Inhibition of NF-κB nuclear translocation via HO-1 activation underlies α-tocopheryl succinate toxicity

Bellezza, Ilaria; Tucci, Arianna; Galli, Francesco; Grottelli, Silvia; Mierla, Anna Lisa; Pilolli, Francesca; Minelli, Alba

doi:10.1016/j.jnutbio.2011.10.012

Cited by 166 publications

(102 citation statements)

References 44 publications

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“…Previous studies showed that upregulation of HO-1 negatively regulates NF-κB activation and inflammatory gene expression [15,16,17,38]. HO-1 also negatively regulates NF-κB activation through production of its metabolites such as CO, bilirubin, and free iron [39,40]. In agreement with this notion, our present results demonstrated that ZY-1A4 treatment increases HO-1 expression, while decreasing NF-κB nuclear translocation.…”

Section: Discussionsupporting

confidence: 91%

Induction of Heme Oxygenase-1 by Sodium 9-Hydroxyltanshinone IIA Sulfonate Derivative Contributes to Inhibit LPS-Mediated Inflammatory Response in Macrophages

Liu

Wang

Xiao

et al. 2015

Cell Physiol Biochem

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Background/Aim: Sodium 9-acetoxyltanshinone IIA sulfonate (ZY-1A4), a novel compound derived from sodium 9-hydroxyltanshinone IIA sulfonate, was synthesized with potential biological activities. This study aimed to explore the effects of ZY-1A4 on lipopolysaccharide (LPS)-triggered inflammatory response and the underlying mechanisms. Methods: Activation of RAW264.7 macrophages was induced by LPS. The effects of ZY-1A4 on inducible nitric oxide synthase (iNOS) expression, nitric oxide (NO) generation, nuclear factor-κB (NF-κB) activation, heme oxygenase-1 (HO-1) expression, and nuclear factor-erythroid 2 related factor 2 (Nrf2) pathway were evaluated to elucidate its underlying mechanisms on inflammatory responses. Results: ZY-1A4 concentration-dependently reduced iNOS expression and NO production, and inhibited c-Jun-N-terminal kinase 1/2 (JNK1/2) phosphorylation and NF-κB activation in LPS-stimulated macrophages. In addition, ZY-1A4 concentration- and time-dependently induced HO-1 expression associated with degradation of Kelch-like ECH-associated protein 1 (Keap1) and nuclear translocation of Nrf2, while the effect of ZY-1A4 was abolished by a phosphoinositide 3-kinase (PI3K) inhibitor LY294002. Intriguingly, pharmacological inactivation of HO-1 with zinc protoporphyrin IX reversed anti-inflammatory effect of ZY-1A4, but the anti-inflammatory effect of ZY-1A4 was largely mimicked by HO-1 by-products carbon monoxide and bilirubin. Furthermore, the inhibitory effect of ZY-1A4 on LPS-induced iNOS expression and NO release was abolished by HO-1 siRNA or LY294002. Conclusion: Our results demonstrated that ZY-1A4 suppressed LPS-induced iNOS expression and NO generation via modulation of NF-κB activation and HO-1 expression. This new finding might shed light to the prevention and therapy of cardiovascular diseases.

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Section: Discussionsupporting

confidence: 91%

Induction of Heme Oxygenase-1 by Sodium 9-Hydroxyltanshinone IIA Sulfonate Derivative Contributes to Inhibit LPS-Mediated Inflammatory Response in Macrophages

Liu

Wang

Xiao

et al. 2015

Cell Physiol Biochem

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“…In addition, cross talk between Nrf2 and NF-B systems has been identified. Nrf2 activation caused by increased HO-1 activity can lead to the inhibition of NF-B nuclear translocation via HO-1 end products, i.e., bilirubin and CO (71). In the present study, results indicated that the Nrf2 activation may be partially responsible for the downregulated expression of NF-B mRNA by lycopene, which can directly scavenge singlet-oxygen and free radicals.…”

