Delivery of Cinnamic Aldehyde Antioxidant Response Activating nanoParticles (ARAPas) for Vascular Applications

Selective delivery of nuclear factor erythroid 2-related factor 2 (Nrf2) activators to the injured vasculature at the time of vascular surgical intervention has the potential to attenuate oxidative stress and decrease vascular smooth muscle cell (VSMC) hyperproliferation and migration towards the inner vessel wall. To this end, we developed a nanoformulation of cinnamic aldehyde (CA), termed Antioxidant Response Activating nanoParticles (ARAPas), that can be readily loaded into macrophages ex vivo. The CA-ARAPas-macrophage system was used to study the effects of CA on VSMC in culture. CA was encapsulated into a pluronic micelle that was readily loaded into both murine and human macrophages. CA-ARAPas inhibits VSMC proliferation and migration, and activates Nrf2. Macrophage-mediated transfer of CA-ARAPas to VSMC is evident after 12 h, and Nrf2 activation is apparent after 24 h. This is the first report, to the best of our knowledge, of CA encapsulation in pluronic micelles for macrophage-mediated delivery studies. The results of this study highlight the feasibility of CA encapsulation and subsequent macrophage uptake for delivery of cargo into other pertinent cells, such as VSMC.

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NRF2/ARE pathway negatively regulates BACE1 expression and ameliorates cognitive deficits in mouse Alzheimer’s models

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1819541116 ◽

2019 ◽

Vol 116 (25) ◽

pp. 12516-12523 ◽

Cited By ~ 21

Author(s):

Gahee Bahn ◽

Jong-Sung Park ◽

Ui Jeong Yun ◽

Yoon Jee Lee ◽

Yuri Choi ◽

...

Keyword(s):

Cognitive Deficits ◽

Redox Regulation ◽

Amyloid Β ◽

Antioxidant Response ◽

Related Factor ◽

Bace1 Expression ◽

Nrf2 Activation ◽

Antioxidant Response Elements ◽

Aβ Generation ◽

Aβ Production

BACE1 is the rate-limiting enzyme for amyloid-β peptides (Aβ) generation, a key event in the pathogenesis of Alzheimer’s disease (AD). By an unknown mechanism, levels of BACE1 and a BACE1 mRNA-stabilizing antisense RNA (BACE1-AS) are elevated in the brains of AD patients, implicating that dysregulation of BACE1 expression plays an important role in AD pathogenesis. We found that nuclear factor erythroid-derived 2-related factor 2 (NRF2/NFE2L2) represses the expression of BACE1 and BACE1-AS through binding to antioxidant response elements (AREs) in their promoters of mouse and human. NRF2-mediated inhibition of BACE1 and BACE1-AS expression is independent of redox regulation. NRF2 activation decreases production of BACE1 and BACE1-AS transcripts and Aβ production and ameliorates cognitive deficits in animal models of AD. Depletion of NRF2 increases BACE1 and BACE1-AS expression and Aβ production and worsens cognitive deficits. Our findings suggest that activation of NRF2 can prevent a key early pathogenic process in AD.

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Abstract 17514: Hydrogen Sulfide Levels and NRF2 Activity are Attenuated in the Setting of Critical Limb Ischemia (CLI)

Circulation ◽

10.1161/circ.130.suppl_2.17514 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Kazi N Islam ◽

David J Polhemus ◽

Erminia Donnarumma ◽

Hiroyuki Otsuka ◽

Shashi Bhushan ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Hydrogen Sulfide ◽

