Miki Takahashi

PHOTOCHEMICAL CYCLOAROMATIZATION OF NON-BENZENOID ENEDIYNES

An efficient photo-Bergman reaction of aliphatic enediynes has been realized. Photolysis of 1 results in the formation of 4 in good yields along with [D2 ]3. Enediyne 4, which has never been isolated in the thermal reaction of 1, arises here by a retro-Bergman reaction of the diradical intermediate 2.

Benzannelation alters the rate limiting step in enediyne cycloaromatization

Abstract The rate-limiting step in the Bergman reaction was changed from cyclization to hydrogen-abstraction by benzannelation. This effect should be attributed to the faster rate of the retro-Bergman cyclization and/or the slower rate of hydrogen abstraction by the aromatic ring condensed 1,4-didehydrobenzene intermediate.

Post-Translational Modifications of the TAK1-TAB Complex

Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) is a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family that is activated by growth factors and cytokines such as TGF-β, IL-1β, and TNF-α, and mediates a wide range of biological processes through activation of the nuclear factor-κB (NF-κB) and the mitogen-activated protein (MAP) kinase signaling pathways. It is well established that activation status of TAK1 is tightly regulated by forming a complex with its binding partners, TAK1-binding proteins (TAB1, TAB2, and TAB3). Interestingly, recent evidence indicates the importance of post-translational modifications (PTMs) of TAK1 and TABs in the regulation of TAK1 activation. To date, a number of PTMs of TAK1 and TABs have been revealed, and these PTMs appear to fine-tune and coordinate TAK1 activities depending on the cellular context. This review therefore focuses on recent advances in the understanding of the PTMs of the TAK1-TAB complex.

The sections’ fractal dimension of grain boundary

Abstract The fractal dimensional increment of the experimentally dynamic recrystallized grain boundary is proportional to logarithm of Zener–Hollomon parameter. The fractal dimensional increment is defined as the fractal dimension of the grain shape minus the Euclidean dimension of certain transection. To draw the geometrical image of the fractal dimensional increment, the basic rule of the sections’ fractal dimension is introduced. The geometrical implication of the fractal dimensional increment is concluded as the fractal dimension of the crossing point distribution on the grain boundary transected by the circumscribing circle or ellipse with the equivalent-area of the grain, and a power law relationship between the Zener–Hollomon parameter and the number of crossing points is found. Therefore, summarizing power laws among the Zener–Hollomon parameter, the differential stress and the number of the crossing points on the grain boundary, the number of crossing points could respond to the differential stress.

FRACTAL GRAIN BOUNDARY MIGRATION

Fractal analysis on experimentally recrystallized quartz grain boundaries has been employed to relate the grain boundary complexities with deformation conditions, such as strain rate and temperature. The fractal dimensional increment of the grain boundaries, defined as (D-1), and the degree of irregularity in grain boundaries, is proportional to the logarithmic of the Zener–Hollomon parameter that is defined by strain rate and temperature (the Arrhenius term). The physical mean of the empirical relationship can be explained theoretically by a new grain boundary migration model (GBM or cell dynamics model) extended by the fractal concepts and the dimension analysis. This is a more general model than the migration growth model for the fractal grain boundaries.

Trans-fatty acids promote proinflammatory signaling and cell death by stimulating the apoptosis signal-regulating kinase 1 (ASK1)-p38 pathway

Food-borne trans-fatty acids (TFAs) are mainly produced as byproducts during food manufacture. Recent epidemiological studies have revealed that TFA consumption is a major risk factor for various disorders, including atherosclerosis. However, the underlying mechanisms in this disease etiology are largely unknown. Here we have shown that TFAs potentiate activation of apoptosis signal-regulating kinase 1 (ASK1) induced by extracellular ATP, a damage-associated molecular pattern leaked from injured cells. Major food-associated TFAs such as elaidic acid (EA), linoelaidic acid, and trans-vaccenic acid, but not their corresponding cis isomers, dramatically enhanced extracellular ATP-induced apoptosis, accompanied by elevated activation of the ASK1-p38 pathway in a macrophage-like cell line, RAW264.7. Moreover, knocking out the ASK1-encoding gene abolished EA-mediated enhancement of apoptosis. We have reported previously that extracellular ATP induces apoptosis through the ASK1-p38 pathway activated by reactive oxygen species generated downstream of the P2X purinoceptor 7 (P2X7). However, here we show that EA did not increase ATP-induced reactive oxygen species generation but, rather, augmented the effects of calcium/calmodulin-dependent kinase II-dependent ASK1 activation. These results demonstrate that TFAs promote extracellular ATP-induced apoptosis by targeting ASK1 and indicate novel TFA-associated pathways leading to inflammatory signal transduction and cell death that underlie the pathogenesis and progression of TFA-induced atherosclerosis. Our study thus provides insight into the pathogenic mechanisms of and proposes potential therapeutic targets for these TFA-related disorders.

Role of YAP Activation in Nuclear Receptor CAR-Mediated Proliferation of Mouse Hepatocytes

Constitutive androstane receptor (CAR) is a xenobiotic-responsive nuclear receptor that is highly expressed in the liver. CAR activation induces hepatocyte proliferation and hepatocarcinogenesis in rodents, but the mechanisms remain unclear. In this study, we investigated the association of CAR-dependent cell proliferation with Yes-associated protein (YAP), which is a transcriptional cofactor controlling organ size and cell growth through the interaction with various transcriptional factors including TEA domain family member (TEAD). In mouse livers, 1,4-bis-(2-[3,5-dichloropyridyloxy])benzene (TCPOBOP) (a mouse CAR [mCAR] activator) treatment increased the nuclear YAP accumulation and mRNA levels of YAP target genes as well as cell-cycle related genes along with liver hypertrophy and verteporfin (an inhibitor of YAP/TEAD interaction) cotreatment tended to attenuate them. Furthermore, in cell-based reporter gene assays, CAR activation enhanced the YAP/TEAD-dependent transcription. To investigate the role of YAP/TEAD activation in the CAR-dependent hepatocyte proliferation, we sought to establish an in vitro system completely reproducing CAR-dependent cell proliferation. Since CAR was only slightly expressed in cultured mouse primary hepatocytes compared with mouse livers and no proliferation was observed after treatment with TCPOBOP, we overexpressed CAR using mCAR expressing adenovirus (Ad-mCAR-V5) in mouse primary hepatocytes. Ad-mCAR-V5 infection and TCPOBOP treatment induced hepatocyte proliferation. Similar results were obtained with immortalized normal mouse hepatocytes as well. In the established in vitro system, CAR-dependent proliferation was strongly inhibited by Yap knockdown and completely abolished by verteporfin treatment. Our present results obtained in in vivo and in vitro experiments suggest that YAP/TEAD activation plays key roles in CAR-dependent proliferation of murine hepatocytes.