Membrane Incorporation, Channel Formation, and Disruption of Calcium Homeostasis by Alzheimer's β-Amyloid Protein

Oligomerization, conformational changes, and the consequent neurodegeneration of Alzheimer's β-amyloid protein (AβP) play crucial roles in the pathogenesis of Alzheimer's disease (AD). Mounting evidence suggests that oligomeric AβPs cause the disruption of calcium homeostasis, eventually leading to neuronal death. We have demonstrated that oligomeric AβPs directly incorporate into neuronal membranes, form cation-sensitive ion channels (“amyloid channels”), and cause the disruption of calcium homeostasis via the amyloid channels. Other disease-related amyloidogenic proteins, such as prion protein in prion diseases or α-synuclein in dementia with Lewy bodies, exhibit similarities in the incorporation into membranes and the formation of calcium-permeable channels. Here, based on our experimental results and those of numerous other studies, we review the current understanding of the direct binding of AβP into membrane surfaces and the formation of calcium-permeable channels. The implication of composition of membrane lipids and the possible development of new drugs by influencing membrane properties and attenuating amyloid channels for the treatment and prevention of AD is also discussed

Apigeninの抗酸化活性に及ぼす配糖体の影響

The antioxidant effects of apigenin without glycoside (APG), apigenin 7-glucoside (APG-Glu) and apigenin 7-gentiobioside (APG-Glu-Glu) on phosphatidylcholine peroxidation were investigated using atomic force microscopy (AFM), and the effects of glycosides on the antioxidant activities of APG were discussed. The Langmuir-Blodgett film of 1-palmitoyl-2-linoleoyl-3-phosphatidylcholine (PLPC) was used as a model biological membrane for AFM. The AFM images clearly indicated that APG glycosides inhibited PLPC peroxidation and that the APG glycoside had a more potent antioxidant effect than APG without glycoside. It is suggested that the antioxidant effect on lipid peroxidation depends on the distribution and orientation of the antioxidant in the lipid membrane

Synthesis and In Vitro Assessment of pH-Sensitive Human Serum Albumin Conjugates of Pirarubicin

In a previous study, we reported on the development of a synthetic polymer conjugate of pirarubicin (THP) that was formed via an acid-labile hydrazone bond between the polymer and the THP. However, the synthetic polymer itself was non-biodegradable, which could lead to unexpected adverse effects. Human serum albumin (HSA), which has a high biocompatibility and good biodegradability, is also a potent carrier for delivering antitumor drugs. The objective of this study was to develop pH-sensitive HSA conjugates of THP (HSA-THP), and investigate the release of THP and the cytotoxicity under acidic conditions in vitro for further clinical development. HSA-THP was synthesized by conjugating maleimide hydrazone derivatives of THP with poly-thiolated HSA using 2-iminothiolane, via a thiol-maleimide coupling reaction. We synthesized two types of HSA-THP that contained different amounts of THP (HSA-THP2 and HSA-THP4). Free THP was released from both of the HSA conjugates more rapidly at an acidic pH, and the rates of release for HSA-THP2 and HSA-THP4 were similar. Moreover, both HSA-THPs exhibited a higher cytotoxicity at acidic pH than at neutral pH, which is consistent with the effective liberation of free THP under acidic conditions. These findings suggest that these types of HSA-THPs are promising candidates for further development

Promoter-Level Transcriptome Identifies Stemness Associated With Relatively High Proliferation in Pancreatic Cancer Cells

Both pancreatic intraepithelial neoplasia (PanIN), a frequent precursor of pancreatic cancer, and intraductal papillary mucinous neoplasm (IPMN), a less common precursor, undergo several phases of molecular conversions and finally develop into highly malignant solid tumors with negative effects on the quality of life. We approached this long-standing issue by examining the following PanIN/IPMN cell lines derived from mouse models of pancreatic cancer: Ptf1a-Cre; KrasG12D; p53f/+ and Ptf1a-Cre; KrasG12D; and Brg1f/f pancreatic ductal adenocarcinomas (PDAs). The mRNA from these cells was subjected to a cap analysis of gene expression (CAGE) to map the transcription starting sites and quantify the expression of promoters across the genome. Two RNA samples extracted from three individual subcutaneous tumors generated by the transplantation of PanIN or IPMN cancer cell lines were used to generate libraries and Illumina Seq, with four RNA samples in total, to depict discrete transcriptional network between IPMN and PanIN. Moreover, in IPMN cells, the transcriptome tended to be enriched for suppressive and inhibitory biological processes. In contrast, the transcriptome of PanIN cells exhibited properties of stemness. Notably, the proliferation capacity of the latter cells in culture was only minimally constrained by well-known chemotherapy drugs such as GSK690693 and gemcitabine. The various transcriptional factor network systems detected in PanIN and IPMN cells reflect the distinct molecular profiles of these cell types. Further, we hope that these findings will enhance our mechanistic understanding of the characteristic molecular alterations underlying pancreatic cancer precursors. These data may provide a promising direction for therapeutic research

