scholarly journals Chronic Diclofenac Exposure Increases Mitochondrial Oxidative Stress, Inflammatory Mediators, and Cardiac Dysfunction

2021 ◽  
Author(s):  
Phung N. Thai ◽  
Lu Ren ◽  
Wilson Xu ◽  
James Overton ◽  
Valeriy Timofeyev ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Energy Production ◽  
Oxygen Species ◽  
Mitochondrial Oxidative Stress ◽  
Cytokines And Chemokines ◽  
Functional Assessments ◽  
Inflammatory Drugs ◽  
Electrocardiographic Recordings

Abstract Purpose Nonsteroidal anti-inflammatory drugs (NSAIDs) are among one of the most commonly prescribed medications for pain and inflammation. Diclofenac (DIC) is a commonly prescribed NSAID that is known to increase the risk of cardiovascular diseases. However, the mechanisms underlying its cardiotoxic effects remain largely unknown. In this study, we tested the hypothesis that chronic exposure to DIC increases oxidative stress, which ultimately impairs cardiovascular function. Methods and Results Mice were treated with DIC for 4 weeks and subsequently subjected to in vivo and in vitro functional assessments. Chronic DIC exposure resulted in not only systolic but also diastolic dysfunction. DIC treatment, however, did not alter blood pressure or electrocardiographic recordings. Importantly, treatment with DIC significantly increased inflammatory cytokines and chemokines as well as cardiac fibroblast activation and proliferation. There was increased reactive oxygen species (ROS) production in cardiomyocytes from DIC-treated mice, which may contribute to the more depolarized mitochondrial membrane potential and reduced energy production, leading to a significant decrease in sarcoplasmic reticulum (SR) Ca2+ load, Ca2+ transients, and sarcomere shortening. Using unbiased metabolomic analyses, we demonstrated significant alterations in oxylipin profiles towards inflammatory features in chronic DIC treatment. Conclusions Together, chronic treatment with DIC resulted in severe cardiotoxicity, which was mediated, in part, by an increase in mitochondrial oxidative stress.

scholarly journals ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

2016 ◽  
Vol 113 (43) ◽  
pp. E6669-E6678 ◽  
Author(s):  
Mark A. Gregory ◽  
Angelo D’Alessandro ◽  
Francesca Alvarez-Calderon ◽  
Jihye Kim ◽  
Travis Nemkov ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mitochondrial Oxidative Stress ◽  
Flt3 Inhibitor ◽  
A Genome ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and drive leukemic cell growth and survival. Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy. We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML.

scholarly journals Metallothionein-I/II Knockout Mice Aggravate Mitochondrial Superoxide Production and Peroxiredoxin 3 Expression in Thyroid after Excessive Iodide Exposure

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Na Zhang ◽  
Lingyan Wang ◽  
Qi Duan ◽  
Laixiang Lin ◽  
Mohamed Ahmed ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Urinary Iodine ◽  
In Vitro Study ◽  
Superoxide Production ◽  
Mitochondrial Oxidative Stress ◽  
Mitochondrial Superoxide ◽  
Iodine Level ◽  
Significant Difference

Purpose. We aim to figure out the effect of metallothioneins on iodide excess induced oxidative stress in the thyroid.Methods. Eight-week-old MT-I/II knockout (MT-I/II KO) mice and background-matched wild-type (WT) mice were used. Mitochondrial superoxide production and peroxiredoxin (Prx) 3 expression were measured.Results. In in vitro study, more significant increases in mitochondrial superoxide production and Prx 3 expression were detected in the MT-I/II KO groups. In in vivo study, significantly higher concentrations of urinary iodine level were detected in MT-I/II KO mice in 100 HI group. Compared to the NI group, there was no significant difference existing in serum thyroid hormones level in either groups (P>0.05), while the mitochondrial superoxide production was significantly increased in 100 HI groups with significantly increased LDH activity and decreased relative cell viability. Compared to WT mice, more significant changes were detected in MT-I/II KO mice in 100 HI groups. No significant differences were detected between the NI group and 10 HI group in both the MT-I/II KO and WT mice groups (P>0.05).Conclusions. Iodide excess in a thyroid without MT I/II protection may result in strong mitochondrial oxidative stress, which further leads to the damage of thyrocytes.

scholarly journals The essential iron-sulfur protein Rli1 is an important target accounting for inhibition of cell growth by reactive oxygen species

2012 ◽  
Vol 23 (18) ◽  
pp. 3582-3590 ◽  
Author(s):  
Alawiah Alhebshi ◽  
Theodora C. Sideri ◽  
Sara L. Holland ◽  
Simon V. Avery
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Ribosomal Subunit ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Sulfur Protein ◽  
Iron Sulfur Protein ◽  
Cellular Components

