Coaggregated E. faecalis with F. nucleatum regulated environmental stress responses and inflammatory effects.

To investigate the cell-cell interactions of intergeneric bacterial species, the study detected the survival of Enterococcus faecalis (Ef) under monospecies or coaggregation state with Fusobacterium nucleatum subsp. polymorphum (Fnp) in environmental stress. Ef and Fnp infected the human macrophages with different forms (Ef and Fnp monospecies, Ef-Fnp coaggregates, Ef + Fnp cocultures) for exploring the immunoregulatory effects and the relevant molecular mechanisms. Meanwhile, the transcriptomic profiles of coaggregated Ef and Fnp were analyzed. Ef was shown to coaggregate with Fnp strongly in CAB within 90 min by forming multiplexes clumps. Coaggregation with Fnp reinforced Ef resistance against unfavorable conditions including alkaline, hypertonic, nutrient-starvation, and antibiotic challenges. Compared with monospecies and coculture species, the coaggregation of Ef and Fnp significantly facilitates both species to invade dTHP-1 cells and aid Ef to survive within the cells. Compared with coculture species, dual-species interaction of Ef and Fnp significantly decreased the levels of pro-inflammatory cytokines IL-6, TNF-α, and chemokines MCP-1 secreted by dTHP-1 cells and lessened the phosphorylation of p38, JNK, and p65 signaling pathways. The transcriptome sequencing results showed that 111 genes were differentially expressed or Ef-Fnp coaggregated species compared to Ef monospecies; 651 genes were differentially expressed for Fnp when coaggregation with Ef. The analysis of KEGG pathway showed that Ef differentially expressed genes (DEGs) were enriched in quorum sensing and arginine biosynthesis pathway; Fnp DEGs were differentially concentrated in lipopolysaccharide (LPS) biosynthesis, biofilm formation, and lysine degradation pathway compared to monospecies. KEY POINTS: • Coaggregated with Fnp aids Ef's survival in environmental stress, especially in root canals after endodontic treatment. • The coaggregation of Ef and Fnp may weaken the pro-inflammatory response and facilitate Ef to evade killed by macrophages. • The coaggregation between Ef and Fnp altered interspecies transcriptional profiles.

WD repeat domain 82 (Wdr82) facilitates mouse iPSCs generation by interfering mitochondrial oxidative phosphorylation and glycolysis.

BACKGROUND: Abundantly expressed factors in the oocyte cytoplasm can remarkably reprogram terminally differentiated germ cells or somatic cells into totipotent state within a short time. However, the mechanism of the different factors underlying the reprogramming process remains uncertain. METHODS: On the basis of Yamanaka factors OSKM induction method, MEF cells were induced and reprogrammed into iPSCs under conditions of the oocyte-derived factor Wdr82 overexpression and/or knockdown, so as to assess the reprogramming efficiency. Meanwhile, the cellular metabolism was monitored and evaluated during the reprogramming process. The plurpotency of the generated iPSCs was confirmed via pluripotent gene expression detection, embryoid body differentiation and chimeric mouse experiment. RESULTS: Here, we show that the oocyte-derived factor Wdr82 promotes the efficiency of MEF reprogramming into iPSCs to a greater degree than the Yamanaka factors OSKM. The Wdr82-expressing iPSC line showed pluripotency to differentiate and transmit genetic material to chimeric offsprings. In contrast, the knocking down of Wdr82 can significantly reduce the efficiency of somatic cell reprogramming. We further demonstrate that the significant suppression of oxidative phosphorylation in mitochondria underlies the molecular mechanism by which Wdr82 promotes the efficiency of somatic cell reprogramming. Our study suggests a link between mitochondrial energy metabolism remodeling and cell fate transition or stem cell function maintenance, which might shed light on the embryonic development and stem cell biology.

A Four Amino Acid Metabolism-Associated Genes (AMGs) Signature for Predicting Overall Survival Outcomes and Immunotherapeutic Efficacy in Hepatocellular Carcinoma.

