scholarly journals GSK-3β, a double-edged sword in Nrf2 regulation: Implications for neurological dysfunction and disease

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1043 ◽  
Author(s):  
Megan Culbreth ◽  
Michael Aschner
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Glycogen Synthase ◽  
Oxidative Stress Response ◽  
Neurological Dysfunction ◽  
Related Factor ◽  
Disease Etiology ◽  
Disease States ◽  
Attractive Therapeutic Target ◽  
Gsk 3Β

In the past decade, it has become evident that glycogen synthase kinase 3β (GSK-3β) modulates the nuclear factor erythroid 2-related factor 2 (Nrf2) oxidative stress response. GSK-3β functions as an inhibitor, both directly in the activation and indirectly in the post-induction of Nrf2. The incidence of oxidative stress in neurological dysfunction and disease has made this signaling pathway an attractive therapeutic target. There is minimal evidence, however, to support a distinctive function for GSK-3β mediated Nrf2 inhibition in nervous system decline, apart from the typical oxidative stress response. In both Alzheimer’s disease and brain ischemia, this pathway has been explored for potential benefits on disease etiology and advancement. Presently, it is unclear whether GSK-3β mediated Nrf2 inhibition markedly influences these disease states. Furthermore, the potential that each has unique function in neurodegenerative decline is unsubstantiated.

scholarly journals The Role of Nuclear Factor-E2-Related Factor 1 in the Oxidative Stress Response in MC3T3-E1 Osteoblastic Cells

2016 ◽  
Vol 31 (2) ◽  
pp. 336 ◽  
Author(s):  
So Young Park ◽  
Sung Hoon Kim ◽  
Hyun Koo Yoon ◽  
Chang Hoon Yim ◽  
Sung-Kil Lim
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Oxidative Stress Response ◽  
Osteoblastic Cells ◽  
Related Factor ◽  
Nuclear Factor

scholarly journals The stress response protein REDD1 promotes diabetes-induced oxidative stress in the retina by Keap1-independent Nrf2 degradation

2020 ◽  
Vol 295 (21) ◽  
pp. 7350-7361 ◽  
Author(s):  
William P. Miller ◽  
Siddharth Sunilkumar ◽  
Joseph F. Giordano ◽  
Allyson L. Toro ◽  
Alistair J. Barber ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Glycogen Synthase ◽  
Critical Role ◽  
Antioxidant Response ◽  
Glycogen Synthase Kinase ◽  
Related Factor ◽  
Diabetic Mice ◽  
Antioxidant Genes ◽  
Deficient Mice

The transcription factor nuclear factor erythroid-2–related factor 2 (Nrf2) plays a critical role in reducing oxidative stress by promoting the expression of antioxidant genes. Both individuals with diabetes and preclinical diabetes models exhibit evidence of a defect in retinal Nrf2 activation. We recently demonstrated that increased expression of the stress response protein regulated in development and DNA damage 1 (REDD1) is necessary for the development of oxidative stress in the retina of streptozotocin-induced diabetic mice. In the present study, we tested the hypothesis that REDD1 suppresses the retinal antioxidant response to diabetes by repressing Nrf2 function. We found that REDD1 ablation enhances Nrf2 DNA-binding activity in the retina and that the suppressive effect of diabetes on Nrf2 activity is absent in the retina of REDD1-deficient mice compared with WT. In human MIO-M1 Müller cell cultures, REDD1 deletion prevented oxidative stress in response to hyperglycemic conditions, and this protective effect required Nrf2. REDD1 suppressed Nrf2 stability by promoting its proteasomal degradation independently of Nrf2's interaction with Kelch-like ECH-associated protein 1 (Keap1), but REDD1-mediated Nrf2 degradation required glycogen synthase kinase 3 (GSK3) activity and Ser-351/Ser-356 of Nrf2. Diabetes diminished inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β) at Ser-9 in the retina of WT mice but not in REDD1-deficient mice. Pharmacological inhibition of GSK3 enhanced Nrf2 activity and prevented oxidative stress in the retina of diabetic mice. The findings support a model wherein hyperglycemia-induced REDD1 blunts the Nrf2 antioxidant response to diabetes by activating GSK3, which, in turn, phosphorylates Nrf2 to promote its degradation.

