Sensitization of Glioma Cells to Tamoxifen-Induced Apoptosis by Pl3-Kinase Inhibitor through the GSK-3β/β-Catenin Signaling Pathway

Malignant gliomas represent one of the most aggressive types of cancers and their recurrence is closely linked to acquired therapeutic resistance. A combination of chemotherapy is considered a promising therapeutic model in overcoming therapeutic resistance and enhancing treatment efficacy. Herein, we show by colony formation, Hochest 33342 and TUNEL staining, as well as by flow cytometric analysis, that LY294002, a specific phosphatidylinositide-3-kinase (PI3K) inhibitor, enhanced significantly the sensitization of a traditional cytotoxic chemotherapeutic agent, tamoxifen-induced apoptosis in C6 glioma cells. Activation of PI3K signaling pathway by IGF-1 protected U251 cells from apoptosis induced by combination treatment of LY294002 and tamoxifen. Interference of PI3K signaling pathway by PI3K subunit P85 siRNA enhanced the sensitization of U251 glioma cells to tamoxifen -induced apoptosis. By Western blotting, we found that combination treatment showed lower levels of phosphorylated AktSer473 and GSK-3βSer9 than a single treatment of LY294002. Further, we showed a significant decrease of nuclear β-catenin by combination treatment. In response to the inhibition of β-catenin signaling, mRNA and protein levels of Survivin and the other three antiapoptotic genes Bcl-2, Bcl-xL, and Mcl-1 were significantly decreased by combination treatment. Our results indicated that the synergistic cytotoxic effect of LY294002 and tamoxifen is achieved by the inhibition of GSK-3β/β-catenin signaling pathway

Simultaneously Transmitting and Reflecting RIS (STAR-RIS) Assisted Multi-Antenna Covert Communication: Analysis and Optimization

This paper investigates the multi-antenna covert communications assisted by a simultaneously transmitting and reflecting reconfigurable intelligent surface (STAR-RIS). In particular, to shelter the existence of covert communications between a multi-antenna transmitter and a single-antenna receiver from a warden, a friendly full-duplex receiver with two antennas is leveraged to make contributions where one antenna is responsible for receiving the transmitted signals and the other one transmits the jamming signals with a varying power to confuse the warden. Considering the worst case, the closed-form expression of the minimum detection error probability (DEP) at the warden is derived and utilized in a covert constraint to guarantee the system performance. Then, we formulate an optimization problem maximizing the covert rate of the system under the covertness constraint and quality of service (QoS) constraint with communication outage analysis. To jointly design the active and passive beamforming of the transmitter and STAR-RIS, an iterative algorithm based on semi-definite relaxation (SDR) method and Dinkelbach’s algorithm is proposed to effectively solve the non-convex optimization problem. Simulation results show that the proposed STAR-RIS-assisted scheme highly outperforms the case with conventional RIS, which validates the effectiveness of the proposed algorithm as well as the superiority of STAR-RIS in guaranteeing the covertness of wireless communications

Licorice extract inhibits the cGAS-STING pathway and protects against non-alcoholic steatohepatitis

Background: Inflammation and fibrosis are typical symptoms of non-alcoholic steatohepatitis (NASH), which is one of the most common chronic liver diseases. The cGAS-STING signaling pathway has been implicated in the progression of NASH, and targeting this pathway may represent a new therapeutic strategy. Licorice is a widely used herb with anti-inflammatory and liver-protective properties. In this study, we assessed the effect of licorice extract on the cGAS-STING pathway.Methods: Bone marrow-derived macrophages (BMDMs) were treated with licorice extract and then stimulated with HT-DNA, 2'3'-cGAMP, or other agonists to activate the cGAS-STING pathway. Quantitative real-time PCR and western blot were conducted to analyze whether licorice extract could affect the cGAS-STING pathway. Methionine and choline-deficient diet (MCD) was used to induce NASH in mice, which were treated with licorice extract (500 mg/kg) by gavage and/or c-176 (15 mg/kg) by intraperitoneal injection every 2 days. After 6 weeks of treatment, histological analysis of liver tissue was performed, along with measurements of plasma biochemical parameters.Results: Licorice extract inhibits cGAS-STING pathway activation. Mechanistically, it might function by inhibiting the oligomerization of STING. Treatment with licorice extract reduced inflammation and fibrosis in MCD diet-induced NASH mice models. Furthermore, we found that the therapeutic effect of combination treatment with licorice extract and C-176 (STING inhibitor) on the pathology and fibrosis of MCD diet-induced NASH models was similar to that of licorice extract or C-176 administered alone.Conclusion: Licorice extract can inhibit the cGAS-STING pathway and improve hepatic inflammation and fibrosis in NASH mice models. It strongly suggests that licorice extract may be a candidate therapeutic for NASH

Genome-wide analysis of FRF gene family and functional identification of HvFRF9 under drought stress in barley

