Abstract.It has previously been demonstrated that the long non-coding RNA (lncRNA) nuclear enriched abundant transcript (NEAT)-1 is increased in multiple cancers and may be associated with cancer development. However, the function and mechanism of NEAT1 in non-small cell lung cancer (NSCLC) has not yet been fully elucidated. In the present study, the expression of NEAT1 in NSCLC was detected using quantitative polymerase chain reaction and association with survival was estimated. The effect of NEAT1 on proliferation was detected by growth curve and cell cycle analysis. Bioinformatics analysis was used to identify miRNAs that interact with NEAT1. Following this, a series of molecular biological techniques were used to verify the mechanism of NEAT1. The results indicated that NEAT1 was highly expressed in NSCLC, and high NEAT1 expression was associated with a shorter overall survival. NEAT1 promoted NSCLC cell growth and affected the cell cycle process in vitro. Furthermore, NEAT1 was observed to bind hsa-miR-377-3p, functioning as a competing endogenous RNA, which resulted in de-repression of its target gene E2F transcription factor 3 (E2F3). E2F3, as an oncogene, may promote NSCLC progression. These results suggested that NEAT1 may promote the development of NSCLC through the miR-377-3p-E2F3 pathway.

Oligo(ethylene glycol)-linked light fluorous tags have been found to be optimal for conjugating to glycans for both high-yield enzymatic glycosylation reactions using one-pot multienzyme (OPME) systems and quick product purification using fluorous solid-phase extraction (FSPE) cartridges. The combination of OPME glycosylation systems and the FSPE cartridge purification scheme provides a highly effective strategy for facile synthesis and purification of glycans.

Xeroderma pigmentosum, complementation group C (XPC) is an accessory recognition gene involved in the nucleotide excision repair (NER) pathway, which is activated during the initial DNA damage recognition stage. It participates in the regulation of DNA damage-induced proliferation and apoptosis. Emerging evidence demonstrates that upregulation of XPC increases the resistance of several tumor cell types to cytotoxic drugs. In addition, it can predict poor patient outcome for non-small cell lung cancer (NSCLC). However, the mechanisms linking upregulation of XPC and drug resistance in lung cancer are still unclear. In the present study, we aimed to confirm whether XPC was involved in the reversal of the cisplatin (DDP) resistance in drug-resistant A549/DDP lung adenocarcinoma cells. RT-PCR and western blot assays were used to examine XPC mRNA and protein expression levels. Cell viability was assessed by CCK-8 assay. The knockdown of XPC was achieved in A549/DDP cells using si-RNA, whereas cell proliferation and apoptosis were assessed by wound healing assay and flow cytometric analysis, respectively. The median inhibitory concentration (IC 50 ) value of DDP was assessed by CCK-8 assay. Western blot assays were conducted for the examination of caspase-9/3, Bax and Bcl-2 protein levels, whereas the activation of the PI3K/Akt/mTOR signaling pathway was investigated in XPC-knockdown cells. High expression of XPC was noted in A549/DDP cells compared with that in A549 cells, which was associated with DDP resistance. XPC silencing significantly inhibited A549/DDP cell proliferation and increased the induction of apoptosis. In addition, XPC knockdown decreased the expression levels of the Akt/mTOR signaling proteins and the expression of their downstream mediator. The data of the present study revealed that XPC inhibition rescued DDP resistance in lung adenocarcinoma cells, which was dependent on the Akt/mTOR signaling pathway. Collectively, XPC may be considered a new strategy for curing DDP-resistant lung cancer and may improve the efficacy of conventional chemotherapy.

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SummaryIn this study, we investigated the protection effect of Vitamin E (Vit E) on formaldehyde (FA) exposure during pregnancy induced apoptosis of cardiomyocytes, and used an HL-1 cell line to confirmed the findings in vivo.Pregnant mice received different doses of FA (0.5 mg/kg, 1.0 mg/kg, 1.5 mg/kg, 0.1 μg Vit E, or 1.5 mg/ kg + 0.1 μg Vit E). TUNEL staining was used to reveal the apoptosis in cardiomyocytes, and SOD, MDA, GSH, Livin, and Caspase-3 in cardiomyocytes were detected by ELISA, RT-PCR, and Western blot. For in vitro study, HL-1 cells were treated with vehicle, 5 μmol/L FA, 25 μmol/L FA, 50 μmol/L FA, 10 mg/L Vit. E, and 50 μmol/L FA+ 10 mg/L Vit E, respectively. CCK-8 assay and flow cytometry were used to evaluate cell vitality and apoptosis. A high dose of FA exposure led to cytotoxicity in both pregnant mice and offspring, as TUNEL staining revealed a significant apoptosis of cardiomyocytes, and the alternation in SOD, GSH, MDA, Livin, and Caspase-3 was found in cardiomyocytes. 0.1 μg Vit. E could reverse high doses of FA exposure induced apoptosis of cardiomyocytes in both pregnant mice and offspring. The in vitro study revealed that FA exposure induced a decrease of cell viability and increased cell apoptosis, as well as oxidative stress in HL-1 cells with alternation in SOD, GSH, MDA, Livin, and Caspase-3.This study revealed a high dose of FA induced oxidative stress and apoptosis of cardiomyocytes in both pregnant mice and offspring, and Vit E supplement during pregnancy reversed the systemic and myocardial toxicity of FA.(Int Heart J 2017; 58: 769-777)

