Synthesis and evaluation of ethyleneoxylated and allyloxylated chalcone derivatives for imaging of amyloid β plaques by SPECT

We report radioiodinated chalcone derivatives as new SPECT imaging probes for amyloid β (Aβ) plaques. The monoethyleneoxy derivative 2 and allyloxy derivative 8 showed a high affinity for Aβ(1-42) aggregates with Ki values of 24 and 4.5 nM, respectively. Fluorescent imaging demonstrated that 2 and 8 clearly stained thioflavin-S positive Aβ plaques in the brain sections of Tg2576 transgenic mice. In vitro autoradiography revealed that [125I]2 displayed no clear accumulation toward Aβ plaques in the brain sections of Tg2576 mice, whereas the accumulation pattern of [125I]8 matched with the presence of Aβ plaques both in the brain sections of Tg2576 mice and an AD patient. In biodistribution studies using normal mice, [125I]2 showed preferable in vivo pharmacokinetics (4.82%ID/g at 2 min and 0.45%ID/g at 60 min), while [125I]8 showed only a modest brain uptake (1.62%ID/g at 2 min) with slow clearance (0.56%ID/g at 60 min). [125I]8 showed prospective binding properties for Aβ plaques, although further structural modifications are needed to improve the blood brain barrier permeability and washout from brain

Effective intraperitoneal gene transfection system using nanobubbles and ultrasound irradiation

In this study, we demonstrate the low toxicity and highly efficient and spatially improvedtransfection of plasmid DNA (pDNA) with liposomal nanobubbles (bubble liposomes [BLs])using ultrasound (US) irradiation in mice. Naked pDNA with BLs was intraperitoneally injected, followed by US irradiation. The injection volume, the duration of US irradiation, and the dose of BLs were optimized. Both BLs and US irradiation were essential to achieve high transgeneexpression from naked pDNA. We observed transgene expression in the entire peritonealtissues, including the peritoneal wall, liver, spleen, stomach and small and large intestines. The area of transfection could be controlled with focused US irradiation. There were few changes in the morphology of the peritoneum, the peritoneal function or serum alanine aminotransferase levels, suggesting the safety of BLs with US irradiation. Using a tissue-clearing method, the spatial distribution of transgene expression was evaluated. BLs with US irradiation delivered pDNA to the submesothelial layer in the peritoneal wall, whereas transgene expression was restricted to the surface layer in the liver and stomach. Therefore, BLs with USirradiation could be an effective and safe method of gene transfection to the peritoneum

Characterization of transgene expression and pDNA distribution of the suctioned kidney in mice

We have previously developed an efficient and safe transfection method for the kidney in mice: renal suction-mediated transfection. In this study, we verified the detailed characteristics of transgene expression and plasmid DNA (pDNA) in mice to develop therapeutic strategies and application to gene function analysis in the kidney. After naked pDNA was administered intravenously, the right kidney was immediately suctioned by a tissue suction device. We examined the spatial distribution of transgene expression and pDNA in the suctioned kidney using tissue clearing by CUBIC, ClearT2, and Scale SQ reagents. Spatial distribution analysis showed that pDNA was transfected into extravascular cells and sufficiently delivered to the deep renal cortex. In addition, we revealed that transgene expression occurred mainly in peritubular fibroblasts of the suctioned kidney by tissue clearing and immunohistochemistry. Next, we confirmed the periods of pDNA uptake and activation of transcription factors nuclear factor-κB and activator protein 1 by luciferase assays. Moreover, the use of a pCpG-free plasmid enabled sustained transgene expression in the suctioned kidney. In conclusion, analyses of the spatial distribution and immunostaining of the section suggest that pDNA and transgene expression occurs mainly in peritubular fibroblasts of the suctioned kidney. In addition, we clarified some factors for efficient and/or sustained transgene expression in the suctioned kidney

Development of alkoxy styrylchromone derivatives for imaging of cerebral amyloid-β plaques with SPECT

Abstract We report here the development of radioiodinated styrylchromone derivatives with alkoxy groups as single photon emission computed tomography (SPECT) imaging probes for cerebral amyloid-β (Aβ) plaques. Among the derivatives, the methoxy derivative 14 and the dimethoxy derivative 15 displayed relatively high affinity for the Aβ(1-42) aggregates with Ki values of 22 and 46 nM, respectively. Fluorescent imaging demonstrated that 14 and 15 clearly labeled thioflavin-S positive Aβ plaques in the brain sections of Tg2576 transgenic mice. In the in vivo studies, [125I]14 and [125I]15 showed high initial brain uptake expressed as the percentage of the injected dose per gram (2.25% and 2.49% ID/g at 2 min, respectively) with favorable clearance (0.12% and 0.20% ID/g at 180 min, respectively) from the brain tissue of normal mice. Furthermore, in vitro autoradiography confirmed that [125I]15 binds thioflavin-S positive regions in Tg2576 mouse brain sections. The derivative 15 may be a potential scaffold for the development of in vivo imaging probes targeting Aβ plaques in the brain. In particular, further structural modifications are required to improve the compounds binding affinity for Aβ

Pharmacodynamic interactions between MDMA and concomitants in MDMA tablets on extracellular dopamine and serotonin in the rat brain.