FHY3 and its homologous protein FAR1 are the founding members of FRS family. They exhibited diverse and powerful physiological functions during evolution, and participated in the response to multiple abiotic stresses. FRF genes are considered to be truncated FRS family proteins. They competed with FRS for DNA binding sites to regulate gene expression. However, only few studies are available on FRF genes in plants participating in the regulation of abiotic stress. With wide adaptability and high stress-resistance, barley is an excellent candidate for the identification of stress-resistance-related genes. In this study, 22 HvFRFs were detected in barley using bioinformatic analysis from whole genome. According to evolution and conserved motif analysis, the 22 HvFRFs could be divided into subfamilies I and II. Most promoters of subfamily I members contained abscisic acid and methyl jasmonate response elements; however, a large number promoters of subfamily II contained gibberellin and salicylic acid response elements. HvFRF9, one of the members of subfamily II, exhibited a expression advantage in different tissues, and it was most significantly upregulated under drought stress. In-situ PCR revealed that HvFRF9 is mainly expressed in the root epidermal cells, as well as xylem and phloem of roots and leaves, indicating that HvFRF9 may be related to absorption and transportation of water and nutrients. The results of subcellular localization indicated that HvFRF9 was mainly expressed in the nuclei of tobacco epidermal cells and protoplast of arabidopsis. Further, transgenic arabidopsis plants with HvFRF9 overexpression were generated to verify the role of HvFRF9 in drought resistance. Under drought stress, leaf chlorosis and wilting, MDA and O2− contents were significantly lower, meanwhile, fresh weight, root length, PRO content, and SOD, CAT and POD activities were significantly higher in HvFRF9-overexpressing arabidopsis plants than in wild-type plants. Therefore, overexpression of HvFRF9 could significantly enhance the drought resistance in arabidopsis. These results suggested that HvFRF9 may play a key role in drought resistance in barley by increasing the absorption and transportation of water and the activity of antioxidant enzymes. This study provided a theoretical basis for drought resistance in barley and provided new genes for drought resistance breeding

An atlas of DNA methylomes in porcine adipose and muscle tissues

It is evident that epigenetic factors, especially DNA methylation, have essential roles in obesity development. Here, using pig as a model, we investigate the systematic association between DNA methylation and obesity. We sample eight variant adipose and two distinct skeletal muscle tissues from three pig breeds living within comparable environments but displaying distinct fat level. We generate 1,381 Gb of sequence data from 180 methylated DNA immunoprecipitation libraries, and provide a genome-wide DNA methylation map as well as a gene expression map for adipose and muscle studies. The analysis shows global similarity and difference among breeds, sexes and anatomic locations, and identifies the differentially methylated regions. The differentially methylated regions in promoters are highly associated with obesity development via expression repression of both known obesity-related genes and novel genes. This comprehensive map provides a solid basis for exploring epigenetic mechanisms of adipose deposition and muscle growth

Detection of recurrent cytogenetic aberrations in multiple myeloma: A comparison between MLPA and iFISH

Multiple myeloma (MM) is a genetically heterogeneous disease with diverse clinical characteristics and outcomes. Recently, multiplex ligation-dependent probe amplification (MLPA) has emerged as an effective and robust method for the detection of cytogenetic aberrations in MM patients. In the present study, MLPA analysis was applied to analyze cytogenetics of CD138 tumor cells of 59 MM samples, and its result was compared, retrospectively, with the interphase fluorescence in situ hybridization (iFISH) data. We firstly established the normal range of each of the 42 diagnostic probes using healthy donor samples. A total of 151 aberrations were detected in 59 patient samples, and 49/59 cases (83.1%) harbored at least one copy number variation. Overall, 0–7 aberrations were detected per case using MLPA, indicating the heterogeneity and complexity of MM cytogenetics. We showed the high efficiency of MLPA and the high congruency of the two methods to assess cytogenetic aberrations. Considering that MLPA analysis is not reliable when the aberration only exits in a small population of tumor cells, it is essential to use both MLPA and iFISH as complementary techniques for the diagnosis of MM

Effects of L1-ORF2 fragments on green fluorescent protein gene expression

The retrotransposon known as long interspersed nuclear element-1 (L1) is 6 kb long, although most L1s in mammalian and other eukaryotic cells are truncated. L1 contains two open reading frames, ORF1 and ORF2, that code for an RNA-binding protein and a protein with endonuclease and reverse transcriptase activities, respectively. In this work, we examined the effects of full length L1-ORF2 and ORF2 fragments on green fluorescent protein gene (GFP) expression when inserted into the pEGFP-C1 vector downstream of GFP. All of the ORF2 fragments in sense orientation inhibited GFP expression more than when in antisense orientation, which suggests that small ORF2 fragments contribute to the distinct inhibitory effects of this ORF on gene expression. These results provide the first evidence that different 280-bp fragments have distinct effects on the termination of gene transcription, and that when inserted in the antisense direction, fragment 280-9 (the 3' end fragment of ORF2) induces premature termination of transcription that is consistent with the effect of ORF2