Discovery of Mycothiogranaticins from Streptomyces vietnamensis GIMV4.0001 and the Regulatory Effect of Mycothiol on the Granaticin Biosynthesis

Granaticins are benzoisochromanequinone polyketides with remarkable antibacterial and anticancer activities. Three sulfur-containing granaticin congeners, mycothiogranaticins A (1), B (2) and granaticin MA (3) were discovered from a granaticin-producing strain of Streptomyces vietnamensis GIMV4.0001. Two of them were structurally determined with mycothiol or N-acetylcysteine moieties and found to be bio-actively reluctant. Disruption of the mshA gene (SVTN_RS20640) that encodes the D-inositol-3-phosphate glycosyltransferase crucial for mycothiol biosynthesis, fully abolished the production of mycothiogranaticins. The result substantiated that the newly discovered mycothiogranaticins are consequences of the combination of the granaticin and mycothiol biosynthetic pathways. The overall granaticin production of the ΔmshA mutant strain was unexpectedly decreased by at least more than 50%, while similar production level of granaticins to that of the wild type strain was observed in an mycothiol-S transferase gene (SVTN_RS22215) disruptant Δmst. These results indicated that the mycothiol deficiency was responsible for the decreased production of granaticins. Mycothiol may positively regulate the biosynthesis of granaticin possibly by maintaining the cellular redox balance. To the best of our knowledge, this is the first report that mycothiol can not only be a direct building block of polyketides but also play a regulatory role in the polyketide biosynthesis.

Financial Performance Under the Influence of the Coronavirus Disease 2019: Effects of Strategic Flexibility and Environmental Dynamics in Big Data Capability

This study draws on the dynamic capabilities view and the firm’s big data capability (BDC) in the new economic environment. It constructs an adjusted intermediary model to study the mechanism of BDC, strategic flexibility, and environmental dynamic affecting financial performance. We find that strategic flexibility plays an intermediary role in the “Converse-U” relationship between BDC and financial performance. Environmental dynamics adjust the relationship between BDC and financial performance positively and smooth the “Converse-U” relationship. The findings suggest building and managing BDC, combining BDC with the management process, and achieving continuous financial performance improvement in a dynamic environment. The paper also puts forward the nonlinear hypothesis, discusses the “Converse-U” relationship between BDC and enterprise financial performance in the Chinese context of digital economy explosion and growth, and considers the intermediary mechanism of strategic flexibility and the regulatory effect of environmental dynamics.

Molecular Mechanism of the Regulatory Effect of Schisandrol A on the Immune Function of Mice Based on a Transcription Factor Regulatory Network

The molecular mechanism of the regulatory effed of schizandrol A (SA) on the immune function of cyclophosphamide-induced immunosuppressive mice was explored in this study. On the basis of 1619 differentially expressed genes related to the regulatory effect of SA on the immune function of mice screened in our previous study, transcription factors and their corresponding target genes were screened in the Transcriptional Regulatory Element Database (TRED), and a transcription factor target gene regulatory network was constructed. The key nodes of the network were statistically analyzed to clarify the role of transcription factors in the regulatory network. The correlation of network genes with diseases was analyzed with an online annotation tool through the Database for Annotation, Visualization and Integrated Discovery (DAVID). Finally, the key factors related to the regulatory effect of SA on the immune function of mice were screened and verified by animal experiments and the detection of related protein expression by western blot analysis. The results showed that SA could alleviate the immunosuppression induced by cyclophosphamide in mice and regulate the protein expression of Jun, Trp53, and Creb1 in the spleen tissue of mice, together with the transcription factors Atf4 and E2f2. SA may thus play a role in the alleviation of some immunity-related diseases (such as cancer) by regulating the immune function of mice through multiple genes and their transcription factors.

Predicting the possible effect of miR-203a-3p and miR-29a-3p on DNMT3B and GAS7 genes expression

Aberrant expression of genes involved in methylation, including DNA methyltransferase 3 Beta (DNMT3B), can cause hypermethylation of various tumor suppressor genes. In this regard, various molecular factors such as microRNAs can play a critical role in regulating these methyltransferase enzymes and eventually downstream genes such as growth arrest specific 7 (GAS7). Accordingly, in the present study we aimed to predict regulatory effect of miRNAs on DNMT3B and GAS7 genes expression in melanoma cell line. hsa-miR-203a-3p and hsa-miR-29a-3p were predicted and selected using bioinformatics software. The Real-time PCR technique was performed to investigate the regulatory effect of these molecules on the DNMT3B and GAS7 genes expression. Expression analysis of DNMT3B gene in A375 cell line showed that there was a significant increase compared to control (p value = 0.0015). Analysis of hsa-miR-203a-3p and hsa-miR-29a-3p indicated the insignificant decreased expression in melanoma cell line compared to control (p value < 0.05). Compared to control, the expression of GAS7 gene in melanoma cells showed a significant decrease (p value = 0.0323). Finally, our findings showed that the decreased expression of hsa-miR-203a-3p and hsa-miR-29a-3p can hypothesize that their aberrant expression caused DNMT3B dysfunction, possible methylation of the GAS7 gene, and ultimately decreased its expression. However, complementary studies are necessary to definite comment.