Section: Discussionsupporting

confidence: 50%

“…4). Decreases in the GSH level in damaged cells can lead to adaptive increases in the intracellular antioxidant defense; an important event of this process is the increase of the nuclear translocation of Nrf2 and its DNA binding capacity (71). The activated Nrf2 can lead to increased GSH levels through inducing the expression of the cysteine-glutamic acid exchange transporter, which protects cells from oxidative stress (71).…”

Section: Discussionmentioning

confidence: 99%

Lycopene Attenuates Colistin-Induced Nephrotoxicity in Mice via Activation of the Nrf2/HO-1 Pathway

Dai

Tang

Deng

et al. 2015

Antimicrob Agents Chemother

102

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bNephrotoxicity is the major dose-limiting factor for the clinical use of colistin against multidrug-resistant (MDR) Gram-negative bacteria. This study aimed to investigate the protective effect of lycopene on colistin-induced nephrotoxicity in a mouse model. Fifty mice were randomly divided into 5 groups: the control group (saline solution), the lycopene group (20 mg/kg of body weight/day administered orally), the colistin group (15 mg/kg/day administered intravenously), the colistin (15 mg/kg/day) plus lycopene (5 mg/kg/day) group, and the colistin (15 mg/kg/day) plus lycopene (20 mg/kg/day) group; all mice were treated for 7 days. At 12 h after the last dose, blood was collected for measurements of blood urea nitrogen (BUN) and serum creatinine levels. The kidney tissue samples were obtained for examination of biomarkers of oxidative stress and apoptosis, histopathological assessment, and quantitative reverse transcription-PCR (qRT-PCR) analysis. Colistin treatment significantly increased concentrations of BUN and serum creatinine, tubular apoptosis/necrosis, lipid peroxidation, and heme oxygenase 1 (HO-1) activity, while the treatment decreased the levels of endogenous antioxidant biomarkers glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). Notably, the changes in the levels of all biomarkers were attenuated in the kidneys of mice treated with colistin by lycopene (5 or 20 mg/kg). Lycopene treatment, especially in the colistin plus lycopene (20 mg/kg) group, significantly downregulated the expression of NF-B mRNA (P < 0.01) but upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and HO-1 mRNA (both P < 0.01) in the kidney compared with the results seen with the colistin group. Our data demonstrated that coadministration of 20 mg/kg/day lycopene can protect against colistin-induced nephrotoxicity in mice. This effect may be attributed to the antioxidative property of lycopene and its ability to activate the Nrf2/HO-1 pathway.

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“…HO-1 is known to play an anti-inflammatory role due to carbon monoxide production and NFkB inhibition. 49 In our study, pretreatment with quercetin and monochloropivaloylquercetin activated Nrf-2/Keap1 signaling by decreasing cytoplasmic expression and inducing nuclear translocation of Nrf-2, resulting in upregulation of downstream genes HO-1 and NQO1 in HNE-treated BV-2 cells. Additionally, COX-2 mRNA stimulation by 4-HNE was inhibited when BV-2 cells were preincubated with quercetin and monochloropivaloylquercetin.…”

Section: Discussionmentioning

confidence: 48%

Effect of the Lipid Peroxidation Product 4-Hydroxynonenal on Neuroinflammation in Microglial Cells: Protective Role of Quercetin and Monochloropivaloylquercetin

