Correction: MiR-181b-5p Downregulates NOVA1 to Suppress Proliferation, Migration and Invasion and Promote Apoptosis in Astrocytoma.

[This corrects the article DOI: 10.1371/journal.pone.0109124.].

UCHL3 induces radiation resistance and acquisition of mesenchymal phenotypes by deubiquitinating POLD4 in glioma stem cells.

BACKGROUND: The high degree of intratumoral genomic heterogeneity is a major obstacle for glioblastoma (GBM) tumors, one of the most lethal human malignancies, and is thought to influence conventional therapeutic outcomes negatively. The proneural-to-mesenchymal transition (PMT) of glioma stem cells (GSCs) confers resistance to radiation therapy in glioblastoma patients. POLD4 is associated with cancer progression, while the mechanisms underlying PMT and tumor radiation resistance have remained elusive. METHOD: Expression and prognosis of the POLD family were analyzed in TCGA, the Chinese Glioma Genome Atlas (CGGA) and GEO datasets. Tumorsphere formation and in vitro limiting dilution assay were performed to investigate the effect of UCHL3-POLD4 on GSC self-renewal. Apoptosis, TUNEL, cell cycle phase distribution, modification of the Single Cell Gel Electrophoresis (Comet), γ-H2AX immunofluorescence, and colony formation assays were conducted to evaluate the influence of UCHL3-POLD4 on GSC in ionizing radiation. Coimmunoprecipitation and GST pull-down assays were performed to identify POLD4 protein interactors. In vivo, intracranial xenograft mouse models were used to investigate the molecular effect of UCHL3, POLD4 or TCID on GCS. RESULT: We determined that POLD4 was considerably upregulated in MES-GSCs and was associated with a meagre prognosis. Ubiquitin carboxyl terminal hydrolase L3 (UCHL3), a DUB enzyme in the UCH protease family, is a bona fide deubiquitinase of POLD4 in GSCs. UCHL3 interacted with, depolyubiquitinated, and stabilized POLD4. Both in vitro and in vivo assays indicated that targeted depletion of the UCHL3-POLD4 axis reduced GSC self-renewal and tumorigenic capacity and resistance to IR treatment by impairing homologous recombination (HR) and nonhomologous end joining (NHEJ). Additionally, we proved that the UCHL3 inhibitor TCID induced POLD4 degradation and can significantly enhance the therapeutic effect of IR in a gsc-derived in situ xenograft model. CONCLUSION: These findings reveal a new signaling axis for GSC PMT regulation and highlight UCHL3-POLD4 as a potential therapeutic target in GBM. TCID, targeted for reducing the deubiquitinase activity of UCHL3, exhibited significant synergy against MES GSCs in combination with radiation.

E2F1-regulated USP5 contributes to the tumorigenic capacity of glioma stem cells through the maintenance of OCT4 stability.

Mesenchymal glioma stem cells (MES GSCs) are a subpopulation of cells in glioblastoma (GBM) that contribute to a worse prognosis owing to their highly aggressive nature and resistance to radiation therapy. Here, OCT4 is characterized as a critical factor in sustaining the stemness phenotype of MES GSC. We find that OCT4 is expressed intensively in MES GSC and is intimately associated with poor prognosis, moreover, OCT4 depletion leads to diminished invasive capacity and impairment of the stem phenotype in MES GSC. Subsequently, we demonstrated that USP5 is a deubiquitinating enzyme which directly interacts with OCT4 and preserves OCT4 stability through its deubiquitination. USP5 was additionally proven to be aberrantly over-expressed in MES GSCs, and its depletion resulted in a noticeable diminution of OCT4 and consequently a reduced self-renewal and tumorigenic capacity of MES GSCs, which can be substantially restored by ectopic expression of OCT4. In addition, we detected the dominant molecule that regulates USP5 transcription, E2F1, with dual luciferase reporter gene analysis. In combination, targeting the E2F1-USP5-OCT4 axis is a potentially emerging strategy for the therapy of GBM.

Highly Reversible Zn-Air Batteries Enabled by Tuned Valence Electron and Steric Hindrance on Atomic Fe-N4-C Sites.

