Edaravone prevents iNOS expression by inhibiting its promoter transactivation and mRNA stability in cytokine-stimulated hepatocytes

Yoshida, Hideyuki; Kwon, A‐Hon; Kaibori, Masaki; Tsuji, Katsushige; Habara, Kozo; Yamada, Masakazu; Kamiyama, Yasuo; Nishizawa, Mikio; Ito, Seiji; Okumura, Tadayoshi

doi:10.1016/j.niox.2007.11.003

Cited by 40 publications

(39 citation statements)

References 51 publications

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“…7A). Drugs such as edaravone (free radical scavenger) [7], FR183998 (Na + /H + exchanger inhibitor) [3,5], insulin-like growth factor I [4] and dexamethasone [41] were found to inhibit iNOS induction partly by suppressing iNOS antisense transcript production in primary cultured hepatocytes (our in vitro model) and in animal models of liver injury. In the case of dexamethasone, it had no effects on either NF-ĸB activation or IL-1RI upregulation as compared with AHCC-SF.…”

Section: Discussionmentioning

confidence: 99%

“…In our previous reports, clinical drugs, which showed liver-protective effects in various animal models of liver injury [1,2,3,4,5], prevented iNOS induction in the liver as well as decreased production of various inflammatory mediators. These drugs also inhibited iNOS induction and NO production in proinflammatory cytokine-stimulated cultured hepatocytes of rats [3,6,7], which is used as a simple in vitro injury model.…”

Section: Introductionmentioning

confidence: 99%

“…IL-1β stimulates the degradation of IĸB after its phosphorylation by IĸB kinase, which is followed by the translocation of NF-ĸB from cytoplasm to the nucleus and DNA binding (NF-ĸB activation). IL-1β also stimulates the upregulation of IL-1RI through activation of PI3K/Akt, which is essential for both transcriptional activation and mRNA stabilization in iNOS induction [7,11,12,13]. In the case of mRNA stabilization, we have reported that natural iNOS gene antisense transcript interacts with 3′-untranslated region (UTR) containing AU-rich elements (ARE) of iNOS mRNA, leading to iNOS mRNA stabilization in IL-1β-stimulated hepatocytes [14].…”

Section: Introductionmentioning

confidence: 99%

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Active Hexose Correlated Compound Inhibits the Expression of Proinflammatory Biomarker iNOS in Hepatocytes

Matsui

Ozaki²,

Oishi³

et al. 2011

Eur Surg Res

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Background/Aims: Excess production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) has been implicated as proinflammatory biomarker in liver injury. The application of active hexose correlated compound (AHCC) as a functional food in complementary and alternative medicine has increased. The possibility that AHCC might inhibit iNOS induction was investigated as a potential liver-protective effect. Methods: Hepatocytes were isolated from rats by collagenase perfusion and cultured. Primary cultured hepatocytes were treated with interleukin-1β in the presence or absence of AHCC-sugar fraction (AHCC-SF). Results and Conclusion: AHCC-SF inhibited the production of NO and reduced expressions of iNOS mRNA and its protein. AHCC-SF had no effects on either IĸB degradation or nuclear factor-ĸB (NF-ĸB) activation. In contrast, AHCC-SF inhibited the upregulation of type I interleukin-1 receptor (IL-1RI) through the inhibition of Akt phosphorylation. Transfection experiments with iNOS promoter-luciferase constructs revealed that AHCC-SF reduced the levels of iNOS mRNA at both promoter transactivation and mRNA stabilization steps. AHCC-SF inhibited the expression of iNOS gene antisense transcript, which is involved in iNOS mRNA stabilization. These findings demonstrate that AHCC-SF suppresses iNOS gene expression through a IĸB/NF-ĸB-independent but Akt/IL-1RI-dependent pathway, resulting in the reduction of NO production. AHCC-SF may have therapeutic potential for various liver injuries.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Active Hexose Correlated Compound Inhibits the Expression of Proinflammatory Biomarker iNOS in Hepatocytes

