scholarly journals Effects of Post‐Resuscitation Normoxic Therapy on Oxygen‐Sensitive Oxidative Stress in a Rat Model of Cardiac Arrest

2021 ◽  
Author(s):  
Yu Okuma ◽  
Lance B. Becker ◽  
Kei Hayashida ◽  
Tomoaki Aoki ◽  
Kota Saeki ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Cardiac Arrest ◽  
Weight Ratio ◽  
Reactive Oxygen ◽  
Oxygen Metabolism ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Multiple Organs ◽  
Oxygen Sensitive

Background Cardiac arrest (CA) can induce oxidative stress after resuscitation, which causes cellular and organ damage. We hypothesized that post‐resuscitation normoxic therapy would protect organs against oxidative stress and improve oxygen metabolism and survival. We tested the oxygen‐sensitive reactive oxygen species from mitochondria to determine the association with hyperoxia‐induced oxidative stress. Methods and Results Sprague–Dawley rats were subjected to 10‐minute asphyxia‐induced CA with a fraction of inspired O 2 of 0.3 or 1.0 (normoxia versus hyperoxia, respectively) after resuscitation. The survival rate at 48 hours was higher in the normoxia group than in the hyperoxia group (77% versus 28%, P <0.01), and normoxia gave a lower neurological deficit score (359±140 versus 452±85, P <0.05) and wet to dry weight ratio (4.6±0.4 versus 5.6±0.5, P <0.01). Oxidative stress was correlated with increased oxygen levels: normoxia resulted in a significant decrease in oxidative stress across multiple organs and lower oxygen consumption resulting in normalized respiratory quotient (0.81±0.05 versus 0.58±0.03, P <0.01). After CA, mitochondrial reactive oxygen species increased by ≈2‐fold under hyperoxia. Heme oxygenase expression was also oxygen‐sensitive, but it was paradoxically low in the lung after CA. In contrast, the HMGB‐1 (high mobility group box‐1) protein was not oxygen‐sensitive and was induced by CA. Conclusions Post‐resuscitation normoxic therapy attenuated the oxidative stress in multiple organs and improved post‐CA organ injury, oxygen metabolism, and survival. Additionally, post‐CA hyperoxia increased the mitochondrial reactive oxygen species and activated the antioxidation system.

scholarly journals Oxidative Stress Level in Onco-Surgical Treatment Dynamics at Patients with Malignant Colo-Rectal Tumors

2020 ◽  
Vol 71 (5) ◽  
pp. 450-461
Author(s):  
Maria Iuliana Gruia ◽  
Serban Marinescu ◽  
Dragos Predescu ◽  
George Jinescu ◽  
Bogdan Socea ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Colorectal Cancer ◽  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Invasive Procedure ◽  
Surgical Excision ◽  
Oxygen Metabolism ◽  
Oxygen Species ◽  
Active Metabolites ◽  
Endogenous Antioxidant

Colorectal cancer (CRC) is one of the most common human malignancies, affecting one of 20 persons in areas with high socio-economic standard. In Romania, the frequency of colorectal cancer is growing rapidly placing the country among countries with an average incidence of the disease. There are some etiologic factors involved and treatment of disease is carried out after proper staging. Biochemical mechanisms underlying malignant transformation in colorectal cancer are not all fully understood, therefore our work trying to enter in the path of oxygen metabolism at patients surgically treated. The aim of the study is to follow the production of active metabolites of oxygen, in the dynamics of the surgical procedure, and how the endogenous natural protection systems are activated, following the invasive procedure. Oxidative stress biochemistry assays, realized before and after surgical excision showed a direct relationship between the production of reactive oxygen species and the presence of tumor, without being able to distinguish exactly if malignant tissue is able to induce oxidative stress, or the latter occurs due to neoplastic changes. Based on the results we can say with certainty that the reactive oxygen species ROS primary attack occurs in the lipids, and then the proteins, following activation of endogenous antioxidant defence.

scholarly journals Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Mariachiara Buccarelli ◽  
Quintino Giorgio D’Alessandris ◽  
Paola Matarrese ◽  
Cristiana Mollinari ◽  
Michele Signore ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Cell Death ◽  
Molecular Mechanisms ◽  
Reactive Oxygen ◽  
Strong Increase ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species

Abstract Background Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults, characterized by a poor prognosis mainly due to recurrence and therapeutic resistance. It has been widely demonstrated that glioblastoma stem-like cells (GSCs), a subpopulation of tumor cells endowed with stem-like properties is responsible for tumor maintenance and progression. Moreover, it has been demonstrated that GSCs contribute to GBM-associated neovascularization processes, through different mechanisms including the transdifferentiation into GSC-derived endothelial cells (GdECs). Methods In order to identify druggable cancer-related pathways in GBM, we assessed the effect of a selection of 349 compounds on both GSCs and GdECs and we selected elesclomol (STA-4783) as the most effective agent in inducing cell death on both GSC and GdEC lines tested. Results Elesclomol has been already described to be a potent oxidative stress inducer. In depth investigation of the molecular mechanisms underlying GSC and GdEC response to elesclomol, confirmed that this compound induces a strong increase in mitochondrial reactive oxygen species (ROS) in both GSCs and GdECs ultimately leading to a non-apoptotic copper-dependent cell death. Moreover, combined in vitro treatment with elesclomol and the alkylating agent temozolomide (TMZ) enhanced the cytotoxicity compared to TMZ alone. Finally, we used our experimental model of mouse brain xenografts to test the combination of elesclomol and TMZ and confirmed their efficacy in vivo. Conclusions Our results support further evaluation of therapeutics targeting oxidative stress such as elesclomol with the aim of satisfying the high unmet medical need in the management of GBM.