Metabolites are important indicators of cancer and mutations in genes involved in amino acid metabolism may influence tumorigenesis. Immunotherapy is an effective cancer treatment option; however, its relationship with amino acid metabolism has not been reported. In this study, RNA-seq data for 371 liver cancer patients were acquired from TCGA and used as the training set. Data for 231 liver cancer patients were obtained from ICGC and used as the validation set to establish a gene signature for predicting liver cancer overall survival outcomes and immunotherapeutic responses. Four reliable groups based on 132 amino acid metabolism-related DEGs were obtained by consistent clustering of 371 HCC patients and a four-gene signature for prediction of liver cancer survival outcomes was developed. Our data show that in different clinical groups, the overall survival outcomes in the high-risk group were markedly low relative to the low-risk group. Univariate and multivariate analyses revealed that the characteristics of the 4-gene signature were independent prognostic factors for liver cancer. The ROC curve revealed that the risk characteristic is an efficient predictor for 1-, 2-, and 3-year HCC survival outcomes. The GSVA and KEGG pathway analyses revealed that high-risk score tumors were associated with all aspects of the degree of malignancy in liver cancer. There were more mutant genes and greater immune infiltrations in the high-risk groups. Assessment of the three immunotherapeutic cohorts established that low-risk score patients significantly benefited from immunotherapy. Then, we established a prognostic nomogram based on the TCGA cohort. In conclusion, the 4-gene signature is a reliable diagnostic marker and predictor for immunotherapeutic efficacy.

Menin regulates lipid deposition in mouse hepatocytes via interacting with transcription factor FoxO1.

Non-alcoholic fatty liver disease (NAFLD) is rapidly being recognized as the leading cause of chronic liver disease worldwide. Men1, encoding protein of menin, is a key causative gene of multiple endocrine neoplasia type 1 syndrome including pancreatic tumor. It is known that insulin that secretes by endocrine tissue pancreatic islets plays a critical role in hepatic metabolism. Mouse model of hemizygous deletion of Men1 was shown to have severe hepatic metabolism disorders. However, the molecular function of menin on lipid deposition in hepatocytes needs to be further studied. Transcriptome sequencing does show that expression suppression of Men1 in mouse hepatocytes widely affect signaling pathways involved in hepatic metabolism, such as fatty acid metabolism, insulin response, glucose metabolism and inflammation. Further molecular studies indicates that menin overexpression inhibits expressions of the fat synthesis genes Srebp-1c, Fas, and Acc1, the fat differentiation genes Pparγ1 and Pparγ2, and the fat transport gene Cd36, thereby inhibiting the fat accumulation in hepatocytes. The biological process of menin regulating hepatic lipid metabolism was accomplished by interacting with the transcription factor FoxO1, which is also found to be critical for lipid metabolism. Moreover, menin responds to insulin in hepatocytes and mediates its regulatory effect on hepatic metabolism. Our findings suggest that menin is a crucial mediation factor in regulating the hepatic fat deposition, suggesting it could be a potential important therapeutic target for NAFLD.

Proteome analysis identified proteins associated with mitochondrial function and inflammation activation crucially regulating the pathogenesis of fatty liver disease.

BACKGROUND: Fatty liver disease prevalently occurs in commercial postpartum dairies, resulting in a worldwide high culling rate because of their subsequent limitations of production and reproduction performance. RESULTS: Fatty liver-specific proteome and acetylome analysis revealed that energy metabolism suppression closely associated with mitochondrial dysfunction and inflammation activation were shown to be remarkable biological processes underlying the development of fatty liver disease, furthermore, acetylation modification of proteins could be one of the main means to modulate these processes. Twenty pivotal genetic factors/genes that differentially expressing and being acetylation modified in liver were identified and proposed to regulate the pathogenesis of fatty liver dairies. These proteins were confirmed to be differentially expressing in individual liver tissue, eight of which being validated via immunohistochemistry assay. CONCLUSIONS: This study provided a comprehensive proteome and acetylome profile of fatty liver of dairy cows, and revealed potential important biological processes and essential regulators in the pathogenesis of fatty liver disease. Expectantly, understanding the molecular mechanisms of the pathogenesis of fatty liver disease in dairies, as an animal model of non-alcoholic fatty liver disease (NAFLD) in human beings, which is a clinico-pathologically defined process associated with metabolic syndrome, could inspire and facilitate the development of efficacious therapeutic drugs on NAFLD.

