Genome-Wide Analysis Identifies Nuclear Factor 1C as a Novel Transcription Factor and Potential Therapeutic Target in SCLC.

INTRODUCTION: Recent insights regarding mechanisms mediating stemness, heterogeneity, and metastatic potential of lung cancers have yet to be fully translated to effective regimens for the treatment of these malignancies. This study sought to identify novel targets for lung cancer therapy. METHODS: Transcriptomes and DNA methylomes of 14 SCLC and 10 NSCLC lines were compared with normal human small airway epithelial cells (SAECs) and induced pluripotent stem cell (iPSC) clones derived from SAEC. SCLC lines, lung iPSC (Lu-iPSC), and SAEC were further evaluated by DNase I hypersensitive site sequencing (DHS-seq). Changes in chromatin accessibility and depths of transcription factor (TF) footprints were quantified using Bivariate analysis of Genomic Footprint. Standard techniques were used to evaluate growth, tumorigenicity, and changes in transcriptomes and glucose metabolism of SCLC cells after NFIC knockdown and to evaluate NFIC expression in SCLC cells after exposure to BET inhibitors. RESULTS: Considerable commonality of transcriptomes and DNA methylomes was observed between Lu-iPSC and SCLC; however, this analysis was uninformative regarding pathways unique to lung cancer. Linking results of DHS-seq to RNA sequencing enabled identification of networks not previously associated with SCLC. When combined with footprint depth, NFIC, a transcription factor not previously associated with SCLC, had the highest score of occupancy at open chromatin sites. Knockdown of NFIC impaired glucose metabolism, decreased stemness, and inhibited growth of SCLC cells in vitro and in vivo. ChIP-seq analysis identified numerous sites occupied by BRD4 in the NFIC promoter region. Knockdown of BRD4 or treatment with Bromodomain and extra-terminal domain (BET) inhibitors (BETis) markedly reduced NFIC expression in SCLC cells and SCLC PDX models. Approximately 8% of genes down-regulated by BETi treatment were repressed by NFIC knockdown in SCLC, whereas 34% of genes repressed after NFIC knockdown were also down-regulated in SCLC cells after BETi treatment. CONCLUSIONS: NFIC is a key TF and possible mediator of transcriptional regulation by BET family proteins in SCLC. Our findings highlight the potential of genome-wide chromatin accessibility analysis for elucidating mechanisms of pulmonary carcinogenesis and identifying novel targets for lung cancer therapy.

Identification of shared pathogenetic mechanisms between COVID-19 and IC through bioinformatics and system biology.

COVID-19 increased global mortality in 2019. Cystitis became a contributing factor in SARS-CoV-2 and COVID-19 complications. The complex molecular links between cystitis and COVID-19 are unclear. This study investigates COVID-19-associated cystitis (CAC) molecular mechanisms and drug candidates using bioinformatics and systems biology. Obtain the gene expression profiles of IC (GSE11783) and COVID-19 (GSE147507) from the Gene Expression Omnibus (GEO) database. Identified the common differentially expressed genes (DEGs) in both IC and COVID-19, and extracted a number of key genes from this group. Subsequently, conduct Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis on the DEGs. Additionally, design a protein-protein interaction (PPI) network, a transcription factor gene regulatory network, a TF miRNA regulatory network, and a gene disease association network using the DEGs. Identify and extract hub genes from the PPI network. Then construct Nomogram diagnostic prediction models based on the hub genes. The DSigDB database was used to forecast many potential molecular medicines that are associated with common DEGs. Assess the precision of hub genes and Nomogram models in diagnosing IC and COVID-19 by employing Receiver Operating Characteristic (ROC) curves. The IC dataset (GSE57560) and the COVID-19 dataset (GSE171110) were selected to validate the models' diagnostic accuracy. A grand total of 198 DEGs that overlapped were found and chosen for further research. FCER1G, ITGAM, LCP2, LILRB2, MNDA, SPI1, and TYROBP were screened as the hub genes. The Nomogram model, built using the seven hub genes, demonstrates significant utility as a diagnostic prediction model for both IC and COVID-19. Multiple potential molecular medicines associated with common DEGs have been discovered. These pathways, hub genes, and models may provide new perspectives for future research into mechanisms and guide personalised and effective therapeutics for IC patients infected with COVID-19.

A Review on the Morphology, Cultivation, Identification, Phytochemistry, and Pharmacology of Kitagawia praeruptora (Dunn) Pimenov.