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研究報

プロポリス由来Caffeic acid phenethyl esterのガングリオシドGD₃単分子膜への分布と作用

The distribution of caffeic acid phenethyl ester (CAPE) isolated from propolis in ganglioside GD₃ (GD₃) monolayer as a model membrane of tumor, and the effect of CAPE on GD₃ were observed by atomic force microscopy (AFM). CAPE distributed in the GD₃ monolayer markedly changed the morphology of GD₃ monolayer from a flat pattern to a percolation pattern. The effect of CAPE on the GD₃ membrane was similar to that of known antitumor compounds, suggesting that CAPE may possess antitumor activities

ネパール産プロポリスの成分研究

Propolis, a complex resinous material collected by honeybees from buds and exudates of certain plant sources neighboring its hive, is considered to possess broad spectrum of biological activities and has historical utilization in folk medicine. Thus, it is extensively being used in health food, pharmaceutical preparations etc. The chemical consistency of propolis is highly dependent on the flora of the region from where it is collected. In this study, we investigated propolis from different geographical locations in Nepal and isolated several known compounds. As a result, we clarified the origins of propolis in Nepal

プロポリス成分カフェ酸エステル類がガングリオシドGD3 単分子膜に及ぼす影響

The distribution of benzyl caffeate (BC), cinnamyl caffeate (CC) and phenethyl caffeate (PC) isolated from propolis in ganglioside GD3 (GD3) monolayer as a model of a tumor membrane, and their effects of the caffeic acid esters on the GD3 monolayer were observed by atomic force microscopy (AFM). BC and PC distributed in the GD3 monolayer markedly changed the morphology of the GD3 monolayer from a flat surface to a percolated pattern, whereas CC distributed in the GD3 monolayer exhibited a broken percolation pattern. The effects of BC and PC on the GD3 membrane were similar to those of known antitumor compounds, suggesting that BC and PC may possess antitumor activity. The activity of CC seems to be weaker than that of BC and PC

リン脂質/ガングリオシドG[D]₃混合単分子膜中へのカフェ酸エステル類の分布と作用

The distribution of benzyl caffeate (BC), cinnamyl caffeate (CC) and phenethyl caffeate (PC) isolatedfrom propolis in mixed dipalmitoylphosphatidylcholine (DPPC)/ganglioside GD3 (GD3) monolayer as amodel of a tumor membrane, and the effects of the caffeic acid esters on the mixed DPPC/GD3monolayer were observed by atomic force microscopy (AFM). BC distributed in the mixed DPPC/GD3monolayer formed a clear percolation pattern. The effect of BC on the mixed DPPC/GD3 membranewas similar to those of known antitumor compounds, suggesting that BC might possess antitumoractivity. The effect of PC on the mixed monolayer seems to be weaker than that of BC; however, onGD3 alone monolayer, the effect was similar to that of BC. It was suggested that the molecular size ofthe caffeic acid esters affected their activity on the mixed DPPC/GD3 monolayer

ガングリオシドG[D3](GD3)単分子膜およびリン脂質/GD3混合単分子膜中へのカフェ酸の分布と作用

The distribution of caffeic acid (CA) in ganglioside GD3 (GD3) monolayer and in mixeddipalmitoylphosphatidylcholine (DPPC)/GD3 monolayer as models of tumor membrane, and the effects ofCA on the GD3 monolayer and the mixed DPPC/GD3 monolayer were observed by atomic forcemicroscopy (AFM). CA distributed in the GD3 monolayer markedly changed the morphology of the GD3monolayer from a flat and uniform surface to a percolated pattern. Furthermore, CA distributed in themixed DPPC/GD3 monolayer clearly changed the morphology of the mixed DPPC/GD3 monolayer froman unclear percolated surface to a typical percolation pattern. The effects of CA on the GD3 membraneand the mixed DPPC/GD3 membrane were similar to those of benzyl caffeate and known antitumorcompounds, suggesting that CA might possess antitumor activity