Neuroprotective mechanisms of mangiferin in neurodegenerative diseases.

The central nervous system (CNS) regulates and coordinates an extensive array of complex processes requiring harmonious regulation of specific genes. CNS disorders represent a large burden on society and cause enormous disability and economic losses. Traditional Chinese medicine (TCM) has been used for many years in the treatment of neurological illnesses, such as Alzheimer's disease, Parkinson's disease, stroke, and depression, as the combination of TCM and Western medicine has superior therapeutic efficacy and minimal toxic side effects. Mangiferin (MGF) is an active compound of the traditional Chinese herb rhizome anemarrhenae, which has antioxidant, anti-inflammation, anti-lipid peroxidation, immunomodulatory, and anti-apoptotic functions in the CNS. MGF has been demonstrated to have therapeutic effects in CNS diseases through a multitude of mechanisms. This review outlines the latest research on the neuroprotective ability of MGF and the diverse molecular mechanisms involved.

Effectiveness of XP-Endo Finisher and passive ultrasonic irrigation on intracanal medicament removal from root canals: a systematic review and meta-analysis.

BACKGROUND: XP-Endo Finisher (XPF) and passive ultrasonic irrigation (PUI) are commonly used in intracanal medicament removal. The effectiveness of these two techniques needs to be compared, and evidence-based research should be conducted. METHODS: A comprehensive literature search was conducted in PubMed, Web of Science, Embase, Cochrane Library, and Google Scholar up to December 20th, 2020. The outcomes of the included trials were pooled into the Cochrane Collaboration's Review Manager 5.3 software. Cochrane's risk-of-bias tool 2.0 was applied to assess the risk of bias. RESULTS: Nine articles were included in this systematic review and processed for data extraction, and eight studies were identified for meta-analysis. In general, the use of PUI showed better medicament removal effectiveness than XPF (odds ratio [OR]: 3.09; 95% confidence interval [CI], 1.96-4.86; P < 0.001). PUI was also significantly more efficient than XPF in the apical third (OR: 3.42; 95% CI, 1.32-8.84; P = 0.01). For trials using sodium hypochlorite (NaOCl) alone, PUI was also significantly more effective than XPF on intracanal medicaments removal (OR: 5.23; 95% CI, 2.79-9.82; P < 0.001). However, there was no significant difference between PUI and XPF when NaOCl and ethylenediaminetetraacetic acid (EDTA) were used in combination (OR: 1.51; 95% CI, 0.74-3.09; P = 0.26). In addition, for studies whose intracanal medicament periods were two weeks, the effectiveness of PUI was statistically better than the XPF (OR: 7.73; 95% CI, 3.71-16.07; P < 0.001). Nevertheless, for trials whose intracanal medicament time was one week or over two weeks, no differences between the XPF and PUI were found (OR: 1.54; 95% CI, 0.74-3.22; P = 0.25) (OR: 1.42; 95% CI, 0.44-4.61; P = 0.56). CONCLUSIONS: The meta-analysis is the first study to quantitatively compare the effectiveness of XPF and PUI techniques on intracanal medicaments removal. With rigorous eligibility criteria, the study only included high-quality randomised controlled trials. The study indicated that PUI might be superior over XPF techniques for removing intracanal medicaments from artificial standardized grooves and cavities in the root canal system. The anatomical areas, irrigation protocol, and intracanal medicaments time may influence the cleaning efficacy.

