Floridoside Exhibits Antioxidant Properties by Activating HO-1 Expression via p38/ERK MAPK Pathway

Floridoside is a low-molecular-weight organic compound, which can be accumulated by red algae under stressful conditions to protect cells via its excellent antioxidant properties. In the present study, we investigated the antioxidant mechanism of floridoside toward human hepatocyte L-02 cells. We found that floridoside had no toxicity to L-02 cells, and no reactive oxidative species were induced by it either. However, the expression of hemoxygenase-1 (HO-1) protein was up-regulated upon exposure to floridoside, and two antioxidant enzymes, superoxide dismutase (SOD) and GSH-Px, were activated by floridoside. Moreover, we investigated the pathway involved in the production of these antioxidants, p38/extracellular signal-regulated kinase (ERK) MAPK-nuclear factor-erythroid-2-related factor 2 (Nrf2) pathway. ERK1/2 and p38 phosphorylation, nuclear translocation of Nrf2, and activation of ARE luciferase activity were observed upon exposure to floridoside. siRNA interference and inhibitor treatment suppressed the HO-1 expression and the phosphorylation of ERK1/2 and p38, respectively. These results indicated that floridoside exerted its antioxidant activity by activating HO-1 expression via p38/ERK MAPK-Nrf2 pathway in human hepatocyte L-02 cells.

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Anti-Inflammatory and Antioxidant Effects of Soroseris hirsuta Extract by regulating iNOS/NF-κB and NRF2/HO-1 Pathways in Murine Macrophage RAW 264.7 Cells

Applied Sciences ◽

10.3390/app11104711 ◽

2021 ◽

Vol 11 (10) ◽

pp. 4711

Author(s):

Woo Jin Lee ◽

Wan Yi Li ◽

Sang Woo Lee ◽

Sung Keun Jung

Keyword(s):

Nitric Oxide ◽

Nuclear Translocation ◽

Antioxidant Properties ◽

Raw 264.7 Cells ◽

Heme Oxygenase 1 ◽

Raw 264.7 ◽

Related Factor ◽

Iκb Kinase ◽

Anti Inflammatory ◽

Antioxidant Effects

Until now, the physiological effects of Soroseris hirsuta were primarily unknown. Here we have evaluated the anti-inflammatory and antioxidant effects of Soroseris hirsuta extract (SHE) on lipopolysaccharide (LPS)-activated murine macrophages RAW 264.7 cells. SHE inhibited nitric oxide expression and inducible nitric oxide synthase expression in RAW 264.7 cells treated with LPS. Moreover, SHE suppressed LPS-induced phosphorylation of IκB kinase, inhibitor of kappa B, p65, p38, and c-JUN N-terminal kinase. Western blot and immunofluorescence analyses showed that SHE suppressed p65 nuclear translocation induced by LPS. Furthermore, SHE inhibited the reactive oxygen species in LPS-treated RAW 264.7 cells. SHE significantly increased heme oxygenase-1 expression and the nuclear translocation of nuclear factor erythroid 2-related factor 2. SHE suppressed LPS-induced interleukin-1β mRNA expression in RAW 264.7 cells. Thus, SHE is a promising nutraceutical as it displays anti-inflammatory and antioxidant properties.

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Natural astaxanthin enhanced antioxidant capacity and improved semen quality through the MAPK/Nrf2 pathway in aging layer breeder roosters

Journal of Animal Science and Biotechnology ◽

10.1186/s40104-021-00633-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Shan Gao ◽

Nuo Heng ◽

Fang Liu ◽

Yong Guo ◽

Yu Chen ◽

...

Keyword(s):

