scholarly journals Triggers for the Nrf2/ARE Signaling Pathway and Its Nutritional Regulation: Potential Therapeutic Applications of Ulcerative Colitis

2021 ◽  
Vol 22 (21) ◽  
pp. 11411
Author(s):  
Hu Liu ◽  
Lee J. Johnston ◽  
Fenglai Wang ◽  
Xi Ma
Keyword(s):  
Ulcerative Colitis ◽  
Signaling Pathway ◽  
Tissue Injury ◽  
Critical Role ◽  
Antioxidant Response ◽  
Activation Process ◽  
Related Factor ◽  
Nutritional Regulation ◽  
Colonic Injury ◽  
Positive Effects

Ulcerative colitis (UC), which affects millions of people worldwide, is characterized by extensive colonic injury involving mucosal and submucosal layers of the colon. Nuclear factor E2-related factor 2 (Nrf2) plays a critical role in cellular protection against oxidant-induced stress. Antioxidant response element (ARE) is the binding site recognized by Nrf2 and leads to the expression of phase II detoxifying enzymes and antioxidant proteins. The Nrf2/ARE system is a key factor for preventing and resolving tissue injury and inflammation in disease conditions such as UC. Researchers have proposed that both Keap1-dependent and Keap1-independent cascades contribute positive effects on activation of the Nrf2/ARE pathway. In this review, we summarize the present knowledge on mechanisms controlling the activation process. We will further review nutritional compounds that can modulate activation of the Nrf2/ARE pathway and may be used as potential therapeutic application of UC. These comprehensive data will help us to better understand the Nrf2/ARE signaling pathway and promote its effective application in response to common diseases induced by oxidative stress and inflammation.

scholarly journals Ginsenoside Rb1 Treatment Attenuates Pulmonary Inflammatory Cytokine Release and Tissue Injury following Intestinal Ischemia Reperfusion Injury in Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Ying Jiang ◽  
Zhen Zhou ◽  
Qing-tao Meng ◽  
Qian Sun ◽  
Wating Su ◽  
...  
Keyword(s):  
Lung Injury ◽  
Signaling Pathway ◽  
Intestinal Ischemia ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Weight Ratio ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Ginsenoside Rb1 ◽  
Intestinal Ischemia Reperfusion

Objective. Intestinal ischemia reperfusion (II/R) injury plays a critical role in remote organ dysfunction, such as lung injury, which is associated with nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. In the present study, we tested whether ginsenoside Rb1 attenuated II/R induced lung injury by Nrf2/HO-1 pathway.Methods. II/R injury was induced in male C57BL/6J mice by 45 min of superior mesenteric artery (SMA) occlusion followed by 2 hours of reperfusion. Ginsenoside Rb1 was administrated prior to reperfusion with or without ATRA (all-transretinoic acid, the inhibitor of Nrf2/ARE signaling pathway) administration before II/R.Results. II/R induced lung histological injury, which is accompanied with increased levels of malondialdehyde (MDA), interleukin- (IL-) 6, and tumor necrosis factor- (TNF-)αbut decreased levels of superoxide dismutase (SOD) and IL-10 in the lung tissues. Ginsenoside Rb1 reduced lung histological injury and the levels of TNF-αand MDA, as well as wet/dry weight ratio. Interestingly, the increased Nrf2 and HO-1 expression induced by II/R in the lung tissues was promoted by ginsenoside Rb1 treatment. All these changes could be inhibited or prevented by ATRA.Conclusion. Ginsenoside Rb1 is capable of ameliorating II/R induced lung injuries by activating Nrf2/HO-1 pathway.

scholarly journals Clostridium butyricum Protects IPEC-J2 Cells from ETEC K88-Induced Oxidative Damage by Activating the Nrf2/ARE Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Caixia Dou ◽  
Zhiyuan Shang ◽  
Jiayun Qiao ◽  
Yimeng Wang ◽  
Haihua Li
Keyword(s):  
Antioxidant Enzymes ◽  
Oxidative Damage ◽  
Signaling Pathway ◽  
Antioxidant Response ◽  
Clostridium Butyricum ◽  
Enterotoxigenic Escherichia Coli ◽  
Multiple Infection ◽  
Control Group ◽  
Related Factor ◽  
Viable Bacteria

