Identification of arnicolide C as a novel chemosensitizer to suppress mTOR/E2F1/FANCD2 axis in non-small cell lung cancer.

BACKGROUND AND PURPOSE: The mammalian target of rapamycin (mTOR) pathway plays critical roles in intrinsic chemoresistance by regulating Fanconi anaemia complementation group D2 (FANCD2) expression. However, the mechanisms by which mTOR regulates FANCD2 expression and related inhibitors are not clearly elucidated. Extracts of Centipeda minima (C. minima) showed promising chemosensitizing effects by inhibiting FANCD2 activity. Here, we have aimed to identify the bioactive chemosensitizer in C. minima extracts and elucidate its underlying mechanism. EXPERIMENTAL APPROACH: The chemosensitizing effects of arnicolide C (ArC), a bioactive compound in C. minima, on non-small cell lung cancer (NSCLC) were investigated using immunoblotting, immunofluorescence, flow cytometry, the comet assay, small interfering RNA (siRNA) transfection and animal models. The online SynergyFinder software was used to determine the synergistic effects of ArC and chemotherapeutic drugs on NSCLC cells. KEY RESULTS: ArC had synergistic cytotoxic effects with DNA cross-linking drugs such as cisplatin and mitomycin C in NSCLC cells. ArC treatment markedly decreased FANCD2 expression in NSCLC cells, thus attenuating cisplatin-induced FANCD2 nuclear foci formation, leading to DNA damage and apoptosis. ArC inhibited the mTOR pathway and attenuated mTOR-mediated expression of E2F1, a critical transcription factor of FANCD2. Co-administration of ArC and cisplatin exerted synergistic anticancer effects in the A549 xenograft mouse model by suppressing mTOR/FANCD2 signalling in tumour tissues. CONCLUSION AND IMPLICATIONS: ArC suppressed DNA cross-linking drug-induced DNA damage response by inhibiting the mTOR/E2F1/FANCD2 signalling axis, serving as a chemosensitizing agent. This provides insight into the anticancer mechanisms of ArC and offers a potential combinatorial anticancer therapeutic strategy.

Nursing Assistant Staffing Model: Implementation and Outcome Evaluation in Taiwan Hospitals.

BACKGROUND: A key policy of the Taiwan healthcare system is promoting the hiring of nursing assistants (NAs) to reduce the workload of nurses. However, few studies in the literature have compared the relative effectiveness of different nurse staffing policies, and no studies have addressed the impact of the NA staffing (NAS) model. PURPOSE: This study explored the current status of the NAS model as implemented in Taiwan hospitals and to investigate the methods used to evaluate the outcomes of NAS model implementation. METHODS: A cross-sectional online survey was performed in hospitals nationwide from June 1 to December 31, 2018. There were 153 government-accredited hospitals being invited to participate in the survey. RESULTS: Of the 139 hospitals that completed the online survey, 26% (36 hospitals) had implemented the NAS model. Many of the hospitals had hired full-time, certified NAs. Most of the tasks assigned to NAs were in the nonprofessional/general and technical work categories. In addition, medical wards were the most frequently assigned workplace, especially on day shifts. Few of the surveyed hospitals had evaluated the effectiveness of the NAS model. Improvement after implementation of the NAS model (based on the 35 outcome indicators) was found to vary significantly. The most commonly used outcome indicator was patient satisfaction. All the stakeholders, including patients, family caregivers, nurses, and nurse supervisors, supported implementation of the NAS model. However, some of the participants expressed concerns regarding the difficulties involved with model implementation. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Although the NAS model may be beneficial, further empirical research is necessary to confirm the contributions of NAs. Additional evidence regarding the benefits of the NAS model for hospital performance and patient outcomes may be expected to motivate more hospital administrators to adopt this model.

Characteristic and Synthesis of High-Temperature Resistant Liquid Crystal Epoxy Resin Containing Boron Nitride Composite.

