds of treatments (Cigarette smoke (CS)/NK alone or CS + NNK) for inducing COPD. FISH assay verified the downregulation of circRNA0001859 both in the mice lung and human bronchial epithelial cell of COPD model. Furthermore,, the level of circRNA0001859 was also downregulated in the peripheral blood of COPD and lung cancer patients. CircRNA0001859 might act as a diagnostic and prognostic biomarker for the treatment of in COPD and AECOPD with Are under the receiver operating characteristic curve (ROC curve) (AUC) of 0.7433 and 0.8717, respectively. CONCLUSION: We explored a novel circRNA0001859, which might act as a potential therapeutic biomarker for the treatment of COPD and AECOPD.

Downregulation of hsa_circ_0007580 inhibits non-small cell lung cancer tumorigenesis by reducing miR-545-3p sponging.

Non-small cell lung cancer (NSCLC) is a highly malignant tumor. Many circular RNAs (circRNAs) are reportedly in regulating the progression of NSCLC. To identify potential therapeutic targets for NSCLC, we conducted a bioinformatics analysis of circRNAs differentially expressed between NSCLC tissues and adjacent normal tissues. Hsa_circ_0007580 was upregulated in NSCLC tumor tissues, and the expression of its host gene (protein kinase Ca) correlated negatively with overall survival. Short-hairpin RNAs were used to knock down hsa_circ_0007580 in NSCLC cells, and gene and protein levels were measured with qRT-PCR and Western blotting, respectively. NSCLC cell proliferation, migration and apoptosis were evaluated with CCK-8 assays, Ki-67 staining, Transwell assays and flow cytometry, respectively. Knocking down hsa_circ_0007580 inhibited proliferation and invasion by NSCLC cells and induced their apoptosis. Dual luciferase reporter assays indicated that miR-545-3p can bind to hsa_circ_0007580 (suggesting that hsa_circ_0007580 sponges miR-545-3p) and to protein kinase Ca (suggesting that miR-545-3p directly inhibits this gene). In a xenograft tumor model, downregulating hsa_circ_0007580 inhibited NSCLC tumorigenesis by inactivating p38/mitogen-activated protein kinase signaling. Thus, silencing hsa_circ_0007580 notably inhibited NSCLC progression in vitro and in vivo, suggesting this circRNA could be a novel treatment target for NSCLC.

miRNA­101­3p.1 as an independent diagnostic biomarker aggravates chronic obstructive pulmonary disease via activation of the EGFR/PI3K/AKT signaling pathway.

Exploring independent biomarkers and delineating pathogenic mechanisms could improve the early diagnosis and treatment of chronic obstructive pulmonary disease (COPD). In the present study, a study was conducted to determine the diagnostic potential of miRNA­101­3p.1 in identifying stable COPD (SCOPD) and acute exacerbation of COPD (AECOPD) patients and to reveal the molecular mechanism by which miRNA­101­3p.1 regulates COPD progression. miRNA­101­3p.1 profiles in peripheral blood mononuclear cells of COPD patients were evaluated. Subsequently, receiver operating characteristic curves were created to demonstrate the diagnostic accuracy of miRNA­101­3p.1 in discriminating SCOPD and AECOPD. Finally, the molecular mechanism by which miRNA­101­3p.1 regulates COPD progression was explored. The present study revealed that patients with COPD, and especially patients with AECOPD, had significantly increased levels of miRNA­101­3p.1 and the level of miRNA­101­3p.1 was closely correlated with CAT score and FEV1% predicted. Notably, miRNA­101­3p.1 accurately discriminated SCOPD and AECOPD. Furthermore, increasing miRNA­101­3p.1 promoted cell proliferation and induced the expression of inflammatory cytokines. Mechanistic investigations revealed that miRNA­101­3p.1 inhibited the expression of von Hippel­Lindau tumor suppressor (pVHL) and ubiquitin conjugating enzyme E2 D1 (UBE2D1). pVHL and UBE2D1 co­upregulated HIF­1α, and HIF­1α mediated activation of the EGFR/PI3K/AKT signaling pathway. The present results collectively demonstrated that miRNA­101­3p.1 could act as an independent biomarker for the diagnosis of SCOPD and AECOPD, and that miRNA­101­3p.1 facilitates COPD progression by activating the EGFR/PI3K/AKT signaling pathway.