Kitagawia praeruptora (Dunn) Pimenov, commonly known as Qianhu in China, is a widely used folk Chinese herbal medicine. This article reviews its botanical traits, ethnopharmacology, cultivation techniques, identification, phytochemical compositions, and pharmacological effects. Over 70 coumarin compounds, including simple coumarins, pyranocoumarins, and furanocoumarins, have been isolated within this plant. Additionally, K. praeruptora contains other components such as flavonoids, fatty acids, benzoic acids, and sterols. This information highlights the importance of utilizing active ingredients and excavating pharmacological effects. With its remarkable versatility, K. praeruptora exhibits a wide range of pharmacological effects. It has been found to possess expectorant and bronchodilator properties, cardiovascular protection, antimicrobial and antioxidant activities, anti-tumor effects, and even antidiabetic properties. It is recommended to focus on the development of new drugs that leverage the active ingredients of K. praeruptora and explore its potential for new clinical applications and holistic utilization.

Insight into covalent conjugates of ß-lactoglobulin with rutin: Characterizing allergenicity, digestibility, and antioxidant properties in vitro.

ß-lactoglobulin (ß-LG) is an essential nutrient in milk, but it is the primary allergen causing dairy allergy in humans. Currently, researchers are focusing on using flavonoids to covalently modify ß-LG for improving its functionality. However, the impact and underlying mechanisms of rutin covalent modification on the functional properties and allergenicity of ß-LG remain unclear. Here, we aim to investigate the changes in allergenicity, digestive characteristics, and antioxidant properties of ß-LG after covalent modification using a combination of spectroscopy, enzyme-linked immunosorbent assay (ELISA), simulated digestion, and antioxidant assays. The results indicate that rutin forms covalent bonds with the free amino group, sulfhydryl group, and tryptophan of ß-LG, leading to alterations in the secondary structure of ß-LG. Furthermore, the modified ß-LG exhibits improved antioxidant capacity and decreased allergenicity, along with reduced resistance to pancreatin digestion in vitro. This study provides novel insights and strategies to expand the functional application of ß-LG.

Identification of pivotal genes with prognostic evaluation value in lung adenocarcinoma by bioinformatics analysis.

Lung cancer remains the leading cause of cancer morbidity and mortality worldwide, and over-diagnosis causes various unnecessary losses in patients' lives and health. How to more effectively screen lung cancer patients and their potential prognostic risk become the focus of our current study. By analyzing the LUAD expression profile in The Cancer Genome Atlas (TCGA), we constructed a weighted gene co-expression network using differentially expressed genes (DEGs) to find the key modules and pivotal genes. A COX proportional risk regression model based on the least absolute shrinkage and selection operator (LASSO) was used to assess the predictive value of the model for the prognosis of LUAD patients. A total of 4107 up-regulated DEGs and 2022 down-regulated DEGs were identified in this study, and enrichment analysis showed that these analyzes were associated with the extracellular matrix of cells and adhesion. Ten gene markers consisting of LDHA, TOP2A, UBE2C, TYMS, TRIP13, EXO1, TTK, TPX2, ZWINT, and UHRF1 were established by extracting the central genes in the key modules, and the upregulation of these genes was accompanied by an increased prognostic risk of patients. Among them, high expression of LDHA, TRIP13, and TTK in LUAD was associated with shorter overall survival and could be used as independent prognostic factors to participate in metabolic processes such as tumor NAD. The present study provides a powerful molecular target for the study of LUAD prognosis and provides a theoretical basis for the diagnosis and treatment of LUAD and the development of targeted inhibitors.

Heterogeneous pattern of gene expression driven by TTN mutation is involved in the construction of a prognosis model of lung squamous cell carcinoma.

Objective: To investigate the impact that TTN mutation had on the gene heterogeneity expression and prognosis in patients with lung adenocarcinoma. Methods: In this study, the Cancer Genome Atlas (TCGA) dataset was used to analyze the TTN mutations in lung adenocarcinoma. Lung adenocarcinoma data was collected from the TCGA database, clinical information of patients was analyzed, and bioinformatics statistical methods were applied for mutation analysis and prognosis survival analysis. The results were verified using the GEO dataset. Results: The incidence of TTN mutations in lung adenocarcinoma was found to be 73%, and it was related to the prognosis of lung adenocarcinoma. Ten genes were screened with significant contributions to prognosis. A prognosis model was constructed and verified by LASSO COX analysis in the TCGA and GEO datasets based on these ten beneficial factors. The independent prognostic factor H2BC9 for TTN mutation-driven gene heterogeneity expression was screened through multi-factor COX regression analysis. Conclusion: Our data showed that the gene heterogeneity expression, which was driven by TTN mutations, prolonged the survival of lung adenocarcinoma patients and provided valuable clues for the prognosis of TTN gene mutations in lung adenocarcinoma.

