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The long non-coding RNA (lncRNA), HAR1A is emerging as a putative tumour suppressor. In non-neoplastic brain cells, REST suppresses HAR1A expression. In gliomas REST acts as an oncogene and is a potential therapeutic target. It is therefore conceivable that REST promotes glioma progression by down-regulating HAR1A. To test this hypothesis, glioma clinical databases were analysed to study: (I) HAR1A/REST correlation; (II) HAR1A and REST prognostic role; (III) molecular pathways associated with these genes. HAR1A expression and subcellular localization were studied in glioblastoma and paediatric glioma cells. REST function was also studied in these cells, by observing the effects of gene silencing on: (I) HAR1A expression; (II) cancer cell proliferation, apoptosis, migration; (III) expression of neural differentiation genes. The same phenotypes (and cell morphology) were studied in HAR1A overexpressing cells. Our results show that REST and HAR1A are negatively correlated in gliomas. Higher REST expression predicts worse prognosis in low-grade gliomas (the opposite is true for HAR1A). REST-silencing induces HAR1A upregulation. HAR1A is primarily detected in the nucleus. REST-silencing dramatically reduces cell proliferation and induces apoptosis, but HAR1A overexpression has no major effect on investigated cell phenotypes. We also show that REST regulates the expression of neural differentiation genes and that its oncogenic function is primarily HAR1A-independent., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Waters et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Two nanometre gold nanoparticles (AuNPs), bearing sugar moieties and/or thiol-polyethylene glycol-amine (PEG-amine), were synthesised and evaluated for their in vitro toxicity and ability to radiosensitise cells with 220 kV and 6 MV X-rays, using four cell lines representing normal and cancerous skin and breast tissues. Acute 3 h exposure of cells to AuNPs, bearing PEG-amine only or a 50:50 ratio of alpha-galactose derivative and PEG-amine resulted in selective uptake and toxicity towards cancer cells at unprecedentedly low nanomolar concentrations. Chemotoxicity was prevented by co-administration of N-acetyl cysteine antioxidant, or partially prevented by the caspase inhibitor Z-VAD-FMK. In addition to their intrinsic cancer-selective chemotoxicity, these AuNPs acted as radiosensitisers in combination with 220 kV or 6 MV X-rays. The ability of AuNPs bearing simple ligands to act as cancer-selective chemoradiosensitisers at low concentrations is a novel discovery that holds great promise in developing low-cost cancer nanotherapeutics. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) is an increasingly popular anticancer treatment that uses photosensitizer, light and tissue oxygen to generate cytotoxic reactive oxygen species (ROS) within illuminated cells. Acting to counteract ROS-mediated damage are various cellular antioxidant pathways. In this study, we combined PDT with specific antioxidant inhibitors to potentiate PDT cytotoxicity in MCF-7 cancer cells. We used disulphonated aluminium phthalocyanine photosensitizer plus various combinations of the antioxidant inhibitors: diethyl-dithiocarbamate (DDC, a Cu/Zn-SOD inhibitor), 2-methoxyestradiol (2-ME, a Mn-SOD inhibitor), l-buthionine sulfoximine (BSO, a glutathione synthesis inhibitor) and 3-amino-1,2,4-triazole (3-AT, a catalase inhibitor). BSO, singly or in combination with other antioxidant inhibitors, significantly potentiated PDT cytotoxicity, corresponding with increased ROS levels and apoptosis. The greatest potentiation of cell death over PDT alone was seen when cells were preincubated for 24 h with 300 μm BSO plus 10 mm 3-AT (1.62-fold potentiation) or 300 μm BSO plus 1 μm 2-ME (1.52-fold), or with a combination of all four inhibitors (300 μm BSO, 10 mm 3-AT, 1 μm 2-ME and 10 μm DDC: 1.4-fold). As many of these inhibitors have already been clinically tested, this work facilitates future in vivo studies. [ABSTRACT FROM AUTHOR]

Abstract: To be effective for tissue repair, satellite cells (the stem cells of adult muscle) must survive the initial activation from quiescence. Using an in vitro model of satellite cell activation, we show that erbB1, erbB2 and erbB3, members of the EGF receptor tyrosine kinase family, appear on satellite cells within 6 h of activation. We show that signalling via erbB2 provides an anti-apoptotic survival mechanism for satellite cells during the first 24 h, as they progress to a proliferative state. Inhibition of erbB2 signalling with AG825 reduced satellite cell numbers, concomitant with elevated caspase-8 activation and TUNEL labelling of apoptotic satellite cells. In serum-free conditions, satellite cell apoptosis could be largely prevented by a mixture of erbB1, erbB3 and erbB4 ligand growth factors, but not by neuregulin alone (erbB3/erbB4 ligand). Furthermore, using inhibitors specific to discrete intracellular signalling pathways, we identify MEK as a pro-apoptotic mediator, and the erbB-regulated factor STAT3 as an anti-apoptotic mediator during satellite cell activation. These results implicate erbB2 signalling in the preservation of a full compliment of satellite cells as they activate in the context of a damaged muscle. [Copyright &y& Elsevier]