Echovirus plays major roles in the natural recombination of Coxsackievirus B3.

Coxsakievirus B3 (CVB3) is a member of enterovirus B (EVB) group, which can cause serious heart diseases such as viral myocarditis. In order to analyze the evolution of CVB3, we performed a recombination analysis of all viral genomes of enterovirus B, and found that there were 19 putative recombination events that produced CVB3. A total of 11 serotypes were found to be involved in the generation of CVB3 progeny virus. These recombination events involved echovirus, EcoV (which includes EcoV6, EcoV9, EcoV14, EcoV15, EcoV17, EcoV21, EcoV24, and EcoV25), CVB4, CVB5, and EVB81, as major or minor parents. The most active, EcoV, which was involved in the 14 of 19 recombination events, acts as one of the parental viruses for CVB3 strains among molecular evolution and recombination events in circulating CVB3. Our study indicates that, EcoV plays major roles in CVB3 recombination, and is involved in the production of 11 new CVB3 recombinant strains.

Intergenotype Recombination among New Norovirus GII.4 Variants in the Complete Genome.

GII.4 noroviruses (NoVs) are a major cause of acute gastroenteritis in humans. A new variant of GII.4, the Sydney variant, has recently become more prevalent on a global scale. Intragenotype recombinations are widespread within the pandemic NoV GII.4 lineage, and are likely to be important forces driving the evolution and emergence of novel GII.4 viruses. In this study, we sought to examine the role that intergenotype recombination has played in the emergence of GII.4 Sydney 2012 variants. The results show that the GII.4 Sydney 2012 variants, Kawasaki194 and CA3477, were intergenotype recombination NoV strains with a GII.4 capsid and a GII.P16 polymerase gene. It has been reported for the first time that GII.4 new variant recombinants come from intergenotype recombination of GII.P16 and GII.4 strains in the complete genome.

The prognostic value of bioinformatics analysis of ECM receptor signaling pathways and LAMB1 identification as a promising prognostic biomarker of lung adenocarcinoma.

The extracellular matrix (ECM) is a complex and dynamic network of cross-linked proteins and a fundamental building block in multicellular organisms. Our study investigates the impact of genes related to the ECM receptor interaction pathway on immune-targeted therapy and lung adenocarcinoma (LUAD) prognosis. This study obtained LUAD chip data (GSE68465, GSE31210, and GSE116959) from NCBI GEO. Moreover, the gene data associated with the ECM receptor interaction pathway was downloaded from the Molecular Signature Database. Differentially expressed genes were identified using GEO2R, followed by analyzing their correlation with immune cell infiltration. Univariate Cox regression analysis screened out ECM-related genes significantly related to the survival prognosis of LUAD patients. Additionally, Lasso regression and multivariate Cox regression analysis helped construct a prognostic model. Patients were stratified by risk score and survival analyses. The prognostic models were evaluated using receiver operating characteristic curves, and risk scores and prognosis associations were analyzed using univariate and multivariate Cox regression analyses. A core gene was selected for gene set enrichment analysis and CIBERSORT analysis to determine its function and tumor-infiltrating immune cell proportion, respectively. The results revealed that the most abundant pathways among differentially expressed genes in LUAD primarily involved the cell cycle, ECM receptor interaction, protein digestion and absorption, p53 signaling pathway, complement and coagulation cascade, and tyrosine metabolism. Two ECM-associated subtypes were identified by consensus clustering. Besides, an ECM-related prognostic model was validated to predict LUAD survival, and it was associated with the tumor immune microenvironment. Additional cross-analysis screened laminin subunit beta 1 (LAMB1) for further research. The survival time of LUAD patients with elevated LAMB1 expression was longer than those with low LAMB1 expression. Gene set enrichment analysis and CIBERSORT analyses revealed that LAMB1 expression correlated with tumor immune microenvironment. In conclusion, a prognostic model of LUAD patients depending on the ECM receptor interaction pathway was constructed. Screening out LAMB1 can become a prognostic risk factor for LUAD patients or a potential target during LUAD treatment.

