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Tetrabromobisphenol A (TBBPA) is widely used in materials like plastics and textiles as a fire retardant. In a previous study, we reported TBBPA might disrupt hippocampal neurogenesis and neurocognitive function in mice. However, the mechanism responsible for these effects has not been established. The present study was undertaken to investigate the potential involvement of oxidative stress and mitochondrial dysfunction in TBBPA-mediated neurotoxicity in neural stem cells. We confirmed TBBPA was more cytotoxic to neural stem cells than to neurons, astrocytes, or fibroblasts, and found that TBBPA-induced neural stem cell apoptosis was accompanied by increased reactive oxygen species generation and mitochondrial dysfunction. At a molecular level, TBBPA-induced apoptosis was determined to be mediated by c-Jun N-terminal kinase-p53 pathway activation. Taken together, these findings suggest that the adverse effects of TBBPA on hippocampal neurogenesis are due to the inhibition of neural stem cell expansion.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and are considered promising therapeutic targets in several neurodegenerative diseases. A number of PPAR agonists have been shown to have neuroprotective properties in the presence of oxidative stress, neuroinflammatory response, and apoptosis in various neurodegenerative disease. MHY908 is a novel PPAR α/γ dual agonist, which has been shown to suppress inflammatory response and attenuate insulin resistance in aged rats and db/db mice. Here, we evaluated the neuroprotective effects of MHY908 in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Pretreatment with MHY908 attenuated MPTP-induced dopaminergic neuronal loss and motor deficit. MPTP-induced glial activations were mitigated by MHY908 in the nigrostriatal pathway, and MHY908 effectively blocked 1-methyl-4-phenylpyridinium (MPP + )-induced cell death and ROS production in SH-SY5Y neuroblastoma cells. Further study revealed MHY908 inhibited MPP + -induced astroglial activation by suppressing NF-κB signaling in primary astrocytes. Taken together, the present study suggests that PPAR α/γ dual agonists be considered potentially useful preventions for PD and other neurodegenerative diseases associated with neuroinflammation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Polycyclic aromatic hydrocarbons (PAHs) are widespread contaminants resulting from the incomplete combustion of organic materials in the environment. The primary concern for the hazardous effect of PAHs is their ability to activate the pathway linked to the aryl hydrocarbon receptor (AhR) and lead to carcinogenesis. While previous research has demonstrated that oxidative stress plays a key role in the AhR-dependent toxic response, the effect of PAHs on the biosynthesis of glutathione (GSH), which is a powerful endogenous antioxidant, has not been extensively investigated. In the present study, we utilized a global metabolomic approach, via high resolution magic angle spinning nuclear magnetic resonance spectroscopy, and identified significant metabolome differences between non-tumorigenic liver cells (BNL CL.2; CL2) and transformed liver cells (BNL 1MEA. 7R.1; 1MEA) chronically exposed to 3-methylcholanthrene (3MC), a well‑known carcinogenic PAH. A significant change that was observed, was a lower GSH level in 1MEA cells compared with that in CL2 cells. This was contrasted by increased levels of precursor metabolites for GSH synthesis, such as S-adenosylmethionine and cysteine. These changes were accompanied by a significantly reduced expression of γ-glutamylcysteine ligase (GCL), known to be the rate‑limiting step of GSH synthesis. Furthermore, the protein level of cysteine dioxygenase was downregulated; however, the concentration of taurine was unaltered. Therefore, the present study demonstrated that cells transformed by chronic exposure to 3MC exhibited inhibition of GSH biosynthesis by suppression of GCL protein expression and reduction of cysteine availability, which may subsequently render cells vulnerable to oxidative stress.

