Synergistic Protection by Isoquercitrin and Quercetin against Glutamate-Induced Oxidative Cell Death in HT22 Cells via Activating Nrf2 and HO-1 Signaling Pathway: Neuroprotective Principles and Mechanisms of Dendropanax morbifera Leaves

Dendropanax morbifera leaves (DML) have long been used as traditional medicine to treat diverse symptoms in Korea. Ethyl acetate-soluble extracts of DML (DMLE) rescued HT22 mouse hippocampal neuronal cells from glutamate (Glu)-induced oxidative cell death; however, the protective compounds and mechanisms remain unknown. Here, we aimed to identify the neuroprotective ingredients and mechanisms of DMLE in the Glu-HT22 cell model. Five antioxidant compounds were isolated from DMLE and characterized as chlorogenic acid, hyperoside, isoquercitrin, quercetin, and rutin by spectroscopic methods. Isoquercitrin and quercetin significantly inhibited Glu-induced oxidative cell death by restoring intracellular reactive oxygen species (ROS) levels and mitochondrial superoxide generation, Ca2+ dysregulation, mitochondrial dysfunction, and nuclear translocation of apoptosis-inducing factor. These two compounds significantly increased the expression levels of nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) in the presence or absence of Glu treatment. Combinatorial treatment of the five compounds based on the equivalent concentrations in DMLE showed that significant protection was found only in the cells cotreated with isoquercitrin and quercetin, both of whom showed prominent synergism, as assessed by drug–drug interaction analysis. These findings suggest that isoquercitrin and quercetin are the active principles representing the protective effects of DMLE, and these effects were mediated by the Nrf2/HO-1 pathway.

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Protective effects of isothiocyanates on blood-CSF barrier disruption induced by oxidative stress

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00518.2011 ◽

2012 ◽

Vol 303 (1) ◽

pp. R1-R7 ◽

Cited By ~ 20

Author(s):

Jianming Xiang ◽

Gina N. Alesi ◽

Ningna Zhou ◽

Richard F Keep

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Neurological Disorders ◽

Nuclear Translocation ◽

Normal Function ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Protective Effects ◽

Brain Response

The choroid plexuses (CPs) form the blood-cerebrospinal fluid (CSF) barrier (BCSFB) and play an important role in maintaining brain normal function and the brain response to injury. Many neurological disorders are associated with oxidative stress that can impact CP function. This study examined the effects of isothiocyanates, an abundant component in cruciferous vegetables, on H2O2-induced BCSFB disruption and CP cell death in vitro. It further examined the potential role of a transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), in isothiocyanate-induced protection. Sulforaphane (SF) significantly reduced H2O2-induced BCSFB disruption as assessed by transepithelial electrical resistance (29 ± 7% reduction vs. 92 ± 2% decrease in controls) and [3H]mannitol permeability. Allyl-isothiocyanate (AITC) had a similar protective effect. H2O2-induced epithelial cell death was also reduced by these isothiocyanates. In primary CP cells, SF and AITC reduced cell death by 42 ± 3% and 53 ± 10%, respectively. Similar protection was found in a CP cell line Z310. Protection was only found with pretreatment for 12–48 h and not with acute exposure (1 h). The protective effects of SF and AITC were associated with Nrf2 nuclear translocation and upregulated expression of antioxidative systems regulated by Nrf2, including heme oxygenase-1, NAD(P)H quinine oxidoreductase, and cysteine/glutamate exchange transporter. Thus isothiocyanates, as diet or medicine, may be a method for protecting BCSFB in neurological disorders.

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Thymoquinone Prevents Dopaminergic Neurodegeneration by Attenuating Oxidative Stress Via the Nrf2/ARE Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2020.615598 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jianjian Dong ◽

Xiaoming Zhang ◽

Shijing Wang ◽

Chenchen Xu ◽

Manli Gao ◽

...

