Analysis of In Vivo Nuclear Factor-κB Activation during Liver Inflammation in Mice: Prevention by Catalase Delivery

Hyoudou, Kenji; Nishikawa, Makiya; Kobayashi, Yuki; Kuramoto, Yukari; Yamashita, Fumiyoshi; Hashida, Mitsuru

doi:10.1124/mol.106.027169

Cited by 21 publications

(19 citation statements)

References 38 publications

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“…The major limitation of this study is that the underlying molecular mechanisms of TAA-induced up-regulation of UGTs have not been addressed. TAA-induced liver injury was typically characterized with oxidative stress and lipid peroxidation (Low et al, 2004;Natarajan et al, 2006;Aller et al, 2008), and the antioxidant treatment was very effective in preventing TAA-induced liver injury (Hyoudou et al, 2007;Tsai et al, 2010). In addition, we found in the study presented here that SLE and DDB, both proven as good antioxidants, could significantly attenuate TAA-induced liver injury and transcriptional up-regulation of UGTs.…”

Section: Discussionsupporting

confidence: 55%

Thioacetamide Intoxication Triggers Transcriptional Up-Regulation but Enzyme Inactivation of UDP-Glucuronosyltransferases

Hao¹,

Zhang²,

Jiang³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Thioacetamide (TAA) is a potent hepatotoxicant and has been widely used to develop experimental liver fibrosis/cirrhosis models. Although the liver toxicity of TAA has been extensively studied, little is known about its potential influence on UDP-glucuronosyltransferases (UGTs) associated with the development of liver fibrosis. The study presented here aimed to uncover the regulation patterns of UGTs in TAA-induced liver fibrosis of rats. Potential counteracting effects of hepatoprotective agents were also determined. TAA treatment for 8 weeks induced a significant transcriptional up-regulation of the major UGT isoforms, including UGT1A1, UGT1A6, and UGT2B1, accompanied with the dramatic elevations of most typical serum biomarkers of liver function and fibrosis scores. Upon TAA intoxication, the mRNA and protein levels of the major UGT isoforms were increased to 1.5-to 2.5-fold and 2.5-to 3.3-fold of that of the normal control, respectively. The hepatoprotective agents Schisandra spp. lignans extract and dimethyl diphenyl bicarboxylate could largely abolish TAA-induced up-regulation of all three UGT isoforms. However, enzyme activities of UGTs remained unchanged after TAA treatment. The dissociation of protein expression and enzyme activity could possibly be attributed to the inactivating effects of TAA, upon a NADPH-dependent bioactivation, on UGTs. This study suggests that the transcriptional up-regulation of UGTs may be an alternative mechanism of their preserved activities in liver fibrosis/cirrhosis.

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Section: Discussionsupporting

confidence: 55%

Thioacetamide Intoxication Triggers Transcriptional Up-Regulation but Enzyme Inactivation of UDP-Glucuronosyltransferases

Hao¹,

Zhang²,

Jiang³

et al. 2011

Drug Metab Dispos

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“…(14,15) NF-κB activity in mouse liver was easily and quantitatively measured in this system, and we demonstrated that NF-κB in liver cells is activated when the liver suffers from thioacetamide-induced injury. (16) Luciferase-based evaluation of NF-κB activity has advantages over conventional EMSA. First, the activity can be measured in live animals, so that the changes of the activity can be traced in individual animals.…”

mentioning

confidence: 99%

“…When plasmid vectors are selectively introduced to a specific type of cell, it is possible to examine the changes in NF-κB activity in those cells. Thus, the elucidation of NF-κB activity in liver cells and tumor cells during hepatic metastasis can help identify new targets for inhibition of tumor metastasis.In the present study, the mouse model developed in our previous study (16) was used to evaluate the changes in NF-κB activity in liver cells when tumor cells enter the hepatic circulation. Murine adenocarcinoma colon26 cells were selected as tumor cells, which were inoculated into the portal vein of synergetic BALB/c mice.…”

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confidence: 99%

Hydrogen peroxide‐mediated nuclear factor κB activation in both liver and tumor cells during initial stages of hepatic metastasis

