Protective effects of E3330, a novel quinone derivative, on galactosamine/tumor necrosis factor-α-induced hepatitis in mice

Nagakawa, Junichi; Hishinuma, Ieharu; Hirota, Kazuo; Miyamoto, Ko Ichiro; Yamanaka, Takashi; Yamatsu, Isao; Katayama, Kouichi

doi:10.1016/0014-2999(92)90286-d

Cited by 21 publications

(12 citation statements)

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“…It induces hepatitis by hindering the synthesis of RNA and protein via reduction in cellular UTP uptake that tips to the hepatic parenchyma necrosis [6, 7]. The quinones, flavones and carotenoids are well known antioxidants that are claimed to be hepatoprotective were evaluated by D-GaLN/LPS hepatic damage model [8, 9]. …”

Section: Introductionmentioning

confidence: 99%

Hepatoprotective activity of Lepidium sativum seeds against D-galactosamine/lipopolysaccharide induced hepatotoxicity in animal model

Raish

Ahmad

Alkharfy

et al. 2016

BMC Complement Altern Med

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BackgroundFulminant hepatic failure (FHF) is clinical syndrome with very poor prognosis and high mortality there is urgent need for the development of safe and non-toxic hepatoprotective agents for the adequate management of hepatitis. Hepatoprotective effect of the Lepidium sativum ethanolic extract (LSEE) was assessed by D-galactosamine-induced/lipopolysaccharide (400 mg/kg and 30 μg/kg) liver damage model in rats.MethodsHepatoprotective activity of LSEE (150 and 300 mg/kg) and silymarin on D-GalN/LPS induced FHF in rat was assessed using several liver function enzyme parameters. Antioxidant properties as antioxidant stress enzymes were assessed in hepatic Liver as well as mRNA expression of cytokines genes such as TNF-α, IL-6, and IL-10 and stress related genes iNOS and HO-1 were determined by RT-PCR. Protein expression of apoptotic genes were evaluated through western blot. MPO and NF-κB DNA-binding activity was analyzed by ELISA. The magnitude of hepatic impairment was investigated through histopathological evaluation.ResultsMarked amelioration of hepatic injuries by attenuation of serum and lipid peroxidation has been observed as comparable with silymarin (25 mg/kg p.o). D-GalN/LPS induced significant decrease in oxidative stress markers protein level, and albumin. LSEE significantly down-regulated the D-GalN/LPS induced pro-inflammatory cytokines TNFα and IL-6 mRNA expression in dose dependent fashion about 0.47 and 0.26 fold and up-regulates the IL-10 by 1.9 and 2.8 fold, respectively. While encourages hepatoprotective activity by down-regulating mRNA expression of iNOS and HO-1. MPO activity and NF-κB DNA-binding effect significantly increased and was mitigated by LSEE in a dose-dependent style as paralleled with silymarin.ConclusionOur data suggests that pretreatment of LSEE down regulates the caspase 3 and up-regulates the BCl2 protein expression. The above findings revealed that Lepidium sativum has significant hepatoprotective activity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12906-016-1483-4) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Hepatoprotective activity of Lepidium sativum seeds against D-galactosamine/lipopolysaccharide induced hepatotoxicity in animal model

Raish

Ahmad

Alkharfy

et al. 2016

BMC Complement Altern Med

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“…Phenolic antioxidants exhibit anti-inflammatory, anticarcinogenic, and antidiabetic activities in animals (Wattenberg et al, 1980;Talalay et al, 1988;Bjorkhem et al, 1991;Nagakawa et al, 1993;Futakuchi et al, 1998;Nishizono et al, 2000). Human beings consume appreciable amounts of the antioxidants from dietary sources, either as natural components or as synthetic food additives (Nunn, 1991;Yang et al, 2001).…”

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confidence: 99%

Inhibition of Nuclear Factor κB by Phenolic Antioxidants: Interplay between Antioxidant Signaling and Inflammatory Cytokine Expression

