miR-181a Post-Transcriptionally Downregulates Oncogenic RalA and Contributes to Growth Inhibition and Apoptosis in Chronic Myelogenous Leukemia (CML)

MicroRNAs (miRNAs) are a class of short RNAs that regulate gene expression through either translational repression or mRNA cleavage. miRNA-181a (miR-181a), one of the many miRNAs conserved among vertebrates, is differentially expressed in a variety of leukemia. However, its function in leukemia, particularly chronic myelogenous leukemia (CML), is poorly understood. Here we have reported the identification of miR-181a targets by combining TargetScan software prediction and expression profiling through overexpression of miR-181a mimic in leukemic K562 cells. Four overlapping genes were found to be the likely targets of miR-181a. Among the four genes, RalA is a downstream molecule of bcr-abl fusion protein in ras signaling pathway. However, its role in CML remains elusive. Luciferase reporter and Western blot assays confirmed that RalA is a direct target of miR-181a. overexpression of miR-181a effectively suppresses cell growth and induces G2-phase arrest and apoptosis partially by targeting RalA in leukemic K562 cells. Using the KEGG database combined with recent publications, downstream signaling pathway of RalA was graphed by cytoscape software. Therefore, our study is the first to report that RalA is directly regulated by miR-181a and plays an important role in CML. The approach of computational prediction combined with expression profiling might be valuable for the identification of miRNA targets in animal

2019 Overview

The CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews, and reports of novel findings of therapeutic relevance to the central nervous system. Its focus includes clinical pharmacology, drug development, and novel methodologies for drug evaluation in neurological and psychiatric diseases. We are pleased to announce that CNS Neuroscience & Therapeutics has become an Open‐Access Journal as of January 2019. This would allow wider dissemination of scientific knowledge and facilitate collaborative efforts toward advancing novel and solid research on the maintenance of brain homeostasis and repairing the aging and dysfunctional brain

Correlation between tongue manifestations and glucose, total cholesterol, and high-density lipoprotein cholesterol in patients with acute cerebral infarction

AbstractObjectiveTo analyze the association between tongue manifestations and the levels of glucose (GLU), total cholesterol (TCH), and high-density lipoprotein cholesterol (HDL-C) in subjects with acute cerebral infarction.MethodsHospitalized patients with first unilateral cerebral infarction in the Neurological Department of Xuanwu Hospital were included and the correlation between tongue fur color, fur nature, and the levels of GLU, TCH, HDL-C were analyzed.ResultsHDL level in the thin fur group was higher than that in the thick fur group (P=0.02). The difference in the levels of GLU, TCH, and HDL-C among the groups was significant (P<0.05), classified in terms of slippery, moist, and dry fur. Further comparison between the groups by Student-Newman-Keuls test showed that GLU level in the dry fur group was the highest. Moreover, the TCH level in the slippery fur group was higher than the other two groups.ConclusionA correlation between tongue manifestations and GLU, TCH, HDL-C was identified in the patients with acute cerebral infarction

Autophagy regulates the maturation of hematopoietic precursors in the embryo

An understanding of the mechanisms regulating embryonic hematopoietic stem cell (HSC) development would facilitate their regeneration. The aorta-gonad-mesonephros region is the site for HSC production from hemogenic endothelial cells (HEC). While several distinct regulators are involved in this process, it is not yet known whether macroautophagy (autophagy) plays a role in hematopoiesis in the pre-liver stage. Here, we show that different states of autophagy exist in hematopoietic precursors and correlate with hematopoietic potential based on the LC3-RFP-EGFP mouse model. Deficiency of autophagy-related gene 5 (Atg5) specifically in endothelial cells disrupts endothelial to hematopoietic transition (EHT), by blocking the autophagic process. Using combined approaches, including single-cell RNA-sequencing (scRNA-seq), we have confirmed that Atg5 deletion interrupts developmental temporal order of EHT to further affect the pre-HSC I maturation, and that autophagy influences hemogenic potential of HEC and the formation of pre-HSC I likely via the nucleolin pathway. These findings demonstrate a role for autophagy in the formation/maturation of hematopoietic precursors.</p

Synthesis and biological evaluation of novel bi-gold mitocans in lung cancer cells

