Expression and prognostic significance of m6A-related genes in TP53-mutant non-small-cell lung cancer.

BACKGROUND: TP53 is an important tumor suppressor gene on human 17th chromosome with its mutations more than 60% in tumor cells. Lung cancer is the highest incidence malignancy in men around the world. N-6 methylase (m6A) is an enzyme that plays an important role in mRNA splicing, translation, and stabilization. However, its role in TP53-mutant non-small-cell lung cancer (NSCLC) remains unknown. METHOD: First, we investigated 17 common m6A regulators' prognostic values in NSCLC. Then, after the establishment of risk signature, we explored the diagnostic value of m6A in TP53-mutant NSCLC. Finally, gene set enrichment analysis (GSEA), gene ontology (GO) enrichment analysis, and differential expression analysis were used to reveal the possible mechanism of m6A regulators affecting TP53-mutant NSCLC patients. RESULTS: Study showed that nine m6A regulators (YTHDC2, METTL14, FTO, METTL16, YTHDF1, HNRNPA2B1, RBM15, KIAA1429, and WTAP) were expressed differently between TP53-mutant and wild-type NSCLC (p < 0.05); and ALKBH5 and HNRNPA2B1 were associated with the prognostic of TP53-mutant patients. After construction of the risk signature combined ALKBH5 and HNRNPA2B1, we divided patients with TP53 mutations into high- and low-risk groups, and there was a significant survival difference between two groups. Finally, 338 differentially expression genes (DEGs) were found between high- and low-risk groups. GO enrichment analysis, PPI network, and GSEA enrichment analysis showed that m6A may affect the immune environment in extracellular and change the stability of mRNA. CONCLUSION: In conclusion, m6A regulators can be used as prognostic predictors in TP53-mutant patients.

Long non-coding RNA LINC01559 exerts oncogenic role via enhancing autophagy in lung adenocarcinoma.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been verified to play fatal role in regulating the progression of lung adenocarcinoma (LUAD). Although lncRNAs play important role in regulating the autophagy of tumor cells, the function and molecular mechanism of LINC01559 in regulating lung cancer development remain to be elucidated. METHOD AND MATERIALS: In this study, we used bioinformatics to screen out autophagy-related lncRNAs from TCGA-LUAD repository. Then the least absolute shrinkage and selection operator (LASSO) regression was applied to establish the signature of autophagy-related lncRNAs so that clinical characteristics and survival in LUAD patients be evaluated. Finally, we selected the most significant differences lncRNA, LINC01559, to verify its function in regulating LUAD progression in vitro. RESULTS: We found high expression of LINC01559 indicates lymph node metastasis and poor prognosis. Besides, LINC01559 promotes lung cancer cell proliferation and migration in vitro, by enhancing autophagy signal pathway via sponging hsa-miR-1343-3p. CONCLUSION: We revealed a novel prognostic model based on autophagy-related lncRNAs, and provide a new therapeutic target and for patients with lung adenocarcinoma named LINC01559.

N-6 methylation-related lncRNA is potential signature in lung adenocarcinoma and influences tumor microenvironment.

BACKGROUND: N-6 methylation (m6A) pushes forward an immense influence on the occurrence and development of lung adenocarcinoma (LUAD). However, the methylation on non-coding RNA in LUAD, especially long non-coding RNA (lncRNA), has not been received sufficient attention. METHODS: Spearman correlation analysis was used to screen lncRNA correlated with m6A regulators expression from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) repositories, respectively. Then, the least absolute shrinkage and selection operator (LASSO) was applied to build a risk signature consisting m6A-related lncRNA. Univariate and multivariate independent prognostic analysis were applied to evaluate the performance of signature in predicting patients' survival. Next, we applied Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) to conduct pathway enrichment analysis of 3344 different expression genes (DEGs). Finally, we set up a competing endogenous RNAs (ceRNA) network to this lncRNA. RESULTS: A total of 85 common lncRNAs were selected to acquire the components related to prognosis. The final risk signature established by LASSO regression contained 11 lncRNAs: ARHGEF26-AS1, COLCA1, CRNDE, DLGAP1-AS2, FENDRR, LINC00968, TMPO-AS1, TRG-AS1, MGC32805, RPARP-AS1, and TBX5-AS1. M6A-related lncRNA risk score could predict the prognostic of LUAD and was significantly associated with clinical pathological. And in the evaluation of lung adenocarcinoma tumor microenvironment (TME) by using ESTIMATE algorithm, we found a statistically significant correlation between risk score and stromal/immune cells. CONCLUSION: M6A-related lncRNA was a potential prognostic and therapy target for lung adenocarcinoma.