Oxidative stress mediated by reactive oxygen species (ROS) is linked to degenerative conditions in humans and damage to an array of cellular components. However, it is unclear which molecular target(s) may be the primary “Achilles’ heel” of organisms, accounting for the inhibitory action of ROS. Rli1p (ABCE1) is an essential and highly conserved protein of eukaryotes and archaea that requires notoriously ROS-labile cofactors (Fe-S clusters) for its functions in protein synthesis. In this study, we tested the hypothesis that ROS toxicity is caused by Rli1p dysfunction. In addition to being essential, Rli1p activity (in nuclear ribosomal-subunit export) was shown to be impaired by mild oxidative stress in yeast. Furthermore, prooxidant resistance was decreased by RLI1 repression and increased by RLI1 overexpression. This Rlip1 dependency was abolished during anaerobicity and accentuated in cells expressing a FeS cluster–defective Rli1p construct. The protein's FeS clusters appeared ROS labile during in vitro incubations, but less so in vivo. Instead, it was primarily55FeS-cluster supply to Rli1p that was defective in prooxidant-exposed cells. The data indicate that, owing to its essential nature but dependency on ROS-labile FeS clusters, Rli1p function is a primary target of ROS action. Such insight could help inform new approaches for combating oxidative stress–related disease.

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 Lycopene Improves In Vitro Development of Porcine Embryos by Reducing Oxidative Stress and Apoptosis

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 230
Author(s):  
Hyo-Gu Kang ◽  
Sanghoon Lee ◽  
Pil-Soo Jeong ◽  
Min Ju Kim ◽  
Soo-Hyun Park ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Caspase 3 ◽  
Developmental Competence ◽  
Oxygen Species ◽  
Cell Numbers ◽  
Porcine Embryo ◽  
Apoptosis Pathways ◽  
Vitro Development

In vitro culture (IVC) for porcine embryo development is inferior compared to in vivo development because oxidative stress can be induced by the production of excessive reactive oxygen species (ROS) under high oxygen tension in the in vitro environment. To overcome this problem, we investigated the effect of lycopene, an antioxidant carotenoid, on developmental competence and the mechanisms involved in mitochondria-dependent apoptosis pathways in porcine embryos. In vitro fertilized (IVF) embryos were cultured in IVC medium supplemented with 0, 0.02, 0.05, 0.1, or 0.2 μM lycopene. The results indicate that 0.1 μM lycopene significantly increased the rate of blastocyst formation and the total cell numbers, including trophectoderm cell numbers, on Day In terms of mitochondria-dependent apoptosis, IVF embryos treated with 0.1 μM lycopene exhibited significantly decreased levels of ROS, increased mitochondrial membrane potential, and decreased expression of cytochrome c on Days 2 and Furthermore, 0.1 μM lycopene significantly decreased the number and percentage of caspase 3-positive and apoptotic cells in Day-6 blastocysts. In addition, Day-2 embryos and Day-6 blastocysts treated with 0.1 μM lycopene showed significantly reduced mRNA expression related to antioxidant enzymes (SOD1, SOD2, CATALASE) and apoptosis (BAX/BCL2L1 ratio). These results indicate that lycopene supplementation during the entire period of IVC enhanced embryonic development in pigs by regulating oxidative stress and mitochondria-dependent apoptosis.

scholarly journals Mechanism of Oxidative Stress in Neurodegeneration

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Sonia Gandhi ◽  
Andrey Y. Abramov
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Free Radicals ◽  
Neurodegenerative Disease ◽  
Reactive Oxygen ◽  
Biological Tissues ◽  
Antioxidant Systems ◽  
Oxygen Species

Biological tissues require oxygen to meet their energetic demands. However, the consumption of oxygen also results in the generation of free radicals that may have damaging effects on cells. The brain is particularly vulnerable to the effects of reactive oxygen species due to its high demand for oxygen, and its abundance of highly peroxidisable substrates. Oxidative stress is caused by an imbalance in the redox state of the cell, either by overproduction of reactive oxygen species, or by dysfunction of the antioxidant systems. Oxidative stress has been detected in a range of neurodegenerative disease, and emerging evidence from in vitro and in vivo disease models suggests that oxidative stress may play a role in disease pathogenesis. However, the promise of antioxidants as novel therapies for neurodegenerative diseases has not been borne out in clinical studies. In this review, we critically assess the hypothesis that oxidative stress is a crucial player in common neurodegenerative disease and discuss the source of free radicals in such diseases. Furthermore, we examine the issues surrounding the failure to translate this hypothesis into an effective clinical treatment.

