PRIMA-1Met suppresses colorectal cancer independent of p53 by targeting MEK

This work was supported by Grant No. 81201779 (Hua Xiong) from the National Natural Science Youth Foundation; Grant No. 81502118 (Yanmei Zou) from the National Natural Science Youth Foundation; Grant No. 2014CFB250 (Yanmei Zou) from the Natural Science Foundation of Hubei Province; Grant No. 81372434 (Huihua Xiong) from the National Natural Science Foundation.PRIMA-1Met is the methylated PRIMA-1 (p53 reactivation and induction of massive apoptosis) and could restore tumor suppressor function of mutant p53 and induce p53 dependent apoptosis in cancer cells harboring mutant p53. However, p53 independent activity of PRIMA-1Met remains elusive. Here we reported that PRIMA-1Met attenuated colorectal cancer cell growth irrespective of p53 status. Kinase profiling revealed that mitogen-activated or extracellular signal-related protein kinase (MEK) might be a potential target of PRIMA-1Met. Pull-down binding and ATP competitive assay showed that PRIMA-1Met directly bound MEK in vitro and in cells. Furthermore, the direct binding sites of PRIMA-1Met were explored by using a computational docking model. Treatment of colorectal cancer cells with PRIMA-1Met inhibited p53-independent phosphorylation of MEK, which in turn impaired anchorage-independent cell growth in vitro. Moreover, PRIMA-1Met suppressed colorectal cancer growth in xenograft mouse model by inhibiting MEK1 activity. Taken together, our findings demonstrate a novel p53-independent activity of PRIMA-1Met to inhibit MEK and suppress colorectal cancer growth.Publisher PDFPeer reviewe

Request pattern change-based cache pollution attack detection and defense in edge computing

Through caching popular contents at the network edge, wireless edge caching can greatly reduce both the content request latency at mobile devices and the traffic burden at the core network. However, popularity-based caching strategies are vulnerable to Cache Pollution Attacks (CPAs) due to the weak security protection at both edge nodes and mobile devices. In CPAs, through initiating a large number of requests for unpopular contents, malicious users can pollute the edge caching space and degrade the caching efficiency. This paper firstly integrates the dynamic nature of content request and mobile devices into the edge caching framework, and introduces an eavesdropping-based CPA strategy. Then, an edge caching mechanism, which contains a Request Pattern Change-based Cache Pollution Detection (RPC2PD) algorithm and an Attack-aware Cache Defense (ACD) algorithm, is proposed to defend against CPAs. Simulation results show that the proposed mechanism could effectively suppress the effects of CPAs on the caching performance and improve the cache hit ratio

Ascorbate antagonizes nickel ion to regulate JMJD1A expression in kidney cancer cells

Abnormal expression of histone demethylase Jumonji domain-containing protein 1A (JMJD1A) is associated with many kinds of cancers. JMJD1A is also a hypoxic response gene and its expression is regulated by hypoxia-inducible factor-1 (HIF-1). In this study, we determined the role of JMJD1A in development and hypoxia pathway. We also measured the expression of JMJD1A and two hypoxia factors glucose transporter 1 (GLUT1) and vascular endothelial growth factor (VEGF) in 786-0 and HEK293 cells treated with different concentrations of NiCl2 (2.5100 M) for 24 h, and found that JMJD1A mRNA and protein were up-regulated with increased concentrations of NiCl2. We then observed that ascorbate could retard the up-regulated effect of NiCl2-induced JMJD1A expression in a dose-dependent manner through decreasing the stability of HIF-1 protein. Immunohistochemical analysis further demonstrated ascorbate antagonized Ni-2-induced up-regulation of JMJD1A expression in 786-0, HEK293, and OS-RC-2 cells. These findings suggest that both Ni-2 and ascorbate can regulate the expression of histone demethylase JMJD1A, which is important for cancer development or inhibition

Expression and significance of histone H3K27 demethylases in renal cell carcinoma

