Evaluation of the Effects of Fucoidans from Fucus Species and Laminaria hyperborea against Oxidative Stress and Iron-Dependent Cell Death

Fucoidans are algal polysaccharides that exhibit protective properties against oxidative stress. The aim of this study was to investigate different fucoidans from brown seaweeds for their ability to protect against iron-dependent oxidative stress (ferroptosis), a main hallmark of retinal and brain diseases, including hemorrhage. We investigated five new high-molecular weight fucoidan extracts from Fucus vesiculosus, F. serratus, and F. distichus subsp. evanescens, a previously published Laminaria hyperborean extract, and commercially available extracts from F. vesiculosus and Undaria pinnatifida. We induced oxidative stress by glutathione depletion (erastin) and H2O2 in four retinal and neuronal cell lines as well as primary cortical neurons. Only extracts from F. serratus, F. distichus subsp. evanescens, and Laminaria hyperborea were partially protective against erastin-induced cell death in ARPE-19 and OMM-1 cells, while none of the extracts showed beneficial effects in neuronal cells. Protective fucoidans also attenuated the decrease in protein levels of the antioxidant enzyme GPX4, a key regulator of ferroptosis. This comprehensive analysis demonstrates that the antioxidant abilities of fucoidans may be cell type-specific, besides depending on the algal species and extraction method. Future studies are needed to further characterize the health-benefiting effects of fucoidans and to determine the exact mechanism underlying their antioxidative abilities.

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Upregulation of Peroxiredoxin 3 Protects Afg3l2-KO Cortical Neurons In Vitro from Oxidative Stress: A Paradigm for Neuronal Cell Survival under Neurodegenerative Conditions

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/4721950 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13

Author(s):

Barbara Bettegazzi ◽

Ilaria Pelizzoni ◽

Floramarida Salerno Scarzella ◽

Lisa Michelle Restelli ◽

Daniele Zacchetti ◽

...

Keyword(s):

Oxidative Stress ◽

Cortical Neurons ◽

Mitochondrial Dynamics ◽

Neuronal Cell ◽

The Other ◽

Antioxidant Defenses ◽

Glutathione Depletion ◽

Other Hand ◽

Peroxiredoxin 3

Several neurodegenerative disorders exhibit selective vulnerability, with subsets of neurons more affected than others, possibly because of the high expression of an altered gene or the presence of particular features that make them more susceptible to insults. On the other hand, resilient neurons may display the ability to develop antioxidant defenses, particularly in diseases of mitochondrial origin, where oxidative stress might contribute to the neurodegenerative process. In this work, we investigated the oxidative stress response of embryonic fibroblasts and cortical neurons obtained from Afg3l2-KO mice. AFG3L2 encodes a subunit of a protease complex that is expressed in mitochondria and acts as both quality control and regulatory enzyme affecting respiration and mitochondrial dynamics. When cells were subjected to an acute oxidative stress protocol, the survival of AFG3L2-KO MEFs was not significantly influenced and was comparable to that of WT; however, the basal level of the antioxidant molecule glutathione was higher. Indeed, glutathione depletion strongly affected the viability of KO, but not of WT MEF, thereby indicating that oxidative stress is more elevated in KO MEF even though well controlled by glutathione. On the other hand, when cortical KO neurons were put in culture, they immediately appeared more vulnerable than WT to the acute oxidative stress condition, but after few days in vitro, the situation was reversed with KO neurons being more resistant than WT to acute stress. This compensatory, protective competence was not due to the upregulation of glutathione, rather of two mitochondrial antioxidant proteins: superoxide dismutase 2 and, at an even higher level, peroxiredoxin 3. This body of evidence sheds light on the capability of neurons to activate neuroprotective pathways and points the attention to peroxiredoxin 3, an antioxidant enzyme that might be critical for neuronal survival also in other disorders affecting mitochondria.

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Insertion of the βGeo Promoter Trap into the Fem1c Gene of ROSA3 Mice

Molecular and Cellular Biology ◽

10.1128/mcb.24.9.3794-3803.2004 ◽

2004 ◽

Vol 24 (9) ◽

pp. 3794-3803 ◽

Cited By ~ 6

Author(s):

Cassandra L. Schlamp ◽

Andrew T. Thliveris ◽

Yan Li ◽

Louis P. Kohl ◽

Claudia Knop ◽

...

