scholarly journals Opa1 Prevents Apoptosis and Cisplatin-Induced Ototoxicity in Murine Cochleae

2021 ◽  
Vol 9 ◽  
Author(s):  
Tingting Dong ◽  
Xuejie Zhang ◽  
Yiqing Liu ◽  
Shan Xu ◽  
Haishuang Chang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Mitochondrial Membrane ◽  
Vital Role ◽  
Mitochondrial Morphology ◽  
Oxygen Species ◽  
Inner Mitochondrial Membrane ◽  
Cochlear Damage

Optic atrophy1 (OPA1) is crucial for inner mitochondrial membrane (IMM) fusion and essential for maintaining crista structure and mitochondrial morphology. Optic atrophy and hearing impairment are the most prevalent clinical features associated with mutations in the OPA1 gene, but the function of OPA1 in hearing is still unknown. In this study, we examined the ability of Opa1 to protect against cisplatin-induced cochlear cell death in vitro and in vivo. Our results revealed that knockdown of Opa1 affects mitochondrial function in HEI-OC1 and Neuro 2a cells, as evidenced by an elevated reactive oxygen species (ROS) level and reduced mitochondrial membrane potential. The dysfunctional mitochondria release cytochrome c, which triggers apoptosis. Opa1 expression was found to be significantly reduced after cell exposed to cisplatin in HEI-OC1 and Neuro 2a cells. Loss of Opa1 aggravated the apoptosis and mitochondrial dysfunction induced by cisplatin treatment, whereas overexpression of Opa1 alleviated cisplatin-induced cochlear cell death in vitro and in explant. Our results demonstrate that overexpression of Opa1 prevented cisplatin-induced ototoxicity, suggesting that Opa1 may play a vital role in ototoxicity and/or mitochondria-associated cochlear damage.

scholarly journals Apoptosis-like cell death upon kinetoplastid induction by compounds isolated from the brown algae Dictyota spiralis

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Olfa Chiboub ◽  
Ines Sifaoui ◽  
Manef Abderrabba ◽  
Mondher Mejri ◽  
José J. Fernández ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Mitochondrial Membrane ◽  
Brown Seaweed ◽  
Cell Permeability ◽  
Oxygen Species ◽  
Potential Drug ◽  
Concentration Cell ◽  
Drug Candidates

Abstract Background The in vitro activity of the brown seaweed Dictyota spiralis against both Leishmania amazonensis and Trypanosoma cruzi was evaluated in a previous study. Processing by bio-guided fractionation resulted in the isolation of three active compounds, classified as diterpenes. In the present study, we performed several assays to detect clinical features associated to cell death in L. amazonensis and T. cruzi with the aim to elucidate the mechanism of action of these compounds on parasitic cells. Methods The aims of the experiments were to detect and evaluate specific events involved in apoptosis-like cell death in the kinetoplastid, including DNA condensation, accumulation of reactive oxygen species and changes in ATP concentration, cell permeability and mitochondrial membrane potential, respectively, in treated cells. Results The results demonstrated that the three isolated diterpenes could inhibit the tested parasites by inducing an apoptosis-like cell death. Conclusions These results encourage further investigation on the isolated compounds as potential drug candidates against both L. amazonensis and T. cruzi. Graphic abstract

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 Midazolam and Dexmedetomidine Affect Neuroglioma and Lung Carcinoma Cell Biology In Vitro and In Vivo

2018 ◽  
Vol 129 (5) ◽  
pp. 1000-1014 ◽  
Author(s):  
Chunyan Wang ◽  
Tanweer Datoo ◽  
Hailin Zhao ◽  
Lingzhi Wu ◽  
Akshay Date ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Proliferation ◽  
Lung Carcinoma ◽  
Mitochondrial Membrane ◽  
Benzodiazepine Receptor ◽  
Tumor Burden ◽  
Oxygen Species ◽  
Peripheral Benzodiazepine Receptor

AbstractEditor’s PerspectiveWhat We Already Know about This TopicWhat This Article Tells Us That Is NewBackgroundSeveral factors within the perioperative period may influence postoperative metastatic spread. Dexmedetomidine and midazolam are widely used general anesthetics during surgery. The authors assessed their effects on human lung carcinoma (A549) and neuroglioma (H4) cell lines in vitro and in vivo.MethodsCell proliferation and migration were measured after dexmedetomidine (0.001 to 10 nM) or midazolam (0.01 to 400 μM) treatment. Expression of cell cycle and apoptosis markers were assessed by immunofluorescence. Mitochondrial membrane potential and reactive oxygen species were measured by JC-1 staining and flow cytometry. Antagonists atipamezole and flumazenil were used to study anesthetic mechanisms of action. Tumor burden after anesthetic treatment was investigated with a mouse xenograft model of lung carcinoma.ResultsDexmedetomidine (1 nM) promoted cell proliferation (2.9-fold in A549 and 2-fold in H4 cells vs. vehicle, P < 0.0001; n = 6), migration (2.2-fold in A549 and 1.9-fold in H4 cells vs. vehicle, P < 0.0001; n = 6), and upregulated antiapoptotic proteins in vitro. In contrast, midazolam (400 μM) suppressed cancer cell migration (2.6-fold in A549 cells, P < 0.0001; n = 4), induced apoptosis via the intrinsic mitochondrial pathway, decreased mitochondrial membrane potential, and increased reactive oxygen species expression in vitro—effects partly attributable to peripheral benzodiazepine receptor activation. Furthermore, midazolam significantly reduced tumor burden in mice (1.7-fold vs. control; P < 0.05; n = 6 per group).ConclusionsMidazolam possesses antitumorigenic properties partly mediated by the peripheral benzodiazepine receptor, whereas dexmedetomidine promotes cancer cell survival through signaling via the α2-adrenoceptor in lung carcinoma and neuroglioma cells.

scholarly journals Treatment of Human Lens Epithelium with High Levels of Nanoceria Leads to Reactive Oxygen Species Mediated Apoptosis

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 441 ◽  
Author(s):  
Belal I. Hanafy ◽  
Gareth W. V. Cave ◽  
Yvonne Barnett ◽  
Barbara Pierscionek
Keyword(s):  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Dose Effect ◽  
Human Lens ◽  
Mitochondrial Morphology ◽  
Oxygen Species ◽  
Significant Uptake ◽  
The Impact

Nanoceria (cerium oxide nanoparticles) have been shown to protect human lens epithelial cells (HLECs) from oxidative stress when used at low concentrations. However, there is a lack of understanding about the mechanism of the cytotoxic and genotoxic effects of nanoceria when used at higher concentrations. Here, we investigated the impact of 24-hour exposure to nanoceria in HLECs. Nanoceria’s effects on basal reactive oxygen species (ROS), mitochondrial morphology, membrane potential, ATP, genotoxicity, caspase activation and apoptotic hallmarks were investigated. Scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDX) studies on isolated mitochondria revealed significant uptake and localization of nanoceria in the mitochondria. At high nanoceria concentrations (400 µg mL−1), intracellular levels of ROS were increased and the HLECs exhibited classical hallmarks of apoptosis. These findings concur with the cells maintaining normal ATP levels necessary to execute the apoptotic process. These results highlight the need for nanoceria dose-effect studies on a range of cells and tissues to identify therapeutic concentrations in vitro or in vivo.

NAC Improves the Differentiation of IPS Cells Into Hematopoietic Progenitors

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2349-2349
Author(s):  
Ina Berniakovich ◽  
Leopoldo Laricchia-Robbio ◽  
Juan Carlos Izpisua
Keyword(s):  
Reactive Oxygen Species