Keyword(s):

Oxidative Stress ◽

Nuclear Translocation ◽

Nigella Sativa ◽

Drug Candidate ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Protective Effects ◽

Quinone Oxidoreductase ◽

Neuroprotective Effects ◽

Antioxidant Genes

Studies have indicated that oxidative stress plays a crucial role in the development of Parkinson’s disease (PD) and other neurodegenerative conditions. Research has also revealed that nuclear factor erythroid 2-related factor 2 (Nrf2) triggers the expression of antioxidant genes via a series of antioxidant response elements (AREs), thus preventing oxidative stress. Thymoquinone (TQ) is the bioactive component of Nigella sativa, a medicinal plant that exhibits antioxidant and neuroprotective effects. In the present study we examined whether TQ alleviates in vivo and in vitro neurodegeneration induced by 1-methyl-4-phenylpyridinium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by acting as an activator of the Nrf2/ARE cascade. We showed that TQ significantly reduced MPP+-mediated cell death and apoptosis. Moreover, TQ significantly elevated the nuclear translocation of Nrf2 and significantly increased the subsequent expression of antioxidative genes such as Heme oxygenase 1 (HO-1), quinone oxidoreductase (NQO1) and Glutathione-S-Transferase (GST). The application of siRNA to silence Nrf2 led to an abolishment in the protective effects of TQ. We also found that the intraperitoneal injection of TQ into a rodent model of PD ameliorated oxidative stress and effectively mitigated nigrostriatal dopaminergic degeneration by activating the Nrf2-ARE pathway. However, these effects were inhibited by the injection of a lentivirus wrapped Nrf2 siRNA (siNrf2). Collectively, these findings suggest that TQ alleviates progressive dopaminergic neuropathology by activating the Nrf2/ARE signaling cascade and by attenuating oxidative stress, thus demonstrating that TQ is a potential novel drug candidate for the treatment of PD.

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Salidroside Alleviates Oxidative Stress and Apoptosis via AMPK/Nrf2 Pathway in DHT-induced Human Granulosa Cell Line KGN

10.21203/rs.3.rs-842159/v1 ◽

2021 ◽

Author(s):

Rui Ji ◽

Fang-yuan Jia ◽

Xin Chen ◽

Ze-hao Wang ◽

Wen-yi Jin ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Line ◽

Nuclear Translocation ◽

Tumor Cell Line ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Protective Effects ◽

Nrf2 Activation ◽

Nrf2 Signaling Pathway ◽

Antioxidant Proteins

Abstract Background: In the past few years, emerging evidence established persistent oxidative stress to be a key player in the pathogenesis of polycystic ovary syndrome (PCOS). Particularly, it damages the function of granulosa cells, and thus hinders the development of follicles. The present study aimed to explore and establish the protective effects of salidroside on dihydrotestosterone (DHT)‐induced Granulosa‐like tumor cell line (KGN), mediated via antioxidant mechanisms.Methods: KGN cells were treated with DHT as a PCOS cell model, and then incubated with salidroside in different concentrations. Apoptosis and reactive oxygen species (ROS) accumulation were assessed by flow cytometry, mitochondrial membrane potential depolarization and the nuclear translocation of Nrf2 were detected by immunofluorescence staining, and the level of apoptosis-related proteins and antioxidant proteins was assessed by western blotting.Results: Salidroside partly reversed DHT mediated effects, via stimulation of nuclear factor erythroid 2‐related factor 2 (Nrf2) signaling pathway and the downstream antioxidant proteins heme oxygenase‐1(HO‐1) and quinine oxidoreductase 1(NQO1). Additionally, knockdown of Nrf2 resulted in a deterioration in DHT‐induced oxidative stress and apoptosis. It partly moderated the protective effects of salidroside as well. Mechanistically, AMPK was identified to be the upstream signaling involved in salidroside‐induced Nrf2 activation, as silencing of AMPK partly prevented the upregulation of Nrf2 and the downstream proteins HO‐1 and NQO1. Conclusion: The present study is the first to effectively demonstrate the inhibitory effect of salidroside on DHT‐stimulated oxidative stress and apoptosis in KGN cells, which was dependent on Nrf2 activation that involved AMPK.

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Neuroprotective Effects of Taraxacum officinale Wigg. Extract on Glutamate-Induced Oxidative Stress in HT22 Cells via HO-1/Nrf2 Pathways

Nutrients ◽

10.3390/nu10070926 ◽

2018 ◽

Vol 10 (7) ◽

pp. 926 ◽

Cited By ~ 6

Author(s):

Shan Huang ◽

Ning Meng ◽

Zhiming Liu ◽

Li Guo ◽

Linsha Dong ◽

...

