G-quadruplex ligand-induced DNA damage response coupled with telomere dysfunction and replication stress in glioma stem cells.

Glioblastoma (GBM) is an invariably fatal brain tumor in which a small subpopulation of self-renewable glioma stem cells (GSCs) contributes to tumor propagation and relapse. Targeting GSCs could therefore have a significant clinical impact for GBM. Telomestatin is a naturally-occurring compound that preferentially impairs GSC growth by perturbing transcription and inducing a DNA damage response. Telomestatin stabilizes G-quadruplexes (G4s), which are guanine-rich four-strand nucleic acid structures observed in vitro and in vivo. However, the mechanism underlying the GSC-selective nature of the DNA damage response remains unknown. Here we demonstrate that GSCs are more susceptible to telomestatin-induced telomere dysfunction and replication stress when compared with GSC-derived non-stem glioma cells (NSGCs). Telomestatin induced dissociation of the telomere-capping protein TRF2 from telomeres, leading to telomeric DNA damage in GSCs-but not in NSGCs. BIBR1532, a telomerase catalytic inhibitor, did not preferentially inhibit GSC growth, suggesting that telomestatin promotes telomere dysfunction in a telomerase-independent manner. GSCs and NSGCs had comparable levels of G4s in their nuclei, and both responded to telomestatin with phosphorylation of RPA2 at Ser33-a hallmark of replication stress. However, activation of the checkpoint kinase Chk1, induction of a DNA damage response, and subsequent growth inhibition occurred only in telomestatin-treated GSCs. These observations suggest that telomestatin impairs GSC growth through removal of TRF2 from telomeres and potent activation of the replication stress response pathway. Therefore, a novel G4-directed therapeutic strategy could specifically target cancer stem cells in GBM.

Individualized Nutritional Management Using Dishcook Improves Nutrition Status Markers in Patients with Intellectual Disability.

Dishcook is a new cooking system that allows individual cooking using a dedicated induction heater. This study investigated whether Dishcook use affects the nutritional value of individuals with intellectual disabilities. This study was conducted on users receiving support from a continuous-employment office in Obama City, Fukui Prefecture, in 2022. Of these participants, 18 (seven women and 11 men) who requested the use of the Dishcook were included in the analysis. The study period was from January to August 2023. The mean age was 48.72±16.24 y. A significant increase in the overall phase angles of the limbs was observed. Triglyceride, LDL cholesterol, HbA1c, and serum zinc levels improved in patients who used the Dishcook. The phase angle obtained using Bioelectrical Impedance Analysis also improved, indicating the usefulness of the Dishcook in treating metabolic diseases and the possibility of individualized nutritional management.

Induction of hydroxycarbonate apatite formation on polyethylene or alumina substrates by spherical vaterite particles deposition.

Hydroxycarbonate apatite (HCA) layers were formed on polyethylene (PE) or alumina substrates by depositing spherical sub-micron vaterite particles and then immersing in simulated body fluid (SBF). HCA formation on vaterite-coated PE was faster than that on coated alumina (3days for PE and 7days for alumina). The adsorption of phosphate ions on the vaterite particles in SBF was studied by monitoring changes in the concentration of phosphorous in SBF and the surface charges of vaterite during the SBF immersion. The phosphorous concentration of SBF in which a vaterite-coated PE was immersed for 1h was lower than that in which a vaterite-coated alumina was immersed. Zeta potential of the vaterite surface deposited on PE drastically decreased after 1h immersion in SBF. The vaterite particles deposited on each substrate immediately adsorbed phosphate ions in SBF. The amount of ions adsorbing on the vaterite surfaces deposited on PE was larger than that on alumina. This was attributed to differences in the surface charges between PE (-16mV) and alumina (+38mV). The phosphate adsorption was predominantly electrostatic therefore related to the surface charge of vaterite particles. The surface charges of substrates may affect the charge of vaterite particles.

Collaborative work on evaluation of ovarian toxicity. 4) Effects of fertility study of 4-vinylcyclohexene diepoxide in female rats.

As part of a collaborative project, 4-vinylcyclohexene diepoxide (VCD), an ovarian toxicant, was intraperitoneally administered to female Sprague-Dawley rats at 0, 5, 20 or 80 mg/kg from 2 weeks prior to mating to Day 7 of gestation. At necropsy, the number of implanted embryos, rate of implantation decreased and the rate of preimplantation loss showed an increasing tendency in the 80 mg/kg group. As for organ weight, decreases in absolute and relative ovary weight were observed in the 80 mg/kg group. Histopathologically, the ovaries showed a decrease in number of small follicles at 80 mg/kg

Synthesis and properties of 1,6,7,12,13,18,19,24-octamethylacenaphthyleno[b,l]tetraphenylene.

The X-ray crystal structure and photophysical properties of 1,6,7,12,13,18,19,24-octamethylacenaphthyleno[b,l]tetraphenylene, which has been synthesized via a Diels-Alder reaction of 5,6,11,12-tetradehydrodibenzo[a,e]cyclooctene and 6,7-dihydro-6-hydroxy-7,9-dimethyl-8H-cyclopenta[a]acenaphthylene-8-one, are reported.

Double elimination protocol for synthesis of 5,6,11,12-tetradehydrodibenzo[a,e]cyclooctene.

A new method for constructing 5,6,11,12-tetradehydrodibenzo[a,e]cyclooctene is described on the basis of one-pot double elimination protocol. The target molecule, which is the smallest cyclophane with alternate arylene-ethynylene linkage, is synthesized in 61 % yield through oxidative dimerization of ortho-(phenylsulfonylmethyl)benzaldehyde. The initial carbon-carbon bond formation between sp(3) carbons followed by stepwise conversion to sp(2) and finally sp carbons bypasses the difficulty encountered in direct coupling of the sp carbon in the terminal acetylene. The mechanism of this process is discussed. The Wittig-Horner-type coupling is a key reaction employed for the carbon-carbon bond formation. Generation of (E)-vinylsulfone moiety in the first coupling between alpha-sulfonyl anion and aldehyde functions is crucial for the effective second coupling to complete the cyclization. The syn-elimination of the (E)-vinylsulfone moieties in the cyclized intermediate furnishes the acetylenic bonds.