Clostridium butyricum (CB) is a naturally occurring probiotic compound that can alleviate the oxidative damage induced by enterotoxigenic Escherichia coli K88 (ETEC K88) in porcine intestinal epithelial (IPEC-J2) cells. In this study, we investigate the molecular mechanism underlying this effect. Based on cell viability, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPX) assessments, the optimal concentration of ETEC K88 was determined to be 1 × 10 3  cfu/mL. Viable bacteria counts in cells pretreated with CB and then infected with ETEC K88 show that CB can adhere to IPEC-J2 cells and that optimal adhesion is achieved at the multiple infection index (MOI) of 50 at 3 h of pretreatment. The results of qPCR indicate that although ETEC significantly decreases the expression levels of antioxidant enzymes regulated by NF-E2-related factor 2 (Nrf2) compared to the control group, CB reverses this effect. To confirm that Nrf2 is directly involved in the mechanism by which CB alleviates oxidative stress, siRNA was used to silence the expression of Nrf2 gene in IPEC-J2 cells. Compared to the NC+ETEC and siRNA+ETEC groups, the expressions of SOD1, SOD2, GPX1, and GPX2 in the NC+CB+ETEC and siRNA+CB+ETEC groups are significantly increased at 12 h and 24 h. This shows that CB can reduce ETEC K88-induced oxidative damage in IPEC-J2 cells by activating the expression of antioxidant enzymes implicated in the Kelch-like ECH-associated protein-1- (Keap1-) Nrf2/antioxidant response element (ARE) signaling pathway.

scholarly journals The Role of Nrf2 in the Antioxidant Cellular Response to Medical Ozone Exposure

2019 ◽  
Vol 20 (16) ◽  
pp. 4009 ◽  
Author(s):  
Mirco Galiè ◽  
Viviana Covi ◽  
Gabriele Tabaracci ◽  
Manuela Malatesta
Keyword(s):  
Cellular Response ◽  
Tissue Injury ◽  
Scientific Evidence ◽  
Antioxidant Response ◽  
Ozone Exposure ◽  
Related Factor ◽  
Cellular Mechanisms ◽  
Medical Ozone ◽  
Living Organisms

Ozone (O3) is a natural, highly unstable atmospheric gas that rapidly decomposes to oxygen. Although not being a radical molecule, O3 is a very strong oxidant and therefore it is potentially toxic for living organisms. However, scientific evidence proved that the effects of O3 exposure are dose-dependent: high dosages stimulate severe oxidative stress resulting in inflammatory response and tissue injury, whereas low O3 concentrations induce a moderate oxidative eustress activating antioxidant pathways. These properties make O3 a powerful medical tool, which can be used as either a disinfectant or an adjuvant agent in the therapy of numerous diseases. In this paper, the cellular mechanisms involved in the antioxidant response to O3 exposure will be reviewed with special reference to the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its role in the efficacy of ozone therapy.

scholarly journals Preventive and Therapeutic Effects of MG132 by Activating Nrf2-ARE Signaling Pathway on Oxidative Stress-Induced Cardiovascular and Renal Injury

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Wenpeng Cui ◽  
Yang Bai ◽  
Ping Luo ◽  
Lining Miao ◽  
Lu Cai
Keyword(s):  
Oxidative Stress ◽  
Oxidative Damage ◽  
Signaling Pathway ◽  
Critical Role ◽  
Renal Diseases ◽  
Therapeutic Effects ◽  
Related Factor ◽  
Responsive Element ◽  
And Function ◽  
Proteasomal Inhibitor

So far, cardiovascular and renal diseases have brought us not only huge economic burden but also serious society problems. Since effective therapeutic strategies are still limited, to find new methods for the prevention or therapy of these diseases is important. Oxidative stress has been found to play a critical role in the initiation and progression of cardiovascular and renal diseases. In addition, activation of nuclear-factor-E2-related-factor-2- (Nrf2-) antioxidant-responsive element (ARE) signaling pathway protects cells and tissues from oxidative damage. As a proteasomal inhibitor, MG132 was reported to activate Nrf2 expression and function, which was accompanied with significant preventive and/or therapeutic effect on cardiovascular and renal diseases under most conditions; therefore, MG132 seems to be a potentially effective drug to be used in the prevention of oxidative damage. In this paper, we will summarize the information available regarding the effect of MG132 on oxidative stress-induced cardiovascular and renal damage, especially through Nrf2-ARE signaling pathway.