Antioxidant Capacity ◽

Hydroxyl Radicals ◽

Semen Quality ◽

Antioxidant Properties ◽

Mitogen Activated Protein Kinase ◽

Control Group ◽

Antioxidant Enzyme Activities ◽

Related Factor ◽

Mrna Levels ◽

Nrf2 Pathway

Abstract Background Natural astaxanthin (ASTA) has strong antioxidant properties and has been widely used as a health product to improve human health. However, the effects of ASTA on the reproductive performance of aging roosters have been poorly studied. We aimed to investigate the effects of dietary ASTA on semen quality and antioxidant capacity in aging roosters and to explore the potential mechanism of semen quality change via anti-oxidation defense system. Methods In the present study, 96 53-week-old Jinghong No. 1 layer breeder roosters were fed a corn-soybean meal basal diet containing 0, 25, 50, or 100 mg/kg ASTA for 6 weeks. Results Semen quality in the ASTA groups remarkably improved than that in the control group, and antioxidant activities, the abilities to scavenge hydroxyl radicals and superoxide anions, increased gradually with ASTA addition (P < 0.05). In addition, the mRNA levels of antioxidant enzymes as well as the mRNA and protein levels of the mitogen-activated protein kinase (MAPK) and nuclear factor-erythroid 2-related factor 2 (Nrf2) were markedly increased in the 50–100 mg/kg ASTA group (P < 0.05). Conclusions Collectively, these results demonstrate that dietary ASTA may improve semen quality by increasing antioxidant enzyme activities and the ability to scavenge hydroxyl radicals, which may be related to upregulation of the MAPK/Nrf2 pathway.

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Autophagy Controls Nrf2-Mediated Dichotomy in Pressure Overloaded Hearts

Frontiers in Physiology ◽

10.3389/fphys.2021.673145 ◽

2021 ◽

Vol 12 ◽

Author(s):

Weiwei Wu ◽

Qingyun Qin ◽

Yan Ding ◽

Huimei Zang ◽

Dong-Sheng Li ◽

...

Keyword(s):

Nuclear Translocation ◽

Pressure Overload ◽

Myocardial Damage ◽

Nuclear Accumulation ◽

Related Factor ◽

Adult Mice ◽

Extracellular Signal ◽

Mechanistic Investigation ◽

Autophagy Inhibition

Burgeoning evidence has indicated that normal autophagy is required for nuclear factor erythroid 2-related factor (Nrf2)-mediated cardiac protection whereas autophagy inhibition turns on Nrf2-mediated myocardial damage and dysfunction in a setting of pressure overload (PO). However, such a concept remains to be fully established by a careful genetic interrogation in vivo. This study was designed to validate the hypothesis using a mouse model of PO-induced cardiomyopathy and heart failure, in which cardiac autophagy and/or Nrf2 activity are genetically inhibited. Myocardial autophagy inhibition was induced by cardiomyocyte-restricted (CR) knockout (KO) of autophagy related (Atg) 5 (CR-Atg5KO) in adult mice. CR-Atg5KO impaired cardiac adaptations while exacerbating cardiac maladaptive responses in the setting of PO. Notably, it also turned off Nrf2-mediated defense while switching on Nrf2-operated tissue damage in PO hearts. In addition, cardiac autophagy inhibition selectively inactivated extracellular signal regulated kinase (ERK), which coincided with increased nuclear accumulation of Nrf2 and decreased nuclear translocation of activated ERK in cardiomyocytes in PO hearts. Mechanistic investigation revealed that autophagy is required for the activation of ERK, which suppresses Nrf2-driven expression of angiotensinogen in cardiomyocytes. Taken together, these results provide direct evidence consolidating the notion that normal autophagy enables Nrf2-operated adaptation while switching off Nrf2-mediated maladaptive responses in PO hearts partly through suppressing Nrf2-driven angiotensinogen expression in cardiomyocytes.

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LPS Stimulation Induces Small Heterodimer Partner Expression Through the AMPK-NRF2 Pathway in Large Yellow Croaker (Larimichthys crocea)

Frontiers in Immunology ◽

10.3389/fimmu.2021.753681 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jianlong Du ◽

Xiaojun Xiang ◽

Dan Xu ◽

Kun Cui ◽

Yuning Pang ◽

...

Keyword(s):

