Nrf2 – Latest Studies

Nrf2 is a field of medical study that is becoming very popular in recent years. Research regarding the topic of Nrf2 now is the topic of mainstream medical conferences such as the Biochemical Conference held at Cambridge University.

The purpose of the meeting was to share progress in the fields of:

The transcription factor Nrf2 is a key mediator of the antioxidant response and is important in inflammation, cancer, multi-drug resistance, autophagy, aging, neurodegeneration, lipogenesis and many other physiological and pathological processes. This meeting will provide an opportunity for researchers interested in Nrf2 to discuss recent developments in this area.

Topics:

  • Structure, function and regulation of Nrf2
  • Repression of Nrf2 by Keap1
  • Role of Nrf2 target genes
  • Importance of Nrf2 in homeostasis and tissue repair
  • Role in chronic diseases, including cancer and cardiovascular disease
  • Keap1-independent mechanisms of Nrf2 repression
  • Nrf2 as a therapeutic target

While conferences only come around every now and again, here are the latest Nrf2 studies on Pubmed.gov

Nrf2-dependent antioxidant response mediated the protective effect of tanshinone IIA on doxorubicin-induced cardiotoxicity
Guo Z, Yan M, Chen L, Fang P, Li Z, Wan Z, Cao S, Hou Z, Wei S, Li W and Zhang B
Doxorubicin (DOX), a potent and widely used anticancer agent, can give rise to severe cardiotoxicity that limits its clinical use by inducing oxidative stress. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the central regulator of cellular responses to electrophilic/oxidative stress, which serves a critical role in maintenance of normal cardiac function. Tanshinone IIA (Tan IIA) has previously been reported to protect against DOX-induced cardiotoxicity. The aim of the present study was to elucidate whether Nrf2 signaling serves a role in the underlying mechanism. In the animal model, DOX induced acute cardiotoxicity, whereas Tan IIA pretreatment reduced the activity of myocardial enzymes, and increased activity of the antioxidant enzymes superoxide dismutase, catalase and glutathione (GSH). Furthermore, Tan IIA pretreatment (3-10 µM) significantly increased the cell viability and markedly restored morphological changes in DOX-injured H9c2 cells, decreased the generation of reactive oxygen species, and increased the level of intracellular GSH. Additionally, Tan IIA pretreatment also induced the nuclear accumulation of Nrf2 and its downstream genes heme oxygenase-1, NAD(P)H dehydrogenase (quinone) 1, and glutamate-cysteine ligase catalytic subunit in both the mice cardiac tissues and H9c2 cells. Nrf2 knockdown by small interfering RNA downregulated Tan IIA-induced Nrf2 activation and reversed the effect of Tan IIA on the DOX-induced inhibition of cell viability. These results suggest that the Nrf2-dependent antioxidant response mediates the protective effect of Tan IIA on DOX-induced cardiotoxicity.
Expression and localization of nuclear factor erythroid 2-related factor 2 in the ovarian tissues of mice at different ages
Sindan N, Bhandari A, Zhao Y, Lu X and Lv J
The aim of the present study was to investigate the expression and localization of nuclear factor erythroid 2-related factor 2 (Nrf2) in the ovaries of mice in different age groups, and to explore the association between Nrf2 and premature ovarian aging. The present study identified the localization of Nrf2 protein by performing immunohistochemical assay of ovarian tissues obtained from mice in different age groups. The mRNA expression levels of Nrf2 were detected via reverse transcription-quantitative polymerase chain reaction, while the expression levels of Nrf2 protein and apoptosis-associated proteins, including Caspase3 and B-cell lymphoma 2 (Bcl-2), were evaluated by western blot analysis. The results revealed that Nrf2 protein was mainly localized in granulosa cells, as well as in the secondary follicles and antral follicles of oocytes. Nrf2 expression levels were significantly lower in mice aged 4 days compared with 12-week-old mice (P<0.05), and the level of Nrf2 was lower in mice aged 40 weeks compared with those aged 12 weeks (P<0.05). In addition, the expression of the apoptosis protein Caspase3 in the ovarian tissue of mice aged 3, 8 and 12 weeks remained markedly greater when compared with those aged 4 days and 40 weeks. Bcl-2, an anti-apoptotic protein, was also significantly expressed in the ovarian tissues of juvenile (4-day-old) mice when compared with mice aged >40 weeks (P<0.05). In conclusion, Nrf2 was highly expressed in the ovarian tissues of mice of childbearing age (8-12 weeks old) and may possibly be involved in ovarian regulatory functions. The results indicated that Nrf2 expression and localization may have important implications in the prevention of ovarian aging.