Prediction of antioxidant peptides using a quantitative structure-activity relationship predictor (AnOxPP) based on bidirectional long short-term memory neural network and interpretable amino acid descriptors.

Antioxidant peptides can protect against free radical-mediated diseases, especially food-derived antioxidant peptides are considered as potential competitors among synthetic antioxidants due to their safety, high activity and abundant sources. However, wet experimental methods can not meet the need for effectively screening and clearly elucidating the structure-activity relationship of antioxidant peptides. Therefore, it is particularly important to build a reliable prediction platform for antioxidant peptides. In this work, we developed a platform, AnOxPP, for prediction of antioxidant peptides using the bidirectional long short-term memory (BiLSTM) neural network. The sequence characteristics of peptides were converted into feature codes based on amino acid descriptors (AADs). Our results showed that the feature conversion ability of the combined-AADs optimized by the forward feature selection method was more accurate than that of the single-AADs. Especially, the model trained by the optimal descriptor SDPZ27 significantly outperformed the existing predictor on two independent test sets (Accuracy = 0.967 and 0.819, respectively). The SDPZ27-based AnOxPP learned four key structure-activity features of antioxidant peptides, with the following importance as steric properties > hydrophobic properties > electronic properties > hydrogen bond contributions. AnOxPP is a valuable tool for screening and design of peptide drugs, and the web-server is accessible at http://www.cqudfbp.net/AnOxPP/index.jsp.

Evaluation of the in vitro antioxidant and antitumor activity of hydroalcoholic extract from Jatropha mollissima leaves in Wistar rats.

Introduction: Despite modern sciences and advancements in new drugs or chemicals, the new era now rushes natural remedies for various illnesses and diseases that lead to end organ damage. In this study, we investigated Jatropha mollissima ethanolic extract's effect against doxorubicin-induced cardiotoxicity and renal toxicity. Methods: To determine phytochemicals, a phytochemical screening was conducted. Various assays were used to measure the antioxidant activity, including the DPPH (2,2-diphenylpicrylhydrazyl), SOD (superoxide dismutase), NO (nitric oxide), and others. The antiproliferative effect of Jm was assessed by MTT assay; morphological analysis was performed using an inverted and phase contrast microscope, ultra morphological analysis of apoptosis with acridine orange (AO)/propidium iodide (PI) staining. Results: It was seen that doxorubicin caused elevated serum markers and abnormal changes in histological patterns. The significant reduction in cardiac and renal marker levels seen in groups given either 400 or 600 mg/kg of crude extract demonstrates that Jm has a protective effect against doxorubicin-induced cardiotoxicity due to the presence of active phytoconstituents having antioxidant potential. There is a dose-dependent decrease in cell viability when using J. mollissima. Apoptosis was observed in the treated cells. Conclusion: In conclusion, our research lends credence to the idea that J. mollissima could be used for cancer management and have cardioprotective and nephroprotective effects.

Definition of a new blood cell count score for early survival prediction for non-small cell lung cancer patients treated with atezolizumab: Integrated analysis of four multicenter clinical trials.

