METTL3-induced circ_0008345 contributes to the progression of colorectal cancer via the microRNA-182-5p/CYP1A2 pathway.

BACKGROUND: Circular RNA (circRNAs) have been found to play major roles in the progression of colorectal cancer (CRC). However, the functions of circ_0008345 (transcribed by PTK2) in regulating CRC development remain undefined. In this study, we aimed to explore the roles and underlying mechanisms of circ_0008345 in CRC. METHODS: RNase R-treated total cellular RNA was used to verify the circular structure of circ_0008345, and a subcellular fractionation assay was performed to detect the subcellular localization of circ_0008345. RNA pull-down and dual-luciferase assays were used to verify the binding relation between microRNA (miR)-182-5p and circ_0008345 and/or CYP1A2. Colony formation assay, EdU, and Transwell assays were performed to detect the biological behavior of CRC cells in vitro, and CRC cells were injected into mice to observe the tumor formation. m6A immunoprecipitation was used to detect the m6A modification of circ_0008345 in CRC cells. RESULTS: Circ_0008345, upregulated in CRC tissues and cells, was mainly present in the cytoplasm. Circ_0008345 bound to miR-182-5p, and miR-182-5p targeted CYP1A2, an oncogene in CRC. The colony formation, mobility, EdU-positive cell rate in vitro, and tumor growth in mice were inhibited after the knockdown of circ_0008345. However, the suppressing effects of sh-circ_0008345 on CRC and CYP1A2 expression were significantly reversed after further knockdown of miR-182-5p. METTL3 was the m6A modifier mediating circ_0008345 expression, and the suppression of METTL3 reduced the expression of circ_0008345. CONCLUSIONS: METTL3-dependent m6A methylation upregulated circ_0008345, which blocked the inhibitory effect of miR-182-5p on CYP1A2, thereby exacerbating the malignant phenotype of CRC cells.

Potential value of expression of receptor accessory protein 4 for evaluating the prognosis of lower-grade glioma patients.

BACKGROUND: REEP4 is involved in the regulation of the biological process of mitosis. Lower grade glioma (LGG), as a malignant tumor, is accompanied by abnormalities in mitosis, but there have been no reports of REEP4 so far. METHODS: We collected transcriptome data, DNA methylation data and the clinical characteristics of thousands of patients with LGG. Various big data analysis methods and molecular biology experiments were employed to reveal the impact of REEP4 on the pathological process of LGG. RESULTS: It was found that the expression of REEP4 was significantly elevated and negatively regulated by its methylation site. Therefore, both the high expression of REEP4 and low methylation state of cg16311504 showed that the patients are correlated with lower patient survival rate. In addition, high REEP4 expression participates in the regulation of various cancer-related cellular signaling pathways, such as the cell cycle, MAPK signaling pathway, NOD-like receptor signaling pathway, etc. More importantly, the level of immune cell infiltration significantly increased in the high expression group of REEP4 in the LGG tumor microenvironment and REEP4 has a high positive correlation with PD-L1 and other immune checkpoints. CONCLUSIONS: In brief, this study is the first to introduce REEP4 in malignant tumors, which can be used as an independent risk factor that participates in the malignant process of LGG. More importantly, REEP4 has the potential to become a new star in the field of anti-tumor treatment.

5-methylcytosine-mediated upregulation of circular RNA 0102913 augments malignant properties of colorectal cancer cells through a microRNA-571/Rac family small GTPase 2 axis.

Circular RNAs (circRNAs) are a class of stable non-coding RNAs that have emerged as key regulators in human diseases including cancer. This study investigates the role of circRNA_0102913 (circ_0102913) in malignant behavior of colorectal cancer (CRC) cells and the underpinning mechanisms. By analyzing CRC-related GSE197991, GSE159669, and GSE223001 datasets, we obtained circ_0102913 as an aberrantly upregulated circRNA in CRC. Increased circ_0102913 expression was detected in CRC tissues and cells. By querying multiple bioinformatics systems (circBank, Circular RNA Interactome, TargetScan, miRDIP, miRwalk, and miRDB), we identified microRNA-571 (miR-571) as a target of circ_0102913 and Rac family small GTPase 2 (RAC2) mRNA as a target of miR-571. Biotinylated-RNA pull-down and/or luciferase assays showed that circ_0102913 bound to miR-571 to restore the expression of RAC2 mRNA. Circ_0102913 silencing or miR-571 overexpression repressed proliferation, migration and invasion, and in vivo tumorigenesis abilities of CRC cells. However, the malignant properties of cells were restored by RAC2 overexpression. The increased circ_0102913 expression in CRC cells was attributed to increased 5-methylcytosine (m5C) modification levels. Silencing of NOP2/Sun RNA methyltransferase 5 reduced the m5C level and therefore reduced stability and expression of circ_0102913 expression in CRC cells. In conclusion, this study demonstrates that m5C-mediated upregulation of circ_0102913 augments malignant properties of CRC cells through a miR-571/RAC2 axis.

