Background: Gallbladder cancer (GBC) is known for its high malignancy and multidrug resistance. Previously, we uncovered that impaired integrity and stability of the elongator complex leads to GBC chemotherapy resistance, but whether its restoration can be an efficient therapeutic strategy for GBC remains unknown.
Methods: RT-qPCR, MS-qPCR and ChIP-qPCR were used to evaluate the direct association between ELP5 transcription and DNA methylation in tumour and non-tumour tissues of GBC. EMSA, chromatin accessibility assays, and luciferase assays were utilized to analysis the DNA methylation in interfering PAX5-DNA interactions. The functional experiments in vitro and in vivo were performed to investigate the effects of DNA demethylating agent decitabine (DAC) on the transcription activation of elongator complex and the enhanced sensitivity of gemcitabine in GBC cells. Tissue microarray contains GBC tumour tissues was used to evaluate the association between the expression of ELP5, DNMT3A and PAX5.
Results: We demonstrated that transcriptional repression of ELP5 in GBC was highly correlated with hypermethylation of the promoter. Mechanistically, epigenetic analysis revealed that DNA methyltransferase DNMT3A-catalysed hypermethylation blocked transcription factor PAX5 activation of ELP5 by disrupting PAX5-DNA interaction, resulting in repressed ELP5 transcription. Pharmacologically, the DNA demethylating agent DAC eliminated the hypermethylated CpG dinucleotides in the ELP5 promoter and then facilitated PAX5 binding and reactivated ELP5 transcription, leading to the enhanced function of the elongator complex. To target this mechanism, we employed a sequential combination therapy of DAC and gemcitabine to sensitize GBC cells to gemcitabine-therapy through epigenetic activation of the elongator complex.
Conclusions: Our findings suggest that ELP5 expression in GBC is controlled by DNA methylation-sensitive induction of PAX5. The sequential combination therapy of DAC and gemcitabine could be an efficient therapeutic strategy to overcome chemotherapy resistance in GBC.
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http://dx.doi.org/10.1186/s13046-021-02186-0 | DOI Listing |
Stud Mycol
December 2024
Westerdijk Fungal Biodiversity Institute, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
The species complex (FLSC) currently comprises 11 phylogenetic species, including accepted names such as , , and , which have mostly been reported in association with citrus and coffee. Many varieties were documented by Wollenweber & Reinking (1935), which is indicative of a wider diversity of species within this group. The lack of type material in some cases, especially for the older names, means that definition by molecular phylogeny is very difficult.
View Article and Find Full Text PDFAdv Sci (Weinh)
December 2024
State Key Laboratory of Radio Frequency Heterogeneous Integration & Key Laboratory of Optoelectronic Devices and Systems, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, 518060, China.
Monitoring the morphological and biochemical information of neurons and glial cells at high temporal resolution in three-dimensional (3D) volumes of in vivo is pivotal for understanding their structure and function, and quantifying the brain microenvironment. Conventional two-photon fluorescence lifetime volumetric imaging speed faces the acquisition speed challenges of slow serial focal tomographic scanning, complex post-processing procedures for lifetime images, and inherent trade-offs among contrast, signal-to-noise ratio, and speed. This study presents a two-photon fluorescence lifetime volumetric projection microscopy using an axially elongated Bessel focus and instant frequency-domain fluorescence lifetime technique, and integrating with a convolutional network to enhance the imaging speed for in vivo neurodynamics mapping.
View Article and Find Full Text PDFChem Asian J
December 2024
Ashoka University, Chemistry, Rajiv Gandhi Educational Hub, India, 131029, Sonipat, INDIA.
The catalytic efficiency of M-H2tpda pincer complexes (M = Mn(I), Fe(II), Co(III)) in CO2 hydrogenation, emphasizing the role of transition metal center variability have been discussed. The DFT analysis demonstrates that complexes with low αR values form weaker M-H bonds, enhancing catalyst reactivity with the elongation of M-H bond. The analysis further displays excellent catalytic performance for Mn-H2tpda (ΔE = 20.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
December 2024
Ocean University of China, School of Medicine and Pharmcy, 5 Yushan Road, 266003, Qingdao, CHINA.
Due to the inaccessibility of β1-4-N-acetylgalactosaminyltransferase for the direct glycan chain elongation, the enzymatic synthesis of 0-series ganglioside with extended backbone has not been explored. In this the sialic acid was enzymatically introduced as an auxiliary group to overcome the limitation of substrate specificity of Campylobacter jejuni β1-4-N-acetylgalactosaminyltransferase (CjCgtA) to achieve the synthesis of desired extended 0-series ganglioside core structures. A bacterial α2-6-sialyltransferase from Photobacterium damselae (Pd2,6ST) exhibits unexpected acceptor substrate specificity for 0-series ganglioside core structures, providing an easy access for the synthesis of complex gangliosides bearing the sialyl N-acetylgalactosamine unit.
View Article and Find Full Text PDFAppl Environ Microbiol
December 2024
Department of Microbiology, Biochemistry, & Molecular Genetics, Rutgers New Jersey Medical School, Newark, New Jersey, USA.
Because of the urgent need for new antibiotics to treat drug-resistant bacterial pathogens, we employed an assay that rapidly screens large quantities of compounds for their ability to interfere with bacterial protein synthesis, in particular, the delivery of amino acids to the ribosome via tRNA and elongation factor Tu (EF-Tu). We have identified a drug lead, named MGC-10, which kills Gram-positive bacteria, including methicillin-resistant (MRSA), with a MIC of 6 µM, while being harmless to mammalian cells in that concentration range. The antibacterial activity of MGC-10 was broad against over 50 strains of antibiotic-resistant samples obtained from hospital infections, where MGC-10 inhibited all tested strains of MRSA.
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