scholarly journals ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease

Antioxidants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 743 ◽  
Author(s):  
Dominic S. A. Simpson ◽  
Peter L. Oliver
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Disease ◽  
Molecular Mechanisms ◽  
Neuronal Damage ◽  
Target Identification ◽  
Second Messengers ◽  
Amyloid Plaque ◽  
Ros Generation ◽  
Global Public Health ◽  
Public Health Burden

Neurodegenerative disorders, such as Alzheimer’s disease, are a global public health burden with poorly understood aetiology. Neuroinflammation and oxidative stress (OS) are undoubtedly hallmarks of neurodegeneration, contributing to disease progression. Protein aggregation and neuronal damage result in the activation of disease-associated microglia (DAM) via damage-associated molecular patterns (DAMPs). DAM facilitate persistent inflammation and reactive oxygen species (ROS) generation. However, the molecular mechanisms linking DAM activation and OS have not been well-defined; thus targeting these cells for clinical benefit has not been possible. In microglia, ROS are generated primarily by NADPH oxidase 2 (NOX2) and activation of NOX2 in DAM is associated with DAMP signalling, inflammation and amyloid plaque deposition, especially in the cerebrovasculature. Additionally, ROS originating from both NOX and the mitochondria may act as second messengers to propagate immune activation; thus intracellular ROS signalling may underlie excessive inflammation and OS. Targeting key kinases in the inflammatory response could cease inflammation and promote tissue repair. Expression of antioxidant proteins in microglia, such as NADPH dehydrogenase 1 (NQO1), is promoted by transcription factor Nrf2, which functions to control inflammation and limit OS. Lipid droplet accumulating microglia (LDAM) may also represent a double-edged sword in neurodegenerative disease by sequestering peroxidised lipids in non-pathological ageing but becoming dysregulated and pro-inflammatory in disease. We suggest that future studies should focus on targeted manipulation of NOX in the microglia to understand the molecular mechanisms driving inflammatory-related NOX activation. Finally, we discuss recent evidence that therapeutic target identification should be unbiased and founded on relevant pathophysiological assays to facilitate the discovery of translatable antioxidant and anti-inflammatory therapeutics.

scholarly journals Metabolic Profiling Analysis Reveals the Potential Contribution of Barley Sprouts against Oxidative Stress and Related Liver Cell Damage in Habitual Alcohol Drinkers

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 459
Author(s):  
Hyerin Park ◽  
Eunok Lee ◽  
Yunsoo Kim ◽  
Hye Yoon Jung ◽  
Kwang-Min Kim ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Fatty Liver ◽  
Molecular Mechanisms ◽  
Learning Algorithm ◽  
Controlled Trial ◽  
Liver Fat ◽  
Glutathione Metabolism ◽  
Ros Generation ◽  
Potential Contribution ◽  
Glutamyl Transferase

Chronic excessive alcohol consumption is associated with multiple liver defects, such as steatosis and cirrhosis, mainly attributable to excessive reactive oxygen species (ROS) production. Barley sprouts (Hordeum vulgare L.) contain high levels of polyphenols that may serve as potential antioxidants. This study aimed to investigate whether barley sprouts extract powder (BSE) relieves alcohol-induced oxidative stress and related hepatic damages in habitual alcohol drinkers with fatty liver. In a 12-week randomized controlled trial with two arms (placebo or 480 mg/day BSE; n = 76), we measured clinical markers and metabolites at the baseline and endpoint to understand the complex molecular mechanisms. BSE supplementation reduced the magnitude of ROS generation and lipid peroxidation and improved the glutathione antioxidant system. Subsequent metabolomic analysis identified alterations in glutathione metabolism, amino acid metabolism, and fatty acid synthesis pathways, confirming the role of BSE in glutathione-related lipid metabolism. Finally, the unsupervised machine learning algorithm indicated that subjects with lower glutathione reductase at the baseline were responders for liver fat content, and those with higher fatigue and lipid oxidation were responders for γ-glutamyl transferase. These findings suggest that BSE administration may protect against hepatic injury by reducing oxidative stress and changing the metabolism in habitual alcohol drinkers with fatty liver.

