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

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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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

Antioxidants ◽

10.3390/antiox10040554 ◽

2021 ◽

Vol 10 (4) ◽

pp. 554

Author(s):

Hye-Jin Park ◽

Ha-Neul Kim ◽

Chul Young Kim ◽

Min-Duk Seo ◽

Seung-Hoon Baek

Keyword(s):

Cell Death ◽

Nuclear Translocation ◽

Interaction Analysis ◽

Cell Model ◽

Antioxidant Compounds ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Protective Effects ◽

Ht22 Cells ◽

Dendropanax Morbifera

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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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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(−)-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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Beyond the 5-HT3 receptors

Human & Experimental Toxicology ◽

10.1177/0960327114562034 ◽

2015 ◽

Vol 34 (9) ◽

pp. 922-931 ◽

Cited By ~ 9

Author(s):

S Khalifeh ◽

G Fakhfouri ◽

SE Mehr ◽

K Mousavizadeh ◽

AR Dehpour ◽

...

Keyword(s):

Oxidative Stress ◽

Caspase 3 ◽

Effective Properties ◽

Neuronal Degeneration ◽

Partial Agonist ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Protective Effects ◽

Α7 Nicotinic Acetylcholine Receptor

Accumulation of reactive oxygen species, such as hydrogen peroxide (H2O2), generated by inflammatory cells or other pathological conditions, leads to oxidative stress, which may contribute to the neuronal degeneration observed in a wide variety of neurodegenerative disorders such as Alzheimer’s disease. Recent investigations have described effective properties of tropisetron, such as antiphlogistic action or protection against β-amyloid induced-neuroinflammation in rats. Our data revealed that H2O2-induced cell death in rat pheochromocytoma cell line (PC12) can be inhibited by tropisetron, as defined by 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide assay, caspase 3 and caspase 12 levels. We further showed that tropisetron exerts its protective effects by upregulation of heme oxygenase-1, glutathione, catalase activity, and nuclear factor-erythroid 2 p45-related factor 2 level. Moreover, tropisetron was recently found to be a partial agonist of α7 nicotinic acetylcholine receptor (α7nAChR). The activation of α7nAChR could inhibit inflammatory and apoptotic signaling pathways in the oxidative stress conditions. In this study, selective α7nAChR antagonists (methyllycaconitine) reversed the effects of tropisetron on caspase 3 level. Our findings indicated that tropisetron can protect PC12 cells against H2O2-induced neurotoxicity through α7nAChR in vitro.

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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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Cpt1a promoted ROS-induced oxidative stress and inflammation in liver injury via the Nrf2/HO-1 and NLRP3 inflammasome signaling pathway

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2020-0165 ◽

2020 ◽

Author(s):

Xigang Luo ◽

Dapeng Sun ◽

Yinxiang Wang ◽

Fengxiang Zhang ◽

Yi Wang

Keyword(s):

Oxidative Stress ◽

Liver Injury ◽

Signaling Pathway ◽

Nlrp3 Inflammasome ◽

Receptor Protein ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Over Expression ◽

Vitro Model

Various liver diseases caused by liver damage seriously affect people’s health. The purpose of this study was to clarify that the effects and mechanism of Carnitine palmitoyltransferase 1 (Cpt1a) on oxidative stress and inflammation in liver injury. It was found that the expression of Cpt1a mRNA was up-regulated in model mice of liver injury. So, over-expression of Cpt1a increased reactive oxygen species (ROS) production and malondialdehyde (MDA) levels, and reduced superoxide dismutase (SOD), glutathione (GSH) and glutathione peroxidase (GSH-px) levels in vitro model of liver injury. It was also shown that over-expression of Cpt1a suppressed the Nuclear factor-erythroid-2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1) signaling pathway. In summary, these data indicate that Cpt1a promotes ROS-induced oxidative stress in liver injury via the Nrf2/HO-1 and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome signaling pathway.

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(10Z)-Debromohymenialdisine from Marine Sponge Stylissa sp. Regulates Intestinal Inflammatory Responses in Co-Culture Model of Epithelial Caco-2 Cells and THP-1 Macrophage Cells

Molecules ◽

10.3390/molecules24183394 ◽

2019 ◽

Vol 24 (18) ◽

pp. 3394 ◽

Cited By ~ 2

Author(s):

Seon Min Lee ◽

Na-Hyun Kim ◽

Sangbum Lee ◽

Yun Na Kim ◽

Jeong-Doo Heo ◽

...