et al. 2008

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Various factors involved in tumor metastasis are regulated by the transcription factor nuclear factor kB (NF-kB). Because NF-kB activation may contribute to establishment of hepatic metastasis, its activation in liver cells and tumor cells was separately evaluated in a mouse model of hepatic metastasis. pNF-kB-Luc, a firefly luciferaseexpressing plasmid DNA depending on the NF-kB activity, was injected into the tail vein of mice by the hydrodynamics-based procedure, a well-established method for gene transfer to BALB/c male mouse liver. The luciferase activity in the liver was significantly increased by an intraportal inoculation of murine adenocarcinoma colon26 cells, but not of peritoneal macrophages, suggesting that the NF-kB in liver cells is activated when tumor cells enter the hepatic circulation. N uclear factor-κB (NF-κB) is a sequence-specific transcription factor that regulates the transcription of various genes, the products of which are involved in various biological processes, including inflammation, immune response, and the initiation and progression of cancer.(1-5) For example, tumor progression and metastasis are regulated by numerous NF-κB-regulated gene products, including matrix metalloproteinases (MMP), adhesion molecules, angiogenic factors and anti-apoptotic factors. Thus, the inhibition of NF-κB activation is a good target for inhibiting tumor growth and metastasis.(6) So far, several compounds, such as BAY11-7082, have been developed to inhibit the NF-κB activity by inhibiting proteasomal degradation of IκBα, the endogenous inhibitor of NF-κB. The activity of NF-κB and other transcription factors has been evaluated by an electrophoretic mobility shift assay (EMSA), which requires isolation of nuclear protein (radio)-labeled probes, and antibodies for its super-shift assay. In marked contrast, plasmid vectors expressing reporter genes under the control of the activity of a transcription factor, such as NF-κB, can be used to measure the activity of transcription factors. Using luciferaseexpressing vectors is a simple, reliable and highly sensitive method of measurement. Cells stably transfected with vectors expressing the luciferase gene in response to the activation of any transcription factor have been developed and used to evaluate the activity of transcription factors in those cells.(8) Transgenic mice that express a luciferase, the transcription of which is dependent on NF-κB activity, have been developed and the NF-κB activation in whole animals has been examined by bioluminescence imaging.(9,10) We have developed a novel experimental system involving the injection of plasmid vectors into the tail vein of mice by the hydrodynamics-based procedure, (11)(12)(13) a wellestablished gene transfer method. (14,15) NF-κB activity in mouse liver was easily and quantitatively measured in this system, and we demonstrated that NF-κB in liver cells is activated when the liver suffers from thioacetamide-induced injury. (16) Luciferase-based evaluation of NF-κB activity has advantages over conventio...

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“…A wide range of proinflammatory mediators can promote NF-κB in HSC/HMF including LPS, TNF-α, IL-1β, angiotensin II and CD40L (Seki et al, 2007). Also, NF-κB can be activated by the generation of ROS in the liver (Hyoudou et al, 2007). The induction of NFκB in association with the activation of HSC often relates to liver damage because it imposes a constraint on HSC apoptosis, further leading to aggregating hepatic fibrosis (Czechowska et al, 2015).…”

Section: Histological Findingsmentioning

confidence: 99%

Antifibrotic candidates of Selenium nanoparticles and selenium in the experimental model

2017

J App Pharm Sci

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This research was designed to compare the efficacy of selenium in nanoscale (SeNPs) with its free form (Se) against liver fibrosis induced by thioacetamide (TAA) in rats. In a completely randomized design, 60 adult female rats were distributed as: Group (1) control (received saline) and other three groups received TAA to induce liver fibrosis (100 mg/kg b.wt of three times a week for 6 weeks). Fifteen rats were termed TAA (Group 2). Rats in group (3) were simultaneously administered SeNPs (0.48 mg/kg/b.wt) orally (TAA+SeNPs). Rats in group (4) were simultaneously administered Se (0.48 mg/kg/b.wt) orally (TAA+Se). TAA injection enhanced liver enzymes activity, oxidative stress markers and inflammatory mediators, while suppressed the activity of the antioxidant enzymes activity versus the control group. SeNPs as well as Se supplementation blunted liver enzymes activity, oxidative stress indicators and inflammatory intermediates, while potentiated the activity of the antioxidant enzymes relative to TAA group. Histological investigation of liver tissue appreciated the biochemical findings. Aforementioned data clearly indicate that the mitigation of oxidative stress and inflammation may be the probable mechanisms by which SeNPs or Se can offer their antifibrotic action. Worth mentioning, SeNPs showed superior effect above Se in its free form in this respect.

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Analysis of In Vivo Nuclear Factor-κB Activation during Liver Inflammation in Mice: Prevention by Catalase Delivery

Cited by 21 publications

References 38 publications

Thioacetamide Intoxication Triggers Transcriptional Up-Regulation but Enzyme Inactivation of UDP-Glucuronosyltransferases

Thioacetamide Intoxication Triggers Transcriptional Up-Regulation but Enzyme Inactivation of UDP-Glucuronosyltransferases

Hydrogen peroxide‐mediated nuclear factor κB activation in both liver and tumor cells during initial stages of hepatic metastasis

Antifibrotic candidates of Selenium nanoparticles and selenium in the experimental model

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