Drug Repurposing: In vitro and in vivo Antimicrobial and Antibiofilm Effects of Bithionol Against Enterococcus faecalis and Enterococcus faecium.

Widespread antibiotic resistance has been reported in enterococcal pathogens that cause life-threatening infections. Enterococci species rapidly acquire resistance and the pace of new antibiotic development is slow. Drug repurposing is a promising approach in solving this problem. Bithionol (BT) is a clinically approved anthelminthic drug. In this study, we found that BT showed significant antimicrobial and antibiofilm effects against Enterococcus faecalis and vancomycin-resistant Entercococcus faecium in vitro, in a dose-dependent manner, by disrupting the integrity of the bacterial cell membranes. Moreover, BT effectively reduced the bacterial load in mouse organs when combined with conventional antibiotics in a peritonitis infection model. Thus, BT has shown potential as a therapeutic agent against E. faecalis- and vancomycin-resistant E. faecium-related infections.

Antibiofilm efficacy of the gold compound auranofin on dual species biofilms of Staphylococcus aureus and Candida sp.

AIMS: Staphylococcus aureus (a bacterial pathogen) and Candida sp. (opportunistic fungi) are two clinically relevant biofilm-forming microbes responsible for a majority of community- and nosocomial-acquired infections. Dual species biofilm formation between S. aureus and Candida sp. extremely enhances the antimicrobial resistance of the micro-organisms and is difficult to treat with antibiotic therapy. Hence, it is crucial to explore new antimicrobial agents. Auranofin (AF) is a mixed ligand gold compound and has recently been repurposed as an antibacterial and antifungal agent. However, the effects of AF against dual species biofilm have remained largely untested. METHODS AND RESULTS: In the present study, by constructing biofilms on microplates and urinary catheter surfaces, AF showed strong planktonic cells and biofilm inhibitory effects against mono- and dual culture models of S. aureus and Candida albicans but only exhibited moderate antibiofilm effects on Candida parapsilosis. Auranofin could be synergistic with subminimal inhibitory concentrations of amphotericin B against S. aureus + C. albicans/C. parapsilosis dual biofilms. Auranofin also showed effective antimicrobial effects on vancomycin-resistant strains. However, the antimicrobial effects of AF were decreased in the presence of heat-inactivated foetal bovine serum. CONCLUSIONS: In summary, AF could effectively inhibit S. aureus and C. albicans mono- and dual biofilm formation in vitro. SIGNIFICANCE AND IMPACT OF THE STUDY: Coexistence between Staphylococcus aureus and Candida sp. in dual biofilms leads to increased resistance to some conventionally used antimicrobials, indicating a need for alternative treatments. This study demonstrates the potential for the Au-containing compound AF in the treatment of dual biofilm infections and encourages further investigation of this treatment for clinical use.

Exosomal circRNAs: biogenesis, effect and application in human diseases.

Exosomes have emerged as critical mediators of intercellular communication, both locally and systemically, by regulating a diverse range of biological processes between cells. Circular RNA (circRNA) is a novel member of endogenous noncoding RNAs with widespread distribution and diverse cellular functions. Recently, circular RNAs have been identified for their enrichment and stability in exosomes. In this review, we outline the origin, biogenesis and function of exosomal circRNAs as well as their roles in various diseases. Although their precise roles and mechanisms of gene regulation remain largely elusive, exosomal circRNAs have potential applications as disease biomarkers and novel therapeutic targets.