Mrna Expression ◽

Underlying Mechanism ◽

Large Yellow Croaker ◽

Related Factor ◽

Larimichthys Crocea ◽

Nrf2 Pathway ◽

New Ideas ◽

Amp Activated Protein Kinase ◽

Lps Treatment ◽

Inhibitor Treatment

The mall heterodimer partner (SHP) plays an important regulatory role in mammal inflammation. The main objective of this study was to investigate the response of SHP to inflammatory stimulation and its underlying mechanism. The shp gene from large yellow croakers, was cloned, and this gene is mainly expressed in the liver and intestine. Lipopolysaccharide (LPS) stimulation induced the mRNA expression and protein level of SHP in macrophages of large yellow croakers. Overexpression of SHP significantly decreased mRNA expression of tnfα, il-1β, il-6 and cox2 induced by LPS treatment in macrophages. LPS stimulation increased the phosphorylation level of Adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK) in macrophages. AMPK inhibitor treatment significantly decreased the expression of SHP induced by LPS while AMPK activator significantly increased the expression of SHP. The nuclear factor-erythroid 2-related factor 2 (NRF2) increased the promoter activity of SHP in large yellow croakers and the level of nuclear NRF2 was increased by LPS stimulation and AMPK activation. NRF2 inhibitor treatment significantly decreased mRNA expression of shp induced by LPS and AMPK activator. In conclusion, LPS can induce SHP expression by activating the AMPK-NRF2 pathway while SHP could negatively regulate LPS-induced inflammation in large yellow croakers. This study may be benefit to the development of immunology of marine fish and provide new ideas for inflammation-related diseases.

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Glucocorticoid-Induced Leucine Zipper Inhibits the Raf-Extracellular Signal-Regulated Kinase Pathway by Binding to Raf-1

Molecular and Cellular Biology ◽

10.1128/mcb.22.22.7929-7941.2002 ◽

2002 ◽

Vol 22 (22) ◽

pp. 7929-7941 ◽

Cited By ~ 119

Author(s):

Emira Ayroldi ◽

Ornella Zollo ◽

Antonio Macchiarulo ◽

Barbara Di Marco ◽

Cristina Marchetti ◽

...

Keyword(s):

T Cell ◽

Protein Kinase ◽

T Cell Activation ◽

Leucine Zipper ◽

Nuclear Translocation ◽

Mapk Pathway ◽

Interleukin 2 ◽

Mitogen Activated Protein Kinase ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal

ABSTRACT Glucocorticoid-induced leucine zipper (GILZ) is a leucine zipper protein, whose expression is augmented by dexamethasone (DEX) treatment and downregulated by T-cell receptor (TCR) triggering. Stable expression of GILZ in T cells mimics some of the effects of glucocorticoid hormones (GCH) in GCH-mediated immunosuppressive and anti-inflammatory activity. In fact, GILZ overexpression inhibits TCR-activated NF-κB nuclear translocation, interleukin-2 production, FasL upregulation, and the consequent activation-induced apoptosis. We have investigated the molecular mechanism underlying GILZ-mediated regulation of T-cell activation by analyzing the effects of GILZ on the activity of mitogen-activated protein kinase (MAPK) family members, including Raf, MAPK/extracellular signal-regulated kinase (ERK) 1/2 (MEK-1/2), ERK-1/2, and c-Jun NH2-terminal protein kinase (JNK). Our results indicate that GILZ inhibited Raf-1 phosphorylation, which resulted in the suppression of both MEK/ERK-1/2 phosphorylation and AP-1-dependent transcription. We demonstrate that GILZ interacts in vitro and in vivo with endogenous Raf-1 and that Raf-1 coimmunoprecipitated with GILZ in murine thymocytes treated with DEX. Mapping of the binding domains and experiments with GILZ mutants showed that GILZ binds the region of Raf interacting with Ras through the NH2-terminal region. These data suggest that GILZ contributes, through protein-to-protein interaction with Raf-1 and the consequent inhibition of Raf-MEK-ERK activation, to regulating the MAPK pathway and to providing a further mechanism underlying GCH immunosuppression.

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Characterization of the Antioxidant Effects of γ-Oryzanol: Involvement of the Nrf2 Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/2987249 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 13

Author(s):

W. Rungratanawanich ◽

G. Abate ◽

M. M. Serafini ◽

M. Guarienti ◽

M. Catanzaro ◽

...

Keyword(s):

