Gene transfer of high-mobility group box 1 box-A domain in a rat acute liver failure model

Masayuki Tanaka, Masahiro Shinoda, Atsushi Takayanagi, Go Oshima, Ryo Nishiyama, Kazumasa Fukuda, Hiroshi Yagi, Tetsu Hayashida, Yohei Masugi, Koichi Suda, Shingo Yamada, Taku Miyasho, Taizo Hibi, Yuta Abe, Minoru Kitago, Hideaki Obara, Osamu Itano, Hiroya Takeuchi, Michiie Sakamoto, Minoru TanabeIkuro Maruyama, Yuukou Kitagawa

研究成果: Article

4 引用 (Scopus)

抄録

Background High-mobility group box 1 (HMGB1) has recently been identified as an important mediator of various kinds of acute and chronic inflammation. The protein encoded by the box-A domain of the HMGB1 gene is known to act as a competitive inhibitor of HMGB1. In this study, we investigated whether box-A gene transfer results in box-A protein production in rats and assessed therapeutic efficacy in vivo using an acute liver failure (ALF) model. Materials and methods Three types of adenovirus vectors were constructed-a wild type and two mutants-and a mutant vector was then selected based on the secretion from HeLa cells. The secreted protein was subjected to a tumor necrosis factor (TNF) production inhibition test in vitro. The vector was injected via the portal vein in healthy Wistar rats to confirm box-A protein production in the liver. The vector was then injected via the portal vein in rats with ALF. Results Western blot analysis showed enhanced expression of box-A protein in HeLa cells transfected with one of the mutant vectors. The culture supernatant from HeLa cells transfected with the vector inhibited TNF-α production from macrophages. Expression of box-A protein was confirmed in the transfected liver at 72 h after transfection. Transfected rats showed decreased hepatic enzymes, plasma HMGB1, and hepatic TNF-α messenger RNA levels, and histologic findings and survival were significantly improved. Conclusions HMGB1 box-A gene transfer results in box-A protein production in the liver and appears to have a beneficial effect on ALF in rats.

元の言語English
ページ(範囲)571-580
ページ数10
ジャーナルJournal of Surgical Research
194
発行部数2
DOI
出版物ステータスPublished - 2015 4 1

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Acute Liver Failure
Genes
HeLa Cells
Proteins
Liver
Tumor Necrosis Factor-alpha
Portal Vein
HMG-Box Domains
Adenoviridae
Transfection
Wistar Rats
Western Blotting
Macrophages
Inflammation
Messenger RNA
Enzymes

ASJC Scopus subject areas

  • Surgery

これを引用

Gene transfer of high-mobility group box 1 box-A domain in a rat acute liver failure model. / Tanaka, Masayuki; Shinoda, Masahiro; Takayanagi, Atsushi; Oshima, Go; Nishiyama, Ryo; Fukuda, Kazumasa; Yagi, Hiroshi; Hayashida, Tetsu; Masugi, Yohei; Suda, Koichi; Yamada, Shingo; Miyasho, Taku; Hibi, Taizo; Abe, Yuta; Kitago, Minoru; Obara, Hideaki; Itano, Osamu; Takeuchi, Hiroya; Sakamoto, Michiie; Tanabe, Minoru; Maruyama, Ikuro; Kitagawa, Yuukou.

:: Journal of Surgical Research, 巻 194, 番号 2, 01.04.2015, p. 571-580.

研究成果: Article

Tanaka, M, Shinoda, M, Takayanagi, A, Oshima, G, Nishiyama, R, Fukuda, K, Yagi, H, Hayashida, T, Masugi, Y, Suda, K, Yamada, S, Miyasho, T, Hibi, T, Abe, Y, Kitago, M, Obara, H, Itano, O, Takeuchi, H, Sakamoto, M, Tanabe, M, Maruyama, I & Kitagawa, Y 2015, 'Gene transfer of high-mobility group box 1 box-A domain in a rat acute liver failure model', Journal of Surgical Research, 巻. 194, 番号 2, pp. 571-580. https://doi.org/10.1016/j.jss.2014.11.022
Tanaka, Masayuki ; Shinoda, Masahiro ; Takayanagi, Atsushi ; Oshima, Go ; Nishiyama, Ryo ; Fukuda, Kazumasa ; Yagi, Hiroshi ; Hayashida, Tetsu ; Masugi, Yohei ; Suda, Koichi ; Yamada, Shingo ; Miyasho, Taku ; Hibi, Taizo ; Abe, Yuta ; Kitago, Minoru ; Obara, Hideaki ; Itano, Osamu ; Takeuchi, Hiroya ; Sakamoto, Michiie ; Tanabe, Minoru ; Maruyama, Ikuro ; Kitagawa, Yuukou. / Gene transfer of high-mobility group box 1 box-A domain in a rat acute liver failure model. :: Journal of Surgical Research. 2015 ; 巻 194, 番号 2. pp. 571-580.
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title = "Gene transfer of high-mobility group box 1 box-A domain in a rat acute liver failure model",
abstract = "Background High-mobility group box 1 (HMGB1) has recently been identified as an important mediator of various kinds of acute and chronic inflammation. The protein encoded by the box-A domain of the HMGB1 gene is known to act as a competitive inhibitor of HMGB1. In this study, we investigated whether box-A gene transfer results in box-A protein production in rats and assessed therapeutic efficacy in vivo using an acute liver failure (ALF) model. Materials and methods Three types of adenovirus vectors were constructed-a wild type and two mutants-and a mutant vector was then selected based on the secretion from HeLa cells. The secreted protein was subjected to a tumor necrosis factor (TNF) production inhibition test in vitro. The vector was injected via the portal vein in healthy Wistar rats to confirm box-A protein production in the liver. The vector was then injected via the portal vein in rats with ALF. Results Western blot analysis showed enhanced expression of box-A protein in HeLa cells transfected with one of the mutant vectors. The culture supernatant from HeLa cells transfected with the vector inhibited TNF-α production from macrophages. Expression of box-A protein was confirmed in the transfected liver at 72 h after transfection. Transfected rats showed decreased hepatic enzymes, plasma HMGB1, and hepatic TNF-α messenger RNA levels, and histologic findings and survival were significantly improved. Conclusions HMGB1 box-A gene transfer results in box-A protein production in the liver and appears to have a beneficial effect on ALF in rats.",
keywords = "Acute liver failure, Adenovirus vectors, Box-A, Gene delivery, High-mobility group box 1",
author = "Masayuki Tanaka and Masahiro Shinoda and Atsushi Takayanagi and Go Oshima and Ryo Nishiyama and Kazumasa Fukuda and Hiroshi Yagi and Tetsu Hayashida and Yohei Masugi and Koichi Suda and Shingo Yamada and Taku Miyasho and Taizo Hibi and Yuta Abe and Minoru Kitago and Hideaki Obara and Osamu Itano and Hiroya Takeuchi and Michiie Sakamoto and Minoru Tanabe and Ikuro Maruyama and Yuukou Kitagawa",
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T1 - Gene transfer of high-mobility group box 1 box-A domain in a rat acute liver failure model