Limb Ischemia ◽

Antioxidant Response ◽

Protein Carbonyl ◽

Related Factor ◽

Mobility Shift ◽

Protein Levels ◽

Nrf2 Activation

Background: Cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MST) are enzymatic sources of hydrogen sulfide (H2S). Functions of H2S are mediated by several targets including ion channels and signaling proteins. Nuclear factor-erythriod 2-related factor 2 (NRF2) is responsible for the expression of antioxidant response element (ARE)-regulated genes and is known to be upregulated by H2S. We examined the levels of H2S producing enzymes, H2S, and NRF2 activation status in skeletal muscle obtained from CLI patients. Methods: Gastrocnemius tissues were attained post amputation from human CLI and aged-matched control patients. Tissue H2S levels were measured using gas chromatography methods coupled with sulfur chemiluminescence. RT-qPCR, immunoblot, and electrophoretic mobility shift assay (EMSA) were used to analyze respective gene expression, protein levels, and DNA binding activity, respectively. Results: We found mRNA and protein levels of CSE, CBS, and 3-MST were significantly decreased in skeletal muscle of CLI (~2 fold, p < 0.05) patients as compared to control. H2S and sulfane sulfur levels were significantly decreased in skeletal muscle of CLI patients. We also observed significant reductions in NRF2 activation (2 fold, p < 0.05) as well as antioxidant proteins, such as CuZn-superoxide dismutase (2 fold, p < 0.05), catalase (2 fold, p < 0.05), and glutathione peroxidase (2 fold, p < 0.05) in skeletal muscle of CLI patients. Biomarkers of oxidative stress, such as malondialdehyde and protein carbonyl formation were significantly increased (2 fold, p < 0.05) in skeletal muscle of CLI patients as compared to age-matched controls. Conclusions: The data demonstrate that H2S bioavailability and NRF2 activation are both attenuated in CLI tissues concomitant with significantly increased oxidative stress. Reductions in the activity of H2S producing enzymes may contribute to the pathogenesis of CLI.

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NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis

Science Translational Medicine ◽

10.1126/scitranslmed.aad6095 ◽

2016 ◽

Vol 8 (334) ◽

pp. 334ra51-334ra51 ◽

Cited By ~ 80

Author(s):

Hui Wang ◽

Xiufei Liu ◽

Min Long ◽

Yi Huang ◽

Linlin Zhang ◽

...

Keyword(s):

Tumor Metastasis ◽

Antioxidant Response ◽

Diabetic Patients ◽

Cancer Tissue ◽

Related Factor ◽

Tissue Samples ◽

Dipeptidyl Peptidase 4 ◽

Potential Biomarker ◽

Nrf2 Activation ◽

Dipeptidyl Peptidase 4 Inhibitors

Cancer is a common comorbidity of diabetic patients; however, little is known about the effects that antidiabetic drugs have on tumors. We discovered that common classes of drugs used in type 2 diabetes mellitus, the hypoglycemic dipeptidyl peptidase–4 inhibitors (DPP-4i) saxagliptin and sitagliptin, as well as the antineuropathic α-lipoic acid (ALA), do not increase tumor incidence but increase the risk of metastasis of existing tumors. Specifically, these drugs induce prolonged activation of the nuclear factor E2–related factor 2 (NRF2)–mediated antioxidant response through inhibition of KEAP1-C151–dependent ubiquitination and subsequent degradation of NRF2, resulting in up-regulated expression of metastasis-associated proteins, increased cancer cell migration, and promotion of metastasis in xenograft mouse models. Accordingly, knockdown ofNRF2attenuated naturally occurring and DPP-4i–induced tumor metastasis, whereas NRF2 activation accelerated metastasis. Furthermore, in human liver cancer tissue samples, increased NRF2 expression correlated with metastasis. Our findings suggest that antioxidants that activate NRF2 signaling may need to be administered with caution in cancer patients, such as diabetic patients with cancer. Moreover, NRF2 may be a potential biomarker and therapeutic target for tumor metastasis.

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Nrf2 activation as a future target of therapy for chronic diseases

Functional Foods in Health and Disease ◽

10.31989/ffhd.v4i12.160 ◽

2014 ◽

Vol 4 (12) ◽

pp. 510 ◽

Cited By ~ 4

Author(s):

Rame Taha ◽

Gilbert Blaise

Keyword(s):