Metallofullerenol alleviates alcoholic liver damage via ROS clearance under static magnetic and electric fields.

Alcoholic liver disease (ALD) is a common chronic redox disease caused by increased alcohol consumption. Abstinence is a major challenge for people with alcohol dependence, and approved drugs have limited efficacy. Therefore, this study aimed to explore a new treatment strategy for ALD using ferroferric oxide endohedral fullerenol (Fe3O4@C60(OH)n) in combination with static magnetic and electric fields (sBE). The primary hepatocytes of 8-9-week-old female BALB/c mice were used to evaluate the efficacy of the proposed combination treatment. A mouse chronic binge ethanol feeding model was established to determine the alleviatory effect of Fe3O4@C60(OH)n on liver injury under sBE exposure. Furthermore, the ability of Fe3O4@C60(OH)n to eliminate •OH was evaluated. Alcohol-induced hepatocyte and mitochondrial damage were reversed in vitro. Additionally, the combination therapy reduced liver damage, alleviated oxidative stress by improving antioxidant levels, and effectively inhibited liver lipid accumulation in animal experiments. Here, we used a combination of magnetic derivatives of fullerenol and sBE to further improve the ROS clearance rate, thereby alleviating ALD. The developed combination treatment may effectively improve alcohol-induced liver damage and maintain redox balance without apparent toxicity, thereby enhancing therapy aimed at ALD and other redox diseases.

Tricarboxylic Acid Cycle Metabolite-Coordinated Biohydrogels Augment Cranial Bone Regeneration Through Neutrophil-Stimulated Mesenchymal Stem Cell Recruitment and Histone Acetylation-Mediated Osteogenesis.

Cranial bone defects remain a major clinical challenge, increasing patients' life burdens. Tricarboxylic acid (TCA) cycle metabolites play crucial roles in facilitating bone tissue regeneration. However, the development of TCA cycle metabolite-modified biomimetic grafts for skull bone regeneration still needs to be improved. The mechanism underlying the release of TCA cycle metabolites from biomaterials in regulating immune responses and mesenchymal stem cell (MSC) fate (migration and differentiation) remains unknown. Herein, this work constructs biomimetic hydrogels composed of gelatin and chitosan networks covalently cross-linked by genipin (CGG hydrogels). A series of TCA cycle metabolite-coordinated CGG hydrogels with strong mechanical and antiswelling performances are subsequently developed. Remarkably, the citrate (Na3Cit, Cit)-coordinated CGG hydrogels (CGG-Cit hydrogels) with the highest mechanical modulus and strength significantly promote skull bone regeneration in rat and murine cranial defects. Mechanistically, using a transgenic mouse model, bulk RNA sequencing, and single-cell RNA sequencing, this work demonstrates that CGG-Cit hydrogels promote Gli1+ MSC migration via neutrophil-secreted oncostatin M. Results also indicate that citrate improves osteogenesis via enhanced histone H3K9 acetylation on osteogenic master genes. Taken together, the immune microenvironment- and MSC fate-regulated CGG-Cit hydrogels represent a highly efficient and facile approach toward skull bone tissue regeneration with great potential for bench-to-bedside translation.

Menin orchestrates hepatic glucose and fatty acid uptake via deploying the cellular translocation of SIRT1 and PPARγ.

