Topotecan alleviates ventilator-induced lung injury via NF-κB pathway inhibition.

OBJECTIVE: We investigated the effect of topotecan on injury and inflammation in a model of ventilator-inducedlunginjury (VILI). METHODS: Acute lung injury (ALI) was induced in mice by high-tidal volume ventilation, and the mice were then treated with topotecan or PBS. Lung tissue and bronchoalveolar lavage fluid were collected to assess pulmonary vascular leaks, inflammation, and cell apoptosis. RESULTS: Compared to PBS treatment, topotecan significantly decreased the ALI score, myeloperoxidase (MPO) content, total protein concentration, and presence of inflammatory cells and inflammatory cytokines in bronchoalveolar lavage fluid. Topotecan also reduced caspase-3 activation and type Ⅱ alveolar epithelial cell apoptosis. Moreover, topotecan inhibited NF-κB expression and activation in the VILI model. CONCLUSION: Topotecan alleviates acute lung injury in the model of VILI through the inhibition of the NF-κB pathway.

Plasma long noncoding RNA IL-7R as a prognostic biomarker for clinical outcomes in patients with acute respiratory distress syndrome.

BACKGROUND: Long non-coding RNAs (lncRNAs) regulate a variety of genes and biological processes. Lnc-IL7R plays a considerable role in the regulation of inflammation, but its prognostic potential in acute respiratory distress syndrome (ARDS) has not been fully explained. In this study, the role of lnc-IL7R as a potential biomarker in ARDS was examined. OBJECTIVE: Role of lnc-IL7R as potential biomarker in ARDS. METHODS: LncRNA-IL7R was isolated from the plasma of patients with ARDS and healthy controls and clinical indexes were obtained within 24 h after admission. The relative expression of lnc-IL7R was obtained by quantitative real-time PCR. The correlations between lnc-IL7R and continuous variables in ARDS were tested using Spearman's coefficients. RESULTS: A total of 85 ARDS patients and 49 healthy controls were included. Plasma lnc-IL7R was significantly down-regulated in ARDS compared with the levels in healthy control individuals, especially in severe ARDS (P < .01). The area under the curve (AUC) of lnc-IL7R for ARDS diagnosis was 0.87 (sensitivity 75.3%, specificity 93.9%). The lnc-IL7R levels were correlated with the severity of ARDS (ρ = -0.31, P = .0215), oxygenation index (ρ = 0.61, P < .001), APACHE II score (ρ = -0.04, P = .0230), CRP (ρ = -0.26, P = .0148) and WBC (ρ = -0.29, P = .0064). Lnc-IL7R relative value ≥ 0.33 showed the lower 28-day mortality in the patients with ARDS(P < .05).The survivors showed higher lnc-IL7R level and lower APACHE II score, SOFA score and length of mechanical ventilation than in the non-survivors (P = .0109, P < .001, P < .001 and P = .017, respectively). CONCLUSIONS: Lnc-IL7R is a novel biomarker for the diagnosis of ARDS and predicts the severity of ARDS and 28-day mortality in this patients cohort. TRIAL REGISTRATION: The study was registered with the Chinese Clinical Trial Registry (ChiCTR-DOD-16008657).

Protein regulator of cytokinesis-1 expression: prognostic value in lung squamous cell carcinoma patients.

BACKGROUND: Protein regulator of cytokinesis-1 (PRC1) has been shown to participate in the completion of cytokinesis, and it is dysregulated in cancer processes. However, its relevance in lung squamous cell carcinoma (SCC) remained largely unknown. We aimed to study the expression pattern of PRC1 and assess its clinical significance in lung SCC. METHODS: PRC1 protein expression in human lung SCC and adjacent normal lung tissues was detected by immunohistochemistry. PRC1 expression was assessed in association with clinicopathological features and clinical outcomes of lung SCC patients. RESULTS: In lung SCC tissues, PRC1 protein expression was significantly higher than those in paired normal lung tissues. The lung SCC patients with PRC1 overexpression had an advanced pathological stage (TNM stage), positive lymph node metastasis, and a shorter overall survival (OS) time more frequently than patients with low PRC1 expression. Additional, PRC1 expression was also shown to be poor as a prognostic factor for OS in patients with lung SCC. CONCLUSIONS: Our study indicated that aberrant expression of PRC1 may point to biochemical recurrence in lung SCC. This highlights its potential as a valuable prognostic marker for lung SCC.

