<div>Abstract<p>N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) is the most prevalent internal RNA modification in mammals that regulates homeostasis and function of modified RNA transcripts. Here, we aimed to investigate the role of YTH m<sup>6</sup>A RNA-binding protein 1 (YTHDF1), a key regulator of m<sup>6</sup>A methylation in gastric cancer tumorigenesis. Multiple bioinformatic analyses of different human cancer databases identified key m<sup>6</sup>A-associated genetic mutations that regulated gastric tumorigenesis. <i>YTHDF1</i> was mutated in about 7% of patients with gastric cancer, and high expression of YTHDF1 was associated with more aggressive tumor progression and poor overall survival. Inhibition of <i>YTHDF1</i> attenuated gastric cancer cell proliferation and tumorigenesis <i>in vitro</i> and <i>in vivo</i>. Mechanistically, YTHDF1 promoted the translation of a key Wnt receptor frizzled7 (<i>FZD7</i>) in an m<sup>6</sup>A-dependent manner, and mutated <i>YTHDF1</i> enhanced expression of FZD7, leading to hyperactivation of the Wnt/β-catenin pathway and promotion of gastric carcinogenesis. Our results demonstrate the oncogenic role of <i>YTHDF1</i> and its m<sup>6</sup>A-mediated regulation of Wnt/β-catenin signaling in gastric cancer, providing a novel approach of targeting such epigenetic regulators in this disease.</p>Significance:<p>This study provides a rationale for controlling translation of key oncogenic drivers in cancer by manipulating epigenetic regulators, representing a novel and efficient strategy for anticancer treatment.</p></div>
It was confirmed that the pupae of Helicoverpa armigera needed brain in the early development stage by the experiment of brain excision. The development of diapause pupae did not need brain in the mid or later development stage. The pupal diapause in H. armigera could be terminated with the injection of active brain, and it was suggested that the activation of brain in diapause-destined H. armigera had descended since prepupal stages. The role of brain in diapause in H. armigera was discussed based on these results.
Breviscapine, a traditional Chinese medicine, is extensively used in clinic to treat cardiovascular diseases and cerebrovascular injury. In this study, we demonstrated the effects of breviscapine on vascular dementia (VD) rats, which were mimicked by permanent occlusion of bilateral common carotid arteries. Breviscapine (2 mg/kg for 14 d) improved the performance of learning and memory of VD rats in Morris water maze, decreased the level of lipid peroxidation and free radicals, and attenuated the pathological alterations, such as nuclear shrink, cellular edema and irregular arrangement of pyramidal layer in the hippocampal CA(1) area. In vitro experiment, breviscapine (50 microg/l) protected cortical neuron from injury and decreased intracellular calcium overloading induced by H2O2 (10 mM). The results suggest that breviscapine has therapeutic effect on cerebral ischemia and vascular dementia.
<p>Supplementary Figures S1-S6. Supplementary Figure S1. 5T4 protein expression in selected preclinical models. Supplementary Figure S2. Effects of MMAF-Ome combined with PF-384. Supplementary Figure S3. Effect of PF-384 combination with auristatin-based agents on cell cycle and Aurora kinase activity. Supplementary Figure S4. Antibody array results and results of western blot for MDA-468 cells treated with 5T4-ADC/PF-384. Supplementary Figure S5. Identification and characterization of auristatin-regulated total and phospho-proteome. Supplementary Figure S6. Effect of single agent treatment of 5T4-ADC, PTX and their combinations on mitosis and microtubule disruption. Supplementary Tables S1-S3. Supplementary Table S1. List of cancer cell lines used in the study. Supplementary Table S2. Results of total- and phospho-proteomics experiment showing GO enrichment categories. Supplementary Table S3. Combination Index (CI) values for Aur101 plus WYE-132 combination.</p>
Time-lapse imaging is often the only way to appreciate fully the many dynamic cell movements critical to neural development. Zebrafish possess many advantages that make them the best vertebrate model organism for live imaging of dynamic development events. This review will discuss technical considerations of time-lapse imaging experiments in zebrafish, describe selected examples of imaging studies in zebrafish that revealed new features or principles of neural development, and consider the promise and challenges of future time-lapse studies of neural development in zebrafish embryos and adults.