Keyword(s):

Cell Death ◽

Ganglion Cells ◽

Neuronal Cell Death ◽

Insertion Site ◽

Neuronal Cell ◽

Pyramidal Cells ◽

Coding Region ◽

Protein Levels ◽

Molecular Events ◽

Promoter Trap

ABSTRACT ROSA3 mice were developed by retroviral insertion of the βGeo gene trap vector. Adult ROSA3 mice exhibit widespread expression of the trap gene in epithelial cells found in most organs. In the central nervous system the highest expression of βGeo is found in CA1 pyramidal cells of the hippocampus, Purkinje cells of the cerebellum, and ganglion cells of the retina. Characterization of the genomic insertion site for βGeo in ROSA3 mice shows that the trap vector is located in the first intron of Fem1c, a gene homologous to the sex-determining gene fem-1 of Caenorhabditis elegans. Transcription of the Rosa3 allele (R3) yields a spliced message that includes the first exon of Fem1c and the βGeo coding region. Although normal processing of the Fem1c transcript is disrupted in homozygous Rosa3 (Fem1cR3/R3 ) mice, some tissues show low levels of a partially processed transcript containing exons 2 and 3. Since the entire coding region of Fem1c is located in these two exons, Fem1cR3/R3 mice may still be able to express a putative FEM1C protein. To this extent, Fem1cR3/R3 mice show no adverse effects in their sexual development or fertility or in the attenuation of neuronal cell death, another function that has been attributed to both fem-1 and a second mouse homolog, Fem1b. Examination of βGeo expression in ganglion cells after exposure to damaging stimuli indicates that protein levels are rapidly depleted prior to cell death, making the βGeo reporter gene a potentially useful marker to study early molecular events in damaged neurons.

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Protective Role of Transduced Tat-Thioredoxin1 (Trx1) against Oxidative Stress-Induced Neuronal Cell Death via ASK1-MAPK Signal Pathway

Biomolecules & Therapeutics ◽

10.4062/biomolther.2020.154 ◽

2021 ◽

Author(s):

Eun Ji Yeo ◽

Won Sik Eum ◽

Hyeon Ji Yeo ◽

Yeon Joo Choi ◽

Eun Jeong Sohn ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Protective Role ◽

Signal Pathway ◽

Mapk Signal Pathway

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Induction of the Nrf2 Pathway by Sulforaphane Is Neuroprotective in a Rat Temporal Lobe Epilepsy Model

Antioxidants ◽

10.3390/antiox10111702 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1702

Author(s):

Sereen Sandouka ◽

Tawfeeq Shekh-Ahmad

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Status Epilepticus ◽

Temporal Lobe Epilepsy ◽

Antioxidant Capacity ◽

Temporal Lobe ◽

Epileptiform Activity ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

The Brain

Epilepsy is a chronic disease of the brain that affects over 65 million people worldwide. Acquired epilepsy is initiated by neurological insults, such as status epilepticus, which can result in the generation of ROS and induction of oxidative stress. Suppressing oxidative stress by upregulation of the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) has been shown to be an effective strategy to increase endogenous antioxidant defences, including in brain diseases, and can ameliorate neuronal damage and seizure occurrence in epilepsy. Here, we aim to test the neuroprotective potential of a naturally occurring Nrf2 activator sulforaphane, in in vitro epileptiform activity model and a temporal lobe epilepsy rat model. Sulforaphane significantly decreased ROS generation during epileptiform activity, restored glutathione levels, and prevented seizure-like activity-induced neuronal cell death. When given to rats after 2 h of kainic acid-induced status epilepticus, sulforaphane significantly increased the expression of Nrf2 and related antioxidant genes, improved oxidative stress markers, and increased the total antioxidant capacity in both the plasma and hippocampus. In addition, sulforaphane significantly decreased status epilepticus-induced neuronal cell death. Our results demonstrate that Nrf2 activation following an insult to the brain exerts a neuroprotective effect by reducing neuronal death, increasing the antioxidant capacity, and thus may also modify epilepsy development.

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Ginsenoside Rb2 suppresses the glutamate-mediated oxidative stress and neuronal cell death in HT22 cells

Journal of Ginseng Research ◽

10.1016/j.jgr.2018.12.002 ◽

2019 ◽

Vol 43 (2) ◽

pp. 326-334 ◽

Cited By ~ 19

Author(s):

Dong Hoi Kim ◽

Dae Won Kim ◽

Bo Hyun Jung ◽

Jong Hun Lee ◽

Heesu Lee ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Ht22 Cells ◽

Ginsenoside Rb2

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Neuroprotective Effects of Tetrahydrocurcumin against Glutamate-Induced Oxidative Stress in Hippocampal HT22 Cells

Molecules ◽

10.3390/molecules25010144 ◽

2019 ◽

Vol 25 (1) ◽

pp. 144 ◽

Cited By ~ 4

Author(s):

Chang-Hyun Park ◽

Ji Hoon Song ◽

Su-Nam Kim ◽

Ji Hwan Lee ◽

Hae-Jeung Lee ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Protein Kinases ◽