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.

scholarly journals (E)-N-(2-(3, 5-Dimethoxystyryl) phenyl) furan-2-carboxamide (BK3C231) induces cytoprotection in CCD18-Co human colon fibroblast cells through Nrf2/ARE pathway activation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Huan Huan Tan ◽  
Noel Francis Thomas ◽  
Salmaan Hussain Inayat-Hussain ◽  
Kok Meng Chan
Keyword(s):  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Cell Model ◽  
Human Colon ◽  
Antioxidant Response ◽  
Heme Oxygenase 1 ◽  
Preventive Strategy ◽  
Related Factor ◽  
Inhibitory Protein ◽  
Nrf2 Signaling Pathway

AbstractCytoprotection involving the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway is an important preventive strategy for normal cells against carcinogenesis. In our previous study, the chemopreventive potential of (E)-N-(2-(3, 5-Dimethoxystyryl) phenyl) furan-2-carboxamide (BK3C231) has been elucidated through its cytoprotective effects against DNA and mitochondrial damages in the human colon fibroblast CCD-18Co cell model. Therefore this study aimed to investigate the molecular mechanisms underlying BK3C231-induced cytoprotection and the involvement of the Nrf2/ARE pathway. The cells were pretreated with BK3C231 before exposure to carcinogen 4-nitroquinoline N-oxide (4NQO). BK3C231 increased the protein expression and activity of cytoprotective enzymes namely NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST) and heme oxygenase-1 (HO-1), as well as restoring the expression of glutamate-cysteine ligase catalytic subunit (GCLC) back to the basal level. Furthermore, dissociation of Nrf2 from its inhibitory protein, Keap1, and ARE promoter activity were upregulated in cells pretreated with BK3C231. Taken together, our findings suggest that BK3C231 exerts cytoprotection by activating the Nrf2 signaling pathway which leads to ARE-mediated upregulation of cytoprotective proteins. This study provides new mechanistic insights into BK3C231 chemopreventive activities and highlights the importance of stilbene derivatives upon development as a potential chemopreventive agent.

scholarly journals Nitrosative Redox Homeostasis and Antioxidant Response Defense in Disused Vastus lateralis Muscle in Long-Term Bedrest (Toulouse Cocktail Study)

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 378
Author(s):  
Dieter Blottner ◽  
Daniele Capitanio ◽  
Gabor Trautmann ◽  
Sandra Furlan ◽  
Guido Gambara ◽  
...  
Keyword(s):  
Defense Response ◽  
Antioxidant Defense ◽  
Vastus Lateralis ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Vastus Lateralis Muscle ◽  
Related Factor ◽  
Label Free ◽  
Positive Effects ◽  
Intervention Protocol

Increased oxidative stress by reactive oxygen species (ROS) and reactive nitrogen species (RNS) is a major determinant of disuse-induced muscle atrophy. Muscle biopsies (thigh vastus lateralis, VL) obtained from healthy male subjects enrolled in the Toulouse Cocktail bedrest (BR) study were used to assess efficacy of an antioxidant cocktail (polyphenols, omega-3, vitamin E, and selenium) to counteract the increased redox homeostasis and enhance the antioxidant defense response by using label-free LC–MS/MS and NITRO-DIGE (nitrosated proteins), qPCR, and laser confocal microscopy. Label-free LC–MS/MS indicated that treatment prevented the redox homeostasis dysregulation and promoted structural remodeling (TPM3, MYH7, MYBPC, MYH1, MYL1, HRC, and LUM), increment of RyR1, myogenesis (CSRP3), and skeletal muscle development (MUSTN1, LMNA, AHNAK). These changes were absent in the Placebo group. Glycolysis, tricarboxylic acid cycle (TCA), oxidative phosphorylation, fatty acid beta-oxidation, and mitochondrial transmembrane transport were normalized in treated subjects. Proteins involved in protein folding were also normalized, whereas protein entailed in ion homeostasis decreased. NITRO-DIGE analysis showed significant protein nitrosylation changes for CAT, CA3, SDHA, and VDAC2 in Treatment vs. Placebo. Similarly, the nuclear factor erythroid 2-related factor 2 (Nrf-2) antioxidant response element (Nrf-2 ARE) signaling pathway showed an enhanced response in the Treatment group. Increased nitrosative redox homeostasis and decreased antioxidant defense response were found in post-BR control (Placebo, n = 10) vs. the antioxidant cocktail treated group (Treatment, n = 10). Taken together, increased nitrosative redox homeostasis and muscle deterioration during BR-driven physical inactivity were prevented, whereas decreased antioxidant nitrosative stress defense response was attenuated by Treatment suggesting positive effects of the nutritional intervention protocol in bedrest.

