Polythiol-containing, recombinant mannosylated-albumin is a superior CD68+/CD206+ Kupffer cell-targeted nanoantioxidant for treatment of two acute hepatitis models

Hitoshi Maeda, Kenshiro Hirata, Hiroshi Watanabe, Yu Ishima, Victor Tuan Giam Chuang, Kazuaki Taguchi, Akihito Inatsu, Manabu Kinoshita, Motohiko Tanaka, Yutaka Sasaki, Masaki Otagiri, Toru Maruyama

Research output: Contribution to journalArticle

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Abstract

Since reactive oxygen species (ROS) derived from Kupffer cells (KC), especially CD68+ KC, play a key role in the induction of hepatic oxidative stress and injuries, we developed a polythiolatedand mannosylated human serum albumin (SH-Man-HSA), which functions as a novel nanoantioxidant for delivering thiol to CD68+ KC. In vitro electron paramagnetic resonance coupled with pharmacokinetics and immunohistochemical studies showed that SH-Man-HSA possessed powerful radical-scavenging activity and rapidly and selectively delivered thiols to the liver via mannose receptor (CD206) on CD68+ cells. SH-Man-HSA significantly improved the survival rate of concanavalin-A (Con-A)-treated mice. Moreover, SH-Man-HSA exhibited excellent hepatoprotective functions, not by decreasing tumor necrosis factor or interferon-γ production that is closely associated with Con-A-induced hepatitis, but by suppressing ROS production. Interestingly, the protective effect of SH-Man-HSA was superior to N-acetyl cysteine (NAC). This could be attributed to the difference in the inhibition of hepatic oxidative stress between the two antioxidants depending on their potential for thiol delivery to the liver. Similar results were also observed for acetaminophen (APAP)-induced hepatopathy models. Flow cytometric data further confirmed that an increase in F4/ 80+/ROS+ cells was dramatically decreased by SH-Man-HSA. The administration of SH-Man-HSA at 4 hours following a Con-A or APAP injection also exhibited a profound hepatoprotective action against these hepatitis models, whereas this was not observed for NAC. It can be concluded therefore that SH-Man-HSA has great potential for use in a rescue therapy for hepatopathy as a nanoantioxidant because of its ability to efficiently and rapidly deliver thiols to CD68+/CD206+ KC.

Original languageEnglish
Article numberA7
Pages (from-to)244-257
Number of pages14
JournalJournal of Pharmacology and Experimental Therapeutics
Volume352
Issue number2
DOIs
Publication statusPublished - 2015 Jan 1
Externally publishedYes

Fingerprint

Kupffer Cells
Hepatitis
Albumins
Sulfhydryl Compounds
Acetaminophen
Concanavalin A
Reactive Oxygen Species
Liver
Therapeutics
Cysteine
Oxidative Stress
mannose-bovine serum albumin conjugate
Electron Spin Resonance Spectroscopy
Serum Albumin
Interferons
Pharmacokinetics
Tumor Necrosis Factor-alpha
Antioxidants
Injections
Wounds and Injuries

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Polythiol-containing, recombinant mannosylated-albumin is a superior CD68+/CD206+ Kupffer cell-targeted nanoantioxidant for treatment of two acute hepatitis models. / Maeda, Hitoshi; Hirata, Kenshiro; Watanabe, Hiroshi; Ishima, Yu; Chuang, Victor Tuan Giam; Taguchi, Kazuaki; Inatsu, Akihito; Kinoshita, Manabu; Tanaka, Motohiko; Sasaki, Yutaka; Otagiri, Masaki; Maruyama, Toru.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 352, No. 2, A7, 01.01.2015, p. 244-257.

Research output: Contribution to journalArticle

Maeda, H, Hirata, K, Watanabe, H, Ishima, Y, Chuang, VTG, Taguchi, K, Inatsu, A, Kinoshita, M, Tanaka, M, Sasaki, Y, Otagiri, M & Maruyama, T 2015, 'Polythiol-containing, recombinant mannosylated-albumin is a superior CD68+/CD206+ Kupffer cell-targeted nanoantioxidant for treatment of two acute hepatitis models', Journal of Pharmacology and Experimental Therapeutics, vol. 352, no. 2, A7, pp. 244-257. https://doi.org/10.1124/jpet.114.219493
Maeda, Hitoshi ; Hirata, Kenshiro ; Watanabe, Hiroshi ; Ishima, Yu ; Chuang, Victor Tuan Giam ; Taguchi, Kazuaki ; Inatsu, Akihito ; Kinoshita, Manabu ; Tanaka, Motohiko ; Sasaki, Yutaka ; Otagiri, Masaki ; Maruyama, Toru. / Polythiol-containing, recombinant mannosylated-albumin is a superior CD68+/CD206+ Kupffer cell-targeted nanoantioxidant for treatment of two acute hepatitis models. In: Journal of Pharmacology and Experimental Therapeutics. 2015 ; Vol. 352, No. 2. pp. 244-257.
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abstract = "Since reactive oxygen species (ROS) derived from Kupffer cells (KC), especially CD68+ KC, play a key role in the induction of hepatic oxidative stress and injuries, we developed a polythiolatedand mannosylated human serum albumin (SH-Man-HSA), which functions as a novel nanoantioxidant for delivering thiol to CD68+ KC. In vitro electron paramagnetic resonance coupled with pharmacokinetics and immunohistochemical studies showed that SH-Man-HSA possessed powerful radical-scavenging activity and rapidly and selectively delivered thiols to the liver via mannose receptor (CD206) on CD68+ cells. SH-Man-HSA significantly improved the survival rate of concanavalin-A (Con-A)-treated mice. Moreover, SH-Man-HSA exhibited excellent hepatoprotective functions, not by decreasing tumor necrosis factor or interferon-γ production that is closely associated with Con-A-induced hepatitis, but by suppressing ROS production. Interestingly, the protective effect of SH-Man-HSA was superior to N-acetyl cysteine (NAC). This could be attributed to the difference in the inhibition of hepatic oxidative stress between the two antioxidants depending on their potential for thiol delivery to the liver. Similar results were also observed for acetaminophen (APAP)-induced hepatopathy models. Flow cytometric data further confirmed that an increase in F4/ 80+/ROS+ cells was dramatically decreased by SH-Man-HSA. The administration of SH-Man-HSA at 4 hours following a Con-A or APAP injection also exhibited a profound hepatoprotective action against these hepatitis models, whereas this was not observed for NAC. It can be concluded therefore that SH-Man-HSA has great potential for use in a rescue therapy for hepatopathy as a nanoantioxidant because of its ability to efficiently and rapidly deliver thiols to CD68+/CD206+ KC.",
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AU - Watanabe, Hiroshi

AU - Ishima, Yu

AU - Chuang, Victor Tuan Giam

AU - Taguchi, Kazuaki

AU - Inatsu, Akihito

AU - Kinoshita, Manabu

AU - Tanaka, Motohiko

AU - Sasaki, Yutaka

AU - Otagiri, Masaki

AU - Maruyama, Toru

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