Oxidative Stress ◽

Chronic Diseases ◽

Therapeutic Potential ◽

Antioxidant Response ◽

Premature Aging ◽

Therapeutic Effects ◽

Related Factor ◽

Nrf2 Activation ◽

Inflammatory Drugs ◽

Therapeutic Alternatives

Background: Chronic inflammation integrally related to oxidative stress has been increasingly recognized as a contributing factor in various chronic diseases such as neurodegenerative diseases, pulmonary diseases, metabolic syndrome, and cardiovascular diseases as well as premature aging. Thus, inhibiting this vicious circle has the potential to delay, prevent progression, and treat those diseases. However, adverse effects of current anti-inflammatory drugs and the failure of exogenous antioxidant encourage scientists to develop new therapeutic alternatives. The nuclear factor E2-related factor 2 (Nrf2) is the transcription factor that is responsible for the expression of antioxidant response element (ARE)-regulated genes and have been described as having many therapeutic effects. In this review, we have discussed the role of oxidative stress in various chronic diseases. Furthermore, we have also explored various novel ways to activate Nrf2 either directly or indirectly, which may have therapeutic potential in attenuating oxidative stress, inflammation and mitochondrial dysfunction that contributes to chronic diseases.Keywords: Oxidative stress, Mitochondria, Inflammation, Nrf2, Nutrition, Chronic diseases

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The antioxidant response favors Leishmania parasites survival, limits inflammation and reprograms the host cell metabolism

PLoS Pathogens ◽

10.1371/journal.ppat.1009422 ◽

2021 ◽

Vol 17 (3) ◽

pp. e1009422

Author(s):

Marta Reverte ◽

Remzi Onur Eren ◽

Baijayanti Jha ◽

Chantal Desponds ◽

Tiia Snäkä ◽

...

Keyword(s):

Host Cell ◽

Tyrosine Kinases ◽

Molecular Mechanisms ◽

Cell Metabolism ◽

Antioxidant Response ◽

Host Immune System ◽

Related Factor ◽

Tissue Destruction ◽

Tnf Α ◽

Nrf2 Activation

The oxidative burst generated by the host immune system can restrict intracellular parasite entry and growth. While this burst leads to the induction of antioxidative enzymes, the molecular mechanisms and the consequences of this counter-response on the life of intracellular human parasites are largely unknown. The transcription factor NF-E2-related factor (NRF2) could be a key mediator of antioxidant signaling during infection due to the entry of parasites. Here, we showed that NRF2 was strongly upregulated in infection with the human Leishmania protozoan parasites, its activation was dependent on a NADPH oxidase 2 (NOX2) and SRC family of protein tyrosine kinases (SFKs) signaling pathway and it reprogrammed host cell metabolism. In inflammatory leishmaniasis caused by a viral endosymbiont inducing TNF-α in chronic leishmaniasis, NRF2 activation promoted parasite persistence but limited TNF-α production and tissue destruction. These data provided evidence of the dual role of NRF2 in protecting both the invading pathogen from reactive oxygen species and the host from an excess of the TNF-α destructive pro-inflammatory cytokine.

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Compound NSC84167 selectively targets NRF2-activated pancreatic cancer by inhibiting asparagine synthesis pathway

Cell Death and Disease ◽

10.1038/s41419-021-03970-8 ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Bingbing Dai ◽

Jithesh J. Augustine ◽

Ya’an Kang ◽

David Roife ◽

Xinqun Li ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Synthetic Lethality ◽