Nuclear Translocation ◽

Antioxidant Properties ◽

Quinone Reductase ◽

Glutathione Synthetase ◽

Heme Oxygenase 1 ◽

Hek 293 ◽

Human Embryonic Kidney Cells ◽

Nrf2 Pathway ◽

Protein Levels ◽

Age Related

γ-Oryzanol (ORY) is well known for its antioxidant potential. However, the mechanism by which ORY exerts its antioxidant effect is still unclear. In this paper, the antioxidant properties of ORY were investigated for its potential effects as a reactive oxygen and nitrogen species (ROS/RNS) scavenger and in activating antioxidant-promoting intracellular pathways utilizing the human embryonic kidney cells (HEK-293). The 24 h ORY exposure significantly prevented hydrogen peroxide- (H2O2-) induced ROS/RNS production at 3 h, and this effect was sustained for at least 24 h. ORY pretreatment also enhanced the activity of antioxidant enzymes: superoxide dismutase (SOD) and glutathione peroxidase (GPX). Interestingly, ORY induced the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) nuclear translocation and upregulation of Nrf2-dependent defensive genes such as NAD(P)H quinone reductase (NQO1), heme oxygenase-1 (HO-1), and glutathione synthetase (GSS) at mRNA and protein levels in both basal condition and after H2O2 insult. Thus, this study suggested an intriguing effect of ORY in modulating the Nrf2 pathway, which is also involved in regulating longevity as well as age-related diseases.

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A Nature-Inspired Nrf2 Activator Protects Retinal Explants from Oxidative Stress and Neurodegeneration

Antioxidants ◽

10.3390/antiox10081296 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1296

Author(s):

Maria Grazia Rossino ◽

Rosario Amato ◽

Marialaura Amadio ◽

Michela Rosini ◽

Filippo Basagni ◽

...

Keyword(s):

Oxidative Stress ◽

Nuclear Translocation ◽

Apoptotic Cell ◽

Antioxidant Properties ◽

Antioxidant Response ◽

Structural Features ◽

Related Factor ◽

Retinal Diseases ◽

Protein Levels ◽

Retinal Explants

Oxidative stress (OS) plays a key role in retinal dysfunctions and acts as a major trigger of inflammatory and neurodegenerative processes in several retinal diseases. To prevent OS-induced retinal damage, approaches based on the use of natural compounds are actively investigated. Recently, structural features from curcumin and diallyl sulfide have been combined in a nature-inspired hybrid (NIH1), which has been described to activate transcription nuclear factor erythroid-2-related factor-2 (Nrf2), the master regulator of the antioxidant response, in different cell lines. We tested the antioxidant properties of NIH1 in mouse retinal explants. NIH1 increased Nrf2 nuclear translocation, Nrf2 expression, and both antioxidant enzyme expression and protein levels after 24 h or six days of incubation. Possible toxic effects of NIH1 were excluded since it did not alter the expression of apoptotic or gliotic markers. In OS-treated retinal explants, NIH1 strengthened the antioxidant response inducing a massive and persistent expression of antioxidant enzymes up to six days of incubation. These effects resulted in prevention of the accumulation of reactive oxygen species, of apoptotic cell death, and of gliotic reactivity. Together, these data indicate that a strategy based on NIH1 to counteract OS could be effective for the treatment of retinal diseases.

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Angelica Polysaccharide Antagonizes 5-FU-Induced Oxidative Stress Injury to Reduce Apoptosis in the Liver Through Nrf2 Pathway

Frontiers in Oncology ◽

10.3389/fonc.2021.720620 ◽

2021 ◽

Vol 11 ◽

Author(s):

Di Zeng ◽

Yaping Wang ◽

Yi Chen ◽

Danyang Li ◽

Guoli Li ◽

...

Keyword(s):

Oxidative Stress ◽

Nuclear Translocation ◽

Normal Liver ◽

Chemotherapeutic Agents ◽

Related Factor ◽

Stress Injury ◽

Normal Liver Cell ◽

Nrf2 Pathway ◽

Bax Protein ◽

Oxidative Stress Injury

Oxidative stress induced by chemotherapeutic agents causes hepatotoxicity. 5-Fluorouracil (5-FU) has been found to have a variety of side effects, but its toxic effect on the liver and the mechanism are still unclear. Angelica polysaccharide (ASP), the main active ingredient of Dang Gui, has antioxidative stress effects. In this study, we investigated the antagonistic effects of ASP on 5-FU-induced injury in the mouse liver and human normal liver cell line MIHA and the possible mechanism. Our results show that ASP inhibited 5-FU-induced the decrease in Bcl-2 protein and the increase in Bax protein. ASP alleviated 5-FU-induced the increase in alanine aminotransferase (ALT), triglyceride (TG), and aspartate aminotransferase (AST) content; hepatic steatosis; and liver fibrosis. ASP restored 5-FU-induced swelling of mitochondria and the endoplasmic reticulum. 5-FU promoted the expression of Keap1 and increased the binding to NF-E2-related factor 2 (Nrf2) to reduce the nuclear translocation of Nrf2, thereby weakening the transcriptional activity of Nrf2 to inhibit the expression of HO-1; reducing the activity of GSH, SOD, and CAT to increase ROS content; and aggravating DNA damage (indicated by the increase in 8-OHdG). However, ASP reversed these reactions. In conclusion, ASP attenuated the 5-FU-induced Nrf2 pathway barrier to reduce oxidative stress injury and thereby inhibit the disorder of lipid anabolism and apoptosis. The study provides a new protectant for reducing the hepatic toxicity caused by 5-FU and a novel target for treating the liver injury.

