Oncogenic DDX46 promotes pancreatic cancer development and gemcitabine resistance by facilitating the JMJD6/CDK4 signaling pathway.

Pancreatic cancer (PAAD) is a fatal malignancy with a poor prognosis. The treatment strategies are quite limited and gemcitabine is the canonical one, which has been proven to improve the prognosis of PAAD patients. However, the treatment efficiency of gemcitabine is far from satisfactory and remains to be further improved. DEAD-Box Helicase 46 (DDX46) is a kind of RNA helicase, which promotes multiple cancers development. However, its role in PAAD is largely unknown. In the present study, we found DDX46 was highly expressed in PAAD tissues and correlated with poor prognosis. Knockdown of DDX46 repressed PAAD cell growth in vitro and in vivo and sensitized PAAD cells to gemcitabine treatment. Mechanically, DDX46 bound to JMJD6 and promoted JMJD6/CDK4 signaling pathway. Overexpression of JMJD6 reversed the anti-tumor function of DDX46 knockdown. Our study found a novel pathological mechanism of PAAD progression and provided a potential therapeutic target to improve gemcitabine efficiency.

Comparative and Functional Analyses Reveal Conserved and Variable Regulatory Systems That Control Lasalocid Biosynthesis in Different Streptomyces Species.

Lasalocid, a representative polyether ionophore, has been successfully applied in veterinary medicine and animal husbandry and also displays promising potential for cancer therapy. Nevertheless, the regulatory system governing lasalocid biosynthesis remains obscure. Here, we identified two conserved (lodR2 and lodR3) and one variable (lodR1, found only in Streptomyces sp. strain FXJ1.172) putative regulatory genes through a comparison of the lasalocid biosynthetic gene cluster (lod) from Streptomyces sp. FXJ1.172 with those (las and lsd) from Streptomyces lasalocidi. Gene disruption experiments demonstrated that both lodR1 and lodR3 positively regulate lasalocid biosynthesis in Streptomyces sp. FXJ1.172, while lodR2 plays a negative regulatory role. To unravel the regulatory mechanism, transcriptional analysis and electrophoretic mobility shift assays (EMSAs) along with footprinting experiments were performed. The results revealed that LodR1 and LodR2 could bind to the intergenic regions of lodR1-lodAB and lodR2-lodED, respectively, thereby repressing the transcription of the lodAB and lodED operons, respectively. The repression of lodAB-lodC by LodR1 likely boosts lasalocid biosynthesis. Furthermore, LodR2 and LodE constitute a repressor-activator system that senses changes in intracellular lasalocid concentrations and coordinates its biosynthesis. LodR3 could directly activate the transcription of key structural genes. Comparative and parallel functional analyses of the homologous genes in S. lasalocidi ATCC 31180T confirmed the conserved roles of lodR2, lodE, and lodR3 in controlling lasalocid biosynthesis. Intriguingly, the variable gene locus lodR1-lodC from Streptomyces sp. FXJ1.172 seems functionally conserved when introduced into S. lasalocidi ATCC 31180T. Overall, our findings demonstrate that lasalocid biosynthesis is tightly controlled by both conserved and variable regulators, providing valuable guidance for further improving lasalocid production. IMPORTANCE Compared to its elaborated biosynthetic pathway, the regulation of lasalocid biosynthesis remains obscure. Here, we characterize the roles of regulatory genes in lasalocid biosynthetic gene clusters of two distinct Streptomyces species and identify a conserved repressor-activator system, LodR2-LodE, which could sense changes in the concentration of lasalocid and coordinate its biosynthesis with self-resistance. Furthermore, in parallel, we verify that the regulatory system identified in a new Streptomyces isolate is valid in the industrial lasalocid producer and thus applicable for the construction of high-yield strains. These findings deepen our understanding of regulatory mechanisms involved in the production of polyether ionophores and provide novel clues for the rational design of industrial strains for scaled-up production.

A Case-Control Study on the Therapeutic Effect of Mediastinoscope-Assisted and Thoracoscope-Assisted Esophagectomy.