Ex Vivo ◽

Protein Translation ◽

Metabolic Reprogramming ◽

Related Factor ◽

Pancreatic Cancers ◽

Nrf2 Activation

AbstractNuclear factor erythroid 2-related factor 2 (NRF2) is aberrantly activated in about 93% of pancreatic cancers. Activated NRF2 regulates multiple downstream molecules involved in cancer cell metabolic reprogramming, translational control, and treatment resistance; however, targeting NRF2 for pancreatic cancer therapy remains largely unexplored. In this study, we used the online computational tool CellMinerTM to explore the NCI-60 drug databases for compounds with anticancer activities correlating most closely with the mRNA expression of NQO1, a marker for NRF2 pathway activity. Among the >100,000 compounds analyzed, NSC84167, termed herein as NRF2 synthetic lethality compound-01 (NSLC01), was one of the top hits (r = 0.71, P < 0.001) and selected for functional characterization. NSLC01 selectively inhibited the viabilities of four out of seven conventional pancreatic cancer cell lines and induced dramatic apoptosis in the cells with high NRF2 activation. The selective anticancer activity of NSLC01 was further validated with a panel of nine low-passage pancreatic patient-derived cell lines, and a significant reverse correlation between log(IC50) of NSLC01 and NQO1 expression was confirmed (r = −0.5563, P = 0.024). Notably, screening of a panel of nine patient-derived xenografts (PDXs) revealed six PDXs with high NQO1/NRF2 activation, and NSLC01 dramatically inhibited the viabilities and induced apoptosis in ex vivo cultures of PDX tumors. Consistent with the ex vivo results, NSLC01 inhibited the tumor growth of two NRF2-activated PDX models in vivo (P < 0.01, n = 7–8) but had no effects on the NRF2-low counterpart. To characterize the mechanism of action, we employed a metabolomic isotope tracer assay that demonstrated that NSLC01-mediated inhibition of de novo synthesis of multiple amino acids, including asparagine and methionine. Importantly, we further found that NSLC01 suppresses the eEF2K/eEF2 translation elongation cascade and protein translation of asparagine synthetase. In summary, this study identified a novel compound that selectively targets protein translation and induces synthetic lethal effects in NRF2-activated pancreatic cancers.

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Dysregulation of Nrf2 in Hepatocellular Carcinoma: Role in Cancer Progression and Chemoresistance

Cancers ◽

10.3390/cancers10120481 ◽

2018 ◽

Vol 10 (12) ◽

pp. 481 ◽

Cited By ~ 40

Author(s):

Azhwar Raghunath ◽

Kiruthika Sundarraj ◽

Frank Arfuso ◽

Gautam Sethi ◽

Ekambaram Perumal

Keyword(s):

Hepatocellular Carcinoma ◽

Transcription Factor ◽

Cancer Progression ◽

Redox Homeostasis ◽

Antioxidant Response ◽

Related Factor ◽

Liver Malignancy ◽

Beneficial Effects ◽

Nrf2 Activation ◽

Key Factor

The liver executes versatile functions and is the chief organ for metabolism of toxicants/xenobiotics. Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the third foremost cause of cancer death worldwide. Oxidative stress is a key factor related with the development and progression of HCC. Nuclear factor erythroid 2 [NF-E2]-related factor 2 (Nrf2) is a cytosolic transcription factor, which regulates redox homeostasis by activating the expression of an array of antioxidant response element-dependent genes. Nrf2 displays conflicting roles in normal, healthy liver and HCC; in the former, Nrf2 offers beneficial effects, whereas in the latter it causes detrimental effects favouring the proliferation and survival of HCC. Sustained Nrf2 activation has been observed in HCC and facilitates its progression and aggressiveness. This review summarizes the role and mechanism(s) of action of Nrf2 dysregulation in HCC and therapeutic options that can be employed to modulate this transcription factor.

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HO-1 underlies resistance of AML cells to TNF-induced apoptosis

Blood ◽

10.1182/blood-2007-07-104042 ◽

2008 ◽

Vol 111 (7) ◽

pp. 3793-3801 ◽

Cited By ~ 90

Author(s):

Stuart A. Rushworth ◽

David J. MacEwan

Keyword(s):

Cell Death ◽

Myeloid Leukemia ◽

Antioxidant Response ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Proinflammatory Response ◽

Nrf2 Activation ◽

Antioxidant Response Elements ◽

Induced Apoptosis ◽

Necrosis Factor

Abstract In human monocytes, tumor necrosis factor (TNF) induces a proinflammatory response. In NF-κB–inhibited monocytes, TNF stimulates cell death/apoptosis. In the present study, we analyzed the response of acute myeloid leukemia (AML) cells to TNF stimulation in conjunction with NF-κB inhibition. In all AML-derived cells tested, NF-κB–inhibited cells were resistant to TNF-induced apoptosis. Further investigation revealed that the cytoprotective gene heme oxygenase-1 (HO-1) was induced in NF-κB–inhibited AML cells in response to TNF stimulation, and HO-1 was responsible for the resistance of AML cells to the cytotoxic actions of TNF. Moreover, after transfection with HO-1 siRNA, the resistance to TNF-induced cell death signals of AML cells was removed. The HO-1 promoter region contains antioxidant-response elements that can bind the transcription factor NF-E2–related factor 2 (Nrf2). We further demonstrated that Nrf2 was activated by TNF under NF-κB–inhibited conditions, to play the major role in up-regulating HO-1 expression and ultimately the fate of AML cells. These results demonstrate a novel mechanism by which TNF-induced cell death is inhibited in AML cells through the induction of HO-1, via Nrf2 activation.

