Molecular Dynamics Simulation-Driven Focused Virtual Screening and Experimental Validation of Inhibitors for MTDH-SND1 Protein-Protein Interaction.

Protein-protein interactions (PPIs), in general, are attractive yet challenging drug targets. As a typical PPI, MTDH-SND1 interaction has recently been reported to be a promising drug target to malignant breast cancer and other cancer types. However, the lack of well-defined deep pockets on the MTDH-SND1 interface makes it a tough target for rational drug discovery attempts. To address this issue, in this study, a long time-scale molecular dynamics (MD) simulation-driven focused screening strategy was proposed and reported. A total of 12 virtual hits were purchased and tested in SPR assay, yielding 10 SND1 binders with micromolar or less affinities. As an example, compound L5, the second best hit with a KD of 2.64 µM, was further assayed in MDA-MB-231 breast cancer cells, showing an antiproliferation IC50 value of 57 µM in a CCK8 assay with a dampened interruption between MTDH and SND1 proteins detected by immunofluorescence colocalization imaging. As the most potent small molecule inhibitor in the class so far, our preliminary study combining molecular dynamics simulation and in vitro cellular functional evidence indicates L5 could serve as a lead compound for future optimization or pharmacologic studies, and the MD-driven focused screening strategy could be useful for other PPI drug discovery attempts.

Regulation of stem cell function and neuronal differentiation by HERV-K via mTOR pathway.

Stem cells are capable of unlimited proliferation but can be induced to form brain cells. Factors that specifically regulate human development are poorly understood. We found that human stem cells expressed high levels of the envelope protein of an endogenized human-specific retrovirus (HERV-K, HML-2) from loci in chromosomes 12 and 19. The envelope protein was expressed on the cell membrane of the stem cells and was critical in maintaining the stemness via interactions with CD98HC, leading to triggering of human-specific signaling pathways involving mammalian target of rapamycin (mTOR) and lysophosphatidylcholine acyltransferase (LPCAT1)-mediated epigenetic changes. Down-regulation or epigenetic silencing of HML-2 env resulted in dissociation of the stem cell colonies and enhanced differentiation along neuronal pathways. Thus HML-2 regulation is critical for human embryonic and neurodevelopment, while it's dysregulation may play a role in tumorigenesis and neurodegeneration.

Ultrasonic features of superficial angiomyxoma in the scrotum: A case image.

Superficial angiomyxoma in the scrotum is a well-circumscribed, ovoid-shaped, heterogeneously echogenic mass in the ultrasonography. On Doppler ultrasonography, vascular flow signals are visible in and around the mass(M).

DNMT1 Mediated CAHM Repression Promotes Glioma Invasion via SPAK/JNK Pathway.

Gliomas are the most common and fatal brain tumors worldwide. Abnormal DNA promoter methylation is an important mechanism for gene loss of tumor suppressors. A long non-coding RNA colorectal adenocarcinoma hypermethylated (CAHM) has been reported to be nearly deleted in glioblastomas (GBMs). Nevertheless, the roles of CAHM in gliomas remain unknown up to now. In the present study, 969 glioma samples downloaded from the CGGA and Gravendeel databases were included. We found that CAHM expression was correlated with glioma grades, molecular subtype, IDH mutation status, and 1q/19p codel status. In glioma cells, CAHM is hypermethylated by DNA methyltransferase1 (DNMT1) and the loss of CAHM expression could be reversed by 5-Aza-2'-deoxycytidine (5-Aza), a specific inhibitor of DNA methyltransferases. Besides, the expression of CAHM was negatively associated with overall survival in both primary and recurrent gliomas. Moreover, the result of Gene Ontology (GO) analysis suggested that CAHM participated in negatively regulating cell development, nervous system development, neurogenesis, and integrin-mediated signaling pathway. Overexpression of CAHM inhibited glioma cell proliferation, clone formation, and invasion. Further exploring results showed that CAHM overexpression suppressed glioma migration and invasion through SPAK/MAPK pathway. Collectively, this study disclosed that CAHM might be a suppressor in gliomas.

NLRC5: new cancer buster?