Parkinson's disease (PD) is the second most common progressive neurodegenerative disease after Alzheimer's disease. PD exhibits clinical symptoms that include tremors, rigidity, and bradykinesia. Many drugs are available to treat PD, such as, L-dopa, COMT inhibitor, MAO-B inhibitor, and dopamine agonists, but these drugs simply compensate for dopamine loss in PD, and therefore, cannot completely suppress its symptoms or progression. Although the causes of PD are not clearly understood, common pathophysiological pathways, such as, oxidative stress, mitochondrial dysfunction, and neuroinflammation are considered to be etiological factors, and thus, many treatments and interventions have been developed to target these pathophysiological factors. This review describes the neuroprotective strategies devised based on current understanding of the pathophysiological mechanisms of PD.

Mitochondrial adenine nucleotide translocator (ANT) plays important roles in the regulation of mitochondrial permeability transition and cell bioenergetics. The mouse has three ANT isoforms (1, 2 and 4) showing tissue-specific expression patterns. Although ANT1 is known to have a pro-apoptotic property, the specific functions of ANT2 have not been well determined. In the present study, ANT2 expression was significantly lower in the aged rat liver and in a liver fibrosis model. To explore the protective role of ANT2 in the liver, we established a hepa1c1c7 cell line overexpressing ANT2. Overexpression of ANT2 caused hepa1c1c7 cells to be more resistant to oxidative stress, and mitochondrial membrane potential (MMP, ∆Ψm) was relatively intact in ANT2-overexpressing cells under oxidative stress. In addition, ANT2 was found to increase ATP production by influencing mitochondrial bioenergetics. These results imply that the hepatoprotective effect of ANT2 is due to the stabilization of MMP and enhanced ATP production, and thus, maintaining ANT2 levels in the liver might be important to enhance resistance to aging and oxidative stress., (© 2012 Informa UK, Ltd.)

2-Deoxy-d-glucose (2DG) is an analog of glucose that is effectively taken up by cells competing with normal glucose but cannot be further utilized to produce energy. It was previously reported that 2DG can mimic the beneficial effects of dietary restriction in experimental models of neurodegenerative disorders and cancer. In the present study, we report that pretreatment with 2DG increases the resistance of neural progenitor cells (NPC) to oxidative insults. 2DG significantly suppressed the proliferation of NPC, and high concentrations of 2DG were toxic to NPC. However, a treatment with a moderate concentration of 2DG protected the NPC against tBHP-induced oxidative stress suggesting that this chemical had hormetic action mimicking dietary restriction. Furthermore, we showed that the protective mechanism of 2DG involved the activation of AMP-activated protein kinase. Our findings demonstrate that 2DG can modulate the cellular responses to oxidative stress and confer cellular resistance in NPC by activating the metabolic regulator.

Senescence marker protein 30 (SMP30) is identified as an important aging marker molecule and known to play multifunctional roles as an intracellular calcium regulatory protein in the signaling process. To elucidate the functional significance of SMP30, we established the stably transfected P19 cell line with SMP30 expression vector. Overexpression of SMP30 slightly suppressed the proliferation of P19 cells. However, SMP30 overexpression was cytoprotective against calcium-mediated stress such as calcium ionophore (A23187), and thapsigargin. We found that SMP30 overexpression reduced the elevated intracellular calcium levels induced by A23187, but not by thapsigargin. In addition, SMP30 transfected P19 cells were more protective to tert-butylhydroperoxide induced cytotoxicity, indicating the antioxidative properties of SMP30. Taken together, our results suggest that external calcium regulation and antioxidant properties are involved in the cytoprotective mechanism of SMP30.

Environmental substances or metabolites induce neuronal damage through oxidative stress. Environmental organic solvent metabolite, 1,2-diacetylbenzene (1,2-DAB), treated rats develop limb weakness with neuropathological damage in both the central and peripheral nervous systems. In this experiment, we examined the relevance of 1,2-DAB-induced toxicity to increased oxidative stress using human dopaminergic neuroblastoma SHSY5Y cells. 1,2-DAB (4, 16, and 32 microM) disrupted cytoskeletal integrity and caused morphological changes. 1,2-DAB significantly decreased cell viability and induced cell cycle arrest in the G(1) phase in a concentration-dependent manner. At higher concentration, it produced apoptosis. Pre-treatment of cells with the antioxidants, GSH or N-acetylcysteine (NAC), effectively blocked 1,2-DAB-mediated cytotoxicity including cell viability, and morphological changes. These results therefore suggest that oxidative stress is involved in environmental metabolite 1,2-DAB-mediated neurotoxicity and that antioxidant treatment can effectively protect the nervous system from environmental hazards.

