scholarly journals Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration

Antioxidants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 647 ◽  
Author(s):  
Anna Picca ◽  
Riccardo Calvani ◽  
Hélio José Coelho-Junior ◽  
Francesco Landi ◽  
Roberto Bernabei ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Quality Control ◽  
Fine Tuning ◽  
Ros Generation ◽  
Molecular Pattern ◽  
Extracellular Compartment ◽  
Common Thread ◽  
Canonical Pathways ◽  
Impaired Quality ◽  
Signal Receptors

Oxidative stress develops as a response to injury and reflects a breach in the cell’s antioxidant capacity. Therefore, the fine-tuning of reactive oxygen species (ROS) generation is crucial for preserving cell’s homeostasis. Mitochondria are a major source and an immediate target of ROS. Under different stimuli, including oxidative stress and impaired quality control, mitochondrial constituents (e.g., mitochondrial DNA, mtDNA) are displaced toward intra- or extracellular compartments. However, the mechanisms responsible for mtDNA unloading remain largely unclear. While shuttling freely within the cell, mtDNA can be delivered into the extracellular compartment via either extrusion of entire nucleoids or the generation and release of extracellular vesicles. Once discarded, mtDNA may act as a damage-associated molecular pattern (DAMP) and trigger an innate immune inflammatory response by binding to danger-signal receptors. Neuroinflammation is associated with a large array of neurological disorders for which mitochondrial DAMPs could represent a common thread supporting disease progression. The exploration of non-canonical pathways involved in mitochondrial quality control and neurodegeneration may unveil novel targets for the development of therapeutic agents. Here, we discuss these processes in the setting of two common neurodegenerative diseases (Alzheimer’s and Parkinson’s disease) and Down syndrome, the most frequent progeroid syndrome.

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.

Protocatechuic Acid Protects Platelets from Apoptosis via Inhibiting Oxidative Stress-Mediated PI3K/Akt/GSK3β Signaling

2021 ◽  
Author(s):  
Fuli Ya ◽  
Kongyao Li ◽  
Hong Chen ◽  
Zezhong Tian ◽  
Die Fan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Caspase 3 ◽  
Protocatechuic Acid ◽  
Human Platelets ◽  
Ros Generation ◽  
Inhibitory Effects ◽  
Platelet Apoptosis ◽  
Phosphatidylserine Exposure ◽  
Underlying Mechanisms

AbstractOxidative stress plays crucial roles in initiating platelet apoptosis that facilitates the progression of cardiovascular diseases (CVDs). Protocatechuic acid (PCA), a major metabolite of anthocyanin cyanidin-3-O-β-glucoside (Cy-3-g), exerts cardioprotective effects. However, underlying mechanisms responsible for such effects remain unclear. Here, we investigate the effect of PCA on platelet apoptosis and the underlying mechanisms in vitro. Isolated human platelets were treated with hydrogen peroxide (H2O2) to induce apoptosis with or without pretreatment with PCA. We found that PCA dose-dependently inhibited H2O2-induced platelet apoptosis by decreasing the dissipation of mitochondrial membrane potential, activation of caspase-9 and caspase-3, and decreasing phosphatidylserine exposure. Additionally, the distributions of Bax, Bcl-xL, and cytochrome c mediated by H2O2 in the mitochondria and the cytosol were also modulated by PCA treatment. Moreover, the inhibitory effects of PCA on platelet caspase-3 cleavage and phosphatidylserine exposure were mainly mediated by downregulating PI3K/Akt/GSK3β signaling. Furthermore, PCA dose-dependently decreased reactive oxygen species (ROS) generation and the intracellular Ca2+ concentration in platelets in response to H2O2. N-Acetyl cysteine (NAC), a ROS scavenger, markedly abolished H2O2-stimulated PI3K/Akt/GSK3β signaling, caspase-3 activation, and phosphatidylserine exposure. The combination of NAC and PCA did not show significant additive inhibitory effects on PI3K/Akt/GSK3β signaling and platelet apoptosis. Thus, our results suggest that PCA protects platelets from oxidative stress-induced apoptosis through downregulating ROS-mediated PI3K/Akt/GSK3β signaling, which may be responsible for cardioprotective roles of PCA in CVDs.