Keyword(s):

Marine Sponge ◽

Nuclear Translocation ◽

Inflammatory Responses ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Nuclear Factor ◽

Subsequent Increase ◽

Vitro Model ◽

Factor Α

Crohn’s disease (CD) and ulcerative colitis (UC), collectively referred to as inflammatory bowel disease (IBD), are autoimmune diseases characterized by chronic inflammation within the gastrointestinal tract. Debromohymenialdisine is an active pyrrole alkaloid that is well known to serve as a stable and effective inhibitor of Chk2. In the present study, we attempted to investigate the anti-inflammatory properties of (10Z)-debromohymenialdisine (1) isolated from marine sponge Stylissa species using an intestinal in vitro model with a transwell co-culture system. The treatment with 1 attenuated the production and gene expression of lipopolysaccharide (LPS)-induced Interleukin (IL)-6, IL-1β, prostaglandin E2 (PGE2), and tumor necrosis factor-α in co-cultured THP-1 macrophages at a concentration range of 1–5 μM. The protein expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 were down-regulated in response to the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) translocation into the nucleus in cells. In addition, we observed that 1 markedly promoted the nuclear translocation of nuclear factor erythroid 2 related factor 2 (Nrf2) and subsequent increase of heme oxygenase-1 (HO-1) expression. These findings suggest the potential use of 1 as a pharmaceutical lead in the treatment of inflammation-related diseases including IBD.

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Neuroprotective Effect of Bergamot Juice in 6-OHDA-Induced SH-SY5Y Cell Death, an In Vitro Model of Parkinson’s Disease

Pharmaceutics ◽

10.3390/pharmaceutics12040326 ◽

2020 ◽

Vol 12 (4) ◽

pp. 326 ◽

Cited By ~ 3

Author(s):

Nadia Ferlazzo ◽

Santa Cirmi ◽

Alessandro Maugeri ◽

Caterina Russo ◽

Giovanni Enrico Lombardo ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Nuclear Translocation ◽

Neuroprotective Effect ◽

Neuroblastoma Cells ◽

Specific Cell ◽

Protective Effects ◽

Human Neuroblastoma

Much evidence suggests that both oxidative stress and apoptosis play a key role in the pathogenesis of Parkinson’s disease (PD). The present study aims to evaluate the protective effect of bergamot juice (BJ) against 6-hydroxydopamine (6-OHDA)- or H2O2-induced cell death. Treatment of differentiated SH-SY5Y human neuroblastoma cells with 6-OHDA or H2O2 resulted in cell death that was significantly reduced by the pre-treatment with BJ. The protective effects of BJ seem to correlate with the reduction of intracellular reactive oxygen species and nitric oxide generation caused by 6-OHDA or H2O2. BJ also attenuated mitochondrial dysfunction, caspase-3 activation, imbalance of pro- and anti-apoptotic proteins, MAPKs activation and reduced NF-ĸB nuclear translocation evoked by neurotoxic agents. Additionally, BJ exhibited excellent antioxidant capability in cell-free assays. Collectively, our results suggest that BJ exerts neuroprotective effect through the interplay with specific cell targets and its antioxidant activity, making it worthy of consideration for the management of neurodegenerative diseases.

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α1-Microglobulin (A1M) Protects Human Proximal Tubule Epithelial Cells from Heme-Induced Damage In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms21165825 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5825 ◽

Cited By ~ 2

Author(s):

Amanda Kristiansson ◽

Sara Davidsson ◽

Maria E. Johansson ◽

Sarah Piel ◽

Eskil Elmér ◽

...

Keyword(s):

Oxidative Stress ◽

Epithelial Cells ◽

Proximal Tubule ◽

Mitochondrial Function ◽

Radical Scavenging ◽

Related Factor ◽

Protective Effects ◽

Cellular Expression ◽

Human Proximal Tubule

Oxidative stress is associated with many renal disorders, both acute and chronic, and has also been described to contribute to the disease progression. Therefore, oxidative stress is a potential therapeutic target. The human antioxidant α1-microglobulin (A1M) is a plasma and tissue protein with heme-binding, radical-scavenging and reductase activities. A1M can be internalized by cells, localized to the mitochondria and protect mitochondrial function. Due to its small size, A1M is filtered from the blood into the glomeruli, and taken up by the renal tubular epithelial cells. A1M has previously been described to reduce renal damage in animal models of preeclampsia, radiotherapy and rhabdomyolysis, and is proposed as a pharmacological agent for the treatment of kidney damage. In this paper, we examined the in vitro protective effects of recombinant human A1M (rA1M) in human proximal tubule epithelial cells. Moreover, rA1M was found to protect against heme-induced cell-death both in primary cells (RPTEC) and in a cell-line (HK-2). Expression of stress-related genes was upregulated in both cell cultures in response to heme exposure, as measured by qPCR and confirmed with in situ hybridization in HK-2 cells, whereas co-treatment with rA1M counteracted the upregulation. Mitochondrial respiration, analyzed with the Seahorse extracellular flux analyzer, was compromised following exposure to heme, but preserved by co-treatment with rA1M. Finally, heme addition to RPTE cells induced an upregulation of the endogenous cellular expression of A1M, via activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-pathway. Overall, data suggest that A1M/rA1M protects against stress-induced damage to tubule epithelial cells that, at least partly, can be attributed to maintaining mitochondrial function.

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