Phenethyl isothiocyanate inhibits metastasis potential of non-small cell lung cancer cells through FTO mediated TLE1 m6A modification.

N6-methyladenosine (m6A) modification is a prevalent RNA epigenetic modification, which plays a crucial role in tumor progression including metastasis. Isothiocyanates (ITCs) are natural compounds and inhibit the tumorigenesis of various cancers. Our previous studies show that ITCs inhibit the proliferation and metastasis of non-small cell lung cancer (NSCLC) cells, and have synergistic effects with chemotherapy drugs. In this study, we investigated the molecular mechanisms underlying the inhibitory effects of ITCs on cancer cell metastasis. We showed that phenethyl isothiocyanate (PEITC) dose-dependently inhibited the cell viability of both NSCLC cell lines H1299 and H226 with IC50 values of 17.6 and 15.2 µM, respectively. Furthermore, PEITC dose-dependently inhibited the invasion and migration of H1299 and H226 cells. We demonstrated that PEITC treatment dose-dependently increased m6A methylation levels and inhibited the expression of the m6A demethylase fat mass and obesity-associated protein (FTO) in H1299 and H226 cells. Knockdown of FTO significantly increased m6A methylation in H1299 and H226 cells, impaired their abilities of invasion and migration in vitro, and enhanced the inhibition of PEITC on tumor growth in vivo. Overexpression of FTO promoted the migration of NSCLC cells, and also mitigated the inhibitory effect of PEITC on migration of NSCLC cells. Furthermore, we found that FTO regulated the mRNA m6A modification of a transcriptional co-repressor Transducin-Like Enhancer of split-1 (TLE1) and further affected its stability and expression. TCGA database analysis revealed TLE1 was upregulated in NSCLC tissues compared to normal tissues, which might be correlated with the metastasis status. Moreover, we showed that PEITC suppressed the migration of NSCLC cells by inhibiting TLE1 expression and downstream Akt/NF-κB pathway. This study reveals a novel mechanism underlying ITC's inhibitory effect on metastasis of lung cancer cells, and provided valuable information for developing new therapeutics for lung cancer by targeting m6A methylation.

In vitro antifungal activities, molecular docking, and DFT studies of 4-amine-3-hydrazino-5-mercapto-1,2,4-triazole derivatives.

Six disubstituted Schiff base compounds were synthesized (A1-A6) and characterized using infrared spectroscopy (IR), elemental analyses (EA), 1H NMR, 13C NMR and HRMS spectroscopic techniques. Crystal structure of A1 has been determined by single crystal X-ray diffraction. The antifungal activities against three fungi were assessed, and the results showed that compounds of A1 and A2 have good activity for Wheat gibberellic with EC50 value of 15.89 and 16.99 mg/L, respectively. Compounds of A3, A4 and A6 have good bioactivity against Maize rough bacteria (the value of EC50 is 8.23, 7.56 and 7.92 mg/L, respectively). According to the result of molecular docking, compounds of A1 and A2 have the smallest docking energy (-8.33, -9.00 kcal/mol). Besides, for A1 and A2, the analysis of highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO) analysis and molecular electrostatic potential map were to further elaborate the reason for the good activity with density functional theory (DFT)-B3LYP/6-31G.

Overexpression of CHD1L is associated with poor survival and aggressive tumor biology in esophageal carcinoma.

Esophageal carcinoma (EC) is a malignancy with high metastatic potential. Chromosomal helicase/ATPase DNA binding protein 1-like (CHD1L) gene is a newly identified oncogene located at Chr1q21, and it is amplified in many solid tumors. However, the status of CHD1L protein expression in EC and its clinical significance is uncertain. This study was designed to investigate the significance of CHD1L expression in human EC and its biological function in EC cells. The expression of CHD1L was examined by immunohistochemistry in 191 surgically resected ECs. The associations between CHD1L expression and clinical pathological parameters and the prognostic value of CHD1L were analyzed. Western blot analysis showed that CHD1L was overexpressed in EC cell lines. In addition, positive CHD1L expression was strongly related to advanced clinical stage (P<0.01), and lymph node metastasis (P<0.01) of EC. The Kaplan-Meier curve indicated that high expression of CHD1L may result in poor prognosis of EC patients (P<0.01), and multivariate analysis showed that CHD1L overexpression was an independent predictor of overall survival. Furthermore, suppression of CHD1L in EC cells increased apoptosis and decreased cell proliferation invasion ability. Our results suggest that CHD1L is a target oncogene with the potential to serve as a novel prognostic biomarker in EC pathogenesis.

Thermal behaviors, nonisothermal decomposition reaction kinetics, thermal safety and burning rates of BTATz-CMDB propellant.

The composite modified double base (CMDB) propellants (nos. RB0601 and RB0602) containing 3,6-bis (1H-1,2,3,4-tetrazol-5-yl-amino)-1,2,4,5-tetrazine (BTATz) without and with the ballistic modifier were prepared and their thermal behaviors, nonisothermal decomposition reaction kinetics, thermal safety and burning rates were investigated. The results show that there are three mass-loss stages in TG curve and two exothermic peaks in DSC curve for the BTATz-CMDB propellant. The first two mass-loss stages occur in succession and the temperature ranges are near apart, and the decomposition peaks of the two stages overlap each other, inducing only one visible exothermic peak appear in DSC curve during 350-550 K. The reaction mechanisms of the main exothermal decomposition processes of RB0601 and RB0602 are all classified as chemical reaction, the mechanism functions are f(alpha)=(1-alpha)(2), and the kinetic equations are dalpha/dt = 10(19.24)(1-alpha)(2)e(-2.32x10(4)/T) and dalpha/dt = 10(20.32)(1-alpha)(2)e(-2.32x10(4)/T). The thermal safety evaluation on the BTATz-CMDB propellants was obtained. With the substitution of 26% RDX by BTATz and with the help of the ballistic modifier in the CMDB propellant formulation, the burning rate can be improved by 89.0% at 8 MPa and 47.1% at 22 MPa, the pressure exponent can be reduced to 0.353 at 14-20 MPa.

Esophageal cancer in Chinese population: no polymorphism in codon 149 of P21(Waf1/Cip1) cyclin dependent kinase gene.

It has recently been suggested that people of the Indian population who carried the codon 149 polymorphism (GAT-->GGT) of P21(Waf1/Cip1) gene were more susceptible to esophageal cancer and oral cancer than the individuals without that polymorphism. Since esophageal cancer is a high incident neoplasm in China, we analysed the same codon of P21(Waf1/Cip1) in the Chinese population. Blood samples from 80 esophageal cancer patients and 80 normal blood donors were collected for DNA extraction. Methods of Polymerase Chain Reaction (PCR) and direct sequencing were used for detection of the polymorphism in codon 149 of P21(Waf1/Cip1). Bioinformatics analysis was also thoroughly performed for this gene. No polymorphism was found in all samples tested. Bioinformatics analysis revealed that the so-called polymorphism of codon 149 reported previously was a wrong one. In conclusion, no polymorphism exists in codon 149 of P21(Waf1/Cip1). It is not appropriate to use it as a susceptible site of the gene in cancer study.