Senescence marker protein 30 (SMP30), an important aging marker molecule, has been identified functionally as a calcium regulatory protein. Recent evidence showed its new assumed role as an effective anti-oxidative property. However, the role of SMP30 in the brain has not been explored. To delineate its role in the brain, we utilized SMP30 knock-out (SMP30 KO) mice in the current study. We focused on the oxidative status of the brain by examining selected oxidative markers in brains of SMP30 KO mice. Results showed that the generation of reactive species (RS) and NADPH oxidase activities were significantly elevated in SMP30 deficient brain. The increased oxidative status in these mice was further confirmed by increased oxidatively modified proteins such as dityrosine formation and carbonylation in the cortex of SMP30 KO mice. Moreover, SMP30 deficient brain showed the increased Mac-1 protein and myeloperoxidase (MPO) activity in the brain, supporting the putative anti-oxidative action of SMP30. Interestingly, the activities of major antioxidant enzymes, superoxide dismutase, catalase and reduced glutathione peroxidase in the brain were not affected by SMP30 depletion. Our results documented that brain SMP30 has a protective action against oxidative damage, without influencing antioxidant enzyme status.

Oxidative stress and inflammation cannot be considered as diseases themselves; however, they are major risk factors for the development and progression of the pathogenesis underlying many illnesses, such as cancer, neurological disorders (including Alzheimer's disease and Parkinson's disease), autoimmune and metabolic disorders, etc. According to the results obtained from extensive studies, oxidative stress–induced biomolecules, such as advanced oxidation protein products, advanced glycation end products, and advanced lipoxidation end products, are critical for an accelerated level of inflammation and oxidative stress–induced cellular damage, as reflected in their strong affinity to a wide range of scavenger receptors. Based on the limitations of antioxidative and anti-inflammatory molecules in practical applications, targeting such interactions between harmful molecules and their cellular receptors/signaling with advances in gene engineering technology, such as CRISPR or TALEN, may prove to be a safe and effective alternative. In this review, we summarize the findings of recent studies focused on the deletion of scavenger receptors under oxidative stress as a development in the therapeutic approaches against the diseases linked to inflammation and the contribution of advanced glycation end products (AGEs), advanced lipid peroxidation products (ALEs), and advanced oxidation protein products (AOPPs). [ABSTRACT FROM AUTHOR]

Background and Purpose Whole-brain irradiation ( WBI) therapy produces learning and memory deficits in patients with brain tumours. Although the pathological cascade of cognitive deficits remains unknown, it may involve reduced neurogenesis within the hippocampus. Baicalein is a flavonoid derived from the roots of Huangqin, Scutellaria baicalensis Georgi, and has been shown to have antioxidant effects. Here, we have investigated the protective effects of baicalein on irradiation-induced impairments in hippocampal neurogenesis and cognitive function. Experimental Approach Radioprotective effects of baicalein were evaluated in C17.2 neural progenitor cells and 6-week-old male C57 BL/6 mice during hippocampal neurogenesis. Mice were given a single dose of 5 Gy WBI. Changes in hippocampal neurogenesis, oxidative stress and BDNF- pCREB signalling were evaluated. Morris water maze and passive avoidance test were used to assess learning and memory. Key Results Baicalein protected neural progenitor cells against irradiation-induced necrotic cell death. Pretreatment with baicalein attenuated the irradiation-induced impairment of hippocampal neurogenesis by modulating oxidative stress and elevating BDNF- pCREB signalling. Furthermore, baicalein prevented the spatial learning and memory retention deficits follwing WBI. Conclusions and Implications Our findings suggest that baicalein can be viewed as a potential therapeutic agent that protects against the impaired neurogenesis induced by WBI, and its neurocognitive consequences. [ABSTRACT FROM AUTHOR]