Proteasomal dysfunction activates the transcription factor SKN-1 and produces a selective oxidative-stress response in Caenorhabditis elegans

2007 ◽  
Vol 409 (1) ◽  
pp. 205-213 ◽  
Author(s):  
Nate W. Kahn ◽  
Shane L. Rea ◽  
Sarah Moyle ◽  
Alison Kell ◽  
Thomas E. Johnson
Keyword(s):  
Oxidative Stress ◽  
Caenorhabditis Elegans ◽  
Stress Response ◽  
Nuclear Localization ◽  
Glutathione Transferase ◽  
Fluorescent Protein ◽  
Oxidative Stress Response ◽  
Specific Gene ◽  
Related Factor ◽  
Green Fluorescent

SKN-1 in the nematode worm Caenorhabditis elegans is functionally orthologous to mammalian NRF2 [NF-E2 (nuclear factor-E2)-related factor 2], a protein regulating response to oxidative stress. We have examined both the expression and activity of SKN-1 in response to a variety of oxidative stressors and to down-regulation of specific gene targets by RNAi (RNA interference). We used an SKN-1–GFP (green fluorescent protein) translational fusion to record changes in both skn-1 expression and SKN-1 nuclear localization, and a gst-4–GFP transcriptional fusion to measure SKN-1 transcriptional activity. GST-4 (glutathione transferase-4) is involved in the Phase II oxidative stress response and its expression is lost in an skn-1(zu67) mutant. In the present study, we show that the regulation of skn-1 is tied to the protein-degradation machinery of the cell. RNAi-targeted removal of most proteasome subunits in C. elegans caused nuclear localization of SKN-1 and, in some cases, induced transcription of gst-4. Most intriguingly, RNAi knockdown of proteasome core subunits caused nuclear localization of SKN-1 and induced gst-4, whereas RNAi knockdown of proteasome regulatory subunits resulted in nuclear localization of SKN-1 but did not induce gst-4. RNAi knockdown of ubiquitin-specific hydrolases and chaperonin components also caused nuclear localization of SKN-1 and, in some cases, also induced gst-4 transcription. skn-1 activation by proteasome dysfunction could be occurring by one or several mechanisms: (i) the reduced processivity of dysfunctional proteasomes may allow oxidatively damaged by-products to build up, which, in turn, activate the skn-1 stress response; (ii) dysfunctional proteasomes may activate the skn-1 stress response by blocking the constitutive turnover of SKN-1; and (iii) dysfunctional proteasomes may activate an unidentified signalling pathway that feeds back to control the skn-1 stress response.

scholarly journals Upregulation of Anti-Oxidative Stress Response Improves Metabolic Changes in L-Selectin-Deficient Mice but Does Not Prevent NAFLD Progression or Fecal Microbiota Shifts

2021 ◽  
Vol 22 (14) ◽  
pp. 7314
Author(s):  
Sreepradha Eswaran ◽  
Anshu Babbar ◽  
Hannah K. Drescher ◽  
Thomas C. A. Hitch ◽  
Thomas Clavel ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Adipose Tissue ◽  
Stress Response ◽  
Immune Cell ◽  
Fecal Microbiota ◽  
Oxidative Stress Response ◽  
Metabolic Changes ◽  
Related Factor ◽  
Alcoholic Fatty Liver ◽  
Deficient Mice

(1) Background: Non-alcoholic fatty liver disease (NAFLD) is a growing global health problem. NAFLD progression involves a complex interplay of imbalanced inflammatory cell populations and inflammatory signals such as reactive oxygen species and cytokines. These signals can derive from the liver itself but also from adipose tissue or be mediated via changes in the gut microbiome. We analyzed the effects of a simultaneous migration blockade caused by L-selectin-deficiency and an enhancement of the anti-oxidative stress response triggered by hepatocytic Kelch-like ECH-associated protein 1 (Keap1) deletion on NAFLD progression. (2) Methods: L-selectin-deficient mice (Lsel−/−Keap1flx/flx) and littermates with selective hepatic Keap1 deletion (Lsel−/−Keap1Δhepa) were compared in a 24-week Western-style diet (WD) model. (3) Results: Lsel−/−Keap1Δhepa mice exhibited increased expression of erythroid 2-related factor 2 (Nrf2) target genes in the liver, decreased body weight, reduced epidydimal white adipose tissue with decreased immune cell frequencies, and improved glucose response when compared to their Lsel−/−Keap1flx/flx littermates. Although WD feeding caused drastic changes in fecal microbiota profiles with decreased microbial diversity, no genotype-dependent shifts were observed. (4) Conclusions: Upregulation of the anti-oxidative stress response improves metabolic changes in L-selectin-deficient mice but does not prevent NAFLD progression and shifts in the gut microbiota.