Efficacy comparison of different moxibustion treatments for allergic rhinitis: A systematic review and Bayesian network meta-analysis.

BACKGROUND: At present, there are many commonly used moxibustion methods in clinical practice, but it is unclear which moxibustion is more suitable for the treatment of allergic rhinitis (AR), so we used a network meta-analysis to analyze the effectiveness of various moxibustion types in the treatment of AR. METHODS: We searched 8 databases for comprehensive inclusion of randomized controlled trials (RCTs) for moxibustion in the treatment of allergic rhinitis. The search time was from the beginning of database establishment to January 2022. The Cochrane Risk of Bias tool was used to analyze the risk of bias of the included RCTs. Bayesian network meta-analysis of the included RCT was performed using the R software GEMTC and the RJAGS package. RESULTS: A total of 38 RCTs were included, involving 4257 patients and 9 types of moxibustion. The network meta-analysis results revealed that heat-sensitive moxibustion (HSM) not only has the best effect in terms of effective rate (Odd ratio [OR]: 32.77, 95% Credible intervals [CrIs]: 1.86-1360.2) among the nine types of moxibustion, but also has good effect in improving the quality of life score (standard mean differences [SMD]: 0.6, 95% CrIs: 0.07-1.29). In terms of improving IgE and VAS scores, various types of moxibustion were comparable to the efficacy of western medicine. CONCLUSION: The results showed that HSM was the most effective treatment for AR compared with other types of moxibustion. Therefore, it can be regarded as a complementary and alternative therapy for AR patients with poor effects of traditional treatment and patients who are susceptible to adverse reactions of western medicine.

KCNJ14 knockdown significantly inhibited the proliferation and migration of colorectal cells.

BACKGROUND: This study attempted to verify the potential of KCNJ14 as a biomarker in colorectal cancer (CRC). METHODS: Data on transcriptomics and DNA methylation and the clinical information of CRC patients were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases. Biological information analysis methods were conducted to determine the role of KCNJ14 in the prognosis, diagnosis, immune cell infiltration, and regulation mechanism of CRC patients. The effect of KCNJ14 on the proliferation and migration of HCT116 and SW480 CRC cell lines was verified by in vitro experiments (MTT, colony-forming, wound healing, and transwell assays). Western blotting was performed to detect the effect of KCNJ14 on the levels of mTOR signalling pathway-related proteins. RESULTS: KCNJ14 expression was remarkably increased in CRC tissues and cell lines, which reduced the overall survival time of patients. KCNJ14 mRNA was negatively regulated by its methylation site cg17660703, which can also endanger the prognosis of patients with CRC. Functional enrichment analysis suggested that KCNJ14 is involved in the mTOR, NOD-like receptor, and VEGF signalling pathways. KCNJ14 expression was positively correlated with the number of CD4 + T cells and negatively correlated with that of CD8 + T cells in the immune microenvironment. KCNJ14 knockdown significantly reduced not only the proliferation and migration of CRC cell lines but also the levels of mTOR signalling pathway-related proteins. CONCLUSIONS: This study not only increases the molecular understanding of KCNJ14 but also provides a potentially valuable biological target for the treatment of colorectal cancer.

The role of mechanosensitive ion channels in the gastrointestinal tract.