Keyword(s):

Oxidative Stress ◽

Oxidative Damage ◽

Neurodegenerative Diseases ◽

Molecular Mechanisms ◽

Nuclear Translocation ◽

Taraxacum Officinale ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Neuroprotective Effects ◽

Ht22 Cells

Oxidative stress-mediated neuron damage is considered an important contributor to the pathogenesis and development of neurodegenerative diseases. Taraxacum officinale has been reported to possess antioxidant activities. However, whether it can protect neurons against oxidative damage and the underlying molecular mechanisms have not been fully determined. In the present study, we examined the neuroprotective effects of ethanol extracts of this plant (ETOW) on glutamate-induced oxidative stress in HT22 cells. Both cell viability and reactive oxygen species (ROS) assays showed that ETOW effectively attenuated glutamate-induced cytotoxicity and ROS generation. Furthermore, our results revealed that ETOW increased the expression of heme oxygenase-1 (HO-1) and promoted the nuclear translocation of nuclear factor erythroid 2-related factor-2 (Nrf2). The inhibitory effects of ETOW on glutamate-stimulated cell toxicity and ROS production were partially reversed by tin protoporphyrin (SnPP), an HO activity inhibitor. Taken together, these results demonstrate that ETOW can protect HT22 cells against glutamate-induced oxidative damage by inducing the Nrf2/HO-1 pathways. Our study supports the idea that Taraxacum officinale Wigg. is a promising agent for preventing neurodegenerative diseases.

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(−)-Loliolide Isolated from Sargassum horneri Protects against Fine Dust-Induced Oxidative Stress in Human Keratinocytes

Antioxidants ◽

10.3390/antiox9060474 ◽

2020 ◽

Vol 9 (6) ◽

pp. 474

Author(s):

Mawalle Kankanamge Hasitha Madhawa Dias ◽

Dissanayaka Mudiyanselage Dinesh Madusanka ◽

Eui Jeong Han ◽

Min Ju Kim ◽

You-Jin Jeon ◽

...

Keyword(s):

Oxidative Stress ◽

Nuclear Translocation ◽

Human Keratinocytes ◽

Sargassum Horneri ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Protective Effects ◽

Fine Dust ◽

Apoptosis Pathway ◽

Sustainable Solutions

The emergence of fine dust (FD) among air pollutants has taken a toll during the past few decades, and it has provided both controversy and a platform for open conversation amongst world powers for finding sustainable solutions and effective treatments for health issues. The present study emphasizes the protective effects of (–)-loliolide (HTT) isolated from Sargassum horneri against FD-induced oxidative stress in human HaCaT keratinocytes. The purification of (–)-loliolide was carried out by centrifugal partition chromatography. HTT did not show any cytotoxicity, and it further illustrated the potential to increase cell viability by reducing the reactive oxygen species (ROS) production in FD-stimulated keratinocytes. Furthermore, HTT suppressed FD-stimulated DNA damage and the formation of apoptotic bodies, and it reduced the population of cells in the sub-G1 apoptosis phase. FD-induced apoptosis was advancing through the mitochondria-mediated apoptosis pathway. The cytoprotective effects of the HTT against FD-stimulated oxidative damage is mediated through squaring the nuclear factor E2-related factor 2 (Nrf2)-mediated heme oxygenase-1 (HO-1) pathway, dose-dependently increasing HO-1 and NAD(P)H dehydrogenase (quinone) 1 (NQO1) levels in the cytosol while concomitantly improving the nuclear translocation of Nrf2. Future studies could implement the protective functionality of HTT in producing pharmaceuticals that utilize natural products and benefit the diseased.

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Protective Effects of GYY4137 on Renal Ischaemia/Reperfusion Injury through Nrf2-Mediated Antioxidant Defence

Kidney & Blood Pressure Research ◽

10.1159/000509933 ◽

2021 ◽

pp. 1-9

Author(s):

Hongmei Zhao ◽

Yun Qiu ◽

Yichen Wu ◽

Hong Sun ◽

Sumin Gao

Keyword(s):