Abstract 263: Differential Effects of 17ß-Estradiol and 16a-Hydroxyestrone in Oxidative Stress and Proliferative Responses in Human Pulmonary Artery Smooth Muscle Cells - Implications in Pulmonary Arterial Hypertension

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Katie Y Hood ◽  
Augusto C Montezano ◽  
Margaret R MacLean ◽  
Rhian M Touyz
Keyword(s):  
Oxidative Stress ◽  
Pulmonary Arterial Hypertension ◽  
Cell Growth ◽  
Arterial Hypertension ◽  
Molecular Mechanisms ◽  
Antioxidant Systems ◽  
Ros Generation ◽  
Ros Production ◽  
Differential Effects ◽  
Pulmonary Arterial

Women develop pulmonary arterial hypertension (PAH) more frequently than men. This may relate, in part, to metabolism of 17β-estradiol (E2), leading to formation of the deleterious metabolite, 16α-hydroxyestrone (16α OHE1), which plays a role in the remodelling of pulmonary arteries. Molecular mechanisms whereby 16αOHE1 influences PASMC remodelling are unclear but ROS may be important, since oxidative stress has been implicated in the pathogenesis of PAH. We hypothesised that E2 and 16αOHE1 leads to Nox-induced ROS production, which promotes PASMC damage. Cultured PASMCs were stimulated with either E2 (1nM) or 16αOHE1 (1nM) in the presence/absence of EHT1864 (100μM, Rac1 inhibitor) or tempol (antioxidant; 10μM). ROS production was assessed by chemiluminescence (O2-) and Amplex Red (H2O2). Antioxidants (thioredoxin, peroxiredoxin 1 and NQ01), regulators of Nrf2 (BACH1, Nrf2) and, marker of cell growth (PCNA) were determined by immunoblotting. E2 increased O2- production at 4h (219 ± 30% vs vehicle; p<0.05), an effect blocked by EHT1864 and tempol. E2 also increased H2O2 generation (152 ± 4%; p<0.05). Thioredoxin, NQ01 and peroxiredoxin1 (71 ± 6%; 78 ± 9%; 69 ± 8%; p<0.05 respectively) levels were decreased by E2 as was PCNA expression (72 ± 2%; p<0.05). 16αOHE1 exhibited a rapid (5 min) and exaggerated increase in ROS production (355 ± 41%; p<0.05), blocked by tempol and EHT1864. This was associated with an increase in Nox4 expression (139 ± 11% vs vehicle, p<0.05). 16αOHE1 increased BACH1, (129 ± 3%; p<0.05), a competitor of Nrf2, which was decreased (92 ± 2%). In contrast, thioredoxin expression was increased by 16aOHE1 (154 ± 22%; p<0.05). PCNA (150 ± 5%) expression was also increased after exposure to 16αOHE1. In conclusion, E2 and 16αOHE1 have differential effects on redox processes associated with PASMC growth. Whereas E2 stimulates ROS production in a slow and sustained manner without effect on cell growth, 16αOHE1 upregulates Nox4 with associated rapid increase in ROS generation and downregulation of antioxidant systems, affecting proliferation. Our findings suggest that E2 -derived metabolites may promote a pro-proliferative PASMC phenotype through Nox4-derived ROS generation. These deleterious effects may impact on vascular remodeling in PAH.

scholarly journals The Neuroprotective Effects ofRatanasampilon Oxidative Stress-Mediated Neuronal Damage in Human Neuronal SH-SY5Y Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Aiqin Zhu ◽  
Zhou Wu ◽  
Jie Meng ◽  
Patrick L. McGeer ◽  
Yi Zhu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Oxidative Dna Damage ◽  
Molecular Mechanisms ◽  
Neuronal Damage ◽  
Mitogen Activated Protein Kinase ◽  
Tibetan Medicine ◽  
Dependent Manner ◽  
Neuroprotective Effects ◽  
Human Neuroblastoma ◽  
Traditional Tibetan Medicine

We previously found thatRatanasampil(RNSP), a traditional Tibetan medicine, improves the cognitive function of mild-to-moderate AD patients living at high altitude, as well as learning and memory in an AD mouse model (Tg2576); however, mechanism underlying the effects of RNSP is unknown. In the present study, we investigated the effects and molecular mechanisms of RNSP on oxidative stress-induced neuronal toxicity using human neuroblastoma SH-SY5Y cells. Pretreatment with RNSP significantly ameliorated the hydrogen peroxide- (H2O2-) induced cytotoxicity of SH-SY5Y cells in a dose-dependent manner (up to 60 μg/mL). Furthermore, RNSP significantly reduced the H2O2-induced upregulation of 8-oxo-2′-deoxyguanosine (8-oxo-dG, the oxidative DNA damage marker) but significantly reversed the expression of repressor element-1 silencing transcription factor (REST) from H2O2associated (100 μM) downregulation. Moreover, RNSP significantly attenuated the H2O2-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase 1/2 (ERK 1/2) in SH-SY5Y cells. These observations strongly suggest that RNSP may protect the oxidative stress-induced neuronal damage that occurs through the properties of various antioxidants and inhibit the activation of MAPKs. We thus provide the principle molecular mechanisms of the effects of RNSP and indicate its role in the prevention and clinical management of AD.