PRC1 contributes to tumorigenesis of lung adenocarcinoma in association with the Wnt/ß-catenin signaling pathway.

BACKGROUND: Protein regulator of cytokinesis-1 (PRC1) belongs to the microtubule-associated proteins (MAPs) family, and is involved in cytokinesis. Recent investigations suggest PRC1 involvement in human carcinogenesis, including breast carcinoma, hepatocellular carcinoma and etc. However, whether PRC1 contributes to lung adenocarcinoma tumorigenesis remains unknown. METHODS: Quantitative reverse-transcription polymerase chain reaction (qRT-PCR), Western blotting and Immunohistochemical staining (IHC) were used to evaluate and contrast the PRC1 expression profile in lung adenocarcinoma and adjacent normal lung tissues. We examined the clinical use of PRC1 in lung adenocarcinoma prognosis. Additionally, the tumorigenesis impact of PRC1 in lung adenocarcinoma cells was verified via in vitro and in vivo metastasis and tumorigenesis assays. Notably, Next Generation Sequencing (NGS) was performed to investigate the molecular mechanism underlying the oncogenic role of PRC1 in lung adenocarcinoma. RESULTS: PRC1 mRNA and protein expressions were upregulated in lung adenocarcinoma tissues compared to adjacent normal lung tissues. PRC1 protein overexpression correlated with lymph node metastasis and was an independent poor prognostic factor for lung adenocarcinoma patients. Our data implied that PRC1 depletion limited the proliferation and invasion of lung adenocarcinoma cells in vitro and lowered tumor development and lung metastasis in vivo. Remarkably, limiting PRC1 substantially prompted G2/M phase cell cycle arrest and apoptosis. Mechanistically, by conducting NGS on PRC1-depleted A549 cells and control cells, we discovered that PRC1 expression was significantly correlated with the Wnt signaling pathway. CONCLUSIONS: This investigation offers confirmation that PRC1 is a prognostic and promising therapeutic biomarker for people with lung adenocarcinoma and takes on a key part in the activation of the Wnt/ß-catenin pathway in lung adenocarcinoma development.

NCAPG2 promotes tumour proliferation by regulating G2/M phase and associates with poor prognosis in lung adenocarcinoma.

NCAPG2 is a component of the condensin II complex and contributes to chromosome segregation via microtubule-kinetochore attachment during mitosis. It is well known that NCAPG2 plays a critical role in cell mitosis; however, the role of altered NCAPG2 expression and its transcriptional regulatory function in cancer development remains mostly unknown. Here, for the first time we reported that NCAPG2 was evidently increased in non-small cell lung cancer tissues compared to adjacent normal lung tissues. Clinicopathological data analysis showed that NCAPG2 overexpression was significantly correlated with lymph node metastasis and pathologic-Tumour Nodes Metastasen stages, and was an independent prognostic factor in lung adenocarcinoma patients. Moreover, siRNA-mediated knockdown of NCAPG2 could inhibit tumour cell growth of lung adenocarcinoma cells (A549 and H1299) in vitro and could significantly lead to cell cycle arrest in the G2 phase. Furthermore, we found that NCAPG2 silencing significantly decreased the expression levels of G2/M phase cell cycle-related protein expressions (Cyclin B1, Cdc2) and increased the expression levels of p27 and p21 through Western blot analysis. Taken together, we demonstrated that increased NCAPG2 expression could regulate cell proliferation and identified as a poor prognostic biomarker in lung adenocarcinoma.

Bisbibenzyl derivatives sensitize vincristine-resistant KB/VCR cells to chemotherapeutic agents by retarding P-gp activity.