scholarly journals miR-148b Functions as a Tumor Suppressor by Targeting Endoplasmic Reticulum Metallo Protease 1 in Human Endometrial Cancer Cells

2018 ◽  
Vol 27 (1) ◽  
pp. 81-88 ◽  
Author(s):  
Jinfeng Qu ◽  
Lei Zhang ◽  
Lanyu Li ◽  
Yujie Su
Keyword(s):  
Oxidative Stress ◽  
Cell Proliferation ◽  
Endoplasmic Reticulum ◽  
Endometrial Cancer ◽  
Stress Response ◽  
Western Blot ◽  
Cancer Cells ◽  
Oxidative Stress Response ◽  
Luciferase Reporter ◽  
Related Factor

This study investigated the tumor-suppressive role of miR-148b in regulating endoplasmic reticulum metalloprotease 1 (ERMP1) expression and the oxidative stress response in endometrial cancer cells. Human endometrial cancer RL95-2 cells were used and transfected with miR-148b mimic, miR-148b inhibitor, or their scrambled negative control. Thereafter, the transfection efficiency was determined by RT-qPCR, and cell proliferation was assessed by MTT assay. The dual-luciferase reporter assay, Western blot, and RT-qPCR were conducted to determine the target gene of miR-148b. ERMP1 is a putative target of miR-148b, and thereby the overexpression and downregulation of ERMP1 on the proliferation of RL95-2 cells were assessed. Next, the expressions of hypoxia-inducible factor 1 (HIF-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) were analyzed by Western blot. Intracellular reactive oxygen species (ROS) was determined using dichlorofluorescin diacetate (DCFDA). Results showed that differential expression of miR-148b or ERMP1 was observed in normal endometrial tissues and endometrial cancerous tissues. Enhanced expression of miR-148b effectively inhibited proliferation of RL95-2 cells. ERMP1 was the target of miR-148b. ERMP1 silencing obviously suppressed proliferation of RL95-2 cells. Thus, miR-148b repressed cell proliferation, likely through downregulating ERMP1. Furthermore, it was observed that miR-148b significantly decreased expression of HIF-1 and Nrf2 by downregulating ERMP1. The intracellular ROS level was enhanced by miR-148b via downregulating ERMP1. To conclude, our results suggested that miR-148b suppressed cell proliferation and regulated the oxidative stress response in human endometrial cancer RL95-2 cells by inhibiting ERMP1.

scholarly journals Nrf2, the Major Regulator of the Cellular Oxidative Stress Response, is Partially Disordered

2021 ◽  
Vol 22 (14) ◽  
pp. 7434
Author(s):  
Nadun C. Karunatilleke ◽  
Courtney S. Fast ◽  
Vy Ngo ◽  
Anne Brickenden ◽  
Martin L. Duennwald ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Cellular Response ◽  
Rational Design ◽  
Oxidative Stress Response ◽  
Full Length ◽  
Related Factor ◽  
Creb Binding Protein ◽  
Physiological Importance ◽  
Kelch Domain

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription regulator that plays a pivotal role in coordinating the cellular response to oxidative stress. Through interactions with other proteins, such as Kelch-like ECH-associated protein 1 (Keap1), CREB-binding protein (CBP), and retinoid X receptor alpha (RXRα), Nrf2 mediates the transcription of cytoprotective genes critical for removing toxicants and preventing DNA damage, thereby playing a significant role in chemoprevention. Dysregulation of Nrf2 is linked to tumorigenesis and chemoresistance, making Nrf2 a promising target for anticancer therapeutics. However, despite the physiological importance of Nrf2, the molecular details of this protein and its interactions with most of its targets remain unknown, hindering the rational design of Nrf2-targeted therapeutics. With this in mind, we used a combined bioinformatics and experimental approach to characterize the structure of full-length Nrf2 and its interaction with Keap1. Our results show that Nrf2 is partially disordered, with transiently structured elements in its Neh2, Neh7, and Neh1 domains. Moreover, interaction with the Kelch domain of Keap1 leads to protection of the binding motifs in the Neh2 domain of Nrf2, while the rest of the protein remains highly dynamic. This work represents the first detailed structural characterization of full-length Nrf2 and provides valuable insights into the molecular basis of Nrf2 activity modulation in oxidative stress response.