The cause of elevated level of amyloid β-peptide (Aβ42) in common late-onset sporadic [Alzheimer's disease (AD)] has not been established. Here, we show that the membrane lipid peroxidation product 4-hydroxynonenal (HNE) is associated with amyloid and neurodegenerative pathologies in AD and that it enhances γ-secretase activity and Aβ42 production in neurons. The γ-secretase substrate receptor, nicastrin, was found to be modified by HNE in cultured neurons and in brain specimens from patients with AD, in which HNE-nicastrin levels were found to be correlated with increased γ-secretase activity and Aβ plaque burden. Furthermore, HNE modification of nicastrin enhanced its binding to the γ-secretase substrate, amyloid precursor protein (APP) C99. In addition, the stimulation of γ-secretase activity and Aβ42 production by HNE were blocked by an HNE-scavenging histidine analog in a 3xTgAD mouse model of AD. These findings suggest a specific molecular mechanism by which oxidative stress increases Aβ42 production in AD and identify HNE as a novel therapeutic target upstream of the γ-secretase cleavage of APP. [ABSTRACT FROM AUTHOR]

Phenformin is a biguanide compound that can modulate glucose metabolism and promote weight loss and is therefore used to treat patients with type-2 diabetes. While phenformin may indirectly affect neurons by changing peripheral energy metabolism, the possibility that it directly affects neurons has not been examined. We now report that phenformin suppresses responses of hippocampal neurons to glutamate and decreases their vulnerability to excitotoxicity. Pretreatment of embryonic rat hippocampal cell cultures with phenformin protected neurons against glutamate-induced death, which was correlated with reduced calcium responses to glutamate. Immunoblot analyses showed that levels of the N-methyl-d-aspartate (NMDA) subunits NR1 and NR2A were significantly decreased in neurons exposed to phenformin, whereas levels of the AMPA receptor subunit GluR1 were unchanged. Whole-cell patch clamp analyses revealed that NMDA-induced currents were decreased, and AMPA-induced currents were unchanged in neurons pretreated with phenformin. Our data demonstrate that phenformin can protect neurons against excitotoxicity by differentially modulating levels of NMDA receptor subunits in a manner that decreases glutamate-induced calcium influx. These findings show that phenformin can modulate neuronal responses to glutamate, and suggest possible use of phenformin and related compounds in the prevention and/or treatment of neurodegenerative conditions. [Copyright &y& Elsevier]

Oxidative stress, mitochondrial dysfunction, and neuroinflammation are strongly associated with the pathogenesis of Parkinson's disease (PD), which suggests that anti-oxidative and anti-inflammatory compounds might provide an alternative treatment for PD. Here, we evaluated the neuroprotective effects of evernic aid (EA), which was screened from a lichen library provided by the Korean Lichen Research Institute at Sunchon National University. EA is a secondary metabolite generated by lichens, including Ramalina, Evernia, and Hypogymnia, and several studies have described its anticancer, antifungal, and antimicrobial effects. However, the neuroprotective effects of EA have not been studied. We found that EA protected primary cultured neurons against 1-methyl-4-phenylpyridium (MPP+)-induced cell death, mitochondrial dysfunction, and oxidative stress, and effectively reduced MPP+-induced astroglial activation by inhibiting the NF-κB pathway. In vivo, EA ameliorated MPTP-induced motor dysfunction, dopaminergic neuronal loss, and neuroinflammation in the nigrostriatal pathway in C57BL/6 mice. Taken together, our findings demonstrate that EA has neuroprotective and anti-inflammatory effects in PD models and suggest that EA is a potential therapeutic candidate for PD. [ABSTRACT FROM AUTHOR]