BACKGROUND: Menin is a scaffold protein encoded by the Men1 gene, which interacts with various transcriptional proteins to activate or repress cellular processes and is a key mediator in multiple organs. Both liver-specific and hepatocyte-specific Menin deficiency promotes high-fat diet-induced liver steatosis in mice, as well as insulin resistance and type 2 diabetic phenotype. The potential link between Menin and hepatic metabolism homeostasis may provide new insights into the mechanism of fatty liver disease. RESULTS: Disturbance of hepatic Menin expression impacts metabolic pathways associated with non-alcoholic fatty liver disease (NAFLD), including the FoxO signaling pathway, which is similar to that observed in both oleic acid-induced fatty hepatocytes model and biopsied fatty liver tissues, but with elevated hepatic Menin expression and inhibited FABP1. Higher levels of Menin facilitate glucose uptake while restraining fatty acid uptake. Menin targets the expression of FABP3/4/5 and also CD36 or GK, PCK by binding to their promoter regions, while recruiting and deploying the cellular localization of PPARγ and SIRT1 in the nucleus and cytoplasm. Accordingly, Menin binds to PPARγ and/or FoxO1 in hepatocytes, and orchestrates hepatic glucose and fatty acid uptake by recruiting SIRT1. CONCLUSION: Menin plays an orchestration role as a transcriptional activator and/or repressor to target downstream gene expression levels involved in hepatic energy uptake by interacting with the cellular energy sensor SIRT1, PPARγ, and/or FoxO1 and deploying their translocations between the cytoplasm and nucleus, thereby maintaining metabolic homeostasis. These findings provide more evidence suggesting Menin could be targeted for the treatment of hepatic steatosis, NAFLD or metabolic dysfunction-associated fatty liver disease (MAFLD), and even other hepatic diseases.

Comprehensive analysis identifies DNA damage repair-related gene HCLS1 associated with good prognosis in lung adenocarcinoma.

Background: Lung cancer is the leading cause of cancer-associated mortality. Lung adenocarcinoma (LUAD) amounts to more than 40% of all lung malignancies. Therefore, developing clinically useful biomarkers for this disease is critical. DNA damage repair (DDR) is a complicated signal transduction process that ensures genomic stability. DDR should be comprehensively analyzed to elucidate their clinical significance and tumor immune microenvironment interactions. Methods: In this study, DDR-related genes (DRGs) were selected to investigate their prognostic impact on LUAD. A regression-based prognostic model was established based on The Cancer Genome Atlas (TCGA)-LUAD cohort and three external Gene Expression Omnibus (GEO) validation cohorts (GSE31210, GSE68465, and GSE72094). The robust, established model could independently predict the clinical outcomes in patients. Then, the prognostic performance of risk profiles was assessed using a time-dependent receiver operating characteristic (ROC) curve, Cox regression, nomogram, and Kaplan-Meier analyses. Furthermore, the potential biological functions and infiltration status of DRGs in LUAD were investigated with ESTIMATE and CIBERSORT. Finally, the effects of HCLS1 on the clinical features, prognosis, biological function, immune infiltration, and treatment response in LUAD were systematically analyzed. Results: Eleven DRGs were constructed to categorize patients into high- and low-risk groups. The risk score was an independent predictor of overall survival (OS). HCLS1 expression was downregulated in LUAD samples and linked with clinicopathological features. Multivariate Cox regression analysis using the Kaplan-Meier plotter revealed that low HCLS1 expression was independently associated with poor OS. Moreover, the HCLS1 high-expression group had higher immune-related gene expression and ESTIMATE scores. It was positively correlated with the infiltration of M1 macrophages, activated memory CD4 T cells, CD8 T cells, memory B cells, resting dendritic cells, and memory CD4 T cells, Tregs, and neutrophils. Conclusions: A new classification system was developed for LUAD according to DDR characteristics. This stratification has important clinical values, reliable prognosis, and immunotherapy in patients with LUAD. Moreover, HCLS1 is a potential prognostic biomarker of LUAD that correlates with the extent of immune cell infiltration in the tumor microenvironment (TME).

Comprehensive characterization of MUC16 mutations in lung adenocarcinoma for immunotherapies and prognosis: An observational study.

