Heme oxygenase 1 mediates anti-inflammatory effects of 2′,4′,6′-tris(methoxymethoxy) chalcone

Lee, Sung Hee; Seo, Geom Seog; Kim, Ji Yeong; Jin, Xing; Kim, Hee‐Doo; Sohn, Dong Hwan

doi:10.1016/j.ejphar.2006.01.005

Cited by 70 publications

(33 citation statements)

References 34 publications

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“…That depletion of intracellular GSH induces Nrf2 expression as a cellular defense mechanism has been proposed (35). In fact, previous studies have been shown that depletion of GSH induced HO-1 expression in different cells (9), including RAW 264.7 cells (12,24), and inhibited LPS-induced NO production (12,24). Moreover, EP has been reported to deplete GSH levels in LPSactivated RAW 264.7 cells, which is responsible for the antiinflammatory effect (36).…”

Section: Discussionmentioning

confidence: 99%

Ethyl Pyruvate Induces Heme Oxygenase-1 Through p38 Mitogen-Activated Protein Kinase Activation by Depletion of Glutathione in RAW 264.7 Cells and Improves Survival in Septic Animals

Jang

Kim

Tsoyi

et al. 2012

Antioxidants & Redox Signaling

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Aims: We investigated the molecular mechanism by which ethyl pyruvate (EP) induces heme oxygenase-1 (HO-1) in RAW 264.7 cells and its effect on survival rate in cecal ligation and puncture (CLP)-induced wild-type (WT) and HO-1 knockout (HO-1 -/ -) septic mice. Results: EP induced HO-1 in a dose-and time-dependent manner, which was mediated through p38 mitogen-activated protein kinase (MAPK) and NF-E2-related factor 2 (Nrf2) signaling cascade in RAW 264.7 cells. EP significantly inhibited the lipopolysaccharide (LPS)-stimulated inducible nitric oxide synthase (iNOS) expression and high-mobility group box 1 (HMGB1) release in RAW 264.7 cells. The inhibitory effect of EP on LPS-stimulated iNOS expression and HMGB1 release was reversed by transfection with siHO-1RNA in RAW 264.7 cells, but EP failed to reduce them in HO-1 -/ -peritoneal macrophages treated with LPS. Moreover, treatment of cells with glutathione ethyl ester (GSH-Et), SB203580 (p38 MAPK inhibitor), siHO-1, or p38-siRNA transfection inhibited anti-inflammatory effect of EP. Interestingly, both HO-1 induction and phosphorylation of p38 by EP were reversed by GSH-Et, and antioxidant redox elementluciferase activity by EP was reversed by SB203580 in LPS-activated cells. EP increased survival and decreased serum HMGB1 in CLP-WT mice, whereas it did not increase survival or decrease circulating HMGB1 in HO-1 -/ -CLP-mice. Innovation and Conclusion: Our work provides new insights into the understanding the molecular mechanism by showing that EP induces HO-1 through a p38 MAPK-and NRF2-dependent pathway by decreasing GSH cellular levels. We conclude that EP inhibits proinflammatory response to LPS in macrophages and increases survival in CLP-induced septic mice by upregulation of HO-1 level, in which p38 MAPK and Nrf2 play an important role. Antioxid. Redox Signal. 17, 878-889.

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Section: Discussionmentioning

confidence: 99%

Ethyl Pyruvate Induces Heme Oxygenase-1 Through p38 Mitogen-Activated Protein Kinase Activation by Depletion of Glutathione in RAW 264.7 Cells and Improves Survival in Septic Animals

Jang

Kim

Tsoyi

et al. 2012

Antioxidants & Redox Signaling

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“…TMMC, a synthetic chalcone derivative, shows effective anti-inflammatory effects in intestinal epithelial cells and murine macrophages [10,17]. In a programme to develop anti-inflammatory drugs, we synthesized derivatives of TMMC and found that MBMC ( Cells were treated with 2 lM MBMC at the indicated time points, and intracellular GSH levels were determined.…”

Section: Discussionmentioning

confidence: 99%

“…Depletion of intracellular GSH may induce Nrf2 expression as a cellular defence mechanism to increase GSH content [16]. It has been shown that depletion of GSH induces HO-1 expression and inhibits nitric oxide production [17].…”

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confidence: 99%

“…We have previously demonstrated that 2¢,4¢,6¢-tris(methoxymethoxy)chalcone (TMMC), a synthetic chalcone derivative, efficiently inhibits nitric oxide production in lipopolysaccharide (LPS)-stimulated macrophages, and treatment of mice with TMMC protected against intestinal inflammatory disease induced by trinitrobenzene sulphonic acid [10,17]. In this study, as part of an effort to develop optimal antiinflammatory drugs, we prepared three additional synthetic TMMC derivatives ( fig.…”

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confidence: 99%

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2′‐Methoxy‐4′6′‐Bis(Methoxymethoxy)Chalcone Inhibits Nitric Oxide Production in Lipopolysaccharide‐Stimulated RAW 264.7 Macrophages