The bifunctional oxygen electrocatalyst is the Achilles' heel of achieving robust reversible Zn-air batteries (ZABs). Herein, durable bifunctional oxygen electrocatalysis in alkaline media is realized on atomic Fe-N4-C sites reinforced by NixCo3-xO4 (NixCo3-xO4@Fe1/NC). Compared with that of pristine Fe1/NC, the stability of the oxygen evolution reaction (OER) is increased 10 times and the oxygen reduction reaction (ORR) performance is also improved. The steric hindrance alters the valence electron at the Fe-N4-C sites, resulting in a shorter Fe-N bond and enhanced stability of the Fe-N4-C sites. The corresponding solid-state ZABs exhibit an ultralong lifespan (>460 h at 5 mA cm-2) and high rate performance (from 2 to 50 mA cm-2). Furthermore, the structural evolution of NixCo3-xO4@Fe1/NC before and after the OER and ORR as well as charge-discharge cycling is explored. This work develops an efficient strategy for improving bifunctional oxygen electrocatalysis and possibly other processes.

Built-in Electric Field Promotes Interfacial Adsorption and Activation of CO2 for C1 Products over a Wide Potential Window.

The unsatisfactory adsorption and activation of CO2 suppress electrochemical reduction over a wide potential window. Herein, the built-in electric field (BIEF) at the CeO2/In2O3 n-n heterostructure realizes the C1 (CO and HCOO-) selectivity over 90.0% in a broad range of potentials from -0.7 to -1.1 V with a maximum value of 98.7 ± 0.3% at -0.8 V. In addition, the C1 current density (-1.1 V) of the CeO2/In2O3 heterostructure with a BIEF is about 2.0- and 3.2-fold that of In2O3 and a physically mixed sample, respectively. The experimental and theoretical calculation results indicate that the introduction of CeO2 triggered the charge redistribution and formed the BIEF at the interfaces, which enhanced the interfacial adsorption and activation of CO2 at low overpotentials. Furthermore, the promoting effect was also extended to CeO2/In2S3. This work gives a deep understanding of BIEF engineering for highly efficient CO2 electroreduction over a wide potential window.

Nitrated T cell epitope linked vaccine targeting CD47 elicits antitumor immune responses and acts synergistically with vaccine targeting PDL1.

Despite the clinical breakthrough made by immune checkpoint blockades (ICB) in cancer immunotherapy, immunosuppressed tumor microenvironment (TME) remains a major impediment in the efficacy of ICB immunotherapy. In this study, we constructed a Nitrated T cell epitope (NitraTh) linked vaccine targeting CD47, namely CD47-NitraTh. CD47-NitraTh could repress the progression of tumor by inducing tumor-specific immune response. Furthermore, combination vaccination with CD47-NitraTh and PDL1-NitraTh could reconstruct tumor associated macrophage, enhance macrophage-mediated phagocytosis for tumor cells, and promote the activation of tumor infiltrating T cells. Notably, by activating chemokine signaling pathway, NitraTh based vaccines reversed immunosuppressed TME, resulting in improved therapeutic outcome for tumor. With the advantage of reversing immunosuppressed TME, NitraTh based vaccine seems an optimal immunotherapy strategy for patients who are not sensitive to antibody based ICB.

Long-cycle Zn-air batteries at high depth of discharge enabled by a robust Zn|electrolyte interface.

It is an urgent need to improve the depth of discharge (DOD) of Zn-air batteries (ZABs), considering that most reported ZABs with long cycle life are realized at low DOD (<1%). In this work, our solid-state ZABs achieved a long cycle life of more than 220 h at 3.2% DOD (the discharge capacity of 10 mA h cm-2 per cycle). Moreover, benefiting from excellent bifunctional oxygen electrocatalysts (Fe@BNC) and robust Zn|electrolyte interface, the ZABs displayed a long cycle life of 120 h even at high DOD of 23.4% and large discharge capacity of 72 mA h cm-2. Additionally, the impact of Zn|electrolyte interface on the cycle time at different DODs is analysed and discussed. The unstable interface exacerbated the dendrite growth and uneven deposition of Zn at high DOD, leading to the decay of the cycle life. The work gives insights into the mechanism of the effect of DOD on the cycle life of the batteries.