Oxidative Stress ◽

Reperfusion Injury ◽

Nuclear Translocation ◽

Organ Damage ◽

Related Factor ◽

Protective Effects ◽

Ischaemia Reperfusion Injury ◽

Renal Ischaemia ◽

Ischaemia Reperfusion ◽

Renal Histology

Introduction/Aims: Hydrogen sulfide (H2S) is considered to be the third most important endogenous gasotransmitter in organisms. GYY4137 is a long-acting donor for H2S, a gas transmitter that has been shown to prevent multi-organ damage in animal studies. We previously reported the effect of GYY4137 on cardiac ischaemia reperfusion injury (IRI) in diabetic mice. However, the role and mechanism of GYY4137 in renal IRI are poorly understood. The aims of this study were to determine whether GYY4137 can effectively alleviate the injury induced by renal ischaemia reperfusion and to explore its possible mechanism. Methods: Mice received right nephrectomy and clipping of the left renal pedicle for 45 min. GYY4137 was administered by intraperitoneal injection for 2 consecutive days before the operation. The model of hypoxia/reoxygenation injury was established in HK-2 cells, which were pre-treated with or without GYY4137. Renal histology, function, apoptosis, and oxidative stress were measured. Western blot was used to measure the target protein after renal IRI. Results: The results indicated that GYY4137 had a clear protective effect on renal IRI as reflected by the attenuation of renal dysfunction, renal tubule injury, and apoptosis. Moreover, GYY4137 remarkably reduced renal IRI-induced oxidative stress. GYY4137 significantly elevated the nuclear translocation of nuclear factor-erythroid-2-related factor 2 (Nrf2) and the expression of antioxidant enzymes regulated by Nrf2, including SOD, HO-1, and NQO-1. Conclusions: GYY4137 alleviates ischaemia reperfusion-induced renal injury through activating the antioxidant effect mediated by Nrf2 signalling.

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Kaempferol Ameliorates Oxygen-Glucose Deprivation/Reoxygenation-Induced Neuronal Ferroptosis by Activating Nrf2/SLC7A11/GPX4 Axis

Biomolecules ◽

10.3390/biom11070923 ◽

2021 ◽

Vol 11 (7) ◽

pp. 923

Author(s):

Yuan Yuan ◽

Yanyu Zhai ◽

Jingjiong Chen ◽

Xiaofeng Xu ◽

Hongmei Wang

Keyword(s):

Lipid Peroxidation ◽

Cell Death ◽

Antioxidant Capacity ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Glucose Deprivation ◽

Oxygen Glucose Deprivation ◽

Related Factor ◽

Protective Effects

Kaempferol has been shown to protect cells against cerebral ischemia/reperfusion injury through inhibition of apoptosis. In the present study, we sought to investigate whether ferroptosis is involved in the oxygen-glucose deprivation/reperfusion (OGD/R)-induced neuronal injury and the effects of kaempferol on ferroptosis in OGD/R-treated neurons. Western blot, immunofluorescence, and transmission electron microscopy were used to analyze ferroptosis, whereas cell death was detected using lactate dehydrogenase (LDH) release. We found that OGD/R attenuated SLC7A11 and glutathione peroxidase 4 (GPX4) levels as well as decreased endogenous antioxidants including nicotinamide adenine dinucleotide phosphate (NADPH), glutathione (GSH), and superoxide dismutase (SOD) in neurons. Notably, OGD/R enhanced the accumulation of lipid peroxidation, leading to the induction of ferroptosis in neurons. However, kaempferol activated nuclear factor-E2-related factor 2 (Nrf2)/SLC7A11/GPX4 signaling, augmented antioxidant capacity, and suppressed the accumulation of lipid peroxidation in OGD/R-treated neurons. Furthermore, kaempferol significantly reversed OGD/R-induced ferroptosis. Nevertheless, inhibition of Nrf2 by ML385 blocked the protective effects of kaempferol on antioxidant capacity, lipid peroxidation, and ferroptosis in OGD/R-treated neurons. These results suggest that ferroptosis may be a significant cause of cell death associated with OGD/R. Kaempferol provides protection from OGD/R-induced ferroptosis partly by activating Nrf2/SLC7A11/GPX4 signaling pathway.

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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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Vascular Protective Role of Samul-Tang in HUVECs: Involvement of Nrf2/HO-1 and NO

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/9580234 ◽

2016 ◽

Vol 2016 ◽

pp. 1-14 ◽

Cited By ~ 6

Author(s):

Eun Sik Choi ◽

Yun Jung Lee ◽

Chang Seob Seo ◽

Jung Joo Yoon ◽

Byung Hyuk Han ◽

...