scholarly journals Inhibition of Oxidative Neurotoxicity and Scopolamine-Induced Memory Impairment by γ-Mangostin: In Vitro and In Vivo Evidence

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Youngmun Lee ◽  
Sunyoung Kim ◽  
Yeonsoo Oh ◽  
Young-Mi Kim ◽  
Young-Won Chin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Memory Impairment ◽  
Neuronal Damage ◽  
Biological Activities ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Ros Generation ◽  
Garcinia Mangostana

Among a series of xanthones identified from mangosteen, the fruit of Garcinia mangostana L. (Guttifereae), α- and γ-mangostins are known to be major constituents exhibiting diverse biological activities. However, the effects of γ-mangostin on oxidative neurotoxicity and impaired memory are yet to be elucidated. In the present study, the protective effect of γ-mangostin on oxidative stress-induced neuronal cell death and its underlying action mechanism(s) were investigated and compared to that of α-mangostin using primary cultured rat cortical cells. In addition, the effect of orally administered γ-mangostin on scopolamine-induced memory impairment was evaluated in mice. We found that γ-mangostin exhibited prominent protection against H2O2- or xanthine/xanthine oxidase-induced oxidative neuronal death and inhibited reactive oxygen species (ROS) generation triggered by these oxidative insults. In contrast, α-mangostin had no effects on the oxidative neuronal damage or associated ROS production. We also found that γ-mangostin, not α-mangostin, significantly inhibited H2O2-induced DNA fragmentation and activation of caspases 3 and 9, demonstrating its antiapoptotic action. In addition, only γ-mangostin was found to effectively inhibit lipid peroxidation and DPPH radical formation, while both mangostins inhibited β-secretase activity. Furthermore, we observed that the oral administration of γ-mangostin at dosages of 10 and 30 mg/kg markedly improved scopolamine-induced memory impairment in mice. Collectively, these results provide both in vitro and in vivo evidences for the neuroprotective and memory enhancing effects of γ-mangostin. Multiple mechanisms underlying this neuroprotective action were suggested in this study. Based on our findings, γ-mangostin could serve as a potentially preferable candidate over α-mangostin in combatting oxidative stress-associated neurodegenerative diseases including Alzheimer’s disease.

scholarly journals MicroRNA-204-5p reduction in rat hippocampus contributes to stress-induced pathology via targeting RGS12 signaling pathway

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Tian Lan ◽  
Ye Li ◽  
Cuiqin Fan ◽  
Liyan Wang ◽  
Wenjing Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Neuronal Damage ◽  
Immunofluorescence Assay ◽  
Electrophysiological Recording ◽  
Protein Signaling ◽  
Oxidative Markers ◽  
Electron Microscopy Analysis ◽  
Stress Damage ◽  
Related Proteins

Abstract Background Neuroinflammation occupies a pivotal position in the pathogenesis of most nervous system diseases, including depression. However, the underlying molecular mechanisms of neuroinflammation associated with neuronal injury in depression remain largely uncharacterized. Therefore, identifying potential molecular mechanisms and therapeutic targets would serve to better understand the progression of this condition. Methods Chronic unpredictable stress (CUS) was used to induce depression-like behaviors in rats. RNA-sequencing was used to detect the differentially expressed microRNAs. Stereotactic injection of AAV virus to overexpress or knockdown the miR-204-5p. The oxidative markers and inflammatory related proteins were verified by immunoblotting or immunofluorescence assay. The oxidative stress enzyme and products were verified using enzyme-linked assay kit. Electron microscopy analysis was used to observe the synapse and ultrastructural pathology. Finally, electrophysiological recording was used to analyze the synaptic transmission. Results Here, we found that the expression of miR-204-5p within the hippocampal dentate gyrus (DG) region of rats was significantly down-regulated after chronic unpredicted stress (CUS), accompanied with the oxidative stress-induced neuronal damage within DG region of these rats. In contrast, overexpression of miR-204-5p within the DG region of CUS rats alleviated oxidative stress and neuroinflammation by directly targeting the regulator of G protein signaling 12 (RGS12), effects which were accompanied with amelioration of depressive-like behaviors in these CUS rats. In addition, down-regulation of miR-204-5p induced neuronal deterioration in DG regions and depressive-like behaviors in rats. Conclusion Taken together, these results suggest that miR-204-5p plays a key role in regulating oxidative stress damage in CUS-induced pathological processes of depression. Such findings provide evidence of the involvement of miR-204-5p in mechanisms underlying oxidative stress associated with depressive phenotype. Graphical Abstract

scholarly journals LncRNA-T199678 Mitigates α-Synuclein-Induced Dopaminergic Neuron Injury via miR-101-3p

