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

Long Non-Coding RNA MALAT1 Protects Human Osteoblasts from Dexamethasone-Induced Injury via Activation of PPM1E-AMPK Signaling
Fan JB, Zhang Y, Liu W, Zhu XH, Xu DW, Zhao JN and Cui ZM
Dexamethasone (Dex) induces injuries to human osteoblasts. In this study, we tested the potential role of the long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (Lnc-MALAT1) in this process.
Genistein attenuates renal fibrosis in streptozotocin‑induced diabetic rats
Jia Q, Yang R, Liu XF, Ma SF and Wang L
The present study aimed to investigate the antifibrogenic effects of genistein (GEN) on the kidney in streptozotocin (STZ)‑induced diabetic rats and to determine the associated mechanisms. Rats were randomized into four groups: Normal control (N), STZ (S), L (STZ + low‑dose GEN) and H (STZ + high‑dose GEN). After 8 weeks, the fasting blood glucose (FBG) level, the ratio of kidney weight to body weight (renal index), 24‑h urine protein, blood urea nitrogen (BUN), serum creatinine (SCr), renal total antioxidant capacity (T‑AOC), superoxide dismutase (SOD), lipid peroxidation (LPO), malondialdehyde (MDA) and hydroxyproline (Hyp) contents were measured. The histomorphology and ultrastructure of the kidney were also assessed. In addition, mRNA expression levels of transforming growth factor‑β1 (TGF‑β1) and protein expression levels of nuclear factor erythroid 2‑related factor 2 (Nrf2), heme oxygenase‑1 (HO‑1), NAD(P)H:quinone oxidoreductase 1 (NQO1), TGF‑β1, mothers against decapentaplegic homolog 3 (Smad3), phosphorylated (p)‑Smad3 and collagen IV were estimated. Compared with group N, the levels of FBG, renal index, 24‑h urine protein, BUN, SCr, LPO, MDA and Hyp were increased, whereas the levels of T‑AOC and SOD were decreased in group S. The structure of renal tissue was damaged, and the expression of Nrf2, HO‑1 and NQO1 were reduced, whereas the expression of TGF‑β1, Smad3, p‑Smad3 and collagen IV were increased in group S. Compared with group S, the aforementioned indices were improved in groups L and H. In conclusion, GEN exhibited reno‑protective effects in diabetic rats and its mechanisms may be associated with the inhibition of oxidative stress by activating the Nrf2‑HO‑1/NQO1 pathway, and the alleviation of renal fibrosis by suppressing the TGF‑β1/Smad3 pathway.
Cyclo(His-Pro) inhibits NLRP3 inflammasome cascade in ALS microglial cells
Grottelli S, Mezzasoma L, Scarpelli P, Cacciatore I, Cellini B and Bellezza I
Neuroinflammation, i.e. self-propelling progressive cycle of microglial activation and neuron damage, as well as improper protein folding, are recognized as major culprits of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). Mutations in several proteins have been linked to ALS pathogenesis, including the G93A mutation in the superoxide dismutase 1 (SOD1) enzyme. SOD1(G93A) mutant is prone to aggregate thus inducing both oxidative stress and neuroinflammation. In this study we used hSOD1(G93A) microglial cells to investigate the effects of the antioxidant and anti-inflammatory cyclic dipeptide (His-Pro) on LPS-induced inflammasome activation. We found that cyclo(His-Pro) inhibits NLRP3 inflammasome activation by reducing protein nitration via reduction in NO and ROS levels, indicative of lower peroxynitrite generation by LPS. Low levels in peroxynitrite are related to NF-κB inhibition responsible for iNOS down-regulation and NO dampening. On the other hand, cyclo(His-Pro)-mediated ROS attenuation, not linked to Nrf2 activation in this cellular model, is ascribed to increased soluble SOD1 activity due to the up-regulation of Hsp70 and Hsp27 expression. Conclusively, our results, besides corroborating the anti-inflammatory properties of cyclo(His-Pro), highlight a novel role of the cyclic dipeptide as a proteostasis regulator, and therefore a good candidate for the treatment of ALS and other misfolding diseases.