Salvia miltiorrhiza Restrains Reactive Oxygen Species-Associated Pulmonary Fibrosis via Targeting Nrf2-Nox4 Redox Balance

2019 ◽  
Vol 47 (05) ◽  
pp. 1113-1131 ◽  
Author(s):  
Li-Ying Peng ◽  
Lin An ◽  
Ning-Yuan Sun ◽  
Yi Ma ◽  
Xiao-Wei Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Pulmonary Fibrosis ◽  
Salvia Miltiorrhiza ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Inhibitory Effects ◽  
Matrix Deposition

Pulmonary fibrosis (PF) is characterized by myofibroblast activation, which can be triggered by oxidative stress. In this study, we investigated the antifibrotic effect of the ethyl acetate extract of Salvia miltiorrhiza (EASM) on PF and examined the underlying molecular mechanism. EASM suppressed myofibroblast activation with reduced extracellular matrix deposition in the lungs of mice subjected to bleomycin (BLM) challenge, demonstrating the inhibitory effects on PF. EASM positively alleviated oxidative stress by upregulating nuclear factor-erythroid 2-related factor 2 (Nrf2) and concomitantly downregulating NADPH oxidase 4 (Nox4) in the lungs of BLM-treated mice. This effect was also observed in an in vitro model of transforming growth factor beta 1 (TGF-[Formula: see text]1)-stimulated fibroblast activation. EASM reduced reactive oxygen species (ROS) generation in fibroblasts by stabilizing Nrf2 protein with promoting kelch-like ECH-associated protein 1 (Keap1) degradation. Nrf2 knockdown in the lungs of BLM-treated mice diminished the inhibitory effects of EASM on fibrosis, providing evidence in vivo to address the unique role of Nrf2. Additionally, EASM inhibited TGF-[Formula: see text]1/Smad3 signaling by downregulating protein kinase C delta (PKC-[Formula: see text] and Smad3 phosphorylation (p-Smad3), which led to suppression of the TGF-[Formula: see text]1-induced fibrogenic response. These results indicate that EASM exhibits potent antifibrotic activity in vitro and in vivo, which might be associated with activation of Nrf2 pathway and inhibition of TGF-[Formula: see text]1/Smad3 pathway. Our findings support that EASM may act as an effective antifibrotic remedy for PF.

scholarly journals Azilsartan Suppresses Osteoclastogenesis and Ameliorates Ovariectomy-Induced Osteoporosis by Inhibiting Reactive Oxygen Species Production and Activating Nrf2 Signaling

2021 ◽  
Vol 12 ◽  
Author(s):  
Bin Pan ◽  
Lin Zheng ◽  
Jiawei Fang ◽  
Ye Lin ◽  
Hehuan Lai ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Signaling Pathways ◽  
Bone Microarchitecture ◽  
Reactive Oxygen ◽  
Related Factor ◽  
Nuclear Factor ◽  
Oxygen Species

Osteoporosis is characterized by a decrease in bone mass and destruction of the bone microarchitecture, and it commonly occurs in postmenopausal women and the elderly. Overactivation of osteoclasts caused by the inflammatory response or oxidative stress leads to osteoporosis. An increasing number of studies have suggested that intracellular reactive oxygen species (ROS) are strongly associated with osteoclastogenesis. As a novel angiotensin (Ang) II receptor blocker (ARB), azilsartan was reported to be associated with the inhibition of intracellular oxidative stress processes. However, the relationship between azilsartan and osteoclastogenesis is still unknown. In this study, we explored the effect of azilsartan on ovariectomy-induced osteoporosis in mice. Azilsartan significantly inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis and downregulated the expression of osteoclast-associated markers (Nfatc1, c-Fos, and Ctsk) in vitro. Furthermore, azilsartan reduced RANKL-induced ROS production by increasing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2). Mechanistically, azilsartan inhibited the activation of MAPK/NF-κB signaling pathways, while Nrf2 silencing reversed the inhibitory effect of azilsartan on MAPK/NF-κB signaling pathways. Consistent with the in vitro data, azilsartan administration ameliorated ovariectomy (OVX)-induced osteoporosis, and decreased ROS levels in vivo. In conclusion, azilsartan inhibited oxidative stress and may be a novel treatment strategy for osteoporosis caused by osteoclast overactivation.

Factor VIII Biosynthesis and the Unfolded Protein Response.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-19-SCI-19
Author(s):  
Randal J. Kaufman
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Protein Misfolding ◽  
Oxygen Species ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
And Oxidative Stress

Abstract Abstract SCI-19 Factor VIII is the protein deficient in the × chromosome-linked bleeding disorder hemophilia A. Previous studies demonstrated that FVIII expression in mammalian cells is limited due to protein misfolding of the newly synthesized polypeptide in the lumen of the endoplasmic reticulum (ER). Although oxidative stress can disrupt protein folding, how protein misfolding and oxidative stress impact each other has not been explored. We have analyzed expression of FVIII to elucidate the relationship between protein misfolding and oxidative stress. Accumulation of misfolded FVIII in the lumen of the ER activates the unfolded protein response (UPR), causes oxidative stress, and induces apoptosis in vitro and in vivo in mice. Strikingly, antioxidant treatment reduces UPR activation, oxidative stress, and apoptosis, and increases FVIII secretion in vitro and in vivo. The findings indicate that reactive oxygen species are a signal generated by misfolded protein in the ER that cause UPR activation and cell death. Genetic or chemical intervention to reduce reactive oxygen species improves protein folding and cell survival and may provide an avenue to treat and/or prevent diseases of protein misfolding. Disclosures No relevant conflicts of interest to declare.

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