Mechanosensation is essential for normal gastrointestinal (GI) function, and abnormalities in mechanosensation are associated with GI disorders. There are several mechanosensitive ion channels in the GI tract, namely transient receptor potential (TRP) channels, Piezo channels, two-pore domain potassium (K2p) channels, voltage-gated ion channels, large-conductance Ca2+-activated K+ (BKCa) channels, and the cystic fibrosis transmembrane conductance regulator (CFTR). These channels are located in many mechanosensitive intestinal cell types, namely enterochromaffin (EC) cells, interstitial cells of Cajal (ICCs), smooth muscle cells (SMCs), and intrinsic and extrinsic enteric neurons. In these cells, mechanosensitive ion channels can alter transmembrane ion currents in response to mechanical forces, through a process known as mechanoelectrical coupling. Furthermore, mechanosensitive ion channels are often associated with a variety of GI tract disorders, including irritable bowel syndrome (IBS) and GI tumors. Mechanosensitive ion channels could therefore provide a new perspective for the treatment of GI diseases. This review aims to highlight recent research advances regarding the function of mechanosensitive ion channels in the GI tract. Moreover, it outlines the potential role of mechanosensitive ion channels in related diseases, while describing the current understanding of interactions between the GI tract and mechanosensitive ion channels.

The role of N6-methyladenosine (m6A) modification in the regulation of circRNAs.

N6-methyladenosine (m6A), the most abundant modification in eukaryotic cells, regulates RNA transcription, processing, splicing, degradation, and translation. Circular RNA (circRNA) is a class of covalently closed RNA molecules characterized by universality, diversity, stability and conservatism of evolution. Accumulating evidence shows that both m6A modification and circRNAs participate in the pathogenesis of multiple diseases, such as cancers, neurological diseases, autoimmune diseases, and infertility. Recently, m6A modification has been identified for its enrichment and vital biological functions in regulating circRNAs. In this review, we summarize the role of m6A modification in the regulation and function of circRNAs. Moreover, we discuss the potential applications and possible future directions in the field.

Record Atomistic Simulation of Crystalline Silicon: Bridging Microscale Structures and Macroscale Properties.

Based on the molecular dynamics software package CovalentMD 2.0, the fastest molecular dynamics simulation for covalent crystalline silicon with bond-order potentials has been implemented on the third highest performance supercomputer "Sunway TaihuLight" in the world (before June 2019), and already obtained 16.0 Pflops (1015 floating point operation per second) in double precision for the simulation of crystalline silicon, which is recordly high for rigorous atomistic simulation of covalent materials. The simulations used up to 160,768 64-core processors, totally nearly 10.3 million cores, to simulate more than 137 billion silicon atoms, where the parallel efficiency is over 80% on the whole machine. The running performance on a single processor reached 15.1% of its theoretical peak at highest. The longitudinal dimension of the simulated system is far beyond the range with scale-dependent properties, while the lateral dimension significantly exceeds the experimentally measurable range. Our simulation enables virtual experiments on real-world nanostructured materials and devices for predicting macroscale properties and behaviors from microscale structures directly, bringing about many exciting new possibilities in nanotechnology, information technology, electronics and renewable energies, etc. © 2019 Wiley Periodicals, Inc.

FOXO3a-Dependent Mechanism of E1A-Induced Chemosensitization.

Gene therapy trials in human breast, ovarian, and head and neck tumors indicate that adenovirus E1A can sensitize cancer cells to the cytotoxic effects of paclitaxel in vitro and in vivo. Resistance to paclitaxel has been reported to occur in cells expressing low levels of the Forkhead transcription factor FOXO3a. In this article, we report that FOXO3a is critical for E1A-mediated chemosensitization to paclitaxel. RNA interference-mediated knockdown of FOXO3a abolished E1A-induced sensitivity to paclitaxel. Mechanistic investigations indicated that E1A indirectly stabilized FOXO3a by acting at an intermediate step to inhibit a ubiquitin-dependent proteolysis pathway involving the E3 ligase ßTrCP and the FOXO3a inhibitory kinase IKKß. E1A derepressed this inhibitory pathway by stimulating expression of the protein phosphatase 2A (PP2A)/C protein phosphatases, which by binding to the TGF-ß-activated kinase TAK1, inhibited its ability to activate IKKß and, thereby, to suppress ßTrCP-mediated degradation of FOXO3a. Thus, by stimulating PP2A/C expression, E1A triggers a signaling cascade that stabilizes FOXO3a and mediates chemosensitization. Our findings provide a leap forward in understanding paclitaxel chemosensitization by E1A, and offer a mechanistic rational to apply E1A gene therapy as an adjuvant for improving therapeutic outcomes in patients receiving paclitaxel treatment.