Mitochondria are promising drug target for cancer treatment. We previously demonstrated that a bi-gold compound BGC2a was more potent than the mono-gold drug auranofin in suppressing cancer cells due to increased gold atom number that led to higher drug accumulation in and thereby inhibition of mitochondria. To exploit the potential of this new strategy, we further designed and synthesized a series of bi-gold mitocans, the compounds targeting mitochondria. The results showed that most of the newly synthesized mitocans exhibited obviously lower IC50 than auranofin, an old drug that is repurposed in clinical trials for cancer treatment. The best mitocan C3P4 was nearly 2-fold more potent than BGC2a in human non-small cell lung cancer A549 cells and mantle cell lymphoma Jeko-1 cells, exhibiting substantial colony formation-suppressing and tumor-suppressing effects in A549 cells xenograft model. C3P4 induced apoptosis in a dose-dependent manner and arrested cell cycle at G0/G1 phase. The mechanistic study showed that C3P4 significantly increased the global reactive oxygen species and mitochondrial superoxide level, and reduced the mitochondrial membrane potential. C3P4 preferentially accumulated in mitochondria as measured by the gold content and substantially inhibited oxygen consumption rate and ATP production. These results further validated our hypothesis that targeting mitochondria would be promising to develop more potent anticancer agents. C3P4 may be further evaluated as a drug candidate for lung cancer treatment

Induction and Resuscitation of the Viable but Non-culturable (VBNC) State in Acidovorax citrulli, the Causal Agent of Bacterial Fruit Blotch of Cucurbitaceous Crops

Acidovorax citrulli is a gram-negative bacterium that infects a wide range of cucurbits causing bacterial fruit blotch (BFB) disease. Copper-based compounds are the most widely-used chemicals for managing BFB and other bacterial diseases in the field. Many bacteria can enter a viable but non-culturable (VBNC) state in response to stress, including exposure to copper, and recover the culturability when favorable conditions return. The present study demonstrates that A. citrulli strain AAC00-1 is able to enter into the VBNC state by treatment with different concentrations of copper sulfate. It took 3 h, 5 and 15 days for all viable cells to lose culturability upon exposure to copper sulfate concentrations of 50, 10, and 5 μM, respectively. The VBNC A. citrulli cells regained culturability when the Cu2+ ions were removed by chelation with EDTA or by transfer of cells to LB broth, a cell-free supernatant from a suspension of AAC00-1, oligotrophic media amended with casein hydrolysate or watermelon seedling juice. We also found that the VBNC cells induced by Cu2+ were unable to colonize or infect watermelon seedlings directly, but the resuscitated cells recovered full virulence equivalent to untreated bacterial cells in the log phase. To the best of our knowledge, this is the first report on the VBNC state in A. citrulli and the factors that facilitate resuscitation and restoration of pathogenicity

Advanced fuel cell based on Perovskite La-SrTiO3 semiconductor as the electrolyte with superoxide-ion conduction

A solid oxide fuel cell’s (SOFC) performance is largely determined by the ionic-conducting electrolyte. A novel approach is presented for using the semiconductor perovskite LaR0.25RSrR0.75RTiOR3R (LST) as the electrolyte by creating surface superionic conduction, and the authors show that the LST electrolyte can deliver superior power density, 908.2 mW·cmP-2P at just 550 °C. The prepared LST materials formed a heterostructure including an insulating core and a super ionic conducting surface layer. The rapid ion transport along the surfaces or grain boundaries was identified as the primary means of oxygen ion conduction. The fuel cell-induced phase transition was observed from the insulating LST to a super OP2-P conductivity of 0.221 S·cmP-1P at 550 °C, leading to excellent current and power outputs

MiR-29a Knockout Aggravates Neurological Damage by Pre-polarizing M1 Microglia in Experimental Rat Models of Acute Stroke

ObjectiveBy exploring the effects of miR-29a-5p knockout on neurological damage after acute ischemic stroke, we aim to deepen understanding of the molecular mechanisms of post-ischemic injury and thus provide new ideas for the treatment of ischemic brain injury.MethodsmiR-29a-5p knockout rats and wild-type SD rats were subjected to transient middle cerebral artery occlusion (MCAO). miR-29a levels in plasma, cortex, and basal ganglia of ischemic rats, and in plasma and neutrophils of ischemic stroke patients, as well as hypoxic glial cells were detected by real-time PCR. The infarct volume was detected by TTC staining and the activation of astrocytes and microglia was detected by western blotting.ResultsThe expression of miR-29a-5p was decreased in parallel in blood and brain tissue of rat MCAO models. Besides, miR-29a-5p levels were reduced in the peripheral blood of acute stroke patients. Knockout of miR-29a enhanced infarct volume of the MCAO rat model, and miR-29a knockout showed M1 polarization of microglia in the MCAO rat brain. miR-29a knockout in rats after MCAO promoted astrocyte proliferation and increased glutamate release.ConclusionKnockout of miR-29a in rats promoted M1 microglial polarization and increased glutamate release, thereby aggravating neurological damage in experimental stroke rat models

Novel Role of NOX in Supporting Aerobic Glycolysis in Cancer Cells with Mitochondrial Dysfunction and as a Potential Target for Cancer Therapy

NAD(P)H oxidase plays a role in cancer metabolism by providing NAD+ to support increased glycolysis