circABCB10 Promotes Malignant Progression of Gastric Cancer Cells by Preventing the Degradation of MYC

Objective. To investigate the role of circABCB10 in gastric cancer and the molecular mechanism of promoting malignant progression of gastric cancer cells by preventing the degradation of MYC by hsa-miR-1252-5p. Methods. The expression of circABCB10 in gastric cancer tissues and cells was detected by real-time quantitative PCR. MTT, Transwell, clone formation, and TUNEL assay were used to detect the effects of circABCB10 on the proliferation, invasion, and apoptosis of gastric cancer cells. A subcutaneous tumor-bearing model was established to study the inhibitory effect of knockdown circABCB10 on gastric cancer proliferation. The dual luciferase reporter gene assay and RNA pull-down assay were used to verify the regulatory effect of circABCB10 on miR-1252-5p and the regulatory effect of miR-1252-5p on MYC. Results. Compared with paracancerous tissues and gastric mucosal epithelial cells, the expression of circABCB10 was significantly increased in human gastric cancer tissues and gastric cancer cells. circABCB10 knockout significantly decreased cell viability and invasion ability and promoted cell apoptosis ( P < 0.01 ). Subcutaneous tumor-bearing experiments in nude mice demonstrated that circABCB10 knockdown inhibited the proliferation of gastric cancer cells. circABCB10 can act as a sponge for miR-1252-5p in gastric cancer cells. Meanwhile, MYC is the target gene of miR-1252-5p. Overexpression of miR-1252-5p and knockdown of MYC reversed the promoting effect of circABCB10 on gastric cancer. Conclusion. circABCB10 can promote the proliferation, invasion, and clonal formation of gastric cancer cells by targeting miR-1252-5p and upregulating the expression of MYC. circABCB10/miR-1252-5p/MYC constitutes the regulatory mechanism of ceRNA.

Dihydroartemisinin Induces Ferroptosis in HCC by Promoting the Formation of PEBP1/15-LO

Relevant researches have recognized the vital role of inducing ferroptosis in the treatment of tumor. The latest findings indicate that PEBP1/15-LO can play an essential role in the process of cell death. However, its role in regulating ferroptosis in hepatocellular carcinoma (simplified by HCC) remains unclear. The previous research of our team has proved that DHA can induce ferroptosis of hepatic stellate cells. In this study, we found that DHA could also induce ferroptosis in HCC cells. Interestingly, DHA induced ferroptosis by promoting the formation of PEBP1/15-LO and promoting cell membrane lipid peroxidation. In addition, we also found that DHA had no obvious regulatory effect on 15-LO, but it could promote PEBP1 protein expression. Importantly, we discovered the upregulation of PEBP1 induced by DHA was related to the inhibition of its ubiquitination degradation. In vivo experiments have also obtained consistent results that DHA can inhibit tumor growth and affect the expression of ferroptosis markers in tumor tissues, which would be partially offset by interference with PEBP1.

Ferritinophagic Flux Was a Driving Force in Determination of Status of EMT, Ferroptosis, and NDRG1 Activation in Action of Mechanism of 2-Pyridylhydrazone Dithiocarbamate S-Acetic Acid

Ferritinophagy is a process of ferritin degradation in lysosomes; however, how its effect on other cellular events, such as epithelial-mesenchymal transition (EMT) and ferroptosis remains elusive. In this study, we determined how ferritinophagic flux influence the status of EMT and ferroptosis in HepG2 cell. Our data revealed that 2-pyridylhydrazone dithiocarbamate s-acetic acid (PdtaA) induced EMT inhibition involved ferritinophagy-mediated ROS production, but addition of ferrostatin-1 could attenuate the effect of PdtaA on the regulation of EMT-related proteins, suggesting that ferroptosis might involve in the EMT regulation. Next, downregulation of Gpx4 and xCT as well as enhanced lipid peroxidation further supported that PdtaA was able to induce ferroptosis. Knockdown of NCOA4 significantly attenuated the regulatory effect of PdtaA on related proteins which highlighted that the strength of ferritinophagic flux (NCOA4/ferritin) was a driving force in determination of the status of EMT and ferroptosis. Furthermore, NDRG1 activation was also observed, and knockdown of NDRG1 similarly influenced the expressions of ferroptosis-related proteins, suggesting that NDRG1 also involved ferroptosis induction, which was first reported. Taken together, PdtaA-induced EMT inhibition, ferroptosis, and NDRG1 activation all depended on the strength of ferritinophagic flux.