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Identification of New Peptides from Fermented Milk Showing Antioxidant Properties: Mechanism of Action

Antioxidants ◽

10.3390/antiox9020117 ◽

2020 ◽

Vol 9 (2) ◽

pp. 117 ◽

Cited By ~ 8

Author(s):

Federica Tonolo ◽

Federico Fiorese ◽

Laura Moretto ◽

Alessandra Folda ◽

Valeria Scalcon ◽

...

Keyword(s):

Antioxidant Properties ◽

Milk Proteins ◽

Fermented Milk ◽

Fermented Foods ◽

Related Factor ◽

Nrf2 Pathway ◽

Wide Range ◽

Health Promoting ◽

Q 14

Due to their beneficial properties, fermented foods are considered important constituents of the human diet. They also contain bioactive peptides, health-promoting compounds studied for a wide range of effects. In this work, several antioxidant peptides extracted from fermented milk proteins were investigated. First, enriched peptide fractions were purified and analysed for their antioxidant capacity in vitro and in a cellular model. Subsequently, from the most active fractions, 23 peptides were identified by mass spectrometry MS/MS), synthesized and tested. Peptides N-15-M, E-11-F, Q-14-R and A-17-E were selected for their antioxidant effects on Caco-2 cells both in the protection against oxidative stress and inhibition of ROS production. To define their action mechanism, the activation of the Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2(Keap1/Nrf2) pathway was studied evaluating the translocation of Nrf2 from cytosol to nucleus. In cells treated with N-15-M, Q-14-R and A-17-E, a higher amount of Nrf2 was found in the nucleus with respect to the control. In addition, the three active peptides, through the activation of Keap1/Nrf2 pathway, led to overexpression and increased activity of antioxidant enzymes. Molecular docking analysis confirmed the potential ability of N-15-M, Q-14-R and A-17-E to bind Keap1, showing their destabilizing effect on Keap1/Nrf2 interaction.

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Astaxanthin Promotes Nrf2/ARE Signaling to Alleviate Renal Fibronectin and Collagen IV Accumulation in Diabetic Rats

Journal of Diabetes Research ◽

10.1155/2018/6730315 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 17

Author(s):

Xiaoyu Zhu ◽

Yongjun Chen ◽

Qing Chen ◽

Huiyuan Yang ◽

Xi Xie

Keyword(s):

Nuclear Translocation ◽

Antioxidant Properties ◽

Collagen Iv ◽

Diabetic Rats ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Stress Effect ◽

Superoxide Dismutase 1 ◽

Antioxidative Stress ◽

Underlying Mechanisms

Astaxanthin (AST), a natural keto-carotenoid classified as a xanthophyll, is well known for its antioxidant properties. AST can ameliorate the pathological characteristics of diabetic nephropathy (DN). However, the underlying mechanisms remain to be explored. This study was aimed at exploring whether AST exerts a protective effect on DN via activating nuclear factor erythroid 2-related factor 2– (Nrf2–) antioxidative response element (ARE) signaling. Streptozotocin-induced diabetic rats were treated with AST for 12 weeks. We found that AST treatment ameliorated renal morphological injury. Reduced fibronectin and collagen IV protein expression were found in the kidneys of diabetic rats. Furthermore, AST promoted the nuclear translocation of Nrf2 and increased its downstream protein heme oxygenase-1 and superoxide dismutase 1 expression. AST also increased the activity of SOD and decreased malondialdehyde generation in the serum of diabetic rats. These results suggest that the renoprotective effect of AST on DN partly depends on Nrf2–ARE signaling. The antioxidative stress effect of AST is responsible for the activation of Nrf2–ARE signaling in DN.

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