PubMed: 22020111

Title
Oxidative stress in health and disease: the therapeutic potential of Nrf2 activation.
Journal
Molecular aspects of medicine
Volume
32
Issue
None
Pages
234-46
Date
2011-08-01
Authors
Bose SK | McCord JM | Gao B | Hybertson BM

Evidence 803725ffa0

Sulforaphane is often considered a ‘‘gold standard’’ among naturally-occurring Nrf2 activators (Agyeman et al., 2011).

Evidence 38b7248e09

The greatest FImax was observed with Protandim at 135-fold, followed by bardoxolone methyl at 67-fold, dimethyl fumarate at 55-fold, and sulforaphane at 21-fold

Evidence e0c90382eb

When compared contemporaneously in the AREc32-based assay, FImax observed was in the order Protandim > bardoxolone methyl > dimethyl fumarate > sulforaphane.

Evidence 240377b798

A recent laboratory study of dimethyl fumarate found that the compound activates Nrf2 in primary astrocytes, but not in the C6 glioma-derived cell line (Wilms et al., 2010), demonstrating that different cells may respond quite differently to Nrf2 activators

Evidence 14431ea13f

While Protandim, bardoxolone methyl, BG-12, and sulforaphane all have been demonstrated to modify gene expression profiles by activation of Nrf2, they have not been compared side by side, in the same cell line, under identical conditions.

Evidence a3b28c2592

This antiporter was recently found to be decreased by repeated cocaine exposure, and restoration of the activity prevented cocaine-primed drug seeking behavior in rats (Baker et al., 2003).

Evidence bd8d215fdc

SLC7A11, induced 76-fold, encodes a cystine/glutamate antiporter responsible for maintaining extracellular glutamate in the brain, and for importing cystine necessary for glutathione synthesis (Albrecht et al., 2010).

Evidence 56511d0e15

The study also found that resveratrol, a putative activator of SIRT1 (Howitz et al., 2003), inhibited Nrf2-dependent transcription, apparently contradicting earlier reports that resveratrol activates Nrf2 (Chen et al., 2005; Ungvari et al., 2010).

Evidence c7897dd8fd

Overexpression of the HSPB8-BAG3 complex also stimulates autophagy and facilitates the clearance of mutated aggregation-prone proteins, the accumulation of which characterizes many neurodegenerative disorders such as Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis (Seidel et al., 2011).

Evidence 9bd002ea7f

TNFSF9 (aka CD137L), induced 19-fold, can induce maturation of human immature monocyte-derived dendritic cells leading to an enhanced capacity of the dendritic cells to stimulate protective T cell responses, as compared to classical dendritic cells (Tang et al., 2011).

Evidence 2792fe6fee

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug.

Evidence 8883796664

In our gene expression data, SIRT1 was induced 1.75-fold by Protandim (p = 0.015).

Evidence 35da14e46a

AKR1B10, induced 72-fold, encodes aldo–keto reductase family 1 member B10 which efficiently detoxifies mutagenic and carcinogenic alpha, beta-unsaturated carbonyls such as 4-hydroxynonenal (Zhong et al., 2009).

Evidence d06a86a2ac

PTGR1 (aka LTB4DH), induced 68-fold, encodes leukotriene B4-12-hydroxydehydrogenase, which is considered to be a key enzyme responsible for biological inactivation of prostaglandins and related eicosanoids (Tai et al., 2002).

Evidence f9dbfcaf87

HMOX1, induced 56-fold, encodes heme oxygenase-1, an antioxidant enzyme considered a hallmark of Nrf2 activation.

Evidence 569eaa9419

A likely explanation for the increased expression of GLRX2 (glutaredoxin 2) and NQO1 (NAD(P)H dehydrogenase, quinone 1) in colon carcinoma and of GLRX (glutaredoxin), HMOX1 (heme oxygenase-1), NQO1, and SOD1 (superoxide dismutase 1) in Alzheimer is that it represents an adaptive attempt to partially compensate for the increased level of oxidative stress associated with these diseases. These antioxidant genes are also upregulated by Protandim, which would provide additional antioxidant protection beyond that achieved by the ROS-dependent induction of these enzymes in the diseased tissues.

Evidence 14db65e12f

AIFM2 (aka AMID), induced 29-fold, is implicated in caspase-independent apoptosis and was found to be downregulated in a majority of human tumors (Wu et al., 2004b).

Evidence 32f98f3b9d

OSGIN1 (aka OKL38), induced 29-fold, is an oxidative stress response gene and a tumor suppressor gene (Yao et al., 2008).

Evidence dcf7aef963

GPX3, induced 20-fold, encodes an important antioxidant enzyme, glutathione peroxidase-3, found normally in plasma and kidney but underexpressed in head and neck cancers (Chen et al., 2011).

Evidence a33a8e981a

SQSTM1, induced 20-fold, encodes sequestosome-1, a participant in the autophagy pathway recently shown to be necessary to avoid premature senescence in human fibroblasts (Kang et al., 2011).

Evidence 1071232bfe

HSPB8, induced 19-fold, is a heat shock protein that forms a complex with BAG3 (also induced 1.43-fold).

Evidence 0868039528

For example, 19 genes products have been associated with atherosclerosis and are up or down-regulated by Protandim. Of these 19 genes, the first 16 listed (84%) were regulated by Protandim in the opposing direction to that taken by the atherosclerosis disease process. The probable benefit of this effect of Protandim is further supported by the fact that of the 11 gene products currently being targeted by drug interventions (Table 1, in bold type), nine of them (Table 1, marked by asterisks) are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the therapeutic intervention.

Evidence 23d09fa8eb

In colon carcinoma, IPA analysis revealed 28 genes associated with the disease that were also modulated by Protandim treatment. Of these, the first 25 listed (89%) were regulated by Protandim in the opposing direction to that taken by the colon carcinoma disease process.

Evidence 3c91b98d45

In addition, Protandim downregulated the one gene targeted by a chemotherapeutic drug, an antimetabolite inhibitor for that gene’s product, thymidylate synthetase

Evidence db79e24260

Bardoxolone methyl appeared to produce a biphasic induction, producing near maximal FI over a range of concentrations from less than 40 nM to 0.4 lM

Evidence 133672b9c9

After 52 weeks, the estimated glomerular filtration rate in the 75 mg/day treatment group had increased by 10.5 ± 1.8 ml/min/1.73 m2 (p < 0.001), representing an increase of about 32% when compared to entry values.

Evidence ef967db506

Patients with relapsing-remitting multiple sclerosis treated with BG-12 for 24 weeks showed significantly fewer new gadolinium-enhancing lesions, with significantly reduced probability of their evolution to T1-hypointense lesions than patients treated with placebo (Macmanus et al., 2011)

Evidence 59450b2708

The study suggests that Nrf2 activation represents a viable new therapeutic approach for renal disease, as similar results are not achievable with currently available therapies

Evidence 09133ff384

These studies suggest that Nrf2 activation may represent a promising new therapeutic approach for multiple sclerosis.

Evidence c78a19ee63

Sirtuin 1 (SIRT1) was shown to decrease acetylation of Nrf2, as well as Nrf2-dependent transcription.

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