Insight on Atomically Dispersed Cu Catalysts for Electrochemical CO2 Reduction.

Electrochemical CO2 reduction (ECO2R) with renewable electricity is an advanced carbon conversion technology. At present, copper is the only metal to selectively convert CO2 into multicarbon (C2+) products. Among them, atomically dispersed (AD) Cu catalysts have received great attention due to the relatively single chemical environment, which are able to minimize the negative impact of morphology, valence state, and crystallographic properties, etc. on product selectivity. Furthermore, the completely exposed atomic Cu sites not only provide space and bonding electrons for the adsorption of reactants in favor of better catalytic activity but also provide an ideal platform for studying its reaction mechanism. This review summarizes the recent progress of AD Cu catalysts as a chemically tunable platform for ECO2R, including the atomic Cu sites dynamic evolution, the catalytic performance, and mechanism. Furthermore, the prospects and challenges of AD Cu catalysts for ECO2R are carefully discussed. We sincerely hope that this review can contribute to the rational design of AD Cu catalysts with enhanced performance for ECO2R.

Circ_0078607 increases platinum drug sensitivity via miR-196b-5p/GAS7 axis in ovarian cancer.

Platinum-based chemotherapy is one of the predominant strategies for treating ovarian cancer (OC), however, platinum resistance greatly influences the therapeutic effect. Circular RNAs (circRNAs) have been found to participate in the pathogenesis of platinum resistance. Our aim was to explore the involvement of circ_0078607 in OC cell cisplatin (DDP) resistance and its potential mechanisms. Circ_0078607, miR-196b-5p, and growth arrest-specific 7 (GAS7) levels were assessed by qPCR. Circ_0078607 stability was assessed by ribonuclease R digestion and actinomycin D treatment. Cell viability of various conic of DDP treatment was measured by CCK-8. The cell proliferation was determined by CCK-8 and colony formation assay. Western blotting was performed for determining GAS7, ABCB1, CyclinD1 and Bcl-2 protein levels. The direct binding between miR-196b-5p and circ_0078607 or GAS7 was validated by dual-luciferase reporter and RIP assay. DDP resistance in vivo was evaluated in nude mice. Immunohistochemistry staining for detecting Ki67 expression in xenograft tumours. Circ_0078607 and GAS7 was down-regulated, but miR-196b-5p was up-regulated in OC samples and DDP-resistant cells. Overexpression of circ_0078607 inhibited DDP resistance, cell growth and induced apoptosis in DDP-resistant OC cells. Mechanistically, circ_0078607 sequestered miR-196b-5p to up-regulate GAS7. MiR-196b-5p mimics reversed circ_0078607 or GAS7 overexpression-mediated enhanced sensitivity. Finally, circ_0078607 improved the sensitivity of DDP in vivo. Circ_0078607 attenuates DDP resistance via miR-196b-5p/GAS7 axis, which highlights the therapeutic potential of circ_0078607 to counter DDP resistance in OC.

Enhanced electron transfer by In doping in SnO2 for efficient CO2 electroreduction to C1 products.

Electrocatalytic CO2 reduction has received great attention for alleviating environmental problems and energy crisis. SnO2-based catalysts are attractive candidates, but they still face problems such as high overpotentials and small current density due to their low intrinsic electrical conductivity and weak activation for CO2. Here, superior selectivity and activity for C1 products (HCOO- and CO) were obtained using In-doped SnO2. The maximum faradaic efficiency was 96.46% at -0.75 V and the partial current density reached -20.12 mA cm-2 at -0.95 V for C1 products. Furthermore, the selectivity for C1 products was over 90% from -0.5 to -1.0 V with a current density of -166.2 mA cm-2 at -1.0 V in flow cells. In ion doping induced electron transfer from Sn species to In and simultaneously generated oxygen vacancies, which improved electrical conductivity and regulated the oxidation state of Sn active sites and provided more active sites. This work emphasizes the role of enhanced electron transfer of catalysts in CO2 electroreduction.