Icariin and icaritin recover UVB-induced photoaging by stimulating Nrf2/ARE and reducing AP-1 and NF-κB signaling pathways: a comparative study on UVB-irradiated human keratinocytes
Hwang E, Lin P, Ngo HTT, Gao W, Wang YS, Yu HS and Yi TH
Icariin (ICA) and icaritin (ICT) exhibit many pharmacological functions including anti-osteoporosis, anti-cardiovascular, and anti-cancer activities; however, there are few comprehensive studies that track the detailed effects on UVB-induced photoaging. The recovery effects of ICA and ICT were investigated in UVB-irradiated human keratinocytes (HaCaTs). The results indicated that ICT and ICA showed strong radical scavenging activity, and the reactive oxygen species (ROS) scavenging activity of ICT was superior. UVB-induced matrix metalloproteinase-1 (MMP-1) expression was blocked by ICA via the inhibition of mitogen-activated protein kinase/activator protein 1 (MAPK/AP-1), which directly reduced extracellular matrix (ECM) degradation. ICT activated nuclear factor erythroid 2 related factor 2 (Nrf2) to improve the anti-oxidative stress capacity and suppress nuclear factor-κB (NF-κB) activation, decreasing vascular endothelial growth factor (VEGF) protein, and inflammatory cytokines induced ECM degrading enzyme secretion. Moreover, ICT was more advantageous to improve transforming growth factor beta 1 (TGF-β1) and procollagen type I expression than ICA, promoting the synthesis of collagen. Therefore, ICA and ICT have potential to treat UVB-induced oxidative stress, inflammation and photoaging, and will be posited as a novel strategy to alleviate photodamage.
Redox-Dependent Expression of Genes Encoding NADPH Oxidase 5 and the Key Antioxidant Enzymes during Formation of Drug Resistance of Tumor Cells to Cisplatin
Kalinina EV, Andreev YA, Petrova AS, Lubova KI, Shtil' AA, Chernov NN, Novichkova MD and Nurmuradov NK
Expression of genes that plays a significant role in the control of cellular redox homeostasis was studied during the development of drug resistance of human ovarian adenocarcinoma SKOV-3 cells to cisplatin. It was found that the development of drug resistance was accompanied by enhanced expression of the genes encoding the key antioxidant enzymes (SOD2, CAT, GPX1, and HO-1) and transcription factor Nrf2, as well as reduced expression of the gene encoding NOX5 isoform of NADPH oxidase. The results testify to redox-dependent development of the adaptive antioxidant response as an important process in the mechanism of formation of resistance to cisplatin.
Oxidative stress responses in human bronchial epithelial cells exposed to cigarette smoke and vapor from tobacco- and nicotine-containing products
Munakata S, Ishimori K, Kitamura N, Ishikawa S, Takanami Y and Ito S
The use of novel tobacco- and nicotine-containing vapor products that do not combust tobacco leaves is on the rise worldwide. The emissions of these products typically contain lower numbers and levels of potentially harmful chemicals compared with conventional cigarette smoke. These vapor products may therefore elicit fewer adverse biological effects. We compared the effects of emissions from different types of such products, i.e., our proprietary novel tobacco vapor product (NTV), a commercially available heat-not-burn tobacco product (HnB), and e-cigarette (E-CIG), and a combustible cigarette in a human bronchial epithelial cell line. The aqueous extract (AqE) of the test product was prepared by bubbling the produced aerosol into medium. Cells were exposed to the AqEs of test products, and then glutathione oxidation, Nrf2 activation, and secretion of IL-8 and GM-CSF were examined. We found that all endpoints were similarly perturbed by exposure to each AqE, but the effective dose ranges were different between cigarette smoke and the tobacco- and nicotine-containing vapors. These results demonstrate that the employed assays detect differences between product exposures, and thus may be useful to understand the relative potential biological effects of tobacco- and nicotine-containing products.
