Exosomal miR-93 derived from hepatocellular carcinoma cell promotes the sorafenib resistance of hepatocellular carcinoma through PTEN/PI3K/Akt pathway.

Exosomal microRNAs (miRNAs) derived from cancer cell is an important regulatory molecule that mediates the formation of tumor drug resistance, but function and mechanisms of exosomal miRNA in sorafenib resistance of hepatocellular carcinoma (HCC) have not been studied. We detected the level and prognosis of miR-93 in HCC by using TCGA HCC database. For confirming the extracted exosome, transmission electron microscopy was used. Cy3-labeled miR-93 and quantitative reverse transcription-polymerase chain reaction were used to prove that exosomal miR-93 derived from HCC cell can be transferred to sensitive HCC cells. CCK8, EdU, and flow cytometer assay were used to confirm the function of exosomal miR-93 in sorafenib resistance of HCC. Bioinformatics software and luciferase reporter assay was used to confirm the direct targeting relationship between PTEN and miR-93. Western blot was used to validate downstream pathways. We found that miR-93 is overexpressed and a prognostic risk factor for the HCC patients. miR-93 was overexpressed in sorafenib resistant HCC cells compared with sensitive cells, and miR-93 contributed to sorafenib resistance of HCC cells through targeting PTEN. miR-93 was enriched in exosomes that secreted from sorafenib resistant cells, and these exosomal miR-93 promote the spread of sorafenib resistant through targeting PTEN to reactivate PI3K/AKT pathway. Therefore, miR-93 can act as a potential therapeutic target for advanced patients with acquired sorafenib resistance.

Metabolomic analysis in Amycolatopsis keratiniphila disrupted the competing ECO0501 pathway for enhancing the accumulation of vancomycin.

Vancomycin is a clinically important glycopeptide antibiotic against Gram-positive pathogenic bacteria, especially methicillin-resistant Staphylococcus aureus. In the mutant strain of Amycolatopsis keratiniphila HCCB10007 Δeco-cds4-27, the production of ECO-0501 was disrupted, but enhanced vancomycin yield by 55% was observed compared with the original strain of A. keratiniphila HCCB10007. To gain insights into the mechanism of the enhanced production of vancomycin in the mutant strain, comparative metabolomics analyses were performed between the mutant strain and the original strain, A. keratiniphila HCCB10007 via GC-TOF-MS and UPLC-HRMS. The results of PCA and OPLS-DA revealed a significant distinction of the intracellular metabolites between the two strains during the fermentation process. 64 intracellular metabolites, which involved in amino acids, fatty acids and central carbon metabolism, were identified as differential metabolites. The high-yield mutant strain maintained high levels of glucose-1-phosphate and glucose-6-phosphate and they declined with the increases of vancomycin production. Particularly, a strong association of fatty acids accumulation as well as 3,5-dihydroxyphenylacetic acid and non-proteinogenic amino acid 3,5-dihydroxyphenylglycine (Dpg) with enhancement of vancomycin production was observed in the high-yield mutant strain, indicating that the consumption of fatty acid pools might be beneficial for giving rise to 3,5-dihydroxyphenylacetic acid and Dpg which further lead to improve vancomycin production. In addition, the lower levels of glyoxylic acid and lactic acid and the higher levels of sulfur amino acids might be beneficial for improving vancomycin production. These findings proposed more advanced elucidation of metabolomic characteristics in the high-yield strain for vancomycin production and could provide potential strategies to enhance the vancomycin production.

5-HT-treated mouse B cells alleviate ulcerative colitis via RIPK1: Insights from proteomic and phosphoproteomic analyses.