Keyword(s):

Vascular Endothelium ◽

Molecular Mechanisms ◽

Water Extract ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Nuclear Factor ◽

Ros Production ◽

Herbal Formula ◽

Protective Effects ◽

Monocyte Adhesion

Samul-Tang (Si-Wu-Tang, SMT), composed of four medicinal herbs, is a well-known herbal formula treating hematological disorder or gynecologic disease. However, vascular protective effects of SMT and its molecular mechanisms on the vascular endothelium, known as the central spot of vascular inflammatory process, are not reported. The aim of this study was to investigate vascular protective effects of SMT water extract in human umbilical vein endothelial cells (HUVECs). Water extract of SMT was prepared and identified by HPLC-PDA analysis. Expression of cell adhesion molecules (CAMs) and heme oxygenase-1 (HO-1) and translocation of nuclear factor-kappa B (NF-κB) and nuclear factor-erythroid 2-related factor 2 (Nrf2) were determined by western blot. Nuclear localization of NF-κB and Nrf2 was visualized by immunofluorescence and DNA binding activity of NF-κB was measured. ROS production, HL-60 monocyte adhesion, and intracellular nitric oxide (NO) were also measured using a fluorescent indicator. SMT suppressed NF-κB translocation and activation as well as expression of CAMs, monocyte adhesion, and ROS production induced by TNF-αin HUVECs. SMT treated HUVECs showed upregulation of HO-1 and NO which are responsible for vascular protective action. Our study suggests that SMT, a traditionally used herbal formula, protects the vascular endothelium from inflammation and might be used as a promising vascular protective drug.

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Hepatoprotective Effect of Polysaccharides Isolated from Dendrobium officinale against Acetaminophen-Induced Liver Injury in Mice via Regulation of the Nrf2-Keap1 Signaling Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/6962439 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 12

Author(s):

Guosheng Lin ◽

Dandan Luo ◽

Jingjing Liu ◽

Xiaoli Wu ◽

Jinfen Chen ◽

...

Keyword(s):

Liver Injury ◽

Signaling Pathway ◽

Nuclear Translocation ◽

Hepatoprotective Effect ◽

Dendrobium Officinale ◽

Regulatory Subunit ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Glutamate Cysteine Ligase ◽

Nrf2 Signaling Pathway

The effect of polysaccharides isolated from Dendrobium officinale (DOP) on acetaminophen- (APAP-) induced hepatotoxicity and the underlying mechanisms involved are investigated. Male Institute of Cancer Research (ICR) mice were randomly assigned to six groups: (1) control, (2) vehicle (APAP, 230 mg/kg), (3) N-acetylcysteine (100 mg/kg), (4) 50 mg/kg DOP, (5) 100 mg/kg DOP, and (6) 200 mg/kg DOP. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the serum and glutathione (GSH), malondialdehyde (MDA), catalase (CAT), total antioxidant capacity (T-AOC), myeloperoxidase (MPO), and reactive oxygen species (ROS) levels in the liver were determined after the death of the mice. The histological examination of the liver was also performed. The effect of DOP on the Kelch-like ECH-associated protein 1- (Keap1-) nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway was evaluated using Western blot analysis and real-time polymerase chain reaction (PCR). The results showed that DOP treatment significantly alleviated the hepatic injury. The decrease in ALT and AST levels in the serum and ROS, MDA, and MPO contents in the liver, as well as the increases in GSH, CAT, and T-AOC in the liver, were observed after DOP treatment. DOP treatment significantly induced the dissociation of Nrf2 from the Nrf2−Keap1 complex and promoted the Nrf2 nuclear translocation. Subsequently, DOP-mediated Nrf2 activation triggered the transcription and expressions of the glutamate–cysteine ligase catalytic (GCLC) subunit, glutamate–cysteine ligase regulatory subunit (GCLM), heme oxygenase-1 (HO-1), and NAD(P)H dehydrogenase quinone 1 (NQO1) in APAP-treated mice. The present study revealed that DOP treatment exerted potentially hepatoprotective effects against APAP-induced liver injury. Further investigation about mechanisms indicated that DOP exerted the hepatoprotective effect by suppressing the oxidative stress and activating the Nrf2−Keap1 signaling pathway.

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