AU - Tanaka, Masayuki

AU - Shinoda, Masahiro

AU - Takayanagi, Atsushi

AU - Oshima, Go

AU - Nishiyama, Ryo

AU - Fukuda, Kazumasa

AU - Yagi, Hiroshi

AU - Hayashida, Tetsu

AU - Masugi, Yohei

AU - Suda, Koichi

AU - Yamada, Shingo

AU - Miyasho, Taku

AU - Hibi, Taizo

AU - Abe, Yuta

AU - Kitago, Minoru

AU - Obara, Hideaki

AU - Itano, Osamu

AU - Takeuchi, Hiroya

AU - Sakamoto, Michiie

AU - Tanabe, Minoru

AU - Maruyama, Ikuro

AU - Kitagawa, Yuukou

PY - 2015/4/1

Y1 - 2015/4/1

N2 - Background High-mobility group box 1 (HMGB1) has recently been identified as an important mediator of various kinds of acute and chronic inflammation. The protein encoded by the box-A domain of the HMGB1 gene is known to act as a competitive inhibitor of HMGB1. In this study, we investigated whether box-A gene transfer results in box-A protein production in rats and assessed therapeutic efficacy in vivo using an acute liver failure (ALF) model. Materials and methods Three types of adenovirus vectors were constructed-a wild type and two mutants-and a mutant vector was then selected based on the secretion from HeLa cells. The secreted protein was subjected to a tumor necrosis factor (TNF) production inhibition test in vitro. The vector was injected via the portal vein in healthy Wistar rats to confirm box-A protein production in the liver. The vector was then injected via the portal vein in rats with ALF. Results Western blot analysis showed enhanced expression of box-A protein in HeLa cells transfected with one of the mutant vectors. The culture supernatant from HeLa cells transfected with the vector inhibited TNF-α production from macrophages. Expression of box-A protein was confirmed in the transfected liver at 72 h after transfection. Transfected rats showed decreased hepatic enzymes, plasma HMGB1, and hepatic TNF-α messenger RNA levels, and histologic findings and survival were significantly improved. Conclusions HMGB1 box-A gene transfer results in box-A protein production in the liver and appears to have a beneficial effect on ALF in rats.

AB - Background High-mobility group box 1 (HMGB1) has recently been identified as an important mediator of various kinds of acute and chronic inflammation. The protein encoded by the box-A domain of the HMGB1 gene is known to act as a competitive inhibitor of HMGB1. In this study, we investigated whether box-A gene transfer results in box-A protein production in rats and assessed therapeutic efficacy in vivo using an acute liver failure (ALF) model. Materials and methods Three types of adenovirus vectors were constructed-a wild type and two mutants-and a mutant vector was then selected based on the secretion from HeLa cells. The secreted protein was subjected to a tumor necrosis factor (TNF) production inhibition test in vitro. The vector was injected via the portal vein in healthy Wistar rats to confirm box-A protein production in the liver. The vector was then injected via the portal vein in rats with ALF. Results Western blot analysis showed enhanced expression of box-A protein in HeLa cells transfected with one of the mutant vectors. The culture supernatant from HeLa cells transfected with the vector inhibited TNF-α production from macrophages. Expression of box-A protein was confirmed in the transfected liver at 72 h after transfection. Transfected rats showed decreased hepatic enzymes, plasma HMGB1, and hepatic TNF-α messenger RNA levels, and histologic findings and survival were significantly improved. Conclusions HMGB1 box-A gene transfer results in box-A protein production in the liver and appears to have a beneficial effect on ALF in rats.

KW - Acute liver failure

KW - Adenovirus vectors

KW - Box-A

KW - Gene delivery

KW - High-mobility group box 1

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