2020 ◽  
Vol 12 ◽  
Author(s):  
Lu-Lu Bu ◽  
Ying-Yu Xie ◽  
Dan-Yu Lin ◽  
Ying Chen ◽  
Xiu-Na Jing ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Dopaminergic Neuron ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Neuronal Damage ◽  
Molecular Target ◽  
Neuron Death ◽  
Abnormal Accumulation ◽  
Neuron Injury

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by dopaminergic neuron death and the abnormal accumulation and aggregation of α-synuclein (α-Syn) in the substantia nigra (SN). Although the abnormal accumulation of α-Syn can solely promote and accelerate the progress of PD, the underlying molecular mechanisms remain unknown. Mounting evidence confirms that the abnormal expression of long non-coding RNA (lncRNA) plays an important role in PD. Our previous study found that exogenous α-Syn induced the downregulation of lncRNA-T199678 in SH-SY5Y cells via a gene microarray analysis. This finding suggested that lncRNA-T199678 might have a potential pathological role in the pathogenesis of PD. This study aimed to explore the influence of lncRNA-T199678 on α-Syn-induced dopaminergic neuron injury. Overexpression of lncRNA-T199678 ameliorated the neuron injury induced by α-Syn via regulating oxidative stress, cell cycle, and apoptosis. Studies indicate lncRNAs could regulate posttranscriptional gene expression via regulating the downstream microRNA (miRNA). To discover the downstream molecular target of lncRNA-T199678, the following experiment found out that miR-101-3p was a potential target for lncRNA-T199678. Further study showed that the upregulation of lncRNA-T199678 reduced α-Syn-induced neuronal damage through miR-101-3p in SH-SY5Y cells and lncRNA-T199678 was responsible for the α-Syn-induced intracellular oxidative stress, dysfunction of the cell cycle, and apoptosis. All in all, lncRNA-T199678 mitigated the α-Syn-induced dopaminergic neuron injury via targeting miR-101-3p, which contributed to promote PD. Our results highlighted the role of lncRNA-T199678 in mitigating dopaminergic neuron injury in PD and revealed a new molecular target for PD.

scholarly journals Interrelation of Oxidative Stress and Inflammation in Neurodegenerative Disease: Role of TNF

2015 ◽  
Vol 2015 ◽  
pp. 1-18 ◽  
Author(s):  
Roman Fischer ◽  
Olaf Maier
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Tissue Regeneration ◽  
Neuronal Damage ◽  
Dual Role ◽  
Cytokine Tumor Necrosis Factor ◽  
The Central Nervous System ◽  
Necrosis Factor

Neuroinflammation and mitochondrial dysfunction are common features of chronic neurodegenerative diseases of the central nervous system. Both conditions can lead to increased oxidative stress by excessive release of harmful reactive oxygen and nitrogen species (ROS and RNS), which further promote neuronal damage and subsequent inflammation resulting in a feed-forward loop of neurodegeneration. The cytokine tumor necrosis factor (TNF), a master regulator of the immune system, plays an important role in the propagation of inflammation due to the activation and recruitment of immune cells via its receptor TNF receptor 1 (TNFR1). Moreover, TNFR1 can directly induce oxidative stress by the activation of ROS and RNS producing enzymes. Both TNF-induced oxidative stress and inflammation interact and cooperate to promote neurodegeneration. However, TNF plays a dual role in neurodegenerative disease, since stimulation via its second receptor, TNFR2, is neuroprotective and promotes tissue regeneration. Here we review the interrelation of oxidative stress and inflammation in the two major chronic neurodegenerative diseases, Alzheimer’s and Parkinson’s disease, and discuss the dual role of TNF in promoting neurodegeneration and tissue regeneration via its two receptors.

scholarly journals Caenorhabditis elegans: A Useful Model for Studying Metabolic Disorders in Which Oxidative Stress Is a Contributing Factor

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Elizabeth Moreno-Arriola ◽  
Noemí Cárdenas-Rodríguez ◽  
Elvia Coballase-Urrutia ◽  
José Pedraza-Chaverri ◽  
Liliana Carmona-Aparicio ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Caenorhabditis Elegans ◽  
Metabolic Disorders ◽  
Molecular Mechanisms ◽  
Second Messengers ◽  
Model Organism ◽  
Human Diseases ◽  
C Elegans ◽  
Molecular Bases