A novel antitumor peptide inhibits proliferation and migration and promotes apoptosis in glioma cells by regulating the MKK6/p38 signaling pathway.

Protein- or peptide-based therapeutics have emerged as an innovative strategy for the treatment of cancer. Our previous research demonstrated that tripartite motif 9 short isoform (TRIM9s) is a tumor suppressor in glioma. In this report, we investigated whether a new peptide derived from TRIM9s, named T9sP, inhibits glioma progression and determined the possible molecular mechanism. The CCK-8 proliferation assay was performed in LN229 and U251 glioma cells. The scratch-wound assay was used to determine the migration of the cells. Apoptosis was assessed by flow cytometry using Annexin V-FITC/PI double staining method. The relative protein expression levels were detected by immunoblot analysis. The cell-penetrating peptide TAT was fused with T9sP to form TAT-T9sP. TAT-T9sP efficiently penetrated through the cell membrane of both LN229 and U251 cells. TAT-T9sP inhibited proliferation and migration and promoted apoptosis of glioma cells. TAT-T9sP activated p38 signaling by upregulating MKK6, and a p38 inhibitor, SB203580, reversed the inhibitory effects of TAT-T9sP on glioma cells. These results indicated the potential of TAT-T9sP for the development of a new anti-glioma medicine.

Long non-coding RNA SUMO1P3 promotes tumour progression by regulating cell proliferation and invasion in glioma.

Gliomas account for 50% of primary brain tumours in the central nervous system. Small ubiquitin-like modifier 1 pseudogene 3 (SUMO1P3), a newly identified long non-coding RNA (lncRNA), serves an oncogenic role in various types of cancer. The aim of the present study was to investigate the effect of SUMO1P3 on glioma progression. The results demonstrated that SUMO1P3 expression was upregulated in glioma tissues and cell lines. Furthermore, SUMO1P3 was associated with a poor overall survival of patients with glioma. The results of the in vitro cell proliferation and flow cytometry assays demonstrated that SUMO1P3-knockdown suppressed cell proliferation and cell cycle. The results of the wound healing and Transwell assays demonstrated that SUMO1P3-knockdown significantly repressed cell migration and invasion. In addition, SUMO1P3 promoted glioma by regulating the expression levels of ß-catenin, cyclin-D1, N-cadherin and E-cadherin. Overall, the results of the present study suggested that SUMO1P3 may act as an oncogene by regulating cell proliferation, cell cycle, cell migration and invasion in glioma, and may represent a novel diagnostic biomarker and therapeutic target for glioma.

High-dimensional hepatopath data analysis by machine learning for predicting HBV-related fibrosis.

Chronic HBV infection, the main cause of liver cirrhosis and hepatocellular carcinoma, has become a global health concern. Machine learning algorithms are particularly adept at analyzing medical phenomenon by capturing complex and nonlinear relationships in clinical data. Our study proposed a predictive model on the basis of 55 routine laboratory and clinical parameters by machine learning algorithms as a novel non-invasive method for liver fibrosis diagnosis. The model was further evaluated on the accuracy and rationality and proved to be highly accurate and efficient for the prediction of HBV-related fibrosis. In conclusion, we suggested a potential combination of high-dimensional clinical data and machine learning predictive algorithms for the liver fibrosis diagnosis.

p62 acts as an oncogene and is targeted by miR-124-3p in glioma.