scholarly journals A Combined Phytochemical and Network Pharmacology Approach to Reveal the Effective Substances and Mechanism of Eomecon chionantha Hance for the Treatment of Ulcerative Colitis

2021 ◽  
Vol 16 (2) ◽  
pp. 1934578X2199296
Author(s):  
Yu-mei Tian ◽  
Hai-lang He ◽  
Ya-ting Cheng ◽  
Li Yi ◽  
Yuan Yang ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Signaling Pathway ◽  
Estrogen Signaling ◽  
Network Pharmacology ◽  
Active Ingredients ◽  
Traumatic Injuries ◽  
Traditional Chinese Herbal Medicine ◽  
Positive Effects ◽  
Theoretical Support ◽  
Th17 Cell Differentiation

Eomecon chionantha Hance (ECH), a traditional Chinese herbal medicine, has been reported for the treatment of traumatic injuries and colitis. The current treatments for ulcerative colitis (UC) are unstable and have side effects, so ECH is potentially useful for treating this condition. However, the active ingredients and pharmacological mechanisms of ECH in treating UC remain unclear. In this study, 21 alkaloids were extracted and purified from the roots of ECH, among which 13 were extracted from this herb for the first time. Our results showed that 12 ingredients may have effective pharmacological effects after absorption, distribution, metabolism, and excretion (ADME) screening. Network pharmacological analysis revealed that the active ingredients may have positive effects on 19 significant signaling pathways, such as on small cell lung cancer, serotonergic synapses, the IL-17 signaling pathway, Th17 cell differentiation, the estrogen signaling pathway, transcriptional misregulation in cancer, the PI3K-Akt signaling pathway, and others by targeting 23 proteins, including MAPK14, RXRA, GSK3B, CDK2, RXRB, HSP90AA1, PTGS2, and ESR1. It is of great benefit to use separation, purification, and network pharmacology together to screen active natural products. This study indicated potential anti-UC mechanisms of the active ingredients of ECH and provides theoretical support for the treatment of UC using ECH.

scholarly journals Induction of human fetal hemoglobin via the NRF2 antioxidant response signaling pathway

Blood ◽  
2011 ◽  
Vol 117 (22) ◽  
pp. 5987-5997 ◽  
Author(s):  
Elizabeth R. Macari ◽  
Christopher H. Lowrey
Keyword(s):  
Signaling Pathway ◽  
Nuclear Translocation ◽  
Fetal Hemoglobin ◽  
Antioxidant Response ◽  
Related Factor ◽  
Antioxidant Response Element ◽  
Globin Mrna ◽  
Response Element ◽  
Hematopoietic Stem ◽  
Globin Promoter

AbstractAlthough hematopoietic stem cell transplantation and gene therapy have the potential to cure β-thalassemia and sickle cell disease, they are not currently available to most people with these diseases. In the near term, pharmacologic induction of fetal hemoglobin (HbF) may offer the best possibility for safe, effective, and widely available therapy. In an effort to define new pathways for targeted drug development for HbF induction, we evaluated the nuclear factor erythroid 2–related factor 2 (NRF2) antioxidant response element signaling pathway. We found that 3 well-known activators of this pathway increased γ-globin mRNA at nontoxic doses in K562 cells. Tert-butylhydroquinone (tBHQ), the most active of these compounds, increased cellular levels and nuclear translocation of NRF2 and binding of NRF2 to the γ-globin promoter. siRNA knockdown of NRF2 inhibited γ-globin induction by tBHQ. When tested in human primary erythroid cells, tBHQ induced NRF2 binding to the γ-globin promoter, increased γ-globin mRNA and HbF, and suppressed β-globin mRNA and HbA, resulting in a > 3-fold increase in the percentage of HbF. These results suggest that drugs that activate the NRF2/antioxidant response element signaling pathway have the potential to induce therapeutic levels of HbF in people with β-hemoglobinopathies.

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