Jin

Lee

Park

et al. 2010

Basic Clin Pharma Tox

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Chalcones have anti-inflammatory properties. Here, we synthesized 2¢-methoxy-4¢6¢-bis(methoxymethoxy)chalcone (MBMC) and examined its anti-inflammatory effects. MBMC inhibited nitric oxide production and inducible nitric oxide synthase (iNOS) expression in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages. MBMC also blocked LPSinduced activation of nuclear factor jB (NF-jB), p38 mitogen-activated protein kinase and c-Jun N-terminal kinase (JNK). MBMC increased haem oxygenase 1 (HO-1) expression and nuclear accumulation of nuclear factor-erythroid 2-related factor 2 (Nrf2), an essential transcription factor for HO-1 induction. Treatment with tin protoporphyrin, a selective inhibitor of HO-1, reversed the inhibition of nitric oxide production by MBMC, suggesting that HO-1 induction mediates MBMC-mediated suppression of nitric oxide production. MBMC treatment rapidly and transiently decreased glutathione (GSH) levels, and treatment with GSH-Et (cell permeable form of GSH) or N-acetylcysteine (precursor of GSH) counteracted the HO-1 and Nrf2 expression elicited by MBMC, indicating that MBMC-induced HO-1 expression requires transient depletion of GSH. In summary, MBMC inhibits LPS-stimulated nitric oxide production via down-regulation of inflammatory pathways (NF-jB, p38 and JNK) and induction of the protective enzyme, HO-1.Nitric oxide, a bioactive free radical, regulates many physiological processes [1]. However, excessive nitric oxide production is implicated in the pathogenesis of various inflammatory diseases, such as haemorrhagic and septic shock, chronic infections and rheumatoid arthritis [2][3][4]. Inducible nitric oxide synthase (iNOS) is induced in response to inflammatory stimuli and catalyses the production of large amounts of nitric oxide during inflammation [5]. Therefore, blocking excessive nitric oxide production through inhibiting iNOS expression may improve abnormal inflammatory responses. iNOS expression is regulated by nuclear factor jB (NF-jB) and mitogen-activated protein kinase (MAPK) pathways [6][7][8].Haem oxygenase 1 (HO-1) has anti-inflammatory properties associated with cytoprotective responses [9,10]. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is critical for HO-1 induction and is activated by diverse oxidants, pro-oxidants, antioxidants and chemopreventive agents [11,12]. Activated Nrf2 accumulates in the nucleus, binds to the antioxidant response element and up-regulates antioxidant enzymes, including HO-1 [13]. The nuclear accumulation of Nrf2 can be regulated by translocation from the cytosol and ⁄ or by increased expression level of Nrf2 [14]. Glutathione (GSH) is an antioxidant that protects cells from oxidative and nitrosative stress [15]. Depletion of intracellular GSH may induce Nrf2 expression as a cellular defence mechanism to increase GSH content [16]. It has been shown that depletion of GSH induces HO-1 expression and inhibits nitric oxide production [17].We have previously demonstrated that 2¢,4¢,6¢-tris(methoxymethoxy)chalcone (TMMC), a syn...

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“…Specific cDNA probes were amplified by RT-PCR using the selective primers and cloned in a TA vector (Promega, Madison, WI, USA). The primers used were as follows: TNF-a sense [16], 5´-TAC TGA ACT TCG GGG TGA TCG GTC C-3´, and antisense, 5´-CAG CCT TGT CCC TTG AAG AGA ACC-3´ (295 bp); and HO-1 sense [17], 5´-CGC AAC AAG CAG AAC CCA-3´, and antisense, 5´-TGA CGC CAT CTG TGA GGG-3´ (507 bp). Prehybridization and hybridization were performed as described previously [16,17].…”

Section: Northern Blot Analysismentioning

confidence: 99%

Isoliquiritigenin, from Dalbergia odorifera, up-regulates anti-inflammatory heme oxygenase-1 expression in RAW264.7 macrophages

et al. 2009

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Heme oxygenase 1 mediates anti-inflammatory effects of 2′,4′,6′-tris(methoxymethoxy) chalcone

Cited by 70 publications

References 34 publications

Ethyl Pyruvate Induces Heme Oxygenase-1 Through p38 Mitogen-Activated Protein Kinase Activation by Depletion of Glutathione in RAW 264.7 Cells and Improves Survival in Septic Animals

Ethyl Pyruvate Induces Heme Oxygenase-1 Through p38 Mitogen-Activated Protein Kinase Activation by Depletion of Glutathione in RAW 264.7 Cells and Improves Survival in Septic Animals

2′‐Methoxy‐4′6′‐Bis(Methoxymethoxy)Chalcone Inhibits Nitric Oxide Production in Lipopolysaccharide‐Stimulated RAW 264.7 Macrophages

Isoliquiritigenin, from Dalbergia odorifera, up-regulates anti-inflammatory heme oxygenase-1 expression in RAW264.7 macrophages

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