Lung adenocarcinoma (LUAD) is a non-small-cell lung cancer and is the leading cause of cancer-related deaths worldwide. Immunotherapy is a promising candidate for LUAD, and tumor mutation burden (TMB) could be a new biomarker to monitor the response of cancer patients to immunotherapy. It is known that the mucin 16 (MUC16) mutation is the most common and affects the progression and prognosis of several cancers. However, whether MUC16 mutations are associated with TMB and tumor-infiltrating immune cells in LUAD is not fully elucidated. All the data were obtained from the cancer genome atlas database to assess the prognostic value and potential mechanism of MUC16 in LUAD. An immune prognostic model (IPM) was developed based on immune-related genes that could be differentially expressed between MUC16MUT and MUC16WT LUAD patients. Later, the IPM effect on the prognosis and immunotherapy of LUAD was comprehensively evaluated. MUC16 was frequently mutated in LUAD, with a mutational frequency of 43.4%, significantly associated with higher TMB and better clinical prognosis. Based on 436 patients with LUAD, an IPM was established and validated to differentiate patients with a low or high risk of poor survival. The univariate and multivariate Cox regression analyses demonstrated that the IPM was an independent prognostic indicator for LUAD patients. Elevated expressions of PD-L1, LAG3, PDCD1, and SIGLEC15, and most of the T-effector and interferon-γ gene signatures, were depicted in the high-risk group. Moreover, the nomogram using the IPM and clinical prognostic factors also predicted the overall survival and clinical utility. Our project developed a robust risk signature depending on the MUC16 status and provided novel insights for individualized treatment options for LUAD patients.

Discovery of rafoxanide as a novel agent for the treatment of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC), which accounts for approximately 85% of all lung cancer cases, is associated with a poor outcome. Rafoxanide is an anthelmintic drug that inhibits tumor growth in certain malignancies. However, its impact on NSCLC remains unknown. In this study, we examined the effect of rafoxanide on NSCLC and dissected the underlying mechanism. The results showed that rafoxanide significantly inhibited the growth, invasion, and migration of NSCLC cells. Besides, rafoxanide can induce NSCLC cell apoptosis and cell cycle arrest in a dose-dependent manner. RNA-seq analysis revealed that genes associated with endoplasmic reticulum stress (ER) stress responses were activated. Mechanistically, we found Rafoxanide can induce ER stress and activate the unfolded protein response (UPR). Apoptosis was activated by excessive ER stress, and autophagy was activated to partially alleviate ER stress. In vivo, we found that rafoxanide inhibited the growth of A549 and H1299 xenograft mouse models without severe side effects. Collectively, the present study indicates that rafoxanide may be a candidate drug for the treatment of NSCLC.

The Nuclear Pore Complex 62 Suppression Inhibits Coxsackievirus B Replication and Inflammatory Response.

Coxsackievirus B3 (CVB3) is one of the major viruses associated with human viral myocarditis, in members of the Picornaviridae order. Cellular localization depends on the activity of nuclear pore complexes, which are composed of nucleoporins (Nups), including Nup62. To better understand interactions between Nup62 and CVB3, we investigated the impact of CVB3 infection on Nup62 levels and the impact of Nup62 production on CVB3 replication in cultured cells. We found that CVB3 infection correlated with decreased Nup62 expression in vitro and that lower levels of Nup62 led to inhibition of CVB3 replication and to decreased activation of AKT and extracellular signal-related kinase. Our study reveals that Nup62 regulates the CVB3 replication during infection.

Synthesis of W-modified CeO2/ZrO2 catalysts for selective catalytic reduction of NO with NH3.

