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 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 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.

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.

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 In vitro Studies on Calcium Oxalate Induced Apoptosis Attenuated by Didymocarpus pedicellata

2021 ◽  
Vol 12 (6) ◽  
pp. 7342-7355
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Cell Death ◽  
Calcium Oxalate ◽  
Reactive Oxygen ◽  
Ethanolic Extract ◽  
Sem Analysis ◽  
Oxygen Species ◽  
Induced Apoptosis

The present study focuses on exploring the antilithiatic potential of Didymocarpus pedicellata, which is valuable in managing renal disorders. Urolithiasis is an idiopathic disorder with a high recurrence and an incidence rate and is of major concern worldwide due to partial and unsatisfactory relief. Calcium oxalate crystals in contact with renal epithelial cells (HK2), causing reactive oxygen species overproduction, oxidative stress, apoptosis resulting in crystal adhesion and internalization. Crystals were modulated by cotreatment with ethanolic extract of D. pedicellata. Cell toxicity assay was assessed using flow cytometry. Cell-crystal interaction, adhesion, and internalization were visualized through Scanning electron microscopy (SEM) analysis and hematoxylin-eosin staining. The lithogenic induction caused impairment of renal function due to oxidative stress, measured by ROS levels. Cell death assays were detected by dual staining methods. Fluorimeter evaluation pointed to active caspase 3 mediated cell death (apoptotic) in oxalate injured cells was attenuated by Didymocarpus pedicellata extract. Alterations in cell adhesion were observed by immunocytochemistry. The current study revealed that the Didymocarpus pedicellata was endowed with antiurolithiatic activity as it displayed increased viability, reduced oxidative stress due to lowered production of intracellular reactive oxygen species (ROS), and decreased apoptosis when oxalate injured HK2 cells were cotreated with the extract.

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.

scholarly journals Attenuating Effect of Chlorella Extract on NLRP3 Inflammasome Activation by Mitochondrial Reactive Oxygen Species

2021 ◽  
Vol 8 ◽  
Author(s):  
Yuya Nakashima ◽  
Kazuhito Gotoh ◽  
Soichi Mizuguchi ◽  
Daiki Setoyama ◽  
Yurie Takata ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Nlrp3 Inflammasome ◽  
Reactive Oxygen ◽  
Food Supplement ◽  
Inflammasome Activation ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Nlrp3 Inflammasome Activation

The NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome has been linked to the pathogenesis of a wide variety of human diseases. Although many drugs and inhibitors have been developed to treat NLRP3-associated diseases, only limited clinical data support their efficacy and safety. Chlorella, a unicellular green alga that is widely and safely used as a food supplement, contains various antioxidants. In this study, we obtained a fat-soluble extract from Chlorella (CE) and demonstrated that it reduced NLRP3 inflammasome activation by inhibiting mitochondrial reactive oxygen species and caspase-1 activation. In addition, CE supplementation attenuated lipopolysaccharide-induced interleukin 1β transcription through activation of hypoxia-inducible factor 1α in vitro and in vivo. As Chlorella is a safe and useful food supplement, it may be a practical pharmacological approach for treating NLRP3-driven diseases.

scholarly journals Chlorella sorokiniana Dietary Supplementation Increases Antioxidant Capacities and Reduces ROS Release in Mitochondria of Hyperthyroid Rat Liver

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 883
Author(s):  
Gaetana Napolitano ◽  
Gianluca Fasciolo ◽  
Giovanna Salbitani ◽  
Paola Venditti
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Thyroid Hormone ◽  
Reactive Oxygen ◽  
Dietary Supplementation ◽  
Chlorella Sorokiniana ◽  
Oxygen Species ◽  
Beneficial Effects

The ability of aerobic organisms to cope with the attack of radicals and other reactive oxygen species improves by feeding on foods containing antioxidants. Microalgae contain many molecules showing in vitro antioxidant capacity, and their food consumption can protect cells from oxidative insults. We evaluated the capacity of dietary supplementation with 1% dried Chlorella sorokiniana strain 211/8k, an alga rich in glutathione, α-tocopherol, and carotenoids, to counteract an oxidative attack in vivo. We used the hyperthyroid rat as a model of oxidative stress, in which the increase in metabolic capacities is associated with an increase in the release of mitochondrial reactive oxygen species (ROS) and the susceptibility to oxidative insult. Chlorella sorokiniana supplementation prevents the increases in oxidative stress markers and basal oxygen consumption in hyperthyroid rat livers. It also mitigates the thyroid hormone-induced increase in maximal aerobic capacities, the mitochondrial ROS release, and the susceptibility to oxidative stress. Finally, alga influences the thyroid hormone-induced changes in the factors involved in mitochondrial biogenesis peroxisomal proliferator-activated receptor-γ coactivator (PGC1-1) and nuclear respiratory factor 2 (NRF-2). Our results suggest that Chlorella sorokiniana dietary supplementation has beneficial effects in counteracting oxidative stress and that it works primarily by preserving mitochondrial function. Thus, it can be useful in preventing dysfunctions in which mitochondrial oxidative damage and ROS production play a putative role.

scholarly journals Mitochondrial Reactive Oxygen Species Are Essential for the Development of Psoriatic Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Soichi Mizuguchi ◽  
Kazuhito Gotoh ◽  
Yuya Nakashima ◽  
Daiki Setoyama ◽  
Yurie Takata ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Mitochondrial Protein ◽  
Reactive Oxygen ◽  
Skin Inflammation ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Immune Mediated ◽  
Important Regulator

Psoriasis is a common immune-mediated, chronic, inflammatory skin disease that affects approximately 2–3% of the population worldwide. Although there is increasing evidence regarding the essential roles of the interleukin (IL)-23/IL-17 axis and dendritic cell (DC)-T cell crosstalk in the development of skin inflammation, the contributions of mitochondrial function to psoriasis are unclear. In a mouse model of imiquimod (IMQ)-induced psoriasiform skin inflammation, we found that hematopoietic cell-specific genetic deletion of p32/C1qbp, a regulator of mitochondrial protein synthesis and metabolism, protects mice from IMQ-induced psoriatic inflammation. Additionally, we demonstrate that p32/C1qbp is an important regulator of IMQ-induced DC activation, both in vivo and in vitro. We also found that p32/C1qbp-deficient DCs exhibited impaired production of IL-1β, IL-23, and mitochondrial reactive oxygen species (mtROS) after IMQ stimulation. Because the inhibition of mtROS suppressed IMQ-induced DC activation and psoriatic inflammation, we presume that p32/C1qbp and mtROS can serve as therapeutic targets in psoriasis.

Sign in / Sign up

Export Citation Format

Share Document