Introduction Chromobox protein homolog 3 (CBX3) has been reported to regulate a variety of cellular biological functions and play an oncogenic role in various tumor. Nevertheless, the role of CBX3 remains vague in ovarian cancer. This research aimed to assess the role and potential regulatory mechanism of CBX3 in ovarian cancer. Material and methods The CBX3 expression was determined by qRT-PCR and western blotting in ovarian cancer tissues and cell lines. Cell proliferation, cycle and apoptosis were detected by using CCK-8 assay and flow cytometry. Transwell and wound healing assay were used to determine cell invasion and migration. Furthermore, the modulation of CBX3 on NCOR2 expression and p53/p21-mediated glycolysis was confirmed. Results The expression of CBX3 was significant elevated in ovarian cancer tissues and cell lines. CBX3 knockdown inhibited cell proliferation, invasion and migration, while promoted G1/S phase blockade and cell apoptosis. Mechanism analysis verified that CBX3 downregulation increased NCOR2 expression and blocked subsequent p53/p21-mediated glucose metabolism. NCOR2 silencing and p53/p21 inhibitor treatment reversed the inhibitory effects of CBX3 knockdown on ovarian cancer cellular function. Conclusions We revealed that CBX3 promoted ovarian cancer progression by promoting p53/p21-mediated glucose metabolism via inhibiting NCOR2. These results provide a theoretical basis for the diagnosis and treatment of ovarian cancer.
<div>AbstractPurpose:<p>This study was to perform preclinical evaluation of a novel class I and IIb HDAC-selective inhibitor, purinostat mesylate, for the treatment of Ph<sup>+</sup> B-cell acute lymphoblastic leukemia (B-ALL).</p>Experimental Design:<p>Biochemical assays were used to test enzymatic activity inhibition of purinostat mesylate. Ph<sup>+</sup> leukemic cell lines and patient cells were used to evaluate purinostat mesylate activity <i>in vitro</i>. BL-2 secondary transplantation Ph<sup>+</sup> B-ALL mouse model was used to validate its efficacy, mechanism, and pharmacokinetics properties <i>in vivo</i>. <i>BCR-ABL(T315I)</i>–induced primary B-ALL mouse model and PDX mouse model derived from relapsed Ph<sup>+</sup> B-ALL patient post TKI treatment were used to determine the antitumor effect of purinostat mesylate for refractory or relapsed Ph<sup>+</sup> B-ALL. Long-term toxicity and hERG blockade assays were used to safety evaluation of purinostat mesylate.</p>Results:<p>Purinostat mesylate, a class I and IIb HDAC highly selective inhibitor, exhibited robust antitumor activity in hematologic cancers. Purinostat mesylate at low nanomolar concentration induced apoptosis, and downregulated BCR-ABL and c-MYC expression in Ph<sup>+</sup> leukemia cell lines and primary Ph<sup>+</sup> B-ALL cells from relapsed patients. Purinostat mesylate efficiently attenuated Ph<sup>+</sup> B-ALL progression and significantly prolonged the survival both in BL-2 secondary transplantation model with clinical patient symptoms of Ph<sup>+</sup> B-ALL, <i>BCR-ABL(T315I)</i>–induced primary B-ALL mouse model, and PDX model derived from patients with relapsed Ph<sup>+</sup> B-ALL post TKI treatment. In addition, purinostat mesylate possesses favorable pharmacokinetics and low toxicity properties.</p>Conclusions:<p>Purinostat mesylate provides a new therapeutic strategy for patients with Ph<sup>+</sup> B-ALL, including those who relapse after TKI treatment.</p></div>
Abstract Traces of the substrates of homovanillic acid(4-11×10−6 mol/l) and L-tyrosine(1-7×10−6 mol/l) can be determined by the formation of the fluorescent dimers with the peroxidase-like conjugates of hemin with proteins.
Engineered Extracellular Vesicles In article number 2204910, Jia Yu, Yanlian Yang, Ling Zhu, and co-workers report an extracellular-vesicle-based nanodrug for the targeting delivery of short interfering RNA (siRNA) against N6-methyladenosine (m6A) reader YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) for the epigenetic and immune regulation of gastric cancer. This versatile nanoplatform provides an efficient and low toxic strategy to inhibit epigenetic regulators and holds great potential in promoting immunotherapy.
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