Cumaoğlu

Agkaya

Ozkul

2019

tjps

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Objectives:The lipid peroxidation-derived aldehyde 4-hydroxynonenal (HNE) has been implicated in a number of oxidative stress-induced inflammatory pathologies such as neurodegenerative diseases and aging. In this regard, we investigated the effects of HNE on neuroinflammatory responses by measuring cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) induction with cytokine production. In addition, we measured nuclear factor erythroid 2-related factor 2 (Nrf-2)/Kelch-like ECH-associated protein 1 (Keap1) signaling proteins, and antioxidant enzymes heme oxygenase-1 (HO-1) and nicotinamide adenine dinucleotide phosphate dehydrogenase, quinone 1 (NQO1), and compared the results with quercetin and monochloropivaloylquercetin (MPQ) pretreated microglial cells. Materials and Methods: Cytotoxicity was determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and production of cytokines was determined by cytokine array. Furthermore, intracellular Nfr2/Keap1 signaling proteins, HO-1, NQO1, and COX-2 expression were analyzed by western blot in 2.5 μM HNE treated BV-2 cells. Results: Inducible nitric oxide synthase (iNOS) and COX-2 mRNA levels were measured with reverse transcription-quantitative polymerase chain reaction. HNE induced both COX-2 mRNA and protein levels, iNOS mRNA expression, and cytokine production. In addition, HNE markedly increased Keap1 levels and decreased cytoplasmic Nrf-2 expression with antioxidant enzyme HO-1 levels. Quercetin and monochloropivaloylquercetin treatment alleviated neuroinflammatory responses in microglial cells, by decreasing COX-2 mRNA expression. Monochloropivaloylquercetin decreased cytoplasmic Keap1 levels and increased nuclear translocation of Nrf-2 resulted in induction of HO-1 and NQO1 expression. Conclusion: These results suggest that HNE could be a link between oxidative stress and inflammation in BV-2 microglia cells. In particular, monochloropivaloylquercetin alleviated inflammation, probably by decreasing the expression of proinflammatory genes and strengthening the antioxidant defense system. Key words: 4-Hydroxynonenal, microglia, quercetin, inflammation, cyclooxygenase-2, hemeoxygenase-1 ÖZ Amaç: Lipit peroksidasyonu ürünü aldehit, 4-hidroinonenal (HNE), nörodejeneratif hastalıklar ve yaşlanma gibi oksidatif strese bağlı inflamatuvar patolojilerle ilişkilendirilmiştir. Bu bağlamda, HNE'nin nöroinflamatuvar cevap üzerine etkisini siklooksijenaz-2 (COX-2), indüklenebilir nitrik oksit sentaz (iNOS) ifadelenmeleri ve sitokin üretimi üzerinden incelenmiştir. Bunlara ek olarak, nükleer faktör eritroid 2-ilişkili faktör 2 (Nrf2)/ Kelch-benzeri ECH-ilişkili protein 1 (Keap1) sinyal proteinleri, antioksidan enzimler hemoksijenaz-1 (HO-1) ve nikotinamid adenin dinükleotit fosfat dehidrojenaz, kinon 1 (NQO1) ifadelenme düzeyleri ölçüldü ve sonuçlar kersetin ve monokloropivaloilkersetin uygulanan hücrelerle karşılaştırılmıştır. Gereç ve Yöntemler: Sitotoksisite MTT (3-(4,5-dimetiltiyazol-2-yl)-2,5-difeniltetrazolyum bromit) indirgenme y...

show abstract

Inhibition of NF-κB nuclear translocation via HO-1 activation underlies α-tocopheryl succinate toxicity

Cited by 166 publications

References 44 publications

Induction of Heme Oxygenase-1 by Sodium 9-Hydroxyltanshinone IIA Sulfonate Derivative Contributes to Inhibit LPS-Mediated Inflammatory Response in Macrophages

Induction of Heme Oxygenase-1 by Sodium 9-Hydroxyltanshinone IIA Sulfonate Derivative Contributes to Inhibit LPS-Mediated Inflammatory Response in Macrophages

Lycopene Attenuates Colistin-Induced Nephrotoxicity in Mice via Activation of the Nrf2/HO-1 Pathway

Effect of the Lipid Peroxidation Product 4-Hydroxynonenal on Neuroinflammation in Microglial Cells: Protective Role of Quercetin and Monochloropivaloylquercetin

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