BACKGROUND: Glioma is the most common central nervous system (CNS) tumour. p62, an important autophagy adaptor, plays a crucial role in cancer. However, the role of p62 in the progression of glioma is poorly characterized. METHODS: We examined the expression of p62 in glioma tissues and cell lines. Then we investigated the function of p62 in vitro, and clarified the mechanism underlying the regulation of p62 expression. RESULTS: We revealed that p62 was upregulated at both the mRNA and protein levels in human glioma tissues irrelevant to isocitrate dehydrogenase (IDH) status. Then, we found that overexpression of p62 promoted glioma progression by promoting proliferation, migration, glycolysis, temozolomide (TMZ) resistance and nuclear factor κB (NF-κB) signalling pathway, and repressing autophagic flux and reactive oxygen species (ROS) in vitro. In accordance with p62 overexpression, knockdown of p62 exerted anti-tumour effects in glioma cells. Subsequently, we demonstrated that miR-124-3p directly targeted the 3'-UTR of p62 mRNA, leading to the downregulation of p62. Finally, we found that p62 function could be partially reversed by miR-124-3p overexpression. CONCLUSIONS: Our results demonstrate that p62 can be targeted by miR-124-3p and acts as an oncogene in glioma, suggesting the potential value of p62 as a novel therapeutic target for glioma.

The long non-coding RNA SNHG14 inhibits cell proliferation and invasion and promotes apoptosis by sponging miR-92a-3p in glioma.

Malignant glioma is one of the most common types of primary brain tumours. Long non-coding RNAs (lncRNAs) have recently emerged as a new class of therapeutic targets for many cancers. In this study, we aimed to explore the functional involvement of small nucleolar RNA host gene 14 (SNHG14) and its potential regulatory mechanism in glioma progression. SNHG14 was found to be downregulated in human glioma tissues and cell lines. SNHG14 significantly inhibited cell viability, reduced cell invasion, and induced apoptosis in glioma cell lines. Furthermore, a correlation analysis demonstrated that there was a negative correlation between SNHG14 expression and miR-92a-3p expression. Bioinformatics prediction and luciferase reporter assays demonstrated that miR-92a-3p could directly bind to SNHG14. miR-92a-3p was significantly upregulated in glioma and acted as an oncogene in glioma cells by inhibiting Bim. Moreover, mechanistic investigations showed that miR-92a-3p could reverse the tumour suppressive effects induced by SNHG14 in glioma, indicating that SNHG14 may act as an endogenous sponge that competes for binding to miR-92a-3p. Our results suggest that SNHG14 and miR-92a-3p may be promising molecular targets for glioma therapy.

Evodiamine activates cellular apoptosis through suppressing PI3K/AKT and activating MAPK in glioma.

BACKGROUND: Glioblastoma multiforme (GBM) is the most malignant primary tumor of the central nervous system and is associated with a very poor prognosis. No further improvements in outcomes have been reported since radiotherapy-temozolomide therapy was introduced. Therefore, developing new agents to treat GBM is important. AIM: This study aimed to evaluate the anti-tumor effect of evodiamine (Evo) on GBM cells, and to determine the underlying mechanisms involved. RESULTS: According to MTT assay results, Evo significantly inhibited the cell proliferation in a time- and dose-dependent manner. Fluorescence microscopy and flow cytometry analyses revealed that Evo induced cell apoptosis in a concentration-dependent manner. Moreover, Evo induced reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) disruption. Finally, Evo induced apoptosis in cancer cells by suppressing PI3K/AKT signaling and inducing MAPK phosphorylation (p38 and JNK, but not ERK) to regulate apoptotic proteins (Bax, Bcl-2, Cytochrome c, Caspase-3, and PARP). CONCLUSION: In summary, Evo inhibits cell proliferation by inducing cellular apoptosis via suppressing PI3K/AKT and activating MAPK in GBM; these results indicate that Evo may be regarded as a new approach for GBM treatment.

Upregulation of the long non-coding RNA SNHG1 predicts poor prognosis, promotes cell proliferation and invasion, and reduces apoptosis in glioma.

