Nrf2-dependent protection from LPS induced inflammatory response and mortality by CDDO-Imidazolide

Thimmulappa, Rajesh K.; Scollick, Catherine; Traore, Kassim; Yates, Melinda S.; Trush, Michael A.; Liby, Karen T.; Sporn, Michael B.; Yamamoto, Masayuki; Kensler, Thomas W.; Biswal, Shyam

doi:10.1016/j.bbrc.2006.10.102

Cited by 319 publications

(291 citation statements)

References 22 publications

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“…The reciprocal regulation between Nrf2 system function and PTEN expression has been suggested by several studies [34,40] . In this study, by using an Nrf2 inhibitor, we found that Nrf2 is causally involved in the effect of metformin on the regulation of PTEN and insulin signaling (Supplementary Figure 3).…”

Section: Discussionmentioning

confidence: 90%

Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling

et al. 2016

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Aim: Accumulating evidence shows that lipopolysaccharides (LPS) derived from gut gram-negative bacteria can be absorbed, leading to endotoxemia that triggers systemic inflammation and insulin resistance. In this study we examined whether metformin attenuated endotoxemia, thus improving insulin signaling in high-fat diet fed mice. Methods: Mice were fed a high-fat diet for 18 weeks to induce insulin resistance. One group of the mice was treated with oral metformin (100 mg·kg -1 ·d -1 ) for 4 weeks. Another group was treated with LPS (50 μg·kg -1 ·d -1 , sc) for 5 days followed by the oral metformin for 10 d. Other two groups received a combination of antibiotics for 7 d or a combination of antibiotics for 7 d followed by the oral metformin for 4 weeks, respectively. Glucose metabolism and insulin signaling in liver and muscle were evaluated, the abundance of gut bacteria, gut permeability and serum LPS levels were measured. Results: In high-fat fed mice, metformin restored the tight junction protein occludin-1 levels in gut, reversed the elevated gut permeability and serum LPS levels, and increased the abundance of beneficial bacteria Lactobacillus and Akkermansia muciniphila. Metformin also increased PKB Ser473 and AMPK T172 phosphorylation, decreased MDA contents and redox-sensitive PTEN protein levels, activated the anti-oxidative Nrf2 system, and increased IκBα in liver and muscle of the mice. Treatment with exogenous LPS abolished the beneficial effects of metformin on glucose metabolism, insulin signaling and oxidative stress in liver and muscle of the mice. Treatment with antibiotics alone produced similar effects as metformin did. Furthermore, the beneficial effects of antibiotics were addictive to those of metformin. Conclusion: Metformin administration attenuates endotoxemia and enhances insulin signaling in high-fat fed mice, which contributes to its anti-diabetic effects.

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Section: Discussionmentioning

confidence: 90%

Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling

et al. 2016

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“…This Nrf2-mediated transcriptional interference appears to be independent of the level of reactive oxygen species. Although the conventional hypothesis is that Nrf2 alleviates inflammation as a secondary consequence of its antireactive oxygen species and anti-oxidation function (25), these results suggest that Nrf2 inhibits the induction of pro-inflammatory cytokine gene transcription. Thus, Nrf2 appears to be the key regulator of two important cytoprotective pathways, anti-inflammation and anti-oxidation.…”

Section: Anti-inflammation By Nrf2mentioning

confidence: 84%

Stress-sensing mechanisms and the physiological roles of the Keap1–Nrf2 system during cellular stress