Matsui

Ozaki²,

Oishi³

et al. 2011

Eur Surg Res

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“…Two signaling pathways, the activation of NF-jB (its translocation from the cytoplasm to the nucleus, and DNA binding) through the degradation of IjB and the upregulation of IL-1RI through the activation of phosphatidylinositol 3-kinase (PI3K)/Akt, are essential for iNOS induction [20,21,39,40]. IL-1b stimulates the degradation of IjB proteins, which is followed by the activation of NF-jB.…”

Section: Effects Of Sivelestat On the Activation Of Nf-jb And Upregulmentioning

confidence: 99%

“…In these studies, drugs showing liver-protective effects inhibited the induction of iNOS and NO production as well as the decreased production of various inflammatory mediators. Furthermore, in vitro experiments with primary cultured rat hepatocytes revealed that these drugs inhibited the induction of iNOS and NO production [17,20,21]. Thus, the prevention of NO production is considered to be one of the indicators of liver protection.…”

Section: Introductionmentioning

confidence: 99%

Sivelestat Suppresses iNOS Gene Expression in Proinflammatory Cytokine-Stimulated Hepatocytes

et al. 2011

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Improving mitochondria and ER stability helps eliminate upper motor neuron degeneration that occurs due to mSOD1 toxicity and TDP‐43 pathology

Genç

Gautam

Gozutok

et al. 2021

Clinical & Translational Med

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Background Upper motor neurons (UMNs) are a key component of motor neuron circuitry. Their degeneration is a hallmark for diseases, such as hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS), and amyotrophic lateral sclerosis (ALS). Currently there are no preclinical assays investigating cellular responses of UMNs to compound treatment, even for diseases of the UMNs. The basis of UMN vulnerability is not fully understood, and no compound has yet been identified to improve the health of diseased UMNs: two major roadblocks for building effective treatment strategies. Methods Novel UMN reporter models, in which UMNs that are diseased because of misfolded superoxide dismutase protein (mSOD1) toxicity and TDP‐43 pathology are labeled with eGFP expression, allow direct assessment of UMN response to compound treatment. Electron microscopy reveals very precise aspects of endoplasmic reticulum (ER) and mitochondrial damage. Administration of NU‐9, a compound initially identified based on its ability to reduce mSOD1 toxicity, has profound impact on improving the health and stability of UMNs, as identified by detailed cellular and ultrastructural analyses. Results Problems with mitochondria and ER are conserved in diseased UMNs among different species. NU‐9 has drug‐like pharmacokinetic properties. It lacks toxicity and crosses the blood brain barrier. NU‐9 improves the structural integrity of mitochondria and ER, reduces levels of mSOD1, stabilizes degenerating UMN apical dendrites, improves motor behavior measured by the hanging wire test, and eliminates ongoing degeneration of UMNs that become diseased both because of mSOD1 toxicity and TDP‐43 pathology, two distinct and important overarching causes of motor neuron degeneration. Conclusions Mechanism‐focused and cell‐based drug discovery approaches not only addressed key cellular defects responsible for UMN loss, but also identified NU‐9, the first compound to improve the health of diseased UMNs, neurons that degenerate in ALS, HSP, PLS, and ALS/FTLD patients.

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Edaravone prevents iNOS expression by inhibiting its promoter transactivation and mRNA stability in cytokine-stimulated hepatocytes

Cited by 40 publications

References 51 publications

Active Hexose Correlated Compound Inhibits the Expression of Proinflammatory Biomarker iNOS in Hepatocytes

Active Hexose Correlated Compound Inhibits the Expression of Proinflammatory Biomarker iNOS in Hepatocytes

Sivelestat Suppresses iNOS Gene Expression in Proinflammatory Cytokine-Stimulated Hepatocytes

Improving mitochondria and ER stability helps eliminate upper motor neuron degeneration that occurs due to mSOD1 toxicity and TDP‐43 pathology

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