Five liquid crystal epoxy resins and composites containing flat boron nitride (f-BN) and spherical boron nitride (s-BN) were successfully synthesized. The chemical structures, crystal diffraction, and thermal conductivity of the liquid crystal (LC) epoxy composites were measured using Nuclear Magnetic Resonance (NMR), Differential Scanning Calorimetry (DSC), X-ray, and Discovery Xenon Flash. In this study, the molecular arrangement of five LC epoxy resins and the thermal conductivity of their composites were carefully discussed. Several different amounts of flat boron nitride and spherical boron nitride were added to the five LC epoxy resins. The influence of nano-scale ceramic materials, f-BN, and s-BN, on the thermal conductivity of the LC epoxy resins, was studied. It is worth noting that the thermal conductivity of the spherical boron nitride composite demonstrated a better result than that of the flat boron nitride composite. In simpler terms, the thermal conductivity of the composites is closely related to the molecular arrangement of the LC resin and the amount of BN added. The results demonstrate that the SBPDAE/s-BN (60%) composite shows the highest thermal conductivity of 9.36 W/mK in the vertical direction. These data prove that the LC alignment of the matrix will greatly enhance the thermal conductivity of the composites.

8-Formylophiopogonanone B induces ROS-mediated apoptosis in nasopharyngeal carcinoma CNE-1 cells.

Cancer is one of the leading causes of death in the world. It is very important to find drugs with high efficiency, low toxicity, and low side effects for the treatment of cancer. Flavonoids and their derivatives with broad biological functions have been recognized as anti-tumor chemicals. 8-Formylophiopogonanone B (8-FOB), a naturally existed homoisoflavonoids with rarely known biological functions, needs pharmacological evaluation. In order to explore the possible anti-tumor action of 8-FOB, we used six types of tumor cells to evaluate in vitro effects of this agent on cell viability and tested the effects on clone formation ability, scratching wound-healing, and apoptosis. In an attempt to elucidate the mechanism of pharmacological action, we examined 8-FOB-induced intracellular oxidative stress and -disrupted mitochondrial function. Results suggested that 8-FOB could suppress tumor cell viability, inhibit cell migration and invasion, induce apoptosis, and elicit intracellular ROS production. Among these six types of tumor cells, the nasopharyngeal carcinoma CNE-1 cells were the most sensitive cancer cells to 8-FOB treatment. Intracellular ROS production played a pivotal role in the anti-tumor action of 8-FOB. Our present study is the first to document that 8-FOB has anti-tumor activity in vitro and increases intracellular ROS production, which might be responsible for its anti-tumor action. The anti-tumor pharmacological effect of 8-FOB is worthy of further investigation.

Concentrations and health risks of heavy metals in five major marketed marine bivalves from three coastal cities in Guangxi, China.

Seafood consumption provides essential elements to humans while also posing risks to human health. A total of 2610 individuals of five edible marine bivalve species (Ruditapes philippinarum, Paphia undulata, Meretrix meretrix, Sinonovacula constricta and Meretrix lyrata) were randomly sampled from six farmer markets in three cities (Beihai, Qinzhou and Fangchenggang) in the southernmost coastal region of China. The concentrations of heavy metals (Cu, Pb, Zn, Cd, Cr, Hg and As) were determined by inductively coupled plasma mass spectrometry (ICP-MS). The estimated daily intake (EDI), target hazard quotient (THQ), total hazard index (HI), and target cancer risk (TR) were calculated to evaluate potential human health risks from bivalve consumption. The mean concentrations of metals in the tissues of bivalves descended in the order Zn > Cu > As > Cd > Cr >Pb > Hg in descending order, and the concentrations varied substantially among the five bivalves. Heavy metal concentrations in edible tissues of most bivalve samples were below the safety limits set by national and international regulations, and there were significant correlations between certain metal concentrations. The EDI values for each metal in each bivalve were significantly lower than the corresponding PTDI (provisional tolerable daily intake) values. Health risk assessment showed that although there is no noncarcinogenic health risk for local residents exposed to individual or combined metals from these bivalves, there is a carcinogenic risk from Cd and Cr exposure. Thus, in the long term, monitoring and controlling bivalve consumption will be important. Although current accumulation levels of bivalves are safe, continued and excessive lifetime consumption over 70 years may pose a target cancer risk.