scholarly journals Hydrogen Nano-Bubble Water Suppresses ROS Generation, Adipogenesis, and Interleukin-6 Secretion in Hydrogen-Peroxide- or PMA-Stimulated Adipocytes and Three-Dimensional Subcutaneous Adipose Equivalents

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 626
Author(s):  
Li Xiao ◽  
Nobuhiko Miwa
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Interleukin 6 ◽  
Lipid Accumulation ◽  
Metabolic Disorders ◽  
Three Dimensional ◽  
Human Keratinocytes ◽  
Ros Generation ◽  
Obese People ◽  
Subcutaneous Adipose

Reactive oxygen species (ROS)-induced oxidative stress in adipose tissue is associated with inflammation and the development of obesity-related metabolic disorders. The aim of this study is to investigate the effects of hydrogen nano-bubble water (HW) on ROS generation, adipogenesis, and interleukin-6 (IL-6) secretion in hydrogen peroxide (H2O2) or phorbol 12-myristate 13-acetate (PMA)-stimulated OP9 adipocytes, and three-dimensional (3D) subcutaneous adipose equivalents. Nanoparticle tracking analysis showed that fresh HW contains 1.17 × 108/mL of nano-sized hydrogen bubbles. Even after 8 to 13 months of storage, approximately half of the bubbles still remained in the water. CellROX® staining showed that HW could diminish H2O2- or PMA-induced intracellular ROS generation in human keratinocytes HaCaT and OP9 cells. We discovered that PMA could markedly increase lipid accumulation to 180% and IL-6 secretion 2.7-fold in OP9 adipocytes. Similarly, H2O2 (5 µM) also significantly stimulated lipid accumulation in OP9 cells and the 3D adipose equivalents. HW treatment significantly repressed H2O2- or PMA-induced lipid accumulation and IL-6 secretion in OP9 adipocytes and the 3D adipose equivalents. In conclusion, HW showed a possibility of repressing oxidative stress, inflammatory response, and adipogenesis at cellular/tissue levels. It can be used for preventing the development of metabolic disorders amongst obese people.

PERK mediates oxidative stress and adipogenesis in Graves’ orbitopathy pathogenesis

2021 ◽  
Author(s):  
JaeSang Ko ◽  
Ji-Young Kim ◽  
Min Kyung Chae ◽  
Eun Jig Lee ◽  
Jin Sook Yoon
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Er Stress ◽  
Adipogenic Differentiation ◽  
Ros Generation ◽  
Mrna Levels ◽  
Graves Orbitopathy ◽  
Orbital Fibroblasts

We examined endoplasmic reticulum (ER) stress-related gene expression in orbital tissues from patients with Graves’ orbitopathy (GO) and the effects of silencing protein kinase RNA-like endoplasmic reticulum kinase (PERK) in primary orbital fibroblast cultures to demonstrate the therapeutic potential of PERK-modulating agents in GO management. The expression of ER stress related genes in orbital tissue harvested from individuals with or without GO was studied using real-time polymerase chain reaction. The role of PERK in GO pathogenesis was examined through small-interfering RNA (siRNA)-mediated silencing in cultured primary orbital fibroblasts. Intracellular reactive oxygen species (ROS) levels induced in response to cigarette smoke extract (CSE) or hydrogen peroxide were measured using 5-(and 6)-carboxy-20,70-dichlorodihydrofluorescein diacetate staining and flow cytometry. Cells were stained with Oil Red O, and adipogenesis-related transcription factor expression was evaluated through western blotting after adipogenic differentiation. PERK, activating transcription factor 4 (ATF4), and CCAAT-enhancer-binding protein (C/EBP)-homologous protein(CHOP)mRNA levels were significantly higher in GO orbital tissues than in non-GO orbital tissues. PERK silencing inhibited CSE- or hydrogen peroxide-induced ROS generation. After adipogenic differentiation, GO orbital fibroblasts revealed decreased lipid droplets and downregulation of C/EBPα, C/EBPβ, and peroxisome proliferator-activator gamma (PPARγ) in PERK siRNA-transfected cells. The orbital tissues of patients with GO were exposed to chronic ER stress and subsequently exhibited enhanced unfolded protein response (especially through the PERK pathway). PERK silencing reduced oxidative stress and adipogenesis in GO orbital fibroblasts in vitro. Our results imply that PERK-modulating agents can potentially be used to manage GO.