Objective. To compare the clinical efficacies of mediastinoscope-assisted and thoracoscope-assisted esophagectomy. Materials and Methods. Seventy-six patients with esophageal cancer who underwent minimally invasive esophagectomy at the General Hospital of Ningxia Medical University between June 2015 and January 2019 were retrospectively evaluated. Among them, 28 patients underwent mediastinoscope-assisted transhiatal esophagectomy (MATHE), and 48 received thoracoscope-assisted transthoracic esophagectomy (TATTE). The perioperative clinical data and follow-up data of the 2 groups were compared. Results. All operations were successful in both groups. MATHE was favorable in terms of operation time, intraoperative blood loss, drainage volume 3 days after surgery, postoperative hospital stay, and hypoproteinemia (P < .05). Lymph node dissections were less than those in the TATTE (P < .05). No significant differences in long-term postoperative complications and survival rate were found between the 2 groups (P > .05). Conclusion. MATHE has the advantages of minimal trauma, shorter operation time, less intraoperative blood loss, and faster recovery. More adequate tumor clearance in terms of lymph node dissection can be achieved with TATTE. However, the comparison of survival rates between the 2 groups is similar.

Chemical Characteristics of Platycodon grandiflorum and its Mechanism in Lung Cancer Treatment.

Objective: The technology, network pharmacology and molecular docking technology of the ultra performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS) were used to explore the potential molecular mechanism of Platycodon grandiflorum (PG) in the treatment of lung cancer (LC). Methods: UPLC-Q-TOF-MS/MS technology was used to analyze the ingredients of PG and the potential LC targets were obtained from the Traditional Chinese Medicine Systems Pharmacology database, and the Analysis Platform (TCMSP), GeneCards and other databases. The interaction network of the drug-disease targets was constructed with the additional use of STRING 11.0. The pathway enrichment analysis was carried out using Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) in Metascape, and then the "Drug-Ingredients-Targets-Pathways-Disease" (D-I-T-P-D) network was constructed using Cytoscape v3.7.1. Finally, the Discovery Studio 2016 (DS) software was used to evaluate the molecular docking. Results: Forty-seven compounds in PG, including triterpenoid saponins, steroidal saponins and flavonoids, were identified and nine main bioactive components including platycodin D were screened. According to the method of data mining, 545 potential drug targets and 2,664 disease-related targets were collected. The results of topological analysis revealed 20 core targets including caspase 3 (CASP3) and prostaglandin-endoperoxide synthase 2 (PTGS2) suggesting that the potential signaling pathway potentially involved in the treatment of LC included MAPK signaling pathway and P13K-AKT signaling pathway. The results of molecular docking proved that the bound of the ingredients with potential key targets was excellent. Conclusion: The results in this study provided a novel insight in the exploration of the mechanism of action of PG against LC.

Design, synthesis and biological evaluation of chrysin long-chain derivatives as potential anticancer agents.

A series of long-chain derivatives of chrysin (compounds 3-22) were synthesized to evaluate for their antiproliferative activities against the human liver cancer cell line HT-29 and EGFR inhibitory activity. Among the compounds tested, compounds hexadecyl 2-(5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yloxy)acetate (10) and N-hexadecyl 2-(5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yloxy)acetamide (20) displayed potent EGFR inhibitory activity with IC(50) values of 0.048 microM and 0.035 microM), comparable to the positive control erlotinib. Docking simulation of compounds 10 and 20 was carried out to illustrate the binding mode of the molecular into the EGFR active site, and the result suggested that compound 10 and 20 can bind the EGFR kinase well. Thus, compounds 10 and 20 with potent EGFR inhibitory activity would be potential anticancer agents.

Design, synthesis and biological evaluation of thiazolidinone derivatives as potential EGFR and HER-2 kinase inhibitors.

Two series of thiazolidinone derivatives designing for potential EGFR and HER-2 kinase inhibitors have been discovered. Some of them exhibited significant EGFR and HER-2 inhibitory activity. Compound 2-(2-(5-bromo-2-hydroxybenzylidene)hydrazinyl)thiazol-4(5H)-one (12) displayed the most potent inhibitory activity (IC(50)=0.09 microM for EGFR and IC(50)=0.42 microM for HER-2), comparable to the positive control erlotinib. Docking simulation was performed to position compound 12 into the EGFR active site to determine the probable binding model. Antiproliferative assay results indicating that some of the thiazolidinone derivatives own high antiproliferative activity against MCF-7. Compound 12 with potent inhibitory activity in tumor growth inhibition would be a potential anticancer agent.