Neuroprotective effect of Capsicum annuum var. abbreviatum against hydrogen peroxide-induced oxidative stress in HT22 hippocampus cells
Byun EB, Park WY, Kim WS, Song HY, Sung NY and Byun EH
Phenolic compounds isolated from pepper (Capsicum annum) have been demonstrated to have neuroprotective effects, whereas the physiological properties of Capsicum annuum var. abbreviatum (CAA) have not been studied. Thus, we investigate the chemical composition and neuroprotective activity of CAA extract (CAAE) in HT22 hippocampus cells against HO-induced neurotoxicity. CAAE treatment resulted in a significant protection of HO-exposed HT22, this protection ultimately occurred through an inhibition of MDA and ROS levels and an induction of SOD activity. Furthermore, CAAE treatment reduced H0-induced apoptosis though decreasing the expression of pro-apoptotic factors (Bax, cytochrome c, and cleaved caspases-3) while increasing the expression of the anti-apoptotic factors (Bcl-2), as well as the accumulation of nucleus-Nrf2-mediated HO-1 signaling. Interestingly, CAAE has a high concentration of unique phenolic compositions (chlrogenic acid, tangeretin, etc.) than other capsicum annum extracts. Altogether, these findings suggest that CAAE can be a useful natural resource for alleviating neurodegenerative diseases.
Discovery of natural flavonoids as activators of Nrf2-mediated defense system: Structure-activity relationship and inhibition of intracellular oxidative insults
Li YR, Li GH, Zhou MX, Xiang L, Ren DM, Lou HX, Wang XN and Shen T
Continuous overproduction of reactive oxygen species (ROS), termed as oxidative stress, plays a crucial role in the onset and progression of many human diseases. Activation of nuclear transcription factor erythroid 2-related factor (Nrf2) by small molecules could eliminate ROS, and thus block the pathogenesis of oxidative stress-induced diseases. In this study, a natural flavonoid library was established and tested for their potential Nrf2 inducing effects. Based on QR inducing effect of flavonoids, their structure-activity relationship (SAR) on Nrf2 induction was summarized, and twenty flavonoids were firstly identified to be potential activators of Nrf2-mediated defensive response. Then, 7-O-methylbiochanin A (7-MBA) was further investigated for its capability on the Nrf2 activation and prevention against oxidative insults in human lung epithelial cells. Further studies indicated that 7-MBA activated Nrf2 signaling pathway and protected human lung epithelial Beas-2B cells against sodium arsenite [As(III)]-induced cytotoxicity in an Nrf2-dependent manner. Activation of Nrf2 by 7-MBA upregulated intracellular antioxidant capacity, which was produced by enhancement of Nrf2 stabilization, blockage of Nrf2 ubiquitination, as well as Nrf2 phosphorylation by mitogen-activated protein kinase (MAPK), protein kinase C (PKC), protein kinase R-like endoplasmic reticulum kinase (PERK), and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K). Taken together, 7-MBA is a novel isoflavone-type Nrf2 activator displaying potential preventive effect against oxidative damages in human lung epithelial cells.
Effects of Ulinastatin on myocardial oxidative stress and inflammation in severely burned rats
He F, Song Y, Ying WJ, Jin XY, Wang ZX, Su JD and Wang GY
By constructing the severe burns model in rat, we explored the effects of different doses of Ulinastatin (UTI) on protecting myocardium from oxidative stress and inflammatory reaction.
Association between glucose-lowering treatment and cancer metastasis among patients with preexisting type 2 diabetes and incident malignancy
Noh Y, Jeon SM and Shin S
Preclinical data suggested that dipeptidyl peptidase-4 (DPP-4) inhibitors may promote metastatic progression of preexisting cancer via nuclear factor erythroid 2 related factor 2 (NRF2) activation. We aimed to investigate the association between different glucose-lowering treatments, including DPP-4 inhibitors and metformin, both with potential NRF2 modulating effects, and new-onset metastatic cancer among type 2 diabetes patients with comorbid incident cancer. This population-based cohort study included 223,530 diabetic patients newly diagnosed with primary cancer during 2009-2011 in Korea. The patients were categorized into five study cohorts in accordance with treatment modalities during the follow-up until the end of 2016: no-antidiabetic drugs (no-AD), metformin, DPP-4 inhibitors, metformin+DPP-4 inhibitors, and insulin treatment. Following propensity score (PS) matching in a 1:1 ratio against the no-AD group, 18,805 patients in metformin, 1,865 in DPP-4 inhibitors, 31,074 in metformin+DPP-4 inhibitors, and 1,895 patients in insulin groups were identified for cohort entry and analyzed against the corresponding number of no-AD patients in each PS-matched comparison pair. Metastatic risk was lower with metformin plus or minus DPP-4 inhibitors (HR 0.84, 95% CI 0.79-0.90 and 0.87, 0.80-0.95, respectively), not significantly associated with DPP-4 inhibitors (0.99, 0.77-1.29) except after thyroid cancer (3.89, 1.01-9.64), and higher with insulin therapy (1.81, 1.46-2.24) compared with no-AD use for all cancers combined. In conclusion, DPP-4 inhibitor therapy was not associated with significant risk of cancer metastasis relative to no-AD therapy, irrespective of patient age and sex, except after thyroid cancer, while metastatic risk was decreased with metformin treatment among type 2 diabetes patients with preexisting cancer. This article is protected by copyright. All rights reserved.