Glucose negatively affects Nrf2/SKN-1-mediated innate immunity in
Li L, Chen Y, Chenzhao C, Fu S, Xu Q and Zhao J
High glucose levels negatively affect immune response. However, the underlying mechanisms are not well understood. Upon infection, the round worm induces multiple gene transcription programs, including the Nrf2/SKN-1-mediated detoxification program, to activate the innate immunity. In this study, we find that high glucose conditions inhibit the SKN-1-mediated immune response to , exacerbate the infection and greatly decrease survival. The effect of glucose shows specificity to SKN-1 pathway, as UPR and UPR that are known to be induced by infection, are not affected. Hyper-activation of SKN-1 by RNAi restores partly the immune response and increases the survival rate in response to . In all, our study reveals a molecular pathway responsible for glucose's negative effect on innate immunity, which could help to better understand diseases associated with hyperglycemia.
Four-octyl itaconate activates Keap1-Nrf2 signaling to protect neuronal cells from hydrogen peroxide
Liu H, Feng Y, Xu M, Yang J, Wang Z and Di G
Four-octyl itaconate (OI), the itaconate's cell-permeable derivative, can activate Nrf2 signaling via alkylation of Keap1 at its cysteine residues. The current study tested the potential neuroprotective function of OI in hydrogen peroxide (HO)-treated neuronal cells.
Small, Thin Graphene Oxide Is Anti-Inflammatory Activating Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) Via Metabolic Reprogramming
Hoyle C, Rivers-Auty J, Lemarchand E, Vranic S, Wang E, Buggio M, Rothwell NJ, Allan SM, Kostarelos K and Brough D
Graphene oxide (GO), an oxidized form of graphene, has potential applications in biomedical research. However, how GO interacts with biological systems, including the innate immune system, is poorly understood. Here we elucidate the effects of GO sheets on macrophages, identifying distinctive effects of GO on inflammatory phenotype. Small, thin (s) GO dose-dependently inhibited release of interleukin (IL)-1β and IL-6, but not tumor necrosis factor (TNF)-α. NLRP3 inflammasome and caspase 1 activation was not affected. The effect of s-GO was pre-translational, as s GO blocked Toll-like receptor 4 dependent expression of Il1b and Il6, but not Nlrp3 or Tnf mRNA transcripts. s-GO was internalized by immortalized bone marrow-derived macrophages, suggesting a potential intracellular action. Uptake of polystyrene beads with similar lateral dimensions and surface charge did not phenocopy the effects of s GO, suggesting that s-GO-mediated inhibition of interleukin expression was not simply due to particle phagocytosis. RNA-Seq analysis established that s-GO had profound effects on the immunometabolism of the cells, leading to activation of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), which inhibited expression of cytokines such as IL 1β and IL-6. Thus, we have identified immunometabolic effects of GO that reveal another dimension to its effects on cells. These findings suggest that s-GO may be used as a valuable tool to generate further insights into inflammatory mechanisms, and inform its potential applications in biomedicine.
Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) inhibition, An Emerging Strategy in Cancer Therapy
Jiang Z, Lu M and You QD
Nrf2 is a pleiotropic transcription factor, especially for its complex and dual effects in cancer. With the continuous growing research of the new regulatory modes and new functions of Nrf2 tumor promoting effects of Nrf2 in malignant transformed tumors has become increasingly clear. Accumulating evidence has established that Nrf2 contributes to the whole process of pathogenesis, progression, metastasis and prognosis of cancer, and Nrf2 could be a promising target in cancer therapy. However, the development of Nrf2 inhibitor is still limited. In this perspective, we will briefly describe the biological function and modulating network of Nrf2, stress its oncogenic role and point out possible ways to inhibit Nrf2, as well as summarize the reported Nrf2 inhibitors.