Caenorhabditis elegansis a powerful model organism that is invaluable for experimental research because it can be used to recapitulate most human diseases at either the metabolic or genomic levelin vivo. This organism contains many key components related to metabolic and oxidative stress networks that could conceivably allow us to increase and integrate information to understand the causes and mechanisms of complex diseases. Oxidative stress is an etiological factor that influences numerous human diseases, including diabetes.C. elegansdisplays remarkably similar molecular bases and cellular pathways to those of mammals. Defects in the insulin/insulin-like growth factor-1 signaling pathway or increased ROS levels induce the conserved phase II detoxification response via the SKN-1 pathway to fight against oxidative stress. However, it is noteworthy that, aside from the detrimental effects of ROS, they have been proposed as second messengers that trigger the mitohormetic response to attenuate the adverse effects of oxidative stress. Herein, we briefly describe the importance ofC. elegansas an experimental model system for studying metabolic disorders related to oxidative stress and the molecular mechanisms that underlie their pathophysiology.

scholarly journals Natural Polysaccharides as Preventive and Therapeutic Horizon for Neurodegenerative Diseases

Pharmaceutics ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 1
Author(s):  
Manel Dhahri ◽  
Mawadda Alghrably ◽  
Hamdoon A. Mohammed ◽  
Syed Lal Badshah ◽  
Noreen Noreen ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Therapeutic Benefit ◽  
Fungal Species ◽  
Therapeutic Effects ◽  
Global Public Health ◽  
Neuroprotective Effects ◽  
Public Health Burden ◽  
Global Cost ◽  
Aging Populations

Neurodegenerative diseases are a serious and widespread global public health burden amongst aging populations. The total estimated worldwide global cost of dementia was US$818 billion in 2015 and has been projected to rise to 2 trillion US$ by 2030. While advances have been made to understand different neurodegenerative disease mechanisms, effective therapeutic strategies do not generally exist. Several drugs have been proposed in the last two decades for the treatment of different types of neurodegenerative diseases, with little therapeutic benefit, and often with severe adverse and side effects. Thus, the search for novel drugs with higher efficacy and fewer drawbacks is an ongoing challenge in the treatment of neurodegenerative disease. Several natural compounds including polysaccharides have demonstrated neuroprotective and even therapeutic effects. Natural polysaccharides are widely distributed in plants, animals, algae, bacterial and fungal species, and have received considerable attention for their wide-ranging bioactivity, including their antioxidant, anti-neuroinflammatory, anticholinesterase and anti-amyloidogenic effects. In this review, we summarize different mechanisms involved in neurodegenerative diseases and the neuroprotective effects of natural polysaccharides, highlighting their potential role in the prevention and therapy of neurodegenerative disease.

Cytotoxicity of mancozeb on Sertoli–germ cell co-culture system: Role of MAPK signaling pathway

2021 ◽  
pp. 074823372110440
Author(s):  
Mohaddeseh Mohammadi-Sardoo ◽  
Ali Mandegary ◽  
Seyed Noureddin Nematollahi-Mahani ◽  
Mahshid Moballegh Nasery ◽  
Mohammad Nabiuni ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Germ Cell ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Primary Cultures ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Ros Generation

Mancozeb (MZB) is a worldwide fungicide for the management of fungal diseases in agriculture and industrial contexts. Human exposure occurs by consuming contaminated plants, drinking water, and occupational exposure. There are reports on MZB’s reprotoxicity such as testicular structure damage, sperm abnormalities, and decrease in sperm parameters (number, viability, and motility), but its molecular mechanism on apoptosis in testis remains limited. To investigate the molecular mechanisms involved in male reprotoxicity induced by MZB, we used primary cultures of mouse Sertoli–germ cells. Cells were exposed to MZB (1.5, 2.5, and 3.5 μM) for 3 h to evaluate viability by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, reactive oxygen species (ROS) generation, and oxidative stress parameters (lipid peroxidation). Cell death and mitogen-activated protein kinase (MAPK) signaling were measured in these cells using flow cytometry and western blotting. In addition, some groups were exposed to N-acetylcysteine (NAC, 5 mM) in the form of co-treatment with MZB. Mancozeb reduced viability and increased the level of intracellular ROS, p38 and c-Jun N-terminal kinases (JNK) MAPK proteins phosphorylation, and apoptotic cell death, which could be blocked by NAC as an inhibitor of oxidative stress. The present study indicated for the first time the toxic manifestations of MZB on the Sertoli–germ cell co-culture. Redox imbalance and p38 and JNK signaling pathway activation might play critical roles in MZB-induced apoptosis in the male reproductive system.

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