Importance: Blood cell count test (BCT) is a robust method that provides direct quantification of various types of immune cells to reveal the immune landscape to predict atezolizumab treatment outcomes for clinicians to decide the next phase of treatment. Objective: This study aims to define a new BCTscore model to predict atezolizumab treatment benefits in non-small lung cell cancer (NSCLC) patients. Design Setting and Participants: This study analyzed four international, multicenter clinical trials (OAK, BIRCH, POPLAR, and FIR trials) to conduct post-hoc analyses of NSCLC patients undergoing atezolizumab (anti-PD-L1) single-agent treatment (n = 1,479) or docetaxel single-agent treatment (n = 707). BCT was conducted at three time points: pre-treatment (T1), the first day of treatment cycle 3 (T2), and first day of treatment cycle 5 (T3). Univariate and multivariate Cox regression analyses were conducted to identify early BCT biomarkers to predict atezolizumab treatment outcomes in NSCLC patients. Main Outcomes and Measures: Overall survival (OS) was used as the primary end point, whereas progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST), clinical benefit (CB), and objective response rate (ORR) were used as secondary end points. Results: The BCT biomarkers of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) at time point T3 and neutrophil-to-monocyte ratio (NMR) at time point T2 with absolute cutoff values of NLR_T3 = 5, PLR_T3 = 180, and NMR_T2 = 6 were identified as strong predictive biomarkers for atezolizumab (Ate)-treated NSCLC patients in comparison with docetaxel (Dtx)-treated patients regarding OS (BCTscore low risk: HR Ate vs. Dtx = 1.54 (95% CI: 1.04-2.27), P = 0.031; high risk: HR Ate vs. Dtx = 0.84 (95% CI: 0.62-1.12), P = 0.235). The identified BCTscore model showed better OS AUC in the OAK (AUC12month = 0.696), BIRCH (AUC12month = 0.672) and POPLAR+FIR studies (AUC12month = 0.727) than that of each of the three single BCT biomarkers. Conclusion and Relevance: The BCTscore model is a valid predictive and prognostic biomarker for early survival prediction in atezolizumab-treated NSCLC patients.

Anti-inflammation of isoliquiritigenin via the inhibition of NF-κB and MAPK in LPS-stimulated MAC-T cells.

BACKGROUND: The application of plant extracts has received great interest for the treatment of bovine mastitis. Isoliquiritigenin (ISL) is a rich dietary flavonoid that has significant antioxidative, anti-inflammatory and anticancer activities. This study was conducted to explore the protective efficacy and related mechanism of ISL against lipopolysaccharide (LPS)-stimulated oxidation and inflammation in bovine mammary epithelial cells (MAC-T) by in vitro experiments. RESULTS: Real-time PCR and ELISA assays indicated that ISL treatment at 2.5, 5 and 10 µg/mL significantly reduced the mRNA and protein expression of the oxidative indicators cyclooxygenase-2 and inducible nitric oxide synthase (P < 0.01), and of the inflammatory cytokines interleukin-6 (P < 0.05), interleukin-1ß (P < 0.01) and tumor necrosis factor-α (P < 0.01) in LPS-stimulated MAC-T cells. Moreover, Western blotting and immunofluorescence tests indicated that the phosphorylation levels of nuclear factor kappa (NF-κB) p65 and the inhibitor of NF-κB were significantly decreased by ISL treatment, thus blocking the nuclear transfer of NF-κB p65. In addition, ISL attenuated the phosphorylation levels of p38, extracellular signal-regulated kinase and c-jun NH2 terminal kinase. CONCLUSIONS: Our data demonstrated that ISL downregulated the LPS-induced inflammatory response in MAC-T cells. The anti-inflammatory and antioxidative activity of ISL involves the NF-κB and MAPK cascades.

MiRNA-99a alleviates inflammation and oxidative stress in lipopolysaccharide-stimulated PC-12 cells and rats post spinal cord injury.

Spinal cord injury (SCI) is caused by spinal fracture after the displacement of the spine or broken bone fragments protruding into the spinal canal, resulting in different degrees of injury to the spinal cord or spinal nerves. Expression levels of miR-99a and nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) in cerebrospinal fluid of SCI patients were analyzed. Rat adrenal gland pheochromocytoma cell line PC-12 were stimulated with lipopolysaccharide (LPS) to mimic the in vitro environment of SCI. A rat mode of SCI was established by laminectomy. Reactive oxygen species (ROS) levels were measured by 2',7'-Dichlorodihydrofluorescein diacetate staining assay. Western blot was conducted to evaluate the expression levels of apoptotic indexes and proinflammatory cytokines. The interaction between miR-99a and NOX4 was verified by dual-luciferase reporter assay. The expression level of miR-99a was reduced while NOX4 expression was upregulated in cerebrospinal fluid of SCI patients and LPS-treated PC-12 cells. LPS impeded cell viability and promoted inflammation, apoptosis and ROS levels of PC-12 cells. Overexpression of miR-99a significantly promoted cell viability and reduced inflammation, apoptosis and oxidative stress in LPS-stimulated PC-12 cells. Dual-luciferase reporter assays verified that NOX4 was a target of miR-99a. Moreover, the expression of NOX4 was reduced in PC-12 cells after transfection with miR-99a mimic. Overexpression of NOX4 partly abolished the protective effect of miR-99a in LPS-treated PC-12 cells. To sum up, miR-99a suppresses NOX4 expression to relieve the LPS-induced inflammation, apoptosis and the progression of oxidative stress in SCI.