The polysaccharide from Inonotus obliquus protects mice from Toxoplasma gondii-induced liver injury
Xu L, Sang R, Yu Y, Li J, Ge B and Zhang X
The study aimed to explore the protective effects and mechanism of Inonotus obliquus polysaccharide (IOP) on liver injury caused by Toxoplasma gondii (T. gondii) infection in mice. The results showed that treatment with IOP significantly decreased the liver coefficient, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA) and nitric oxide (NO), and increased the contents of antioxidant enzyme superoxide dismutase (SOD) and glutathione (GSH). IOP effectively decreased the expression of serum tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), interferon-γ (IFN-γ) and interluekin-4 (IL-4) in T. gondii-infected mice. In agreement with these observations, IOP also alleviated hepatic pathological damages caused by T. gondii. Furthermore, we found that IOP down-regulated the levels of toll-like receptor 2 (TLR2) and toll-like receptor 4 (TLR4), phosphorylations of nuclear factor-κappaB (NF-κB) p65 and inhibitor kappaBα (IκBα), whereas up-regulated the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). These findings suggest that IOP possesses hepatoprotective effects against T. gondii-induced liver injury in mice, and such protection is at least in part due to its anti-inflammatory effects through inhibiting the TLRs/NF-κB signaling axis and the activation of an antioxidant response by inducing the Nrf2/HO-1 signaling.
Protective efficacy of crocetin and its nanoformulation against cyclosporine A-mediated toxicity in human embryonic kidney cells
Pradhan J, Mohanty C and Sahoo SK
This study is aimed to formulate crocetin-loaded lipid Nanoparticles (NPs) and to evaluate its antioxidant properties in a cyclosporine A-mediated toxicity in Human Embryonic Kidney (HEK-293) cells in vitro.
Sub-acute restraint stress progressively increases oxidative/nitrosative stress and inflammatory markers while transiently upregulating antioxidant gene expression in the rat hippocampus
Chen HC, Lee JK, Yip T, Sernia C, Lavidis NA and Spiers JG
We have previously demonstrated that acute stress decreases neuronal nitric oxide synthase (NOS) expression in the hippocampus despite increased concentrations of nitric oxide which may indicate feedback inhibition of neuronal NOS expression via inducible NOS-derived nitric oxide. Moreover, the hippocampus undergoes an initial oxidative/nitrosative insult that is rapidly followed by upregulation of protective antioxidants, including the zinc-binding metallothioneins, in order to counter this and restore redox balance following acute stress exposure. In the present study, we have utilized indicators of oxidative/nitrosative stress, members of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, antioxidant metallothioneins, and neuroinflammatory markers to observe the changes occurring in the hippocampus following short term repeated stress exposure. Male Wistar rats were subjected to control conditions or 6hours of restraint stress applied for 1, 2, or 3 days (n=8 per group) after which the hippocampus was isolated for redox assays and relative gene expression. The hippocampus showed increased oxidative stress, transient dys-homeostasis of total zinc, and increased expression of the Nrf2 pathway members. Moreover, repeated stress increased nitrosative status, nitric oxide metabolites, and 3-nitrotyrosine, indicative of nitrosative stress in the hippocampus. However, levels of neuronal NOS decreased over all stress treatment groups, while increases were observed in inducible NOS and xanthine dehydrogenase. In addition to inducible NOS, mRNA expression of other inflammatory markers including interleukin-6 and interleukin-1β also increased even in the presence of increased anti-inflammatory glucocorticoids. Together, these results demonstrate that despite increases in antioxidant expression, sub-acute stress causes an inflammatory phenotype in the hippocampus by inducing oxidative/nitrosative stress, zinc dys-homeostasis, and the accumulation of nitrotyrosinated proteins which is likely driven by increased inducible NOS signaling.
Anti-Carcinogenic Glucosinolates in Cruciferous Vegetables and Their Antagonistic Effects on Prevention of Cancers
Soundararajan P and Kim JS
Glucosinolates (GSL) are naturally occurring β-d-thioglucosides found across the cruciferous vegetables. Core structure formation and side-chain modifications lead to the synthesis of more than 200 types of GSLs in Brassicaceae. Isothiocyanates (ITCs) are chemoprotectives produced as the hydrolyzed product of GSLs by enzyme myrosinase. Benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC) and sulforaphane ([1-isothioyanato-4-(methyl-sulfinyl) butane], SFN) are potential ITCs with efficient therapeutic properties. Beneficial role of BITC, PEITC and SFN was widely studied against various cancers such as breast, brain, blood, bone, colon, gastric, liver, lung, oral, pancreatic, prostate and so forth. Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a key transcription factor limits the tumor progression. Induction of ARE (antioxidant responsive element) and ROS (reactive oxygen species) mediated pathway by Nrf2 controls the activity of nuclear factor-kappaB (NF-κB). NF-κB has a double edged role in the immune system. NF-κB induced during inflammatory is essential for an acute immune process. Meanwhile, hyper activation of NF-κB transcription factors was witnessed in the tumor cells. Antagonistic activity of BITC, PEITC and SFN against cancer was related with the direct/indirect interaction with Nrf2 and NF-κB protein. All three ITCs able to disrupts Nrf2-Keap1 complex and translocate Nrf2 into the nucleus. BITC have the affinity to inhibit the NF-κB than SFN due to the presence of additional benzyl structure. This review will give the overview on chemo preventive of ITCs against several types of cancer cell lines. We have also discussed the molecular interaction(s) of the antagonistic effect of BITC, PEITC and SFN with Nrf2 and NF-κB to prevent cancer.