In this paper, a series of tungsten-zirconium mixed binary oxides (denoted as W m ZrO x ) were synthesized via co-precipitation as supports to prepare Ce0.4/W m ZrO x catalysts through an impregnation method. The promoting effect of W doping in ZrO2 on selective catalytic reduction (SCR) performance of Ce0.4/ZrO2 catalysts was investigated. The results demonstrated that addition of W in ZrO2 could remarkably enhance the catalytic performance of Ce0.4/ZrO2 catalysts in a broad temperature range. Especially when the W/Zr molar ratio was 0.1, the Ce0.4/W0.1ZrO x catalyst exhibited the widest active temperature window of 226-446 °C (NO x conversion rate > 80%) and its N2 selectivity was almost 100% in the temperature of 150-450 °C. Moreover, the Ce0.4/W0.1ZrO x catalyst also exhibited good SO2 tolerance, which could maintain more than 94% of NO x conversion efficiency after being exposed to a 100 ppm SO2 atmosphere for 18 h. Various characterization results manifested that a proper amount of W doping in ZrO2 was not only beneficial to enlarge the specific surface area of the catalyst, but also inhibited the growth of fluorite structure CeO2, which were in favor of CeO2 dispersion on the support. The presence of W was conducive to the growth of a stable tetragonal phase crystal of ZrO2 support, and a part of W and Zr combined to form W-Zr-O x solid super acid. Both of them resulted in abundant Lewis acid sites and Brønsted acid sites, enhancing the total surface acidity, thus significantly improving NH3 species adsorption on the surface of the Ce0.4/W0.1ZrO x catalyst. Furthermore, the promoting effect of adding W on SCR performance was also related to the improved redox capability, higher Ce3+/(Ce3+ + Ce4+) ratio and abundant surface chemisorbed oxygen species. The in situ DRIFTS results indicated that nitrate species adsorbed on the surface of the Ce0.4/W0.1ZrO x catalyst could react with NH3 due to the activation of W. Therefore, the reaction pathway over the Ce0.4/W0.1ZrO x catalyst followed both Eley-Rideal (E-R) and Langmuir-Hinshelwood (L-H) mechanisms at 250 °C.

The Regulatory Effect of Coaggregation Between Fusobacterium nucleatum and Streptococcus gordonii on the Synergistic Virulence to Human Gingival Epithelial Cells.

In subgingival plaque biofilms, Fusobacterium nucleatum is closely related to the occurrence and development of periodontitis. Streptococcus gordonii, as an accessory pathogen, can coaggregate with periodontal pathogens, facilitating the subgingival colonization of periodontal pathogens. Studies have shown that F. nucleatum can coaggregate with S. gordonii and colonize the subgingival plaque. However, most studies have focused on monocultures or coinfection of species and the potential impact of coaggregation between the two species on periodontal interactions to human gingival epithelial cells (hGECs) remains poorly understood. The present study explored the effect of coaggregation between F. nucleatum and S. gordonii on subgingival synergistic virulence to hGECs. The results showed that coaggregation inhibited the adhesion and invasion of F. nucleatum to hGECs compared with that in the F. nucleatum monoculture and coinfection group. Coaggregation and coinfection with F. nucleatum both enhanced S. gordonii adhesion to hGECs, but neither of the two groups affected S. gordonii invasion to hGECs compared with S. gordonii monoculture. The gene expression levels of TLR2 and TLR4 in hGECs in the coaggregation group were higher than those in the monoculture groups but lower than those in the coinfection group. Compared with coinfection, the coaggregation inhibited apoptosis of hGECs and promoted the secretion of the proinflammatory cytokines TNF-α and IL-6 by hGECs, showed a synergistic inflammatory effect, while coaggregation inhibited the secretion of the anti-inflammatory cytokine TGF-ß1. Coaggregation enhanced the phosphorylation of p65, p38, and JNK proteins and therefore activated the NF-κB and MAPK signaling pathways. Pretreatment with a pathway antagonist/inhibitor decreased the phosphorylation levels of proteins and the secretion of TNF-α and IL-6. In conclusion, coaggregation inhibited the adhesion and invasion of F. nucleatum to hGECs. However, it enhanced the adhesion of S. gordonii to hGECs. Compared with coinfection, coaggregation inhibited the apoptosis of hGECs. The coaggregation coordinately promoted the secretion of TNF-α and IL-6 by hGECs through the TLR/NF-κB and TLR/MAPK signaling pathways while inhibiting the secretion of TGF-ß1, thus aggravating the inflammatory response of hGECs.