3,4-methylenedioxymethamphetamine (MDMA) is a psychoactive stimulant abused by young people as the recreational drug ecstasy. Other compounds, either deliberately added or present as byproducts, are often found in MDMA tablets and can unexpectedly interact with each other. The aim of this study was to evaluate the pharmacodynamic effects of interactions caused by concomitants in MDMA tablets on extracellular dopamine and serotonin (5-HT) by microdialysis in the striatum of ethylcarbamate-anesthetized rats. Baseline levels of dopamine and 5-HT in the striatum were 16.5±7.7 and 3.5±1.7 nM (mean±standard deviation), respectively. After a single administration of MDMA (10 mg/kg, i.p.), a dramatic increase in extracellular dopamine (Cmax: 36.1-fold vs. baseline) and 5-HT levels (Cmax: 9.3-fold vs. baseline) was observed. When rats were co-administered with methamphetamine (1, 5 or 10 mg/kg) with MDMA, the dopamine levels induced by MDMA increased in a methamphetamine-dose-dependent manner (Cmax: 2.5-, 3.5-, and 3.8-fold vs. MDMA). A similar trend was observed in 5-HT levels (Cmax: 1.1-, 1.3-, and 1.8-fold vs. MDMA). In contrast, ketamine and caffeine showed synergistic effects on the monoamine levels induced by MDMA, whereas the individual administration of either of these compounds did not affect monoamine levels. Ketamine (1, 5 mg/kg) decreased the dopamine levels induced by MDMA (Cmax: 0.9- and 0.7-fold vs. MDMA) and increased the 5-HT levels induced by MDMA (Cmax: 1.4- and 1.6-fold vs. MDMA), and co-administration of caffeine (20 mg/kg) with MDMA increased dopamine levels (Cmax: 1.7-fold vs. MDMA). These results suggest that exposure to multiple drugs in addition to MDMA can have neurotoxic effects

Quantification of Greenhouse Gas Emissions from Wood-Plastic Recycled Composite (WPRC) and Verification of the Effect of Reducing Emissions through Multiple Recycling

Wood-plastic recycled composite (WPRC) is a building material that uses certain amounts of recycled wood and/or plastic materials contained in wood-plastic composites. They are characterized by multiple recycling processes in which products that become post-consumer materials are technically able to be recycled to produce WPRC products. However, there is no research case that quantifies the effect of reducing greenhouse gas (GHG) emissions for the feature of multiple recycling. In this study, we quantified GHG emissions during the life cycle of WPRC that was manufactured by companies certified to the Japanese Industrial Standard (JIS) A 5741, using the life cycle assessment method. The following conclusions were revealed in this study. (1) The GHG emission of the targeted WPRC was 3489 kg-CO2e/t, and the emission rates from the WPRC production process and the combustion of WPRC waste were found to be particularly high. (2) It was found that setting the recycled material rate of plastic materials to 100% would reduce GHG emissions by 28% (1316 kg-CO2e/t) compared to when the recycled material rate was 0%. (3) It was also found that GHG emissions can be reduced by up to about 28% by multiple recycling of WPRC. It can be said that this study set a benchmark of GHG emissions for WPRC produced in Japan

Peptide-Based Cancer-Targeted DDS and Molecular Imaging

argeting cancer cell-surface receptors is an attractive approach for cancer treatment and diagnosis. Peptides having high binding affinities to receptors overexpressed in cancer cells are useful because of their simple structure, low immunogenicity, and easy, cost-effective chemical synthesis. A number of peptide ligands have been developed for cancer cell-surface receptors and applied to nanoparticles with anticancer drugs, genes, small interfering RNAs (siRNAs), and molecular imaging agents. In particular, recent findings have revealed that peptide-modified PEGylated liposome-encapsulated drugs are effective in cancer-targeted therapy and cancer cell-specific imaging. This review discusses peptide-modified nanoparticles for drug delivery systems (DDS) and molecular imaging, focusing on peptide ligands for somatostatin receptors, integrin, transferrin receptor, human epidermal growth factor 2 (HER2), etc. In addition, methods to improve binding affinity or endosomal escape with spacer peptides and stimuli (internal and external) are discussed

地域における木材流通を再構築するための新たなシステムの検証と付加価値の創出

application/pdf地域産業の重要な構成要素である中小規模の製材工場とそこに原木を供給する生産者の間で構築される地域レベルでの流通を再構築するための合理的なシステムの検討と新たな付加価値の創出を行った。 木材の流通構造の調査では、林業・木材産業の関係事業者から収集したデータをもとにした分析により、林業事業者の収益構造および主に三重県、京都府を対象とした地域材の流通構造を解明した。 地域材利用の新たな付加価値として、温室効果ガス排出量の削減効果、地域への経済波及効果に関する分析を行い、それぞれ定量的な評価を行うことで優位性を明らかにした。Forestry companies and small and medium-sized sawmills are important components of the local industry. We examined a rational system for reconstructing the regional level timber distribution constructed between the two and created new added value. The study of the distribution structure of timber involved an analysis of data collected from businesses involved in the forestry and timber industry. The results elucidated the profit structure of forestry businesses and the distribution structure of regional timber mainly in Mie and Kyoto prefectures. As new added value of using local timber, we analyzed the effect of reducing greenhouse gas emissions and the economic ripple effect on the region. The superiority of each was clarified through quantitative evaluation.2018年度～2021年度科学研究費補助金(若手研究)研究成果報告書18K1450