<p>Abstract</p> <p>Background</p> <p>The histone H3K27 demethylases UTX and JMJD3 are important regulatory factors that modulate gene expression by altering the physical state of chromatin. Previous studies have indicated an abnormal H3K27 methylation status in carcinogenesis. We therefore investigated the expression patterns of UTX and JMJD3 in renal cell carcinoma (RCC) and their roles in cancer development.</p> <p>Methods</p> <p>The mRNA expression levels of the <it>UTX</it> and <it>JMJD3</it> genes were determined in cancer tissues and adjacent normal tissues in 36 patients with primary RCC, using quantitative real-time-polymerase chain reaction. The UTX and JMJD3 protein contents were measured by western blotting and immunohistochemical analysis.</p> <p>Results</p> <p><it>UTX</it> and <it>JMJD3</it> transcripts were significantly increased in cancer tissues compared to normal tissues (P < 0.05). mRNA levels of the inhibitor of cyclin-dependent kinases 4 and 6 <it>p16INK4a</it> were also increased in cancer tissues (P < 0.001). Western blotting indicated that levels of both demethylases were increased in cancer tissues. The level of tri-methylated H3K27 (H3K27me3) was lower in cancer tissues compared to normal tissues, but expression of the H3K27 methyltransferase EZH2 was increased (P < 0.05). These results suggest that the two H3K27 demethylases may play critical roles in the regulation of H3K27 methylation status in RCC. Immunohistochemical analysis confirmed that UTX and JMJD3 expression were upregulated in cancer tissues compared to adjacent tissues.</p> <p>Conclusions</p> <p>This study demonstrated that UTX and JMJD3 were upregulated in cancer tissues, suggesting that they may be involved in the development of primary RCC. The potential roles of H3K27 demethylases as biomarkers in the early diagnosis of RCC need to be further explored.</p

An effective power improving method of magnetic field energy harvesters using a series-connected capacitor for wireless sensors in smart grids

The low power density of a magnetic field energy harvester (MFEH) limits its applicability. Conventional methods for improving power harvesting, e.g., increasing the volume of the magnetic core, cannot effectively increase the output power density of the MFEH and it increases the burden on the transmission lines. An in-depth investigation reveals that by adding an optimal series-connected capacitor before the rectifier, the output power of the MFEH can be maximized. By reducing the net voltage applied to the magnetizing inductance, the flux accumulation is slower, lengthening the energy harvesting time, and the output power is increased. Furthermore, the output power can be maximized with an optimal series-connected capacitor. The design method of the optimal series-connected capacitor is theoretically analyzed in this article, which is only related to the load characteristics. In addition, the proposed method has a simple structure and can effectively improve the system power density of the MFEH. An experimental prototype is constructed to verify the effectiveness of the proposed method, and the results agree well with the theoretical analysis. Compared with the conventional MFEH without a series-connected capacitor, the method presented in this article can increase the harvested power by approximately 50%. © 1986-2012 IEEE

The growth morphologies of GaN layer on Si(111) substrate

International audienceThe growth morphologies of metalorganic chemical vapor deposition (MOCVD) grown GaN layer on Si(1 1 1) substrate were studied using atomic force microscopy and transmission electron microscopy. It was found that the growth process of GaN/Si(1 1 1) consisted of two cycles of island growth and coalescence. These two cycles process differs markedly from that of one cycle process reported. The stress of evolving GaN layers on Si(1 1 1) was characterized by measuring the lattice constant c of GaN using X-ray diffraction (XRD) technique. It was proposed that the large tensile stress within the film during growth initiated this second island growth cycle, and the interaction between the GaN islands with high orientational fluctuation on the buffer layer induced this large tensile growth stress when coalescence occurred

Self‐propagating Combustion Triggered Synthesis of 3D Lamellar Graphene/BaFe12O19 Composite and Its Electromagnetic Wave Absorption Properties

The synthesis of 3D lamellar graphene/BaFe12O19 composites was performed by oxidizing graphite and sequentially self‐propagating combustion triggered process. The 3D lamellar graphene structures were formed due to the synergistic effect of the tremendous heat induced gasification as well as huge volume expansion. The 3D lamellar graphene/BaFe12O19 composites bearing 30 wt % graphene present the reflection loss peak at −27.23 dB as well as the frequency bandwidth at 2.28 GHz (&lt; −10 dB). The 3D lamellar graphene structures could consume the incident waves through multiple Reflection and scattering within the layered structures, Prolonging the propagation path of electromagnetic waves in the absorbers