Physicochemical and molecular transformation of novel functional peptides from Baijiu.

A novel strategy for screening and identifying peptides present in Baijiu was developed based on magnetic solid-phase extraction with magnetic S-doped graphene (M-G-S) as adsorbent combined with ultrahigh-performance liquid chromatography with high resolution tandem mass spectrometry. In total, 28 peptides consisting of amino acids from 3 to 9 were preliminarily identified, and significantly higher in the number than that of direct concentration and SPE with C18 as the adsorbent. Six peptides were confirmed with their corresponding synthetic reference standards by comparing their retention time, high resolution MS/MS spectra, and NMR spectroscopic studies. Parallel reaction monitoring integrated with the internal standard method was utilized to quantify identified peptides with concentrations ranging from 1.14 to 10.25 ng mL-1, and prediction results of bioactivity comprising antioxidation or ACE inhibitors were obtained. These discoveries were conducive to understanding the versatility benefit of Baijiu and paved the way to study the interaction between peptides and volatile substances.

Hookah Smoke Mediates Cancer-Associated Epigenomic and Transcriptomic Signatures in Human Respiratory Epithelial Cells.

INTRODUCTION: Although communal smoking of hookah by means of water pipes is perceived to be a safe alternative to cigarette smoking, the effects of hookah smoke in respiratory epithelia have not been well characterized. This study evaluated epigenomic and transcriptomic effects of hookah smoke relative to cigarette smoke in human respiratory epithelial cells. METHODS: Primary normal human small airway epithelial cells from three donors and cdk4 and hTERT-immortalized small airway epithelial cells and human bronchial epithelial cells were cultured for 5 days in normal media with or without cigarette smoke condensates (CSCs) or water pipe condensates (WPCs). Cell count, immunoblot, RNA sequencing, quantitative real-time reverse-transcriptase polymerase chain reaction, methylation-specific polymerase chain reaction, and quantitative chromatin immunoprecipitation techniques were used to compare effects of hookah and cigarette smoke on cell proliferation, global histone marks, gene expression, and promoter-related chromatin structure. RESULTS: CSC and WPC decreased global H4K16ac and H4K20me3 histone marks and mediated distinct and overlapping cancer-associated transcriptome signatures and pathway modulations that were cell line dependent and stratified across lung cancer cells in a histology-specific manner. Epiregulin encoding a master regulator of EGFR signaling that is overexpressed in lung cancers was up-regulated, whereas FILIP1L and ABI3BP encoding mediators of senescence that are repressed in lung cancers were down-regulated by CSC and WPC. Induction of epiregulin and repression of FILIP1L and ABI3BP by these condensates coincided with unique epigenetic alterations within the respective promoters. CONCLUSIONS: These findings support translational studies to ascertain if hookah-mediated epigenomic and transcriptomic alterations in cultured respiratory epithelia are detectable and clinically relevant in hookah smokers.

Anti-inflammation of epicatechin mediated by TMEM35A and TMPO in bovine mammary epithelial cell line cells and mouse mammary gland.