Abstract 107: Apocynin Attenuates Isoproterenol-induced Myocardial Injury: Implications For Targeting Nadph Oxidase In Myocardial Fibrogenesis

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Yu Chen ◽  
Jingang Cui ◽  
Qinbo Yang ◽  
Chenglin Jia ◽  
Minqi Xiong ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Myocardial Fibrosis ◽  
Myocardial Injury ◽  
Oxidase Inhibitor ◽  
Ros Generation ◽  
Dependent Manner ◽  
Expression Of Genes ◽  
Therapeutic Development ◽  
Myocardial Injuries

Myocardial fibrosis results from cardiac injuries caused by various pathophysiological mechanisms including myocardial infarction, leading to destruction of myocardial architecture and progressive cardiac dysfunction. Oxidative stress is likely involved in myocardial ischemic injury and the subsequent tissue remodeling mediated by myocardial fibrogenesis. Our current study aimed to evaluate the implication of NADPH oxidase in overproduction of reactive oxygen species and its contribution to the pathogenesis of myocardial fibrogenesis after ischemic injuries. The effects of Apocynin, a selective NADPH oxidase inhibitor, were evaluated in the mouse model of isoproterenol-induced myocardial injury by histopathological approaches and whole-genome gene expression profiling. The results demonstrated that Apocynin was able to inhibit the development of ISO-induced myocardial necrotic lesions and fibrogenesis in a dose-dependent manner. Moreover, the preventive effects of Apocynin on myocardial injuries were associated with suppressed expression of genes implicated in inflammation responses and extracellular matrix, which were remarkably upregulated by isoproterenol administration. In summary, o ur study provides proof-of-concept for the involvement of NADPH oxidase-mediated ROS generation in myocardial ischemic injuries and fibrogenesis, which will benefit the mechanism-based therapeutic development targeting NADPH oxidase and oxidative stress in treating myocardial fibrosis and related disorders.

miR-187 modulates cardiomyocyte apoptosis and oxidative stress in myocardial infarction mice via negatively regulating DYRK2

2021 ◽  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Protective Effect ◽  
Myocardial Infarct ◽  
Annexin V ◽  
Cardiomyocyte Apoptosis ◽  
Ros Generation ◽  
Downstream Target

Myocardial infarction is a serious representation of cardiovescular disease, MicroRNAs play a role in modifying I/R injury and myocardial infarct remodeling. The present study therefore examined the potential role of miR-187 in cardiac I/R injury and its underlying mechanisms. miR-187 was inhibited or overexpressed in cardiomyocytes H/R models by pretreatment with miR-187 mimic or inhibitor to confirm the function of miR-187 in H/R. DYRK2 was inhibited or overexpressed in cardiomyocytes H/R models by pretreatment with DYRK2 inhibitor. A myocardium I/R mouse model was established. Circulating levels of miR-187 or DYRK2 was detected by quantitative realtime PCR and protein expression was detected by western blotting. The cell viability in all groups was determined by MTT assay and the apoptosis ratio was detected by flow cytometry after staining with Annexin V-FITC. The effect of miR-187 on cellular ROS generation was examined by DCFH-DA. The level of lipid peroxidation and SOD expression were determined by MDA and SOD assay. The findings indicated that miR-187 may be a possible regulator in the protective effect of H/R-induced cardiomyocyte apoptosis, cellular oxidative stress and leaded to DYRK2 suppression at a posttranscriptional level. Moreover, the improvement of miR-187 on H/R-induced cardiomyocyte injury contributed to the obstruction of DYRK2 expression. In addition, these results identified DYRK2 as the functional downstream target of miR-187 regulated myocardial infarction and oxidative stress.These present work provided the first insight into the function of miR-187 in successfully protect cardiomyocyte both in vivo and in vitro, and such a protective effect were mediated through the regulation of DYRK2 expression.