Isoliquiritigenin Provides Protection and Attenuates Oxidative Stress-Induced Injuries via the Nrf2-ARE Signaling Pathway After Traumatic Brain Injury
Zhang M, Huang LL, Teng CH, Wu FF, Ge LY, Shi YJ, He ZL, Liu L, Jiang CJ, Hou RN, Xiao J, Zhang HY and Chen DQ
Traumatic brain injury (TBI) is a serious public health and medical problem worldwide. Oxidative stress plays a vital role in the pathogenesis of TBI. Nuclear factor erythroid 2-related factor 2 (Nrf2), an important factor in the cellular defense against oxidative stress, is activated following TBI. In this study, the protective effects of Isoliquiritigenin (ILG), a promising antioxidant stress drug, was evaluated as a protective agent against TBI. In a mouse model of controlled cortical impact Injury, we found that the ILG administration reduced the Garcia neuroscore, injury histopathology, brain water content, cerebral vascular permeability, the expression of cleaved caspase3, aquaporin-4, glial fibrillary acidic protein and the increased the expression of neurofilament light chain protein, indicating the protective effects against TBI in vivo. ILG treatment after TBI also restored the oxidative stress and promoted the Nrf2 protein transfer from the cytoplasm to the nucleus. We then used Nrf2-/- mice to test the protective effect of Nrf2 during ILG treatment of TBI. Our findings indicated that Nrf2-/- mice had greater brain injury and oxidative stress than wild-type (WT) mice and ILG was less effective at inhibiting oxidative stress and repairing the brain injury than in the WT mice. In vitro studies in SY5Y cells under oxygen glucose deprivation/re-oxygenation stimulation yielded results that were consistent with those obtained in vivo showing that ILG promotes Nrf2 protein transfer from the cytoplasm to the nucleus. Taken together, our findings demonstrate that Nrf2 is an important protective factor against TBI-induced injuries, which indicates that the protective effects of ILG are mediated by inhibiting oxidative stress after TBI via a mechanism that involves the promotion of Nrf2 protein transfer from the cytoplasm to the nucleus.
Scutellarin alleviates blood-retina-barrier oxidative stress injury initiated by activated microglia cells during the development of diabetic retinopathy
Mei X, Zhang T, Ouyang H, Lu B, Wang Z and Ji L
The breakdown of blood-retinal barrier (BRB) is an early and typical event during the development of diabetic retinopathy (DR). Scutellarin (SC) is a natural flavonoid. This study aims to investigate the protection of SC from BRB damage via focusing on inhibiting microglia-initiated inflammation and subsequent oxidative stress injury. SC attenuated BRB breakdown and the reduced expression of claudin-1 and claudin-19 in STZ-induced diabetic mice. SC reduced microglia cells activation both in vivo and in vitro. The results of transendothelial/transepithelial electrical resistance (TEER/TER) and fluorescein isothiocyanate (FITC)-conjugated dextran cell permeability assay showed that SC attenuated BRB damage induced by D-glucose (25 mM)-stimulated microglia BV2 cells. SC suppressed nuclear factor κB (NFκB) activation and tumor necrosis factor (TNF)-α expression induced by D-glucose (25 mM) in BV2 cells. SC decreased the phosphorylation of extracellular regulated protein kinase (ERK)1/2 both in vivo and in vitro. MEK1/2 inhibitor U0126 reduced the D-glucose-induced NFκB nuclear accumulation and TNFα expression in BV2 cells. Next, SC improved the decreased expression of claudin-1 and claudin-19, the increased BRB damage and cellular reactive oxygen species (ROS) formation, and enhanced nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) in TNFα-treated human retinal endothelial cells (HRECs) and APRE19 cells. Moreover, the SC-provided alleviation on BRB breakdown in STZ-induced diabetic mice was diminished in Nrf2 knock-out mice. In conclusion, SC alleviates BRB breakdown via abrogating retinal inflammatory responses and subsequent oxidative stress injury initiated by microglia cells that is activated by hyperglycemia during DR development.
