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  1. Article ; Online: Development of p62-Keap1 protein–protein interaction inhibitors as doxorubicin-sensitizers against non-small cell lung cancer

    Daisuke Yasuda / Ippei Yoshida / Riyo Imamura / Daiki Katagishi / Kyoko Takahashi / Hirotatsu Kojima / Takayoshi Okabe / Yoshinobu Ichimura / Masaaki Komatsu / Tadahiko Mashino / Tomoyuki Ohe

    Results in Chemistry, Vol 4, Iss , Pp 100609- (2022)

    2022  

    Abstract: Aberrant hyperactivation of nuclear factor erythroid 2-related factor 2 (Nrf2) has been reported in non-small cell lung cancer through overexpression of the p62/sequestosome1 protein, resulting in the acquisition of malignancy and drug resistance. We ... ...

    Abstract Aberrant hyperactivation of nuclear factor erythroid 2-related factor 2 (Nrf2) has been reported in non-small cell lung cancer through overexpression of the p62/sequestosome1 protein, resulting in the acquisition of malignancy and drug resistance. We previously discovered compounds termed K67 and KOA153 that overcome chemotherapy resistance in human hepatocellular carcinoma cell lines by inhibiting the protein–protein interactions between p62 and Kelch-like ECH-associated protein 1 (Keap1), an Nrf2 suppressor. Herein, we synthesized analogs of K67 and KOA153 and investigated their potential as doxorubicin sensitizers against a human non-small cell lung cancer A549 cell line that is addicted to Nrf2 via overexpression of p62. KOA153 and the newly synthesized amide compounds exhibited significant doxorubicin-sensitizing activity without cytotoxicity. In addition, dimethylamide derivatives activated Nrf2 in HEK293 cells expressing normal levels of p62. Therefore, dimethylamide derivatives are likely novel type of anticancer agents.
    Keywords Nrf2 ; Keap1 ; p62 ; Doxorubicin ; NSCLC ; Chemistry ; QD1-999
    Language English
    Publishing date 2022-01-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Molecular action of larvicidal flavonoids on ecdysteroidogenic glutathione S-transferase Noppera-bo in Aedes aegypti

    Kazue Inaba / Kana Ebihara / Miki Senda / Ryunosuke Yoshino / Chisako Sakuma / Kotaro Koiwai / Daisuke Takaya / Chiduru Watanabe / Akira Watanabe / Yusuke Kawashima / Kaori Fukuzawa / Riyo Imamura / Hirotatsu Kojima / Takayoshi Okabe / Nozomi Uemura / Shinji Kasai / Hirotaka Kanuka / Takashi Nishimura / Kodai Watanabe /
    Hideshi Inoue / Yuuta Fujikawa / Teruki Honma / Takatsugu Hirokawa / Toshiya Senda / Ryusuke Niwa

    BMC Biology, Vol 20, Iss 1, Pp 1-

    2022  Volume 20

    Abstract: Abstract Background Mosquito control is a crucial global issue for protecting the human community from mosquito-borne diseases. There is an urgent need for the development of selective and safe reagents for mosquito control. Flavonoids, a group of ... ...

    Abstract Abstract Background Mosquito control is a crucial global issue for protecting the human community from mosquito-borne diseases. There is an urgent need for the development of selective and safe reagents for mosquito control. Flavonoids, a group of chemical substances with variable phenolic structures, such as daidzein, have been suggested as potential mosquito larvicides with less risk to the environment. However, the mode of mosquito larvicidal action of flavonoids has not been elucidated. Results Here, we report that several flavonoids, including daidzein, inhibit the activity of glutathione S-transferase Noppera-bo (Nobo), an enzyme used for the biosynthesis of the insect steroid hormone ecdysone, in the yellow fever mosquito Aedes aegypti. The crystal structure of the Nobo protein of Ae. aegypti (AeNobo) complexed with the flavonoids and its molecular dynamics simulation revealed that Glu113 forms a hydrogen bond with the flavonoid inhibitors. Consistent with this observation, substitution of Glu113 with Ala drastically reduced the inhibitory activity of the flavonoids against AeNobo. Among the identified flavonoid-type inhibitors, desmethylglycitein (4′,6,7-trihydroxyisoflavone) exhibited the highest inhibitory activity in vitro. Moreover, the inhibitory activities of the flavonoids correlated with the larvicidal activity, as desmethylglycitein suppressed Ae. aegypti larval development more efficiently than daidzein. Conclusion Our study demonstrates the mode of action of flavonoids on the Ae. aegypti Nobo protein at the atomic, enzymatic, and organismal levels.
    Keywords Aedes aegypti ; Ecdysone ; Ecdysteroid ; Flavonoid ; Glutathione S-transferase ; Insect growth regulator ; Biology (General) ; QH301-705.5
    Subject code 500
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming

    Tetsuya Saito / Yoshinobu Ichimura / Keiko Taguchi / Takafumi Suzuki / Tsunehiro Mizushima / Kenji Takagi / Yuki Hirose / Masayuki Nagahashi / Tetsuro Iso / Toshiaki Fukutomi / Maki Ohishi / Keiko Endo / Takefumi Uemura / Yasumasa Nishito / Shujiro Okuda / Miki Obata / Tsuguka Kouno / Riyo Imamura / Yukio Tada /
    Rika Obata / Daisuke Yasuda / Kyoko Takahashi / Tsutomu Fujimura / Jingbo Pi / Myung-Shik Lee / Takashi Ueno / Tomoyuki Ohe / Tadahiko Mashino / Toshifumi Wakai / Hirotatsu Kojima / Takayoshi Okabe / Tetsuo Nagano / Hozumi Motohashi / Satoshi Waguri / Tomoyoshi Soga / Masayuki Yamamoto / Keiji Tanaka / Masaaki Komatsu

    Nature Communications, Vol 7, Iss 1, Pp 1-

    2016  Volume 16

    Abstract: Dysregulation of p62 has been implicated in tumorigenesis. Here, the authors show that p62 promotes hepatocellular carcinoma by reprogramming glucose and glutamine metabolism through Nrf2 and present a novel compound that can inhibit p62 action thus ... ...

    Abstract Dysregulation of p62 has been implicated in tumorigenesis. Here, the authors show that p62 promotes hepatocellular carcinoma by reprogramming glucose and glutamine metabolism through Nrf2 and present a novel compound that can inhibit p62 action thus sensitizing cancer cells to chemotherapy.
    Keywords Science ; Q
    Language English
    Publishing date 2016-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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