Long non-coding RNAs (lncRNAs), which are non-coding RNAs with a length above 200 nucleotides, have emerged as novel and important gene expression modulators in carcinogenesis. Recent evidence indicates that the lncRNA small nucleolar RNA host gene 1 (SNHG1) functions as an oncogene in several types of human cancers. However, its function in the development of glioma remains unknown. The aim of this research was to investigate the clinical aspects and biological mechanisms of SNHG1 in glioma. SNHG1 expression was measured in glioma tissues and cell lines by quantitative real-time PCR (qRT-PCR). The association between SNHG1 expression in tissues and clinicopathological characteristics and prognosis in glioma patients was also explored. Gain-of-function and loss-of-function studies using SNHG1 cDNA and siRNA, respectively, were used to investigate the role of SNHG1 in cell proliferation, invasion and apoptosis in glioma. SNHG1 was highly expressed in glioma tissues, and its upregulation was closely related to old age. Kaplan-Meier analysis showed that high expression of SNHG1 was significantly associated with poor overall survival (OS). Functionally, ectopic expression of SNHG1 enhanced cell proliferation and cell invasion and reduced cell apoptosis in vitro, while SNHG1 knockdown reversed these effects. Taken together, our findings indicate that SNHG1 functions as an oncogene in glioma and may serve as a novel therapeutic target in future treatments.

δ-Opioid Receptor Activation and MicroRNA Expression in the Rat Heart Under Prolonged Hypoxia.

BACKGROUND: Hypoxic/ischemic injury to the heart is a frequently encountered clinical problem with limited therapeutic options. Since microRNAs (miRNAs) are involved in hypoxic/ischemic events, and δ-opioid receptor (DOR) activation is known to protect against hypoxic/ischemic injury, we speculated on the involvement of DOR activation in altering miRNA expression in the heart under hypoxic conditions. The present study aimed to test our hypothesis. METHODS: Male Sprague Dawley rats were exposed to hypoxia (9.5-10% O2) for 1, 5, or 10 days with or without DOR activation. The target miRNAs were selected from TaqMan low-density array (TLDA) data and were further analyzed by quantitative real-time PCR. RESULTS: We found that: 1) hypoxia alters the miRNA expression profiles depending on the hypoxic duration; 2) DOR activation shifts miRNA expression profiles in normoxic conditions and upregulates miR-128a-3p, miR-134-5p, miR-135a, miR-193a-3p, miR-196a, miR-324-3p, and miR-338; and 3) DOR activation modifies hypoxia-induced changes in miRNA expression and increases the levels of miR-128a-3p, miR-134-5p, miR-135a, miR-193a-3p, miR-196a, miR-324-3p, miR-141, miR-200b, and miR-324-3p. For example, miR-196c-5p decreased by 50% while miR-135a-5p increased 2.9 fold after 10 days under hypoxic conditions. Moreover, DOR activation further strengthened the hypoxia-induced increase of the levels of miR-7a-5p. When DOR was activated using UFP-512, the level of miR-107-3p significantly increased 1 day after the administration of UFP-512, but gradually decreased back to normal under normoxia. CONCLUSION: Hypoxia significantly modifies the miRNA profile in the heart, which can be mimicked or modified by DOR activation. Defining the targeted pathways that regulate the diverse cellular and molecular functions of miRNAs may provide new insights into potential therapies for hypoxic/ischemic injury of the heart.

A serum 6-miRNA panel as a novel non-invasive biomarker for meningioma.

Circulating microRNAs (miRNAs) hold great promise as novel clinically blood-based biomarkers for cancer diagnosis and prognosis. However, little is known about their impact in meningioma. The TLDA assay was performed as an initial survey to determine the serum miRNA expression profile in two pooled samples from 20 pre-operative meningiomas and 20 matched healthy controls. Selected candidate miRNAs were subsequently validated individually in another 210 patients and 210 healthy controls from two independent cohorts by qRT-PCR. The serum levels of miR-106a-5p, miR-219-5p, miR-375, and miR-409-3p were significantly increased, whereas the serum levels of miR-197 and miR-224 were markedly decreased. The area under the ROC curve (AUC) for the six combined miRNAs was 0.778. The 4 increased miRNAs were significantly decreased, while the 2 decreased miRNAs were significantly increased after tumor removal. Furthermore, the expression levels of miR-224 were associated with sex, and the expression levels of miR-219-5p were positively associated with the clinical stages of meningioma. Finally, the high expression of miR-409-3p and low expression of miR-224 were significantly correlated with higher recurrence rates. The present study revealed that the panel of 6 serum miRNA may have the potential to be used clinically as an auxiliary tool for meningioma patients.