Apoptotic Cell ◽

Curcuma Longa ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Ht22 Cells ◽

Mitogen Activated Protein Kinases ◽

Mitogen Activated Protein

In the central nervous system, glutamate is a major excitable neurotransmitter responsible for many cellular functions. However, excessive levels of glutamate induce neuronal cell death via oxidative stress during acute brain injuries as well as chronic neurodegenerative diseases. The present study was conducted to examine the effect of tetrahydrocurcumin (THC), a major secondary metabolite of curcumin, and its possible mechanism against glutamate-induced cell death. We prepared THC using curcumin isolated from Curcuma longa (turmeric) and demonstrated the protective effect of THC against glutamate-induced oxidative stress in HT22 cells. THC abrogated glutamate-induced HT22 cell death and showed a strong antioxidant effect. THC also significantly reduced intracellular calcium ion increased by glutamate. Additionally, THC significantly reduced the accumulation of intracellular oxidative stress induced by glutamate. Furthermore, THC significantly diminished apoptotic cell death indicated by annexin V-positive in HT22 cells. Western blot analysis indicated that the phosphorylation of mitogen-activated protein kinases including c-Jun N-terminal kinase, extracellular signal-related kinases 1/2, and p38 by glutamate was significantly diminished by treatment with THC. In conclusion, THC is a potent neuroprotectant against glutamate-induced neuronal cell death by inhibiting the accumulation of oxidative stress and phosphorylation of mitogen-activated protein kinases.

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1-O-Hexyl-2,3,5-Trimethylhydroquinone Ameliorates l-DOPA-Induced Cytotoxicity in PC12 Cells

Molecules ◽

10.3390/molecules24050867 ◽

2019 ◽

Vol 24 (5) ◽

pp. 867 ◽

Cited By ~ 2

Author(s):

Hyun Park ◽

Jong Kang ◽

Myung Lee

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Pc12 Cells ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Mitogen Activated Protein Kinase ◽

Protective Effects ◽

Extracellular Signal ◽

Dopaminergic Neuronal Cell ◽

Mitogen Activated Protein

1-O-Hexyl-2,3,5-trimethylhydroquinone (HTHQ) has previously been found to have effective anti-oxidant and anti-lipid-peroxidative activity. We aimed to elucidate whether HTHQ can prevent dopaminergic neuronal cell death by investigating the effect on l-DOPA-induced cytotoxicity in PC12 cells. HTHQ protected from both l-DOPA-induced cell death and superoxide dismutase activity reduction. When assessing the effect of HTHQ on oxidative stress-related signaling pathways, HTHQ inhibited l-DOPA-induced phosphorylation of sustained extracellular signal-regulated kinases (ERK1/2), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK1/2). HTHQ also normalized l-DOPA-reduced Bcl-2-associated death protein (Bad) phosphorylation and Bcl-2-associated X protein (Bax) expression, promoting cell survival. Taken together, HTHQ exhibits protective effects against l-DOPA-induced cell death through modulation of the ERK1/2-p38MAPK-JNK1/2-Bad-Bax signaling pathway in PC12 cells. These results suggest that HTHQ may show ameliorative effects against oxidative stress-induced dopaminergic neuronal cell death, although further studies in animal models of Parkinson’s disease are required to confirm this.

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Cerebral Ischemia Causes Dysregulation of Synaptic Adhesion in Mouse Synaptosomes

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600510 ◽

2007 ◽

Vol 28 (1) ◽

pp. 99-110 ◽

Cited By ~ 15

Author(s):

Willard J Costain ◽

Ingrid Rasquinha ◽

Jagdeep K Sandhu ◽

Peter Rippstein ◽

Bogdan Zurakowski ◽

...

Keyword(s):

Cell Death ◽

Cerebral Ischemia ◽

Adhesion Molecules ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Artery Occlusion ◽

Synaptic Proteins ◽

Mrna Levels ◽

Neuronal Nuclei ◽

Protein Levels

Synaptic pathology is observed during hypoxic events in the central nervous system in the form of altered dendrite structure and conductance changes. These alterations are rapidly reversible, on the return of normoxia, but are thought to initiate subsequent neuronal cell death. To characterize the effects of hypoxia on regulators of synaptic stability, we examined the temporal expression of cell adhesion molecules (CAMs) in synaptosomes after transient middle cerebral artery occlusion (MCAO) in mice. We focused on events preceding the onset of ischemic neuronal cell death (< 48 h). Synaptosome preparations were enriched in synaptically localized proteins and were free of endoplasmic reticulum and nuclear contamination. Electron microscopy showed that the synaptosome preparation was enriched in spheres (≈650 nm in diameter) containing secretory vesicles and postsynaptic densities. Forebrain mRNA levels of synaptically located CAMs was unaffected at 3 h after MCAO. This is contrasted by the observation of consistent downregulation of synaptic CAMs at 20 h after MCAO. Examination of synaptosomal CAM protein content indicated that certain adhesion molecules were decreased as early as 3 h after MCAO. For comparison, synaptosomal Agrn protein levels were unaffected by cerebral ischemia. Furthermore, a marked increase in the levels of p-Ctnnb1 in ischemic synaptosomes was observed. p-Ctnnb1 was detected in hippocampal fiber tracts and in cornu ammonis 1 neuronal nuclei. These results indicate that ischemia induces a dysregulation of a subset of synaptic proteins that are important regulators of synaptic plasticity before the onset of ischemic neuronal cell death.

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