Epicatechin (EC) has significant antiinflammation, antioxidation, and anticancer activities. It also provides a new alternative treatment for mastitis, which can result in great economic losses in the dairy industry if left untreated. The purpose of this study was to investigate the anti-inflammatory effects of EC on mastitis and the underlying mechanism using in vivo and in vitro systems. The use of ELISA and immunohistochemistry assays showed that EC treatment at 1.5, 7.5, 15, and 30 mg/mL decreased protein expression of inflammatory mediators, including cyclooxygenase-2 and inducible nitric oxide synthase; inflammatory cytokines, which were composed of IL-1ß, TNF-α, and IL-6 in lipopolysaccharide (LPS)-stimulated bovine mammary epithelial cell line (MAC-T); and mouse mammary gland, together with reduced filtration of T lymphocytes in the mouse mammary gland. Furthermore, EC treatment reduced LPS-induced phosphorylation levels of p65 and inhibitor of NF-κB, and blocked nuclear translocation of p65 as revealed by western blot and immunofluorescence test in MAC-T cells and the mouse mammary gland. Epicatechin also attenuated LPS-induced phosphorylation levels of mitogen-activated protein kinase members (i.e., p38, c-Jun N-terminal kinase 1/2 and extracellular regulated protein kinases 1/2). Using RNA-seq and tandem mass tag analyses, upregulation of TMEM35A and TMPO proteins was disclosed in MAC-T cells cotreated with LPS and EC. Although clustered regularly interspaced short palindromic repeats/Cas9-based knockdown of TMEM35A and TMPO attenuated abundance of phosphorylated (p)-p65, p-p38, TNF-α, and iNOS, overexpression of TMEM35A reversed EC-mediated effects in TMPO knockdown cells. Moreover, interaction between TMEM35A and TMPO was detected using the co-immunoprecipitation method. In conclusion, our data demonstrated that EC inhibited LPS-induced inflammatory response in MAC-T cells and the mouse mammary gland. Importantly, TMEM35A mediated the transmembrane transport of EC, and the interaction between TMEM35A and TMPO inhibited MAPK and NF-κB pathways.

Sirt1 deficiency upregulates glutathione metabolism to prevent hepatocellular carcinoma initiation in mice.

Sirtuin-1 (SIRT1) is involved in various metabolic pathways, including fatty acid synthesis and gluconeogenesis in the liver. However, its role in initiation and progression of liver cancer remains unclear. Studying Sirt1 liver-specific knockout (LKO) mice in combination with diethylnitrosamine (DEN) treatment, we demonstrated that loss of Sirt1 rendered mice resistant to DEN-induced hepatocellular carcinoma (HCC) development. RNA-seq revealed that livers from LKO mice exhibited an enrichment in glutathione metabolism eight months after DEN challenge. Sirt1 deficiency elevated the expression of glutathione-s-transferase family genes by increasing the level of Nrf2, a key regulator of glutathione metabolism. Hence, LKO livers displayed a reductive environment with an increased ratio of GSH to GSSG and an elevated GSH level. Furthermore, using CRISPR knockout techniques, we confirmed that the impairment of HCC formation in LKO mice is mainly dependent on NRF2 signaling. Meanwhile, HCC induced by DEN could be blocked by the administration of N-acetyl cysteine (NAC) when administered one month after DEN challenge. However, NAC treatment starting five months after DEN injection was not able to prevent tumor development. In conclusion, our findings indicate that a reductive environment orchestrated by glutathione metabolism at an early stage can prevent the initiation of HCC.

Thin-layered MoS2 nanoflakes vertically grown on SnO2 nanotubes as highly effective room-temperature NO2 gas sensor.

The unique properties of heterostructure materials make them become a promising candidate for high-performance room-temperature (RT) NO2 sensing. Herein, a p-n heterojunction consisting of two-dimensional (2D) MoS2 nanoflakes vertically grown on one-dimensional (1D) SnO2 nanotubes (NTs) was fabricated via electrospinning and subsequent hydrothermal route. The sulfur edge active sites are fully exposed in the MoS2@SnO2 heterostructure due to the vertically oriented thin-layered morphology features. Moreover, the interface of p-n heterojunction provides an electronic transfer channel from SnO2 to MoS2, which enables MoS2 act as the generous electron donor involved in NO2 gas senor detection. As a result, the optimized MoS2@SnO2-2 heterostructure presents an impressive sensitivity and selectivity for NO2 gas detection at RT. The response value is 34.67 (Ra/Rg) to 100 ppm, which is 26.5 times to that of pure SnO2. It also exhibits a fast response and recovery time (2.2 s, 10.54 s), as well as a low detection limit (10 ppb) and as long as 20 weeks of stability. This simple fabrication of high-performance sensing materials may facilitate the large-scale production of RT NO2 gas sensors.

UHRF1 Is a Novel Druggable Epigenetic Target in Malignant Pleural Mesothelioma.