Methylglyoxal disturbs the expression of antioxidant, apoptotic and glycation responsive genes and triggers programmed cell death in human leukocytes
de Souza Prestes A, Dos Santos MM, Ecker A, de Macedo GT, Fachinetto R, Bressan GN, da Rocha JBT and Barbosa NV
Methylglyoxal (MG) is a α-dycarbonyl compound derived mainly from glycolysis, whose accumulation is harmful for cells and tissues. Here, we evaluated the cytotoxic effects induced by MG in leukocytes after an acute exposure, measuring as endpoints of toxicity some markers of oxidative stress and programmed cell death. Human leukocytes were isolated and incubated with MG at concentrations ranging from 0.1 to 10 mM for 2.5 h, and subsequently prepared for assays based in flow cytometry, gene expression and immunoreactivity profile. The cells exposed to higher concentrations of MG had significant loss of viability, increased reactive species (RS) production and apoptosis/necrosis rate. These phenomena were accompanied by morphological changes (increased size and granularity) and disruption in mRNA expression of antioxidant, apoptotic and glycation-responsive genes, particularly: Nrf2 (Nuclear factor (erythroid-derived 2)-like 2), SOD1 (CuZn-superoxide dismutase), SOD2 (Mn-superoxide dismutase), GSR (glutathione-S-reductase), BAX (BAX-associated X protein), BCL-2 (BCL-2-associated X protein), AIF (apoptosis inducing factor), GLO-1 (glyoxalase-1) and RAGE (receptor for advanced glycation end products). The mRNA expression of CASP 9 and CASP 3 (caspase-9 and 3) as well as the immunoreactivity of proteins were not changed by MG. Collectively, our data provide evidence that MG activates programmed cell death pathways in leukocytes and that this effect seems to be associated with disturbances in cell redox signaling.
Nociceptive behavior induced by chemotherapeutic paclitaxel and beneficial role of antioxidative pathways
Miao H, Xu J, Xu D, Ma X, Zhao X and Liu L
Paclitaxel is used for the treatment of several types of cancers. However, one of the significant limiting complications of paclitaxel is painful peripheral neuropathy during its therapy. In this study we examined the engagement of antioxidative signal pathway of the dorsal root ganglion (DRG) in mechanical and thermal hypersensitivity evoked by paclitaxel. Behavioral test was performed to determine mechanical and thermal sensitivity in rats. Western Blot analysis and ELISA were used to examine expression of Nrf2-antioxidant response element (ARE) and superoxide dismutases (SOD); and the levels of products of oxidative stress in the DRG. Our results show that paclitaxel increased mechanical and thermal sensitivity as compared with vehicle control animals. Paclitaxel also impaired Nrf2-ARE and SOD in the DRG and amplified products of oxidative stress, namely 8-isoprostaglandin F2alpha and 8-hydroxy-2'-deoxyguanosine. Systemic administration of SOD mimetic using tempol, antioxidant vitamin C or blocking oxidative pathway using NADPH oxidase inhibitor (GKT137831) attenuated mechanical and thermal hypersensitivity induced by paclitaxel. This inhibitory effect was accompanied with decreases of proinflammatory cytokines (PICs) such as IL-1beta, IL-6 and TNF-alpha in the DRG. In conclusion, the data revealed impairment of Nrf2-ARE and heightened oxidative and PIC signals in the DRG of paclitaxel rats, leading to neuropathic pain. Balancing of reactive oxygen species by supplying antioxidants and/or inhibiting NADPH oxidase appears significant to yield beneficial effects in neuropathic pain conditions after chemotherapeutic paclitaxel.

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