Ma¹,

Kinneer²,

Ye³

et al. 2003

Mol Pharmacol

110

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Phenolic antioxidants inhibit the induction of inflammatory cytokines by inflammatory stimuli. Here, we analyzed the mechanism by which the antioxidants inhibit LPS-induced expression of tumor necrosis factor ␣ (TNF␣) in macrophages. Hydroquinone and tert-butyl hydroquinone, prototypes of phenolic antioxidants, block lipopolysaccharide (LPS)-induced transcription of TNF␣ and a nuclear factor (NF)-B-mediated reporter gene expression, suggesting NF-B as a target in the inhibition. Analyses of the NF-B activation pathway revealed that the antioxidants do not inhibit LPS-induced activation of the IB kinase activity, degradation of IB␣, or translocation of activated NF-B into the nucleus, but they do block the formation of NF-B/DNA binding complexes. In vitro experiments showed that the antioxidants do not directly interfere with DNA binding of NF-B. Structure-activity analyses suggest that inhibition of NF-B function involves the redox cycling property of the antioxidants. These findings implicate a redox-sensitive factor important for the binding of NF-B to its DNA recognition sequence as a target molecule in the inhibition of NF-B function and inflammatory cytokine expression by phenolic antioxidants.

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“…This supports our hypothesis that the redox role is independent of the APE1 DNA repair function. The APE1 redox inhibitor, BQP, was initially identified as a small molecule that inhibited TNF-α production in vivo [32,54] using hepatitis models and LPS-stimulated macrophages including mononuclear cells and Kupffer cells. TNF-α is known to induce apoptosis in neurodegenerative diseases [55].…”

Section: Discussionmentioning

confidence: 99%

Role of APE1 in differentiated neuroblastoma SH-SY5Y cells in response to oxidative stress: Use of APE1 small molecule inhibitors to delineate APE1 functions

Jiang¹,

Guo

Fishel³

et al. 2009

DNA Repair

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Oxidative DNA damage has been implicated in a number of central nervous system pathologies. The base excision repair (BER) pathway is one of the most important cellular protection mechanisms that respond to oxidative DNA damage. Human apurinic (apyrimidinic) endonuclease/redox effector factor (APE1/Ref-1 or APE1) is an essential enzyme in the BER pathway and is expressed in both mitotic and post-mitotic cells in humans. In neurons, a reduction of APE1 expression increases chemotherapy-induced cytotoxicity, while overexpression of APE1 protects cells against the cytotoxicity. However, given the multiple functions of APE1, knockdown of total APE1 is not completely informative of whether it is the redox or DNA repair activity, or interactions with other proteins. Therefore, the use of selective small molecules that can block each function independent of the other is of great benefit in ascertaining APE1 function in post-mitotic cells. In this study, we chose differentiated SH-SY5Y cells as our post-mitotic cell line model to investigate whether a druginduced decrease in APE1 DNA repair or redox activity contributes to the growth and survival of post-mitotic cells under oxidative DNA damaging conditions. Here, we demonstrate that overexpression of WT-APE1 or C65-APE1 (repair competent) results in significant increase in cell viability after exposure to H 2 O 2 . However, the 177/226-APE1 (repair deficient) did not show a protective effect. This phenomenon was further confirmed by the use of methoxyamine (MX), which blocks the repair activity of APE1 that results in enhanced cell killing and apoptosis in differentiated SH-SY5Y cells and in neuronal cultures after oxidative DNA damaging treatments. Blocking APE1 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflict of interest:No conflicts of interest were disclosed. NIH Public Access

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Protective effects of E3330, a novel quinone derivative, on galactosamine/tumor necrosis factor-α-induced hepatitis in mice

Cited by 21 publications

References 15 publications

Hepatoprotective activity of Lepidium sativum seeds against D-galactosamine/lipopolysaccharide induced hepatotoxicity in animal model

Hepatoprotective activity of Lepidium sativum seeds against D-galactosamine/lipopolysaccharide induced hepatotoxicity in animal model

Inhibition of Nuclear Factor κB by Phenolic Antioxidants: Interplay between Antioxidant Signaling and Inflammatory Cytokine Expression

Role of APE1 in differentiated neuroblastoma SH-SY5Y cells in response to oxidative stress: Use of APE1 small molecule inhibitors to delineate APE1 functions

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