Oxysophocarpine Retards the Growth and Metastasis of Oral Squamous Cell Carcinoma by Targeting the Nrf2/HO-1 Axis
Liu R, Peng J, Wang H, Li L, Wen X, Tan Y, Zhang L, Wan H, Chen F and Nie X
Nuclear factor erythroid 2-related factor 2 (Nrf2) is an oncogene in various types of cancers, including oral squamous cell carcinoma (OSCC). Oxysophocarpine (OSC) is a natural alkaloid that has multiple pharmacological activities. However, the biological functions and molecular mechanism underlying the effects of OSC on the growth and metastasis of OSCC are unclear.
Oxidative Stress-Protective and Anti-Melanogenic Effects of Loliolide and Ethanol Extract from Fresh Water Green Algae,
Park SH, Choi E, Kim S, Kim DS, Kim JH, Chang S, Choi JS, Park KJ, Roh KB, Lee J, Yoo BC and Cho JY
Loliolide is a monoterpenoid hydroxylactone found in many algae, including fresh water green algae, . To date, loliolide and compounds in have not been studied systematically with respect to skin pharmacology. In this study, we investigated oxidative stress-protective and anti-melanogenic effects of loliolide and ethanol extract (Pj-EE), known to contain loliolide, in human keratinocyte (HaCaT) cells and mouse melanoma (B16F10) cells. Loliolide suppressed the transcription of genes encoding matrix metalloproteinases (MMPS), which were induced in HaCaT cells by hydrogen peroxide (H₂O₂) treatment. Loliolide and Pj-EE not only reduced the melanin secretion and content in B16F10 cells but also increased the expression of the antioxidant proteins nuclear factor (erythroid-derived 2)-like 2 (NRF2) and heme oxygenase-1 (HO-1) in HaCaT cells subjected to H₂O₂ treatment. Furthermore, loliolide and Pj-EE decreased expression of the anti-melanogenic protein microphthalmia-associated transcription factor (MITF) and tyrosinase in B16F10 cells subjected to α-melanocyte-stimulating hormone (α-MSH) treatment. Our findings demonstrate that loliolide and Pj-EE have antioxidant and anti-melanogenic effects on skin.
Pterostilbene Reduces Acetaminophen-Induced Liver Injury by Activating the Nrf2 Antioxidative Defense System via the AMPK/Akt/GSK3β Pathway
Fan X, Wang L, Huang J, Lv H, Deng X and Ci X
Pterostilbene (Pts), a natural dimethylated analog of resveratrol from blueberries, exerts antioxidative and anti-apoptotic effects in various diseases. This study aims to investigate the protective effects and mechanism of Pts against acetaminophen (APAP)-induced hepatotoxicity in vivo.
Activation of Nrf2/HO-1 Pathway by Nardochinoid C Inhibits Inflammation and Oxidative Stress in Lipopolysaccharide-Stimulated Macrophages
Luo JF, Shen XY, Lio CK, Dai Y, Cheng CS, Liu JX, Yao YD, Yu Y, Xie Y, Luo P, Yao XS, Liu ZQ and Zhou H
The roots and rhizomes of have neuroprotection and cardiovascular protection effects. However, the specific mechanism of is not yet clear. Nardochinoid C (DC) is a new compound with new skeleton isolated from and this study for the first time explored the anti-inflammatory and anti-oxidant effect of DC. The results showed that DC significantly reduced the release of nitric oxide (NO) and prostaglandin E (PGE) in lipopolysaccharide (LPS)-activated RAW264.7 cells. The expression of pro-inflammatory proteins including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were also obviously inhibited by DC in LPS-activated RAW264.7 cells. Besides, the production of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were also remarkably inhibited by DC in LPS-activated RAW264.7 cells. DC also suppressed inflammation indicators including COX-2, PGE, TNF-α, and IL-6 in LPS-stimulated THP-1 macrophages. Furthermore, DC inhibited the macrophage M1 phenotype and the production of reactive oxygen species (ROS) in LPS-activated RAW264.7 cells. Mechanism studies showed that DC mainly activated nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, increased the level of anti-oxidant protein heme oxygenase-1 (HO-1) and thus produced the anti-inflammatory and anti-oxidant effects, which were abolished by Nrf2 siRNA and HO-1 inhibitor. These findings suggested that DC could be a new Nrf2 activator for the treatment and prevention of diseases related to inflammation and oxidative stress.