Regulation of histone demethylase KDM6B by hypoxia-inducible factor-2 alpha

Lysine (K)-specific demethylase 6B (KDM6B) is a histone H3K27 demethylase, which specifically catalyzes the demethylation of H3 lysine-27 tri/dimethylation (H3K27me3/2). KDM6B can activate gene transcription by promoting transcriptional elongation which is associated with RNA polymerase II and related elongation factors. So KDM6B is important for the regulation of gene expression. Previous studies have indicated that several histone demethylases such as KDM3A, KDM4B, and KDM4C are regulated by hypoxia-inducible factor (HIF). But, the effect of hypoxia on KDM6B is not fully understood. In this study, we found that the expression levels of KDM6B mRNA and protein are modestly up-regulated under hypoxia (1% O-2) or mimic hypoxia (desferrioxamine mesylate or CoCl2 treatment) (P < 0.05). The result of RNAi shows that the up-regulation of KDM6B is dependent on HIF-2 alpha, but not on HIF-1 alpha. The result of chromatin immunoprecipitation assay indicates that there is a hypoxia response element in KDM6B promoter (-4041 to -4037). The result of Co-IP assay indicates that KDM6B can form complex with HIF-2 alpha or HIF-1 alpha. The knockdown experiment implies that KDM6B is a potential regulator for HIF-2 alpha target genes. These data demonstrate that KDM6B is a new hypoxia response gene regulated by HIF-2 alpha. Our results also show that KDM6B is a potential coactivator of HIF-alpha, which is important for the activation of hypoxia response genes

Effects of 'Healthy' Fecal Microbiota Transplantation against the Deterioration of Depression in Fawn-Hooded Rats.

Depression is a recurrent, heterogeneous mood disorder occurring in more than 260 million people worldwide. Gut microbiome dysbiosis is associated with the development of depressive-like behaviors by modulating neuro-biochemical metabolism through the microbiome-gut-brain (MGB) axis. Fecal microbiota transplantation (FMT) has been proposed as a potential therapeutic solution for depression, but the therapeutic efficiency and mechanism are unknown. Here, we performed an FMT from Sprague-Dawley (SD) rats ('healthy' controls) to Fawn-hooded (FH) rats (depression model). Pre-FMT, the FH rats exhibited significantly elevated depressive-like behaviors and distinct neurotransmitter and cytokine levels compared with SD rats. Post-FMT, FH recipients receiving FH fecal microbiota (FH-FH rats) showed aggravated depressive-like behaviors, while the ones receiving SD microbiota (FH-SD rats) had significantly alleviated depressive symptoms, a significant increase in hippocampal neurotransmitters, and a significant decrease of some hippocampal cytokines than FH-FH rats. SD-FMT resulted in the FH-SD rats' gut microbiome resembling the SD donors, and a significant shift in the serum metabolome but not the hippocampal metabolome. Co-occurrence analysis suggests that SD-FMT prevented recipients' depression development via the significant decrease of gut microbial species such as Dialister sp., which led to the recipients' metabolic modulation in serum and hippocampus through the enteric nervous system, the intestinal barrier, and the blood-brain barrier. Our results provided new data pointing to multiple mechanisms of interaction for the impact of gut microbiome modulation on depression therapy. IMPORTANCE Depression is a chronic, recurrent mental disease, which could make the patients commit suicide in severe cases. Considering that gut microbiome dysbiosis could cause depressive symptoms in animals through the MGB axis, the modification of gut microbiota is expected to be a potential therapy for depression, but the daily administration of probiotics is invalid or transient. In this study, we demonstrated that the gut microbiome transferred from a healthy rat model to a depressive rat model could regulate the recipient's neurobiology and behavior via the systematic alternation of the depressive gut microbiota followed by the serum and hippocampal metabolism. These results underline the significance of understanding the impact of gut microbiota on mental disorders and suggest that 'healthy' microbiota transplantation with the function to solve the host's cerebral inflammation may serve as a novel therapeutic strategy for depression