scholarly journals Inhibition of TRIM32 Attenuates the Apoptosis, Oxidative Stress and Inflammatory Injury of Podocytes Induced by High Glucose by Affecting the Akt/GSK-3β/Nrf2 Pathway

2021 ◽  
Author(s):  
Zhao Chen ◽  
Lifang Tian ◽  
Li Wang ◽  
Xiaotao Ma ◽  
Fuqian Lei ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Inflammatory Response ◽  
High Glucose ◽  
Glycogen Synthase ◽  
Related Factor ◽  
Protective Effects ◽  
Gsk 3Β ◽  
Induced Apoptosis

Abstract Hyperglycemia-induced oxidative stress of podocytes exerts a major role in the pathological process of diabetic nephropathy. Tripartite motif-containing protein 32 (TRIM32) has been reported as a key protein in the modulation of cellular apoptosis and oxidative stress under various pathological processes. However, whether TRIM32 participates in the regulation of high glucose (HG)-induced injury in podocytes has not been investigated. The aims of this work were to assess the possible role of TRIM32 in mediating HG-induced apoptosis, oxidative stress and inflammatory response in podocytes in vitro. Herein, our results showed a marked increase in TRIM32 expression in HG-exposed podocytes. Loss-of-function experiments showed that the knockdown of TRIM32 improved the viability of HG-stimulated podocytes, and suppressed HG-induced apoptosis, oxidative stress and inflammatory response in podocytes. Further investigation revealed that the inhibition of TRIM32 enhanced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling associated with modulation of the Akt/glycogen synthase kinase-3β (GSK-3β) axis in podocytes following HG exposure. However, the suppression of Akt abrogated the TRIM32-knockdown-mediated activation of Nrf2 in HG-exposed podocytes. In addition, the knockdown of Nrf2 markedly abolished the TRIM32-inhibition-induced protective effects in HG-exposed podocytes. In summary, the results of this work show that the inhibition of TRIM32 protects podocytes from HG-induced injury by potentiating Nrf2 signaling via the modulation of Akt/GSK-3β signaling. This study indicates a potential role of TRIM32 in mediating podocyte injury during the progression of diabetic nephropathy.

scholarly journals Targeting Glycogen Synthase Kinase-3βfor Therapeutic Benefit against Oxidative Stress in Alzheimer's Disease: Involvement of the Nrf2-ARE Pathway

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Katja Kanninen ◽  
Anthony R. White ◽  
Jari Koistinaho ◽  
Tarja Malm
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Therapeutic Effects ◽  
Related Factor ◽  
Nrf2 Pathway ◽  
Gsk 3Β

Specific regions of the Alzheimer's disease (AD) brain are burdened with extracellular protein deposits, the accumulation of which is concomitant with a complex cascade of overlapping events. Many of these pathological processes produce oxidative stress. Under normal conditions, oxidative stress leads to the activation of defensive gene expression that promotes cell survival. At the forefront of defence is the nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that regulates a broad spectrum of protective genes. Glycogen synthase kinase-3β (GSK-3β) regulates Nrf2, thus making this kinase a potential target for therapeutic intervention aiming to boost the protective activation of Nrf2. This paper aims to review the neuroprotective role of Nrf2 in AD, with special emphasis on the role of GSK-3β in the regulation of the Nrf2 pathway. We also examine the potential of inducing GSK-3β by small-molecule activators, dithiocarbamates, which potentially exert their beneficial therapeutic effects via the activation of the Nrf2 pathway.

The Role of Nuclear Factor-E2-Related Factor 1 in Oxidative Stress Response in Osteoblast Cells

2011 ◽  
pp. P1-185-P1-185
Author(s):  
So Young Park ◽  
Seong Mi Choi ◽  
Si Hoon Lee ◽  
Su Jin Park ◽  
Sungkil Lim
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Oxidative Stress Response ◽  
Related Factor ◽  
Nuclear Factor ◽  
Osteoblast Cells
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