Emodin enhances antitumor effect of paclitaxel on human non-small-cell lung cancer cells in vitro and in vivo.

Background: Non-small-cell lung cancer (NSCLC) was known as the most malignant tumor. Paclitaxel (PTX) is the effective drug used for the treatment of NSCLC; however, it also exhibits severe side effects. Emodin could induce apoptosis of NSCLC cells and serve as a potential cancer therapeutic agent. However, the effects of combination of emodin with PTX on NSCLC remain unclear. Thus, this study aimed to investigate the effects of emodin in combination with PTX on A549 cells. Materials and methods: The effects of combination treatment on the proliferation, apoptosis and invasion of NSCLC cells were evaluated by CCK-8, flow cytometric and TUNEL assays, respectively. In addition, Western blotting was used to detect the expressions of Bax, Bcl-2, active caspase 3, p-Akt and ERK in cells. Results: Combination of emodin with PTX synergistically inhibited the proliferation of A549 cells in vitro. In addition, we found that emodin significantly enhanced PTX-induced apoptosis in A549 cells via increasing the expressions of Bax and active caspase 3 and decreasing the levels of Bcl-2, p-Akt and p-ERK. Moreover, emodin markedly enhanced antitumor effect of PTX on A549 xenograft without significant side effects in vivo. Conclusion: Our findings indicated that emodin could significantly enhance antitumor effect of PTX in vitro and in vivo. Therefore, the combination of emodin with PTX may serve as a potential strategy for the treatment of patients with NSCLC.

Factors Associated With Prolonged Viral Shedding in Patients With Avian Influenza A(H7N9) Virus Infection.

Background: Data are limited on the impact of neuraminidase inhibitor (NAI) treatment on avian influenza A(H7N9) virus RNA shedding. Methods: In this multicenter, retrospective study, data were collected from adults hospitalized with A(H7N9) infection during 2013-2017 in China. We compared clinical features and A(H7N9) shedding among patients with different NAI doses and combination therapies and evaluated factors associated with A(H7N9) shedding, using Cox proportional hazards regression. Results: Among 478 patients, the median age was 56 years, 71% were male, and 37% died. The median time from illness onset to NAI treatment initiation was 8 days (interquartile range [IQR], 6-10 days), and the median duration of A(H7N9) RNA detection from onset was 15.5 days (IQR, 12-20 days). A(H7N9) RNA shedding was shorter in survivors than in patients who died (P < .001). Corticosteroid administration (hazard ratio [HR], 0.62 [95% confidence interval {CI}, .50-.77]) and delayed NAI treatment (HR, 0.90 [95% CI, .91-.96]) were independent risk factors for prolonged A(H7N9) shedding. There was no significant difference in A(H7N9) shedding duration between NAI combination treatment and monotherapy (P = .65) or between standard-dose and double-dose oseltamivir treatment (P = .70). Conclusions: Corticosteroid therapy and delayed NAI treatment were associated with prolonged A(H7N9) RNA shedding. NAI combination therapy and double-dose oseltamivir treatment were not associated with a reduced A(H7N9) shedding duration as compared to standard-dose oseltamivir.

Matrine increases the inhibitory effects of afatinib on H1975 cells via the IL­6/JAK1/STAT3 signaling pathway.