Abstract MP30: Circulating Sars-cov-2 Spike Protein 1 Causes Microarteriolar Oxidative Stress, Endothelial Dysfunction And Enhanced Thromboxane And Endothelin Contractility That Are Prevented By Spironolactone.

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Dan Wang ◽  
Christopher S Wilcox
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Fluorescence Microscopy ◽  
Vascular Dysfunction ◽  
Microvascular Complications ◽  
Spike Protein ◽  
Ros Generation ◽  
Intravenous Injections ◽  
Novel Model

Introduction and hypothesis: Following bodily entry, the SARS-CoV-2 virus undergoes pulmonary replication with release of circulating viral spike protein 1 (SP1) into the bloodstream. Uptake of SP1 by endothelial cells might provoke vascular dysfunction and thrombosis. We hypothesized that spironolactone could prevent microvascular complications from circulating SP1 in COVID-19. Methods: male C57Bl/6 mice received spironolactone (100 mg · kg -1 · d -1 PO x 3d) or vehicle and intravenous injections of recombinant full-length human SP1 (10 μg per mouse) or vehicle. They were euthanized after 3 days. Mesenteric resistant arterioles (n=4 per group) were dissected and mounted on isometric myographs. Acetylcholine-induced EDRF responses and L-NAME-inhibitable NO generation (DAF-FM fluorescence) were studied in pre-constricted vessels and contraction to endothelin 1 (ET1) or thromboxane (U-46, 619) and ET1-induced ROS (PEG-SOD inhibitable ethidium: dihydroethidium fluorescence) were studied by fluorescence microscopy in other vessels. Results: SP1 reduced acetylcholine-induced EDRF (17 ± 3 vs 27 ± 5 % mean ± sem; P < 0.05) and NO generation (0.21 ± 0.03 vs 0.36 ± 0.04, F 1 /F 0 ; P < 0.05) while increasing contraction to ET1 (10 -7 mol·l -1 : 124 ± 13 vs 89 ± 4 %; P < 0.05) and U-46, 619 (10 -6 mol·l -1 :114± 5 vs 87± 6 %; P < 0.05) and ET1-induced ROS generation(0.30± 0.08 vs 0.09± 0.03; P < 0.05). Spironolactone did not modify any of these responses in vessels from normal mice but prevented all the effects of SP1. Conclusion: these preliminary studies provide a novel model to study COVID-19 vasculopathy. They indicate that spironolactone can provide protection from microvascular oxidative stress, endothelial dysfunction and enhanced contractility and might thereby moderate COVID-19 complications.

scholarly journals Ox-LDL induced endothelial progenitor cells oxidative stress via p38/Keap1/Nrf2 pathway

2021 ◽  
Author(s):  
Qijun Jiang ◽  
Chengpeng Li ◽  
Zhigang Gong ◽  
Zhigang Li ◽  
Shifang Ding
Keyword(s):  
Oxidative Stress ◽  
Membrane Potential ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Nuclear Translocation ◽  
Tube Formation ◽  
Ros Generation ◽  
Endothelial Progenitor ◽  
Migration Ability ◽  
Nrf2 Pathway