5-hydroxytryptamine (5-HT) exerts various physiological effects on the intestine through different signaling pathways and molecular transmission mechanisms, including pro- and anti-inflammatory effects. Adoptive transfer of regulatory B cells (Bregs) into colitis mice has exhibited significant therapeutic benefits. We aimed to elucidate the mechanism through which 5-HT-treated B cells alleviate ulcerative colitis. To this end, we analyzed the proteomic and phosphoproteomic profiles of 5-HT-stimulated B cells from naïve mice. We identified 3124 phosphorylation sites in proteins via tandem mass tagging and found 110 differential peptides after protein phosphorylation. Furthermore, we obtained three differential proteins, RIPK1, ATXN2l, and Q8C5K5 through integration of both proteomic datasets. We discovered and validated that 5-HT binds to 5-HT7R and increases the expression of RIPK1 in B cells. We propose a theoretical and experimental basis for further research on the RIPK1 signaling pathway, kinase prediction, and phosphorylation sites in ulcerative colitis. SIGNIFICANCE: Some researchers demonstrated that 5-HT can effectively suppress colitis through a variety of molecular mechanisms. Our study discovered and consistently validated the 5-HT/5-HT7R/RIPK1 pathway, further clarifying the molecular mechanism through which 5-HT stimulates B cells to alleviate intestinal inflammation.

Exosomal miR-19a derived from melanoma cell promotes the vemurafenib resistance of malignant melanoma through directly targeting LRIG1 to reactivate AKT and MAPK pathway.

Exosomes derived from neighboring v-raf murine sarcoma viral oncogene homolog B1 inhibitor (BRAFi)-resistant melanoma cells mediate the formation of resistance in melanoma cells sensitive to BRAFi. The function and molecular mechanisms of exosomal miRNA in BRAFi resistance of melanoma have not been studied. We found that the expression of miR-19a in BRAFi resistant melanoma cells was significantly higher than that in sensitive cells, and miR-19a contributes to the resistance of melanoma cells to BRAFi by targeting immunoglobulin-like domains protein 1 (LRIG1). miR-19a was highly enriched in exosomes secreted from BRAFi resistant melanoma cells, and these exosomal miR-19a promote the spread of BRAFi resistant. The reactivation of Protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) pathways is the main reason for the BRAFi resistant of melanoma cells. We demonstrated that exosomal miR-19a derived from melanoma cell promotes the formation and spread of BRAFi resistant in melanoma through targeting LRIG1 to reactivate AKT and MAPK pathway. Therefore, miR-19a may serve as a potential therapeutic target in melanoma patients with acquired drug resistance.

Reduced-Toxicity and Highly Luminescent Germanium-Lead Perovskites Enabled by Strain Reduction for Light-Emitting Diodes.

Germanium-lead (Ge-Pb) perovskites provide a promising solution for perovskite optoelectronic devices with reduced toxicity. However, Ge-Pb perovskite light-emitting diodes (PeLEDs) with >30 mol % Ge showed low emission efficiencies [Yang, D.; Zhang, G.; Lai, R.; Cheng, Y.; Lian, Y.; Rao, M.; Huo, D.; Lan, D.; Zhao, B.; Di, D. Germanium-Lead Perovskite Light-Emitting Diodes. Nat. Commun. 2021, 12 (1), 4295]. Here, we apply strain engineering to effectively improve the light emission efficiency and stability of Ge-Pb perovskite films and PeLEDs with 30 and 60 mol % Ge, through A-site modulation. The maximum external quantum efficiencies of the Ge-Pb PeLEDs with 30 and 60 mol % Ge are 8.5% and 3.0% at 3.32 mA cm-2 (∼922 cd m-2) and 0.53 mA cm-2 (∼60 cd m-2), respectively. Time-resolved transient absorption spectroscopy analysis of Ge-Pb perovskite films on different hole-transport layers shows that incorporating 30 mol % Ge into the perovskite with mixed A-site cations can effectively suppress trap-assisted recombination. Further analysis of their current density-voltage (J-V) curves reveals the efficiency loss mechanisms of Ge-Pb PeLEDs with high Ge fractions, indicating the possibility of further improvements.