Suzuki

Yamamoto

2017

Journal of Biological Chemistry

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336

272

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Edited by Ruma BanerjeeTranscription factor Nrf2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. Nrf2 induces the expression of detoxification and antioxidant enzymes and suppresses the induction of pro-inflammatory cytokine genes. Keap1 (Kelch-like ECH-associated protein 1) is an adaptor subunit of Cullin 3-based E3 ubiquitin ligase. Keap1 regulates the activity of Nrf2 and acts as a sensor for oxidative and electrophilic stresses. In this review, we discuss the molecular mechanisms by which the Keap1-Nrf2 system senses and regulates the cellular response to environmental stresses. In particular, we focus on the multiple stress-sensing mechanisms of Keap1 and novel regulatory functions of Nrf2.Our body is equipped with a defense system that up-regulates the expression levels of cytoprotective enzyme genes. Nrf2 is the central player in the inducible expression of cellular defense enzymes (1, 2). Nrf2 belongs to the CNC (cap-n-collar) subfamily of basic region-leucine zipper-type transcription factors (3). Nrf2 dimerizes with one of the small Maf proteins (sMaf). The Nrf2-sMaf heterodimer binds to the antioxidantresponse element (ARE) 2 or electrophile-response element located in the regulatory regions of many cytoprotective enzyme genes (1, 4 -6). In this way, Nrf2 activates a wide range of cellular defense processes, thereby eliminating harmful substances.Keap1 acts as an E3 ubiquitin ligase substrate-recognition subunit and specifically targets Nrf2 (7-10). In the absence of stress, Nrf2 is efficiently ubiquitinated by the Keap1-Cul3 E3 ligase and degraded rapidly through the proteasome pathway, such that cellular Nrf2 activity is constitutively suppressed. Upon exposure to oxidative or electrophilic stresses, Keap1 loses its ability to ubiquitinate Nrf2, allowing Nrf2 to accumulate in the nucleus and activate its target genes.Recent studies expanded our knowledge on the targets of the Keap1-Nrf2 system, and the molecular mechanisms underpinning how this system senses a variety of environmental stresses. Keap1 primarily regulates Nrf2 in the cytoplasm; however, a Keap1-independent mechanism utilizing ␤-TrCP (␤-transducin repeat-containing protein) in the nucleus also operates (11). Anti-inflammation by Nrf2Several hundred Nrf2 target genes have been identified through gene expression profiling analysis and chromatin immunoprecipitation (ChIP) analysis (12-17). The Nrf2 target genes identified in these studies include enzymes involved in detoxification, anti-oxidation, and metabolism, as summarized in Fig. 1 (18).In addition to protecting against oxidative and xenobiotic insults, Nrf2 has also been known to attenuate inflammation (19). Nrf2 deficiency exacerbates inflammation, such as sepsis, pleurisy, and emphysema, in a variety of murine models (20 -22). In human clinical studies, the Nrf2 inducer Tecfidera (dimethyl fumarate) has been approved for the treatment of multiple sclerosis (23, 24)-at least in part based on its antiinflammatory function. Thus, N...

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“…In vivo, DMF treatment of experimental autoimmune encephalomyelitis (EAE) was also associated with a Th2 bias, which may be a consequence of induction of antigen-presenting antiinflammatory type II dendritic cells (DCs) (11). Consistent with these observations, results indicate Nrf2 itself may regulate innate and adaptive T-cell immune responses in models of organ-specific inflammation (12,13), including EAE (14,15). Nevertheless, although DMF demonstrated prominent reduction of inflammatory measures of MS (8,9), it is not clear that this benefit is mediated through activation of Nrf2.…”

mentioning

confidence: 77%

Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2

Schulze-Topphoff

Varrin‐Doyer

Pekarek

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

254

213

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Dimethyl fumarate (DMF) (BG-12, Tecfidera) is a fumaric acid ester (FAE) that was advanced as a multiple sclerosis (MS) therapy largely for potential neuroprotection as it was recognized that FAEs are capable of activating the antioxidative transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. However, DMF treatment in randomized controlled MS trials was associated with marked reductions in relapse rate and development of active brain MRI lesions, measures considered to reflect CNS inflammation. Here, we investigated the antiinflammatory contribution of Nrf2 in DMF treatment of the MS model, experimental autoimmune encephalomyelitis (EAE). C57BL/6 wild-type (WT) and Nrf2-deficient (Nrf2 −/− ) mice were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 (p35-55) for EAE induction and treated with oral DMF or vehicle daily. DMF protected WT and Nrf2 −/− mice equally well from development of clinical and histologic EAE. The beneficial effect of DMF treatment in Nrf2 −/− and WT mice was accompanied by reduced frequencies of IFN-γ and IL-17-producing CD4 + cells and induction of antiinflammatory M2 (type II) monocytes. DMF also modulated B-cell MHC II expression and reduced the incidence of clinical disease in a B-cell-dependent model of spontaneous CNS autoimmunity. Our observations that oral DMF treatment promoted immune modulation and provided equal clinical benefit in acute EAE in Nrf2 −/− and WT mice, suggest that the antiinflammatory activity of DMF in treatment of MS patients may occur through alternative pathways, independent of Nrf2.multiple sclerosis | dimethyl fumarate | Nrf2 | EAE | M2 monocytes

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Nrf2-dependent protection from LPS induced inflammatory response and mortality by CDDO-Imidazolide

Cited by 319 publications

References 22 publications

Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling

Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling

Stress-sensing mechanisms and the physiological roles of the Keap1–Nrf2 system during cellular stress

Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2

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