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The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: a systematic review of human intervention trials

Molecular Biology Reports ◽

10.1007/s11033-020-06041-x ◽

2021 ◽

Author(s):

Tom Clifford ◽

Jarred P. Acton ◽

Stuart P. Cocksedge ◽

Kelly A. Bowden Davies ◽

Stephen J. Bailey

Keyword(s):

Systematic Review ◽

Assessment Tool ◽

Cochrane Collaboration ◽

Risk Of Bias ◽

Related Factor ◽

Human Intervention ◽

Nrf2 Activation ◽

Dietary Phytochemicals ◽

Intervention Trials

AbstractWe conducted a systematic review of human trials examining the effects of dietary phytochemicals on Nrf2 activation. In accordance with the PRISMA guidelines, Medline, Embase and CAB abstracts were searched for articles from inception until March 2020. Studies in adult humans that measured Nrf2 activation (gene or protein expression changes) following ingestion of a phytochemical, either alone or in combination were included. The study was pre-registered on the Prospero database (Registration Number: CRD42020176121). Twenty-nine full-texts were retrieved and reviewed for analysis; of these, eighteen were included in the systematic review. Most of the included participants were healthy, obese or type 2 diabetics. Study quality was assessed using the Cochrane Collaboration Risk of Bias Assessment tool. Twelve different compounds were examined in the included studies: curcumin, resveratrol and sulforaphane were the most common (n = 3 each). Approximately half of the studies reported increases in Nrf2 activation (n = 10); however, many were of poor quality and had an unclear or high risk of bias. There is currently limited evidence that phytochemicals activate Nrf2 in humans. Well controlled human intervention trials are needed to corroborate the findings from in vitro and animal studies.

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Modulation of Nrf2 and NF-κB Signaling Pathways by Naturally Occurring Compounds in Relation to Cancer Prevention and Therapy. Are Combinations Better Than Single Compounds?

International Journal of Molecular Sciences ◽

10.3390/ijms22158223 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8223

Author(s):

Violetta Krajka-Kuźniak ◽

Wanda Baer-Dubowska

Keyword(s):

Cancer Prevention ◽

Signaling Pathways ◽

Current Knowledge ◽

Cancer Chemoprevention ◽

Antioxidant Response ◽

Natural Food ◽

Related Factor ◽

Nuclear Factor ◽

Edible Plant ◽

Prevention And Therapy

Nrf2 (nuclear factor erythroid 2-related factor 2) and NF-κB (nuclear factor–kappa B) signaling pathways play a central role in suppressing or inducing inflammation and angiogenesis processes. Therefore, they are involved in many steps of carcinogenesis through cooperation with multiple signaling molecules and pathways. Targeting both transcription factors simultaneously may be considered an equally important strategy for cancer chemoprevention and therapy. Several hundreds of phytochemicals, mainly edible plant and vegetable components, were shown to activate Nrf2 and mediate antioxidant response. A similar number of phytochemicals was revealed to affect NF-κB. While activation of Nrf2 and inhibition of NF-κB may protect normal cells against cancer initiation and promotion, enhanced expression and activation in cancer cells may lead to resistance to conventional chemo- or radiotherapy. Most phytochemicals, through different mechanisms, activate Nrf2, but others, such as luteolin, can act as inhibitors of both Nrf2 and NF-κB. Despite many experimental data confirming the above mechanisms currently, limited evidence exists demonstrating such activity in humans. Combinations of phytochemicals resembling that in a natural food matrix but allowing higher concentrations may improve their modulating effect on Nrf2 and NF-κB and ultimately cancer prevention and therapy. This review presents the current knowledge on the effect of selected phytochemicals and their combinations on Nrf2 and NF-κB activities in the above context.

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