P-glycoprotein (P-gp) is known to mediate multidrug resistance (MDR) by acting as an efflux pump to actively transport chemotherapeutic agents out of carcinoma cells. Inhibition of P-gp function may represent one of the strategies to reverse MDR. We have previously reported that marchantin C (MC), a macrocyclic bisbibenzyl compound from liverworts, exerts anti-tumor activity as an antimitotic agent. This study was designed to evaluate the possible modulatory effect of MC and its three synthetic derivatives (MC1, MC2 and MC3) on P-gp in VCR-resistant KB/VCR cells. Results of the cytotoxicity assay revealed that MC was the most potent inhibitor of cell proliferation in both KB and KB/VCR cells among these four compounds, while the three MC-derived chemicals had little anti-proliferative activity under the same condition. However, in P-gp-expressing MDR cells, analysis of potency of these compounds in enhancing cytotoxicity of VCR led to the identification of MC2 as a more effective chemical on reversal of resistance. Further study showed that MC2 was able to reduce efflux of rhodamine-123, and in turn, increase the accumulation of rhodamine-123 and adriamycin in KB/VCR cells, indicating that MC2 re-sensitized cells to VCR by inhibition of the P-gp transport activity. In addition, the combination of MC2 and VCR at a concentration that does not inhibit cell growth resulted in an induction of apoptosis in KB/VCR cells. These results suggest that MC2, as a novel and effective inhibitor of P-gp, may find potential application as an adjunctive agent with conventional chemotherapeutic drugs to reverse MDR in P-gp overexpressing cancer cells.

Labdane diterpenoids and highly methoxylated bibenzyls from the liverwort Frullania inouei.

Four undescribed labdane diterpenoids, 1,2-dehydro-3,7-dioxo-manoyl oxide (1), 1,2-dehydro-7 beta-hydroxy-3-oxo-manoyl oxide (2), 3,7-dioxo-manoyl oxide (3), and 3beta-hydroxy-7-oxo-manoyl oxide (4) together with three known diterpenoids (5-7) and four highly methoxylated bibenzyls (8-11) were isolated from the liverwort Frullania inouei. The absolute structures of 1-4 were established by combined analysis of NMR data, CD data coupled with TDDFT CD calculations, and single-crystal X-ray diffraction measurement. Cytotoxicity tests to human tumor KB, KB/VCR, K562 or K562/A02 cells showed bibenzyls 8-11 inhibited cell proliferation with ID(50) values ranging from 11.3 to 49.6 microM and overcame the multidrug resistance (MDR) with the reversal fold (RF) values ranging from 3.19 to 10.91 (5 microM) for vincristine-resistant KB/VCR and RF values from 4.40 to 8.26 (5 microM) for adriamycin-resistant K562/A02 cells, respectively. However, none of the diterpenoids were found to be active (ID(50)>50 microM).

Synthesis and multidrug resistance reversal activity of dihydroptychantol A and its novel derivatives.

The macrocyclic bisbibenzyl dihydroptychantol A (DHA), previously isolated from Asterella angusta, was synthesized and showed significant multidrug resistance (MDR) reverting activity in chemoresistant cancer cells. In an attempt to discover more potent MDR reversal agents for efficient cancer chemotherapy, DHA derivatives with thiazole rings (19-22) were synthesized, and their cytotoxicities and MDR reversal activities were evaluated in adriamycin-resistant K562/A02, vincristine-resistant KB/VCR and in their parental cells by MTT assays. In response to treatment with each compound, the K562 cell line was the most sensitive, and the vincristine-resistant KB/VCR cell line was the most resistant. Marked decreases in K562 and K562/A02 cell viability were detectable after treatment with the synthesized derivatives of DHA, while less inhibitory effects on cell growth were observed in chemical-resistant KB/VCR and KB cells. Moreover, among the tested compounds, the intermediate 17 and the analogues 19, 20, and 21 showed potent MDR reversal activities and increased vincristine cytotoxicity in KB/VCR cells, with the reversal fold ranges from 10.54 to 13.81 (10microM), which is 3.2-4.3-fold stronger than the natural product DHA.