A Mutational Analysis of GJB2, SLC26A4, MT-RNA1, and GJB3 in Children with Nonsyndromic Hearing Loss in the Henan Province of China.

BACKGROUND: Hearing impairment is one of the most common neurosensory disorders afflicting humans. Approximately half of all cases have a genetic etiology. The distribution and frequency of genetic mutations that cause deafness differ significantly by ethnic group and geographic region. METHODS: 130 sporadic nonsyndromic hearing loss (NSHL) children from the Henan province were subjected to microarray-based mutation detection. Nine pathogenic mutations were detected in four of the most common deafness-related genes (GJB2, GJB3, SLC26A4, and MT-RNA1). RESULTS: Fifty percent of the analyzed patients (65/130) were shown to have genetic defects known to be related to deafness. Slightly >30% (41/130) had biallelic pathogenic mutations. One patient had pathogenic mutations in their mitochondrial genes (MT-RNA1); no mutations were detected in the GJB3 gene. Twenty-three (17.69%) patients were carriers of a single mutation in a recessive gene; these findings alone, however, cannot be interpreted as a cause of hearing loss. Utilizing this molecular strategy, we were able to arrive at a conclusive diagnosis for 42 of the NSHL children. CONCLUSION: Genetic factors play a major role in sporadic NSHL patients from the Henan province, but it is clear that our screen needs to be expanded to include additional genes and alleles. Screening of potential pathogenic genes is important for patient risk assessment.

SIRT1 induces epithelial-mesenchymal transition by promoting autophagic degradation of E-cadherin in melanoma cells.

Melanoma is highly metastatic, and understanding of its molecular mechanism is urgently needed for the development of therapeutic targets and prognostic assessment for metastatic melanoma. SIRT1 is a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, belonging to the mammalian sirtuin family. It has been reported that SIRT1 is associated with metastasis in various cancers. However, the molecular mechanism of SIRT1 in melanoma metastasis remains to be clarified. Here we report that SIRT1 induces the epithelial-mesenchymal transition (EMT) by accelerating E-cadherin degradation via autophagy and facilitates melanoma metastasis. Initially, we found that SIRT1 expression was frequently elevated in metastatic melanoma compared with primary melanoma. In addition, SIRT1 induced the EMT and promoted cell migration and invasion by decreasing E-cadherin expression. Further work demonstrated that SIRT1 accelerated the autophagic degradation of E-cadherin through deacetylation of Beclin 1. In addition, inhibition of autophagy recovered E-cadherin expression and suppressed cell migration and invasion by delaying the degradation of E-cadherin in SIRT1-overexpressing cells. Overall, our findings reveal a novel molecular mechanism for SIRT1 in melanoma metastasis, indicating that SIRT1 may serve as a viable therapeutic target for metastatic melanoma.

Meloxicam inhibits biofilm formation and enhances antimicrobial agents efficacy by Pseudomonas aeruginosa.

Microbial biofilms are communities of surface-adhered cells enclosed in a matrix of extracellular polymeric substances. Bacterial cells in biofilm are 10~1,000-fold more resistant to antimicrobials than the planktonic cells. Burgeoning antibiotic resistance in Pseudomonas aeruginosa biofilm has necessitated the development of antimicrobial agents. Here, we have investigated the antibiofilm effect of meloxicam against P. aeruginosaPAO1 and its potential mechanisms. Further, we have explored whether meloxicam could enhance the susceptibility of bacterial biofilms to treatment with conventional antimicrobials. Here, we found that meloxicam could significantly inhibit PAO1 biofilm formation in a dose-dependent manner at the concentration without influence on planktonic cell growth. Meloxicam could also significantly inhibit the motilities, production of extracellular matrix, and expression of quorum sensing-related genes and virulence factors of PAO1. Furthermore, synergistic interaction was observed when meloxicam combined with tetracycline, gentamicin, tobramycin, ciprofloxacin, ceftriaxone, ofloxacin, norfloxacin, ceftazidime, and DNase at subminimal inhibitory concentrations against PAO1 bioiflm. Collectively, our study lays the foundation for further investigation of repurposing meloxicam as a topical antibiofilm agent to treat P. aeruginosa biofilm-related infections.