Resistance to epidermal growth factor receptor (EGFR) inhibitors is of primary concern in the treatment of non­small­cell lung cancer (NSCLC) with EGFR mutations. To investigate the effects of matrine on H1975 cells and to examine a novel, potential treatment option for NSCLC, the present study measured cell viability, apoptotic rate, interleukin 6 (IL­6) expression and activation of the janus kinase (JAK) 1/signal transducer and activator of transcription (STAT)3 signaling pathway in cells treated with or without matrine, in the presence or absence of afatinib. The results demonstrated that matrine treatment inhibited cell growth, decreased B­cell lymphoma 2 (Bcl­2) expression and induced apoptosis. Matrine treatment additionally decreased the mRNA and protein levels of IL­6 and inhibited activation of the JAK1/STAT3 signaling pathway in H1975 cells in a dose­dependent manner. H1975 cells treated with IL­6 small interfering RNA exhibited a decrease in Bcl­2 expression levels and cell viability. Treatment with a combination of matrine and afatinib demonstrated increased inhibitory effects on the growth rate of H1975 cells. The findings of the present study suggested that matrine treatment decreases IL­6 expression, inhibits activation of the JAK1/STAT3 signaling pathway, reduces the expression levels of Bcl­2 and inhibits cell growth. Furthermore, matrine treatment was demonstrated to increase the inhibitory effects of afatinib on H1975 cells with the T790M EGFR mutation.

Preparation, characterization and anticancer activity of norcantharidin-loaded poly(ethylene glycol)-poly(caprolactone) amphiphilic block copolymer micelles.

In this study, a novel amphiphilic block copolymer biomaterial - poly (ethylene glycol)-poly (caprolactone) (PEG-PCL), was used to entrap norcantharidin (NCTD), taking advantage of self-assembly theory. Dialysis and volatilization dialysis were used to prepare copolymer micelles. Drug-loaded micelles were compared with blank micelles in terms of their particle diameter, morphology and IR spectral characteristics. The results revealed that there was no significant difference in respect of morphology and IR spectrum, but particle size differed. Drug-loaded micelles had a smaller particle size than blank micelles. Three important factors influencing particle size, the drug loading content (LC) and the drug entrapment efficiency (EE) of the NCTD-loaded micelles, were studied. The results indicated that the method of preparation and the type of organic solvent had a significant influence on the size of the micelles. LC and EE were greatly affected by the ratio of NCTD to copolymer. In vitro release of NCTD from the conjugate micelles showed that its release rate depended on the pH of the phosphate buffer solution (PBS). The amount released was higher at lower pH than under neutral conditions. In vitro antitumor activity of the NCTD conjugate against human hepatoma (HepG2) cell line and human lung cancer (A549) cell line was evaluated by the MTT method. Micelles loaded with NCTD demonstrated greater and more satisfactory cell viability inhibition than the free drug. In vivo antitumor activity of drug-loaded micelles was investigated in mice bearing S180 mouse sarcoma. NCTD-loaded micelles displayed tumor inhibition effects, better than the free drug. As a new drug delivery system, copolymer micelles present many advantages including easy formulation, good water solubility, low toxicity and high treatment efficacy, and show great potential as carriers of hydrophobic drugs.

Receptor-mediated, tumor-targeted gene delivery using folate-terminated polyrotaxanes.

Safe and effective gene delivery is essential to the success of gene therapy. We synthesized and characterized a novel nonviral gene delivery system in which folate (FA) molecules were functioned as blockers on cationic polyrotaxanes (PR) composed of poly(ethylenimine) (PEI)(600)-grafted α-cyclodextrin rings linearized on polyethylene glycol to form FA-terminated PR-PEI(600) (FPP). The FA terminal caps of FPP target cell surfaces abundant in FA receptor (FR), a common feature of tumor cells. The structure of FPP was characterized by using (1)H nuclear magnetic resonance ((1)H NMR). The delivery particle was composed of chemically bonded PEG (4000), α-cyclodextrins (CD), and PEI (600 Da) at a molar ratio of 1:17:86.7, and the particle size and zeta potential of FPP/pDNA polyplexes were measured using dynamic light scattering. FPP/pDNA exhibited a lower cytotoxicity, strong specificity to FR, and high efficiency of delivering DNA to target cells in vitro and in vivo with the reporter genes. Furthermore, the FPP/DNA complex showed an enhanced antitumor effect in the nude mice compared with other delivery systems, such as PEI-25K. Together, these results suggest that FPP may be useful for gene therapy.