Synthesis and Thermal Characteristic of Liquid Crystalline Polyoxetane Containing Trans-Stilbene Side Group.

A series of fourteen liquid crystalline monomers and polyoxetanes containing trans-biphenyl side group have been successfully synthesized. The thermal and mesomorphic properties of monomers (1M~14M) and polymers (1P~14P) are measured using DSC, POM, and X-ray. All of the series monomers present enantiotropic smectic H and smectic G phase and the series polymers show enantiotropic smectic A phase which three polymers contained exhibit smectic E. Polyoxetanes have been used as a cationic ring-opening polymerization of oxetane monomers bearing a pendant trans-stilbene mesogenic unit including different spacer length and terminal alkyl length.

8-Formylophiopogonanone B Antagonizes Paraquat-Induced Hepatotoxicity by Suppressing Oxidative Stress.

Flavonoids are some of the most important natural products with a variety of physiological activities. 8-Formylophiopogonanone B (8-FOB) is a naturally existing homoisoflavonoid in Ophiopogon japonicus. Paraquat (PQ) has been widely used as a potent herbicide and has high toxicity in humans. The goal of the present study was to investigate whether 8-FOB could protect against PQ-induced hepatotoxicity in vitro and in vivo. We first tested the protective effects of 8-FOB on PQ-induced cytotoxicity in L02 cells by determining cell viability, intracellular oxidative stress levels, mitochondrial function, and apoptosis in vitro. To verify the protective effects of 8-FOB, we pretreated mice with 8-FOB and assessed liver function, hepatic oxidative stress, and histopathological changes after PQ administration. Our results revealed that 8-FOB could antagonize PQ-induced hepatotoxicity in vitro and in vivo. The antagonistic effects could be attributed to suppressing oxidative stress, preserving mitochondrial function, and inhibiting apoptosis. The present study is the first to document that 8-FOB, a homoisoflavonoid compound, is an effective antioxidant for antagonizing PQ-induced hepatotoxicity.

Lipoic acid antagonizes paraquat-induced vascular endothelial dysfunction by suppressing mitochondrial reactive oxidative stress.

Paraquat (PQ) is a widely used herbicide in the agricultural field. The lack of an effective antidote is the significant cause of high mortality in PQ poisoning. Here, we investigate the antagonistic effects of alpha lipoic acid (α-LA), a naturally existing antioxidant, on PQ toxicity in human microvascular endothelial cells (HMEC-1). All the doses of 250, 500 and 1000 µM α-LA significantly inhibited 1000 µM PQ-induced cytotoxicity in HMEC-1 cells. α-LA pretreatment remarkably diminished the damage to cell migration ability, recovered the declined levels of the vasodilator factor nitric oxide (NO), elevated the expression level of endothelial nitric oxide synthases (eNOS), and inhibited the upregulated expression of vasoconstrictor factor endothelin-1 (ET-1). Moreover, α-LA pretreatment inhibited reactive oxygen species (ROS) generation, suppressed the damage to the mitochondrial membrane potential (ΔΨ m) and mitigated the inhibition of adenosine triphosphate (ATP) production in HMEC-1 cells. These results suggested that α-LA could alleviate PQ-induced endothelial dysfunction by suppressing oxidative stress. In summary, our present study provides novel insight into the protective effects and pharmacological potential of α-LA against PQ toxicity in microvascular endothelial cells.

Characterization of Somatic Mutations in Air Pollution-Related Lung Cancer.