Diclofenac, a widely used non-steroidal anti-inflammatory drug, can cause liver damage via its metabolic activation by hepatic CYP450s and UGT2B7. Fasting can affect drug-induced liver injury by modulating the hepatic metabolism, but its influence on diclofenac hepatotoxicity is unknown. Thus, we investigated diclofenac-induced liver damage after fasting in mice, and the cellular events were examined. Male ICR mice fasted for 16 h showed the elevation of CYP3A11, but the decreases of UGT2B7, glutathione (GSH), and GSH S-transferase-μ/-π levels in the livers. Diclofenac (200 mg/kg) injection into the mice after 16-h fasting caused more significant liver damage compared to that in the diclofenac-treated fed mice, as shown by the higher serum ALT and AST activities. Diclofenac-promoted hepatic oxidative stress (oxidized proteins, 4-hydroxynonenal, and malondialdehyde), endoplasmic reticulum (ER) stress (BiP, ATF6, and CHOP), and apoptosis (cleaved caspase-3 and cleaved PARP) were enhanced by fasting. Autophagic degradation was inhibited in the diclofenac-treated fasting mice compared to that of the corresponding fed mice. The results suggest that fasting can make the liver more susceptible to diclofenac toxicity by lowering GSH-mediated detoxification; increased oxidative/ER stresses and apoptosis and suppressed autophagic degradation may be the cellular mechanisms of the aggravated diclofenac hepatotoxicity under fasting conditions. [Display omitted] • Fasting potentiated diclofenac-induced liver injury in mice. • Fasting increased diclofenac-promoted oxidative stress, ER stress, and apoptosis. • Fasting aggravated diclofenac-induced suppression of autophagic degradation. • Fasting increased hepatic CYP3A11, but decreased GSH and GST levels. • Fasting decreased GSH-mediated diclofenac detoxification. [ABSTRACT FROM AUTHOR]

Abstract: Senescence marker protein 30 (SMP30) was recently identified as gluconolactonase, which is involved in vitamin C (VC) biosynthesis. Therefore, the antioxidant property of SMP30 is thought to be mediated by its gluconolactonase function. However, pathologic effects of SMP30 deficiency independent of VC biosynthesis have not been studied in models of neurodegenerative diseases. In the present study, we evaluated the effect of SMP30 deficiency on Parkinson’s disease (PD) in SMP30 knockout (KO) mice. Wild type and SMP30 KO mice supplemented with VC were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our results showed that MPTP-induced dopaminergic neuronal loss and motor function impairment were more significant in the SMP30 KO mice. Reactive oxygen species generation and microglia activation were higher in MPTP-treated SMP30 KO mice. However, SMP30 deficiency mitigated MPTP-induced astrocyte activation and glia-derived neurotrophic factor production. Cultures of astrocytes recovered from wild type and SMP30 KO mice revealed that SMP30 deficiency abolished 1-methyl-4-phenyl-pyridinium-induced astroglial activation by blocking the extracellular signal-regulated kinase pathway. Taken together, our findings demonstrate for the first time that SMP30 deficiency increases the severity of PD and suggest a beneficial role of SMP30 in protective astrocyte activation in response to neurodegeneration. The present study shows that modulation of astrocytic SMP30 can be a promising target for treating PD. [Copyright &y& Elsevier]

Abstract: Mitochondria produce ATP, regulate apoptosis, and maintain calcium homeostasis, and thus, mitochondrial dysfunction critically impairs nervous system development. Furthermore, the disruption of oxidative phosphorylation (OXPHOS) in mitochondria could lead to energy depletion and elevate oxidative stress. In the present study, the authors investigated how perturbation of the respiratory chain and bioenergetics affects neural progenitor cells (NPCs). Mitochondrial OXPHOS was impaired by inhibiting electron transfer using the antimycin A and ATP synthase inhibitor oligomycin. It was found that oligomycin impaired NPCs proliferation and was toxic at high concentrations, whereas antimycin A-treated cells showed no changes in NPCs proliferation. Although ROS production was elevated concentration-dependently by both inhibitors, oligomycin-treated C17.2 NPCs, but not antimycin A-treated NPCs, showed a significantly higher cell death rate and lower levels of intracellular ATP. These findings suggest that bioenergetic considerations are critically important for cell viability regulation in NPCs. Taken together, the present study shows that OXPHOS disruption can have a neurotoxic effect on NPCs, and thus, adversely influence the developing brain and the neurogenic capacity of the adult brain. [Copyright &y& Elsevier]