scholarly journals Atomoxetine produces oxidative stress and alters mitochondrial function in human neuron-like cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Juan Carlos Corona ◽  
Sonia Carreón-Trujillo ◽  
Raquel González-Pérez ◽  
Denise Gómez-Bautista ◽  
Daniela Vázquez-González ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Mitochondrial Function ◽  
Reactive Oxygen ◽  
Therapeutic Effects ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Mitochondrial Mass ◽  
Norepinephrine Reuptake Inhibitor ◽  
Norepinephrine Reuptake

Abstract Atomoxetine (ATX) is a non-stimulant drug used in the treatment of attention-deficit/hyperactivity disorder (ADHD) and is a selective norepinephrine reuptake inhibitor. It has been shown that ATX has additional effects beyond the inhibition of norepinephrine reuptake, affecting several signal transduction pathways and alters gene expression. Here, we study alterations in oxidative stress and mitochondrial function in human differentiated SH-SY5Y cells exposed over a range of concentrations of ATX. We found that the highest concentrations of ATX in neuron-like cells, caused cell death and an increase in cytosolic and mitochondrial reactive oxygen species, and alterations in mitochondrial mass, membrane potential and autophagy. Interestingly, the dose of 10 μM ATX increased mitochondrial mass and decreased autophagy, despite the induction of cytosolic and mitochondrial reactive oxygen species. Thus, ATX has a dual effect depending on the dose used, indicating that ATX produces additional active therapeutic effects on oxidative stress and on mitochondrial function beyond the inhibition of norepinephrine reuptake.

scholarly journals Survival Signaling by C-RAF: Mitochondrial Reactive Oxygen Species and Ca2+ Are Critical Targets

2008 ◽  
Vol 28 (7) ◽  
pp. 2304-2313 ◽  
Author(s):  
Andrey V. Kuznetsov ◽  
Julija Smigelskaite ◽  
Christine Doblander ◽  
Manickam Janakiraman ◽  
Martin Hermann ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Cell Death ◽  
Reactive Oxygen ◽  
Ros Production ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Mitochondrial Ros ◽  
Survival Signaling ◽  
First Time

ABSTRACT Survival signaling by RAF occurs through largely unknown mechanisms. Here we provide evidence for the first time that RAF controls cell survival by maintaining permissive levels of mitochondrial reactive oxygen species (ROS) and Ca2+. Interleukin-3 (IL-3) withdrawal from 32D cells resulted in ROS production, which was suppressed by activated C-RAF. Oncogenic C-RAF decreased the percentage of apoptotic cells following treatment with staurosporine or the oxidative stress-inducing agent tert-butyl hydroperoxide. However, it was also the case that in parental 32D cells growing in the presence of IL-3, inhibition of RAF signaling resulted in elevated mitochondrial ROS and Ca2+ levels. Cell death is preceded by a ROS-dependent increase in mitochondrial Ca2+, which was absent from cells expressing transforming C-RAF. Prevention of mitochondrial Ca2+ overload after IL-3 deprivation increased cell viability. MEK was essential for the mitochondrial effects of RAF. In summary, our data show that survival control by C-RAF involves controlling ROS production, which otherwise perturbs mitochondrial Ca2+ homeostasis.

scholarly journals Inorganic Nitrite Supplementation Improves Endothelial Function With Aging

Hypertension ◽  
2021 ◽  
Author(s):  
Matthew J. Rossman ◽  
Rachel A. Gioscia-Ryan ◽  
Jessica R. Santos-Parker ◽  
Brian P. Ziemba ◽  
Kara L. Lubieniecki ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Endothelial Function ◽  
Sodium Nitrite ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Young Control ◽  
No Bioavailability ◽  
Old Mice

To determine the efficacy of inorganic nitrite supplementation on endothelial function in humans and mechanisms of action, we performed (1) a randomized, placebo-controlled, parallel-group clinical trial with sodium nitrite (80 mg/day, 12 weeks) in older adults (N=49, 68±1 year) and (2) reverse-translation experiments in young (6 months) and old (27 months) c57BL/6 mice. In the clinical trial, sodium nitrite increased plasma nitrite ( P <0.05) and was well tolerated. Brachial artery flow-mediated dilation (endothelial function) was increased 28% versus baseline after nitrite supplementation ( P <0.05) but unchanged with placebo. Nitrotyrosine, a marker of oxidative stress, was reduced by 45% versus baseline in biopsied endothelial cells after nitrite, but not placebo, treatment. Plasma from nitrite-treated, but not placebo-treated, subjects decreased whole-cell (CellROX) and mitochondria-specific (MitoSOX) reactive oxygen species in cultured human umbilical vein endothelial cells ( P <0.05). Old mice (old [27 months] control, n=9) had ≈30% lower ex vivo carotid artery endothelium-dependent dilation (EDD) versus young mice (young [6 months] control, n=9) due to reduced NO bioavailability ( P <0.05). Nitrite supplementation (drinking water, 50 mg/L, 8 weeks) restored EDD and NO bioavailability in old mice (n=10) to (6 months) control. Mitochondrial reactive oxygen species suppression of EDD was present in old control (increased EDD with a mitochondrial-targeted antioxidant, P <0.05) but not in young control or old mice supplemented with sodium nitrite. A mitochondrial reactive oxygen species inducer (rotenone) further impaired EDD in old control ( P <0.05); young control and old mice supplemented with sodium nitrite were protected. Markers of mitochondrial health were greater in aorta of old mice supplemented with sodium nitrite versus old control ( P <0.05). Inorganic nitrite supplementation improves endothelial function with aging by increasing NO, decreasing mitochondrial reactive oxygen species/oxidative stress, and increasing mitochondrial stress resistance. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02393742.

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