Air pollution has been classified as Group 1 carcinogenic to humans, but the underlying tumorigenesis remains unclear. In Xuanwei City of Yunnan Province, the lung cancer incidence is among the highest in China attributed to severe air pollution generated by combustion of smoky coal, providing a unique opportunity to dissect lung carcinogenesis of air pollution. Here we analyzed the somatic mutations of 164 non-small cell lung cancers (NSCLCs) from Xuanwei and control regions (CR) where smoky coal was not used. Whole genome sequencing revealed a mean of 289 somatic exonic mutations per tumor and the frequent C:G â†’ A:T nucleotide substitutions in Xuanwei NSCLCs. Exome sequencing of 2010 genes showed that Xuanwei and CR NSCLCs had a mean of 68 and 22 mutated genes per tumor, respectively (p < 0.0001). We found 167 genes (including TP53, RYR2, KRAS, CACNA1E) which had significantly higher mutation frequencies in Xuanwei than CR patients, and mutations in most genes in Xuanwei NSCLCs differed from those in CR cases. The mutation rates of 70 genes (e.g., RYR2, MYH3, GPR144, CACNA1E) were associated with patients' lifetime benzo(a)pyrene exposure. This study uncovers the mutation spectrum of air pollution-related lung cancers, and provides evidence for pollution exposure-genomic mutation relationship at a large scale.

Study on the effect of BMSCs-EGFP-tk as mediator of HSV1-tk/GCV suicide gene therapy directed against A549 in vitro.

This study aims to observe the expression of HSV1-tk in mouse bone marrow mesenchymal stem cells (BMSCs-EGFP-tk) and detect the inhibition and killing effects of BMSCs as mediator of HSV1-tk/GCV on A549 cells in vitro, which can provide the experimental basis for gene therapy of lung cancer. We constructed the recombinant plasmid Vector pDON-AI-2 Neo-HSV1-tk-IRES2-EGFP with genetic engineering methods. Then we obtained the virus-like particles with infection ability after packaging the virus. The recombinant plasmid was transfected into mouse bone marrow mesenchymal stem cells in vitro. The expressions of EGFP in cells were observed by fluorescence microscopy and HSV1-tk gene was detected with RT-PCR. At last, the A549 cells and BMSCs-EGFP-tk cells were co-cultured with in vitro contact method, and the effect of BMSCs-EGFP-tk/GCV system was determined by MTT. Results indicated that the biological characteristics of BMSCs-EGFP-tk were consistent with those of BMSCs and fluorescent light expression and HSV1-tk gene expression can persist at least 15 days. The A549 cells and BMSCs-EGFP-tk cells were co-cultured and BMSCs-EGFP-tk:A549 = 2:1, adding 1 µg/mL GCV, the theory mortality is 58.44%, but actually the mortality is 90%. There is almost no difference between BMSCs-EGFP-tk and BMSCs cells in biological characteristics. The growth of A549 cells have an obviously inhibition and the bystander effect is outstanding in vitro after co-culture and this experiment lays solid foundation for the future research.

Largazole Arrests Cell Cycle at G1 Phase and Triggers Proteasomal Degradation of E2F1 in Lung Cancer Cells.

Aberration in cell cycle has been shown to be a common occurrence in lung cancer, and cell cycle inhibitor represents an effective therapeutic strategy. In this study, we test the effects of a natural macrocyclic depsipeptide largazole on lung cancer cells and report that this compound potently inhibits the proliferation and clonogenic activity of lung cancer cells but not normal bronchial epithelial cells. Largazole arrests cell cycle at G1 phase with up-regulation of the expression of cyclin-dependent kinase inhibitor p21. Interestingly, largazole enhances the E2F1-HDAC1 binding affinity and induces a proteasomal degradation of E2F1, leading to suppression of E2F1 function in lung cancer but not normal bronchial epithelial cells. Because E2F1 is overexpressed in lung cancer tumor samples, these data indicate that largazole is an E2F1-targeting cell cycle inhibitor, which bears therapeutic potentials for this malignant neoplasm.