Abstract: 1,2-Diacetylbenzene (DAB) is a neurotoxic minor metabolite of 1,2-diethylbenzene or naphthalene reaction product with OH radical. DAB causes central and peripheral neuropathies that lead to motor neuronal deficits. However, the potent effects and molecular mechanisms of DAB on neural progenitor cells and hippocampus are unknown. In the current study, we report the DAB damage at lower doses (less than 50μM) to neural progenitor cell (NPC) in vitro and hippocampal neurogenesis in vivo. DAB significantly suppressed NPC proliferation with increased reactive oxygen species (ROS) production in a dose-dependent manner. The suppression of NPC proliferation was effectively blunted by the action of an antioxidant, N-acetyl cysteine. Six-week-old male C57BL/6 mice were treated with 1 or 5mg/kg DAB for 2weeks. DAB significantly suppressed NPC proliferation in the dentate gyrus of the hippocampus, indicating impaired hippocampal neurogenesis. Increased ROS production and the formation of oxidative stress-associated dinitrophenyl adducts were detected in the hippocampal homogenates of DAB-treated mice. DAB activated Mac-1-positive immune cells which are involved in inflammatory process in the hippocampus. Taken together, these results confirm that oxidative stress by DAB might be cause of adverse effects in NPC proliferation and hippocampal neurogenesis. [Copyright &y& Elsevier]

Abstract: Acrylamide (ACR) is a well-known neurotoxin in mammalian species that causes neuropathy characterized by ataxia and skeletal muscle weakness. Therefore, ACR-mediated axon damage in the central and peripheral nervous systems is considered to be central-peripheral axonopathy. However, the molecular mechanisms underlying ACR''s toxicity to neural progenitor cells are unknown. This study investigated the adverse effects of ACR on mouse multipotent neural progenitor cells and adult hippocampal neurogenesis. ACR significantly reduced the proliferation of neural progenitor cells, and high ACR concentrations induced apoptotic and necrotic cell death. We found that elevated intracellular levels of reactive oxygen species were involved in ACR-mediated cytotoxicity. Interestingly, the administration of ACR to young mice resulted in a significant decrease in the number of newly generated cells in the dentate gyrus of the hippocampus, suggesting an impairment of adult neurogenesis. These results suggest that ACR''s deleterious effects on the central nervous system are due to the death of neural progenitor cells and impaired adult neurogenesis. [Copyright &y& Elsevier]

Abstract: Vitamin C (VC) has a strong antioxidant function evident as its ability to scavenge superoxide radicals in vitro. We verified that this property actually exists in vivo by using a real-time imaging system in which Lucigenin is the chemiluminescent probe for detecting superoxide in senescence marker protein-30 (SMP30)/gluconolactonase (GNL) knockout (KO) mice, which cannot synthesize VC in vivo. SMP30/GNL KO mice were given 1.5g/L VC [VC(+)] for 2, 4, or 8 weeks or denied VC [VC(−)]. At 4 and 8 weeks, VC levels in brains from VC(−) KO mice were <6% of that in VC(+) KO mice. Accordingly, superoxide-dependent chemiluminescence levels determined by ischemia-reperfusion at the 4- and 8 weeks test intervals were 3.0-fold and 2.1-fold higher, respectively, in VC(−) KO mice than in VC(+) KO mice. However, total superoxide dismutase activity and protein levels were not altered. Thus, VC depletion specifically increased superoxide generation in a model of the living brain. [Copyright &y& Elsevier]