INTRODUCTION: Ubiquitin-like with plant homeodomain and ring finger domains 1 (UHRF1) encodes a master regulator of DNA methylation that has emerged as an epigenetic driver in human cancers. To date, no studies have evaluated UHRF1 expression in malignant pleural mesothelioma (MPM). This study was undertaken to explore the therapeutic potential of targeting UHRF1 in MPM. METHODS: Microarray, real-time quantitative reverse transcription-polymerase chain reaction, immunoblot, and immunohistochemistry techniques were used to evaluate UHRF1 expression in normal mesothelial cells (NMCs) cultured with or without asbestos, MPM lines, normal pleura, and primary MPM specimens. The impact of UHRF1 expression on MPM patient survival was evaluated using two independent databases. RNA-sequencing, proliferation, invasion, and colony formation assays, and murine xenograft experiments were performed to evaluate gene expression and growth of MPM cells after biochemical or pharmacologic inhibition of UHRF1 expression. RESULTS: UHRF1 expression was significantly higher in MPM lines and specimens relative to NMC and normal pleura. Asbestos induced UHRF1 expression in NMC. The overexpression of UHRF1 was associated with decreased overall survival in patients with MPM. UHRF1 knockdown reversed genomewide DNA hypomethylation, and inhibited proliferation, invasion, and clonogenicity of MPM cells, and growth of MPM xenografts. These effects were phenocopied by the repurposed chemotherapeutic agent, mithramycin. Biochemical or pharmacologic up-regulation of p53 significantly reduced UHRF1 expression in MPM cells. RNA-sequencing experiments exhibited the pleiotropic effects of UHRF1 down-regulation and identified novel, clinically relevant biomarkers of UHRF1 expression in MPM. CONCLUSIONS: UHRF1 is an epigenetic driver in MPM. These findings support the efforts to target UHRF1 expression or activity for mesothelioma therapy.

Anti-Inflammatory Activity of Oligomeric Proanthocyanidins Via Inhibition of NF-κB and MAPK in LPS-Stimulated MAC-T Cells.

Oligomeric proanthocyanidins (OPCs), classified as condensed tannins, have significant antioxidation, anti-inflammation and anti-cancer effects. This study was performed to investigate the anti-inflammatory effects of OPCs and the mechanism underlying these effects in lipopolysaccharide (LPS)-stimulated bovine mammary epithelial cells (MAC-T). Real-time PCR and ELISA assays indicated that OPC treatment at 1, 3 and 5 µg/ml significantly reduced the mRNA and protein, respectively, of oxidant indicators cyclooxygenase-2 (COX-2) (p < 0.05) and inducible nitric oxide synthase (iNOS) (p < 0.01) as well as inflammation cytokines interleukin (IL)-6 (p < 0.01), IL-1ß (p < 0.01) and tumor necrosis factor-α (TNF-α) (p < 0.05) in LPS-induced MAC-T cells. Moreover, OPCs downregulated LPSinduced phosphorylation of p65 and inhibitor of nuclear factor kappa B (NF-κB) (IκB) in the NF-κB signaling pathway (p < 0.01), and they inhibited p65 translocation from the cytoplasm to the nucleus as revealed by immunofluorescence test and western blot. Additionally, OPCs decreased phosphorylation of p38, extracellular signal regulated kinase and c-jun NH2-terminal kinase in the MAPK signaling pathway (p < 0.01). In conclusion, the anti-inflammatory and antioxidant activities of OPCs involve NF-κB and MAPK signaling pathways, thus inhibiting expression of pro-inflammatory factors and oxidation indicators. These findings provide novel experimental evidence for the further practical application of OPCs in prevention and treatment of bovine mastitis.

SIRT1 modulates cell cycle progression by regulating CHK2 acetylation-phosphorylation.

Both the stress-response protein, SIRT1, and the cell cycle checkpoint kinase, CHK2, play critical roles in aging and cancer via the modulation of cellular homeostasis and the maintenance of genomic integrity. However, the underlying mechanism linking the two pathways remains elusive. Here, we show that SIRT1 functions as a modifier of CHK2 in cell cycle control. Specifically, SIRT1 interacts with CHK2 and deacetylates it at lysine 520 residue, which suppresses CHK2 phosphorylation, dimerization, and thus activation. SIRT1 depletion induces CHK2 hyperactivation-mediated cell cycle arrest and subsequent cell death. In vivo, genetic deletion of Chk2 rescues the neonatal lethality of Sirt1-/- mice, consistent with the role of SIRT1 in preventing CHK2 hyperactivation. Together, these results suggest that CHK2 mediates the function of SIRT1 in cell cycle progression, and may provide new insights into modulating cellular homeostasis and maintaining genomic integrity in the prevention of aging and cancer.