Trimetazidine Attenuates Cardiac Dysfunction in Endotoxemia and Sepsis by Promoting Neutrophil Migration
Chen J, Wang B, Lai J, Braunstein Z, He M, Ruan G, Yin Z, Wang J, Cianflone K, Ning Q, Chen C and Wang DW
Cardiac dysfunction can be a fatal complication during severe sepsis. The migration of neutrophils is significantly impaired during severe sepsis. We sought to determine the role of trimetazidine (TMZ) in regulation of neutrophil migration to the heart in a mouse model of sepsis and endotoxemia, and to identify the mechanism whereby TMZ confers a survival advantage. C57/BL6 mice were (1) injected with LPS followed by 24-h TMZ administration, or (2) treated with TMZ (20 mg/kg/day) for 1 week post cecal ligation and puncture (CLP) operation. Echocardiography and Millar system detection showed that TMZ alleviated cardiac dysfunction and histological staining showed the failure of neutrophils migration to heart in both LPS- and CLP-induced mice. Bone marrow transplantation revealed that TMZ-pretreated bone marrow cells improved LPS- and CLP-induced myocardial dysfunction and enhanced neutrophil recruitment in heart. In CXCL2-mediated chemotaxis assays, TMZ increased neutrophils migration via AMPK/Nrf2-dependent up-regulation of CXCR2 and inhibition of GRK2. Furthermore, using luciferase reporter gene and chromatin immunoprecipitation assays, we found that TMZ promoted the binding of the Nrf2 and CXCR2 promoter regions directly. Application of CXCR2 inhibitor completely reversed the protective effects of TMZ . Co-culture of neutrophils and cardiomyocytes further validated that TMZ decreased LPS-induced cardiomyocyte pyroptosis by targeting neutrophils. Our findings suggested TMZ as a potential therapeutic agent for septic or endotoxemia associated cardiac dysfunction in mice.   What is the current knowledge on the topic? Migration of neutrophils is significantly impaired during severe sepsis, but the underlying mechanisms remain unknown. What question did this study address? The effects of TMZ on cardiac dysfunction via neutrophils migration. What this study adds to our knowledge TMZ attenuated LPS-induced cardiomyocyte pyroptosis and cardiac dysfunction by promoting neutrophils recruitment to the heart tissues via CXCR2. How this might change clinical pharmacology or translational science Our findings suggested TMZ as a potential therapeutic agent for septic cardiac dysfunction.
Hypoxia modulates the antioxidant effect of hydroxytyrosol in MCF-7 breast cancer cells
Calahorra J, Martínez-Lara E, De Dios C and Siles E
Although cancer is multifactorial, a strong correlation between this pathology and increased oxidative stress has long been stablished. Hypoxia, inherent to solid tumors, increases reactive oxygen species and should be taken into account when analyzing the response of tumor cells to antioxidants. The Mediterranean diet has been related to a lower incidence of cancer, and particularly of breast cancer. Given that hydroxytyrosol (HT) is largely responsible for the antioxidant properties of olive oil, we have performed a comprehensive and comparative study of its effect on the oxidative stress response of the human breast cancer cell line MCF-7 in hypoxia and normoxia. Our results demonstrate that the antioxidant action of HT is particularly effective in a hypoxic environment. Moreover, we have observed that this polyphenol modulates the transcription and translation of members of the PGC-1α/ERRα and PGC-1α/Nrf2 pathways. However, while the transcriptional effects of HT are similar in normoxic and hypoxic conditions, its translational action is less prominent and partially attenuated in hypoxia, and therefore cannot completely explain the antioxidant effect of HT. Consequently, our results underscore that the hypoxic environment of tumor cells should be considered when analyzing the effect of bioactive compounds. Besides, this study also points to the importance of assessing the regulatory role of HT at both mRNA and protein level to get a complete picture of its effects.

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