Abstract Background In many studies, endothelial progenitor cells (EPCs) highly expressing antioxidant protein were induced oxidative stress and apoptosis by Oxidized-low density lipoprotein (ox-LDL). Nrf2 which was resently reported to regulate the antioxidant genes and cellular redox regulators was highly expressed in EPCs. However, its role in ox-LDL induced EPCs oxidative stress and apoptosis has not been fully illustrated. Methods EPCs isolated from human peripheral blood mononuclear cells were treated with different concentration of ox-LDL, Keap1 siRNA and a specific p38 MAPK inhibitor SB203580, then used to assay the whole cellular Nrf2 (total Nrf2, t-Nrf2), cytoplasmic Nrf2 (c-Nrf2), nuclear Nrf2 (n- Nrf2), NAD(P) H:quinone oxidoreductase 1 (NQO1) protein levels and Bax /Bcl-2 with western blot, NQO1 mRNA levels with RT-PCR, ROS level with H2DCF-DA, the loss/disruption of mitochondrial membrane potential (MMP) with JC-1, apoptosis with Annexin-V and PI,migration ability with transwell chambers and tube formation. Results The ox-LDL treatment decreased the n-Nrf2/Histone H3 to c-Nrf2/GAPDH ratio, NQO1 mRNA and protein expression levels. Treatment of ox-LDL enhanced the ROS production, induced loss of membrane potential, increase in cell shrinkage, pyknotic nuclei and apoptosis of EPCs. The Keap1 knockdown with Keap1 siRNA increased the nuclear translocation of Nrf2, the NQO1 mRNA and protein transcription levels, and prevented ox-LDL induced ROS generation and formation of JC-1 monomers. Treatment of ox-LDL increased the activation of p38. Pretreatment with SB203580 significantly eliminated ox-LDL induced the inhibition of Nrf2 nuclear translocation, the depression of the mRNA transcription levels of NQO-1, the ROS generation and the formation of JC-1 monomers in EPCs. The pretreatment of Keap1 siRNA decreased the Bax/Bcl-2 ratio which was increased by the treatment of ox-LDL in EPCs. The ox-LDL treatment decreased EPCs migration activity and tube formation. Whereas the pre-treatment with Keap1 siRNA preserved the migration ability and tube formation of EPCs Conclusion Ox-LDL induced EPCs oxidative stress and apoptosis via p38/Keap1/Nrf2 pathway.

scholarly journals Detecting Validated Intracellular ROS Generation with 18F-dihydroethidine-Based PET

2021 ◽  
Author(s):  
Edward C. T. Waters ◽  
Friedrich Baark ◽  
Zilin Yu ◽  
Filipa Mota ◽  
Thomas R. Eykyn ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Contractile Function ◽  
Ex Vivo ◽  
Glutathione Depletion ◽  
Ros Generation ◽  
Cardiac Contractile ◽  
Rat Hearts ◽  
Intracellular Ros ◽  
Cardiac Contractile Dysfunction

Abstract Purpose To determine the sensitivity of the 18F-radiolabelled dihydroethidine analogue ([18F]DHE) to ROS in a validated ex vivo model of tissue oxidative stress. Procedures The sensitivity of [18F]DHE to various ROS-generating systems was first established in vitro. Then, isolated rat hearts were perfused under constant flow, with contractile function monitored by intraventricular balloon. Cardiac uptake of infused [18F]DHE (50–150 kBq.min−1) was monitored by γ-detection, while ROS generation was invoked by menadione infusion (0, 10, or 50 μm), validated by parallel measures of cardiac oxidative stress. Results [18F]DHE was most sensitive to oxidation by superoxide and hydroxyl radicals. Normalised [18F]DHE uptake was significantly greater in menadione-treated hearts (1.44 ± 0.27) versus control (0.81 ± 0.07) (p < 0.05, n = 4/group), associated with concomitant cardiac contractile dysfunction, glutathione depletion, and PKG1α dimerisation. Conclusion [18F]DHE reports on ROS in a validated model of oxidative stress where perfusion (and tracer delivery) is unlikely to impact its pharmacokinetics.

Sign in / Sign up

Export Citation Format

Share Document