Gemcitabine (GEM)-based chemotherapy is the standard regimen for the treatment of pancreatic cancer (PC). However, chemoresistance is a major challenge in PC treatment. Reliable biomarkers are urgently needed to predict the response to GEM-based therapies. GEM-sensitive (GEM-S) and GEM-resistant (GEM-R) pancreatic carcinoma xenograft models were established, and GEM monotherapy and GEM plus nanoparticle albumin-bound paclitaxel (nab-PTX) doublet therapy were administered to GEM-S/R tumor-bearing mice. Metabolomic mass spectrometry (MS) analysis of serum, liver, and tumor samples was performed using an ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometer. The results showed that both GEM monotherapy and combination therapy significantly inhibited the tumor growth in GEMS subgroup. However, in the GEM-R subgroup, tumor growth was not significantly inhibited by GEM monotherapy, but was significantly suppressed by GEM combination therapy. Metabolic profiling analysis by hierarchical cluster analysis and partial least squares discriminant analysis showed that the differences in metabolites were most significant in serum of three types of samples in the GEM-S/R subgroups, regardless of the administration of GEM monotherapy or combination therapy. The differential metabolite analysis of serum samples revealed 38 and 26 differential metabolites between the GEM-R and GEMS subgroups treated with GEM monotherapy or combination therapy, and four common discriminating metabolites were investigated: 3-hydroxyadipic acid, D-galactose, lysophosphatidylcholine (LysoPC) (P-16:0), and tetradecenoyl-L-carnitine. The relative amounts of the four metabolites changed significantly and consistently after GEM monotherapy or combination therapy. The levels of these four metabolites Wu et al.

Cancer is still a major health problem around the world. The treatment failure of cancer has largely been attributed to drug resistance. Competitive endogenous RNAs (ceRNAs) are involved in various biological processes and thus influence the drug sensitivity of cancers. However, a comprehensive characterization of drug-sensitivity-related ceRNAs has not yet been performed. In the present study, we constructed 15 ceRNA networks across 15 anti-cancer drug categories, involving 217 long noncoding RNAs (lncRNAs), 158 microRNAs (miRNAs), and 1,389 protein coding genes (PCGs). We found that these ceRNAs were involved in hallmark processes such as “self-sufficiency in growth signals,” “insensitivity to antigrowth signals,” and so on. We then identified an intersection ceRNA network (ICN) across the 15 anti-cancer drug categories. We further identified interactions between genes in the ICN and clinically actionable genes (CAGs) by analyzing the co-expressions, protein-protein interactions, and transcription factor-target gene interactions. We found that certain genes in the ICN are correlated with CAGs. Finally, we found that genes in the ICN were aberrantly expressed in tumors, and some were associated with patient survival time and cancer stage.

IMPORTANCE: This is a study of lipid metabolic gene expression patterns to discover precision medicine for sepsis.OBJECTIVES: Sepsis patients experience poor outcomes including chronic critical illness (CCI) or early death (within 14 d). We investigated lipid metabolic gene expression differences by outcome to discover therapeutic targets. DESIGN, SETTING, AND PARTICITPANTS:Secondary analysis of samples from prospectively enrolled sepsis patients (first 24 hr) and a zebrafish endotoxemia model for drug discovery. Patients were enrolled from the emergency department or ICU at an urban teaching hospital. Enrollment samples from sepsis patients were analyzed. Clinical data and cholesterol levels were recorded. Leukocytes were processed for RNA sequencing and reverse transcriptase polymerase chain reaction. A lipopolysaccharide zebrafish endotoxemia model was used for confirmation of human transcriptomic findings and drug discovery. MAIN OUTCOMES AND MEASURES:The derivation cohort included 96 patients and controls (12 early death, 13 CCI, 51 rapid recovery, and 20 controls) and the validation cohort had 52 patients (6 early death, 8 CCI, and 38 rapid recovery). RESULTS:The cholesterol metabolism gene 7-dehydrocholesterol reductase (DHCR7) was significantly up-regulated in both derivation and validation cohorts in poor outcome sepsis compared with rapid recovery patients and in 90-day nonsurvivors (validation only) and validated using RT-qPCR analysis. Our zebrafish sepsis model showed up-regulation of dhcr7 and several of the same lipid genes up-regulated in poor outcome human sepsis (dhcr24, sqlea, cyp51, msmo1, and ldlra) compared with controls. We then tested six lipid-based drugs in the zebrafish endotoxemia model. Of these, only the Dhcr7 inhibitor AY9944 completely rescued zebrafish from lipopolysaccharide death in a model with 100% lethality. CONCLUSIONS: DHCR7, an important cholesterol metabolism gene, was upregulated in poor outcome sepsis patients warranting external validation. This pathway may serve as a potential therapeutic target to improve sepsis outcomes.