Effects of human serum and apo-Transferrin on Staphylococcus epidermidis RP62A biofilm formation.

Biofilm-associated Staphylococcus epidermidis infections present clinically important features due to their high levels of resistance to traditional antibiotics. As a part of human innate immune system, serum shows different degrees of protection against systemic S. epidermidis infection. We investigated the ability of human serum as well as serum component to inhibit the formation of, and eradication of mature S. epidermidis biofilms. In addition, the synergistic effect of vancomycin combined with apo-Transferrin was checked. Human serum exhibited significant antibiofilm activities against S. epidermidis at the concentration without affecting planktonic cell growth. However, there was no effect of human serum on established biofilms. By component separation, we observed that antibiofilm effect of serum components mainly due to the proteins could be damaged by heat inactivation (e.g., complement) or heat-stable proteins ≥100 kDa. In addition, serum apo-Transferrin showed modest antibiofilm effect, but without influence on S. epidermidis initial adhesion. And there was a synergistic antibiofilm interaction between vancomycin and apo-Transferrin against S. epidermidis. Our results indicate that serum or its components (heat-inactivated components or heat-stable proteins ≥100 kDa) could inhibits S. epidermidis biofilm formation. Besides, apo-Transferrin could partially reduce the biofilm formation at the concentration that does not inhibit planktonic cell growth.

Effects of norspermidine on Pseudomonas aeruginosa biofilm formation and eradication.

Biofilms are defined as aggregation of single cell microorganisms and associated with over 80% of all the microbial infections. Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen capable of leading to various infections in immunocompromised people. Recent studies showed that norspermidine, a kind of polyamine, prevented and disrupted biofilm formation by some Gram-negative bacterium. In this study, the effects of norspermidine on P. aeruginosa biofilm formation and eradication were tested. Microtiter plate combined with crystal violet staining was used to study the effects of norspermidine on P. aeruginosa initial attachment, then we employed SEM (scanning electron microscope), qRT-PCR, and QS-related virulence factor assays to investigate how norspermidine prevent biofilm formation by P. aeruginosa. We reported that high-dose norspermidine had bactericide effect on P. aeruginosa, and norspermidine began to inhibit biofilm formation and eradicate 24-h mature biofilm at concentration of 0.1 and 1 mmol/L, respectively, probably by preventing cell-surface attachment, inhibiting swimming motility, and downregulating QS-related genes expression. To investigate the potential utility of norspermidine in preventing device-related infections, we found that catheters immersed with norspermidine were effective in eradicating mature biofilm. These results suggest that norspermidine could be a potent antibiofilm agent for formulating strategies against P. aeruginosa biofilm.

Catalytic hydrothermal conversion of carboxymethyl cellulose to value-added chemicals over metal-organic framework MIL-53(Al).

Catalytic hydrolysis of biomass over solid catalysts can be one of the most efficient pathways for a future sustainable society dependent on cellulose biomass. In this work metal-organic framework MIL-53(Al) without any functionalization was directly employed as an efficient heterogeneous catalyst for the hydrolysis of carboxymethyl cellulose (CMC) to 5-hydroxymethyl-furaldehyde (5-HMF) in aqueous phase. A 5-HMF molar yield of 40.3% and total reducing sugar (TRS) molar yield of 54.2% were obtained with water as single solvent at 473 K for 4 h. The catalyst could be reused three times without losing activity to a greater extent. With the remarkable advantages such as the use of water as single solvent and MIL-53(Al) as a novel heterogeneous green catalyst, the work provides a new platform for the production of value added chemicals and liquid fuels from biomass.