Recent decades, there is significant progress in understanding the mechanisms of tumor progression and immune evasion. The newly discovered protein NLRC5 is demonstrated to participate in regulating cancer immune escape through enhancing MHC class I genes expression in certain tumors. Nevertheless, increasing evidence has revealed that NLRC5 is up-regulated in some other tumors and promote tumor development and progression. The purpose of this review is to describe the role of NLRC5 in tumors and discuss whether NLRC5 can be a potential target in cancer treatment.

LncRNA-ATB in cancers: what do we know so far?

Cancer-related deaths did not apparently decrease in the past decades despite aggressive treatments. It's reported that cancer will become the leading cause of death worldwide in the twenty-first century. Increasing evidence has revealed that lncRNAs will emerge as promising cancer biomarkers or therapeutic targets in cancer treatment. LncRNA-ATB, a long noncoding RNA activated by TGF-ß, was found to be abnormally expressed in certain cancers and participate in the development and progression of tumors. In addition, aberrant lncRNA-ATB expression was also associated with clinical characteristics of tumors. The purpose of this review is to summarize functions and underlying mechanisms of lncRNA-ATB in tumors, and discuss whether lncRNA-ATB can be a biomarker and therapeutic target in cancers.

LncRNA-ATB promotes TGF-ß-induced glioma cells invasion through NF-κB and P38/MAPK pathway.

Glioma constitutes the most aggressive primary intracranial malignancy in adults. We previously showed that long noncoding RNA activated by TGF-ß (lncRNA-ATB) promoted the glioma cells invasion. However, whether lncRNA-ATB is involved in TGF-ß-mediated invasion of glioma cells remains unknown. In this study, quantitative real-time polymerase chain reaction and western blot analysis were used for detecting the mRNA and protein expression of related genes, respectively. Transwell assay was performed to assess the impact of lncRNA-ATB on TGF-ß-induced glioma cells migration and invasion. Immunofluorescence staining was utilized to characterize related protein distribution. Results showed that TGF-ß upregulated lncRNA-ATB expression in glioma LN-18 and U251 cells. Overexpression of lncRNA-ATB activated nuclear factor-κB (NF-κB) pathway and promoted P65 translocation into the nucleus, thus facilitated glioma cells invasion stimulated by TGF-ß. Similarly, lncRNA-ATB markedly enhanced TGF-ß-mediated invasion of glioma cells through activation P38 mitogen-activated protein kinase (P38/MAPK) pathway. Moreover, both the NF-κB selected inhibitor pyrrolidinedithiocarbamate ammonium and P38/MAPK specific inhibitor SB203580 partly reversed lncRNA-ATB induced glioma cells invasion mediated by TGF-ß. Collectively, this study revealed that lncRNA-ATB promotes TGF-ß-induced glioma cell invasion through NF-κB and P38/MAPK pathway and established a detailed framework for understanding the way how lncRNA-ATB performs its function in TGF-ß-mediated glioma invasion.

Activated T cells induce proliferation of oligodendrocyte progenitor cells via release of vascular endothelial cell growth factor-A.

Neuroinflammatory diseases such as multiple sclerosis are characterized by infiltration of lymphocytes into the central nervous system followed by demyelination and axonal degeneration. While evidence suggests that activated T lymphocytes induce neurotoxicity and impair function of neural stem cells, the effect of T cells on oligodendrocyte progenitor cells (OPCs) is still uncertain, partly due to the difficulty in obtaining human OPCs. Here we studied the effect of activated T cells on OPCs using OPCs derived from human hematopoietic stem cells or from human fetal brain. OPCs were exposed to supernatants (sups) from activated T cells. Cell proliferation was determined by EdU incorporation and CellQuanti-Blue assays. Surprisingly, we found that sups from activated T cells induced OPC proliferation by regulating cell cycle progression. Vascular endothelial growth factor A (VEGF-A) transcripts were increased in T cells after activation. Immunodepletion of VEGF-A from activated T cell sups significantly attenuated its effect on OPC proliferation. Furthermore, VEGF receptor 2 (VEGFR2) was expressed on OPCs and its inhibition also attenuated activated T cell-induced OPC proliferation. Thus, activated T cells have a trophic role by promoting OPC proliferation via the VEGFR2 pathway.

Visible-light-induced selective defluoroalkylations of polyfluoroarenes with alcohols.

To provide α-polyfluoroarylalcohols, a novel protocol for the selective defluoroalkylation of polyfluoroarenes with easily accessible alcohols was reported via the cooperation of photoredox and hydrogen atom transfer (HAT) strategies with the assistance of Lewis acids under visible light irradiation. The protocol featured broad scope, excellent regioselectivity for both C-H and C-F bond cleavages, and mild conditions. Mechanistic studies suggested that the reaction occurred through Lewis acid-promoted HAT to provide an alkyl radical and sequential addition to polyfluoroarenes. Impressively, the regioselectivity for C-F cleavage was verified with the Fukui function. The feasibility and application of this protocol on fluoroarene synthesis were well illustrated by gram-scale synthesis under both batch and flow conditions, late-stage decoration of bioactive compounds, and further transformations of the fluoroarylalcohols.

Super-enhancers: A new frontier for glioma treatment.

Glioma is the most common primary malignant tumor in the human brain. Although there are a variety of treatments, such as surgery, radiation and chemotherapy, glioma is still an incurable disease. Super-enhancers (SEs) are implicated in the control of tumor cell identity, and they promote oncogenic transcription, which supports tumor cells. Inhibition of the SE complex, which is required for the assembly and maintenance of SEs, may repress oncogenic transcription and impede tumor growth. In this review, we discuss the unique characteristics of SEs compared to typical enhancers, and we summarize the recent advances in the understanding of their properties and biological role in gene regulation. Additionally, we highlight that SE-driven lncRNAs, miRNAs and genes are involved in the malignant phenotype of glioma. Most importantly, the application of SE inhibitors in different cancer subtypes has introduced new directions in glioma treatment.

Meg3 Induces EMT and Invasion of Glioma Cells via Autophagy.

BACKGROUND: Glioma is one of the most common malignant tumors. Glioblastoma (grade IV) is considered the most malignant form of human brain tumors. Maternal expression gene 3 (Meg3) encodes a non-coding RNA (ncRNA) that plays an important role in the development and progression of cancer. However, the role of Meg3 in glioma cells remains largely unclear. METHODS: Reverse transcription-quantitative (RT-q) PCR was conducted to evaluate the mRNA expression related to cell autophagy and EMT while protein expression was detected by Western blotting. Staining of acidic vacuoles and immunofluorescence staining were used to detect autophagy. The ability of cells to migrate and invade was detected by Transwell migration and invasion assays. RESULTS: In the present study, it was found that the overexpression of Meg3 induced EMT, migration and invasion of glioma cells, whereas Meg3 overexpression induced autophagy of glioma cells. More importantly, the inhibition of autophagy impaired the EMT of glioma cells. In addition, Meg3-induced EMT, migration and invasion could be partially reversed by autophagy inhibitors, chloroquine (CQ) and Lys05, in glioma cells. CONCLUSION: All data suggest that Meg3 induces EMT and invasion of glioma cells via autophagy. Overall, the findings of the present study demonstrate the importance of Meg3 in the molecular etiology of glioma, which also indicate its potential applications in the treatment of glioma.

A central role for MeCP2 in the epigenetic repression of miR-200c during epithelial-to-mesenchymal transition of glioma.

BACKGROUND: The epithelial-to-mesenchymal transition (EMT) has been linked to the regulation of glioma progression. However, the underlying signaling mechanisms that regulate EMT are poorly understood. METHODS: Quantitative real-time PCR (RT-qPCR) and western blot were performed to detect the expression of MeCP2 in glioma tissues and cell lines. MeCP2 functions were tested with cell immunofluorescence staining and western blot. For in vivo experiments, mouse xenograft model was used to investigate the effects of MeCP2 on glioma. ChIP and Co-IP were used to detect the relationships among MeCP2, miR-200c and Suv39H1. RESULTS: In this study, we found that MeCP2 was frequently up-regulated in human glioma tissues and cell lines. MeCP2 knockdown remarkably induced cell epithelial phenotype and inhibited mesenchymal marker ZEB1 and ZEB2 in vitro and in vivo. In addition, MeCP2 in glioma tissues was negatively correlated with miR-200c expression, and miR-200c overexpression partially abrogated mesenchymal phenotype induced by MeCP2. More importantly, we showed that MeCP2 recruited H3K9 to the promoter of miR-200c by interacting with SUV39H1, resulting in EMT of glioma cells. CONCLUSIONS: This study for the first time reveals MeCP2 as a novel regulator of EMT in glioma and suggest that MeCP2 inhibition may represent a promising therapeutic option for suppressing EMT in glioma.

Highly Stabilized Ni-Rich Cathode Material with Mo Induced Epitaxially Grown Nanostructured Hybrid Surface for High-Performance Lithium-Ion Batteries.

Capacity fading induced by unstable surface chemical properties and intrinsic structural degradation is a critical challenge for the commercial utilization of Ni-rich cathodes. Here, a highly stabilized Ni-rich cathode with enhanced rate capability and cycling life is constructed by coating the molybdenum compound on the surface of LiNi0.815Co0.15Al0.035O2 secondary particles. The infused Mo ions in the boundaries not only induce the Li2MoO4 layer in the outermost but also form an epitaxially grown outer surface region with a NiO-like phase and an enriched content of Mo6+ on the bulk phase. The Li2MoO4 layer is expected to reduce residential lithium species and promote the Li+ transfer kinetics. The transition NiO-like phase, as a pillaring layer, could maintain the integrity of the crystal structure. With the suppressed electrolyte-cathode interfacial side reactions, structure degradation, and intergranular cracking, the modified cathode with 1% Mo exhibits a superior discharge capacity of 140 mAh g-1 at 10 C, a superior cycling performance with a capacity retention of 95.7% at 5 C after 250 cycles, and a high thermal stability.

Exosomal lncRNA­ATB activates astrocytes that promote glioma cell invasion.

Glioma invasion is a main cause of a poor prognosis and relapse in patients suffering from the disease. However, the molecular mechanisms responsible for glioma cell invasion remain poorly understood. In this study, the characteristics of exosomes were identified using electron microscope (TEM), and western blot analysis. The potential mechanism of long non­coding RNA (lncRNA) activated by TGF­ß (lncRNA­ATB) was demonstrated using luciferase reporter assays and RNA immunoprecipitation. We found that glioma cell­derived exosomes promoted the activation of astrocytes and had the ability to shuttle long non­coding RNA (lncRNA) activated by TGF­ß (lncRNA­ATB) to astrocytes. More importantly, lncRNA­ATB activated astrocytes through the suppression of microRNA (miRNA or miR)­204­3p in an Argonaute 2 (Ago2)­dependent manner. Furthermore, astrocytes activated by lncRNA­ATB in turn promoted the migration and invasion of glioma cells. Taken together, the findings of this study suggest that lncRNA­ATB may play an important role in modulating glioma microenvironment through exosomes. Thus, a better understanding of this process may provide implications for the prevention of highly invasive glioma.

Constructing a Protective Pillaring Layer by Incorporating Gradient Mn4+ to Stabilize the Surface/Interfacial Structure of LiNi0.815Co0.15Al0.035O2 Cathode.

Nickel-rich layered oxides are regarded as very promising materials as cathodes for lithium-ion batteries because of their environmental benignancy, low cost, and high energy density. However, insufficient cycle performance and poor thermotic characteristics induced by structural degradation at high potentials and elevated temperatures pose challenging hurdles for nickel-rich cathodes. Here, a protective pillaring layer, in which partial Ni2+ ions occupy Li slabs induced by gradient Mn4+, is integrated into the primary particle of LiNi0.815Co0.15Al0.035O2 to stabilize the surface/interfacial structure. With the stable outer surface provided by the enriched Mn4+ gradient concentration and the pillar effect of the NiO-like phase, Mn-incorporated quaternary cathodes show enhanced structural stability and improved Li+ diffusion as well as lithium-storage properties. Compared with the severe capacity fade of a pure layered structure, the cathode with gradient Mn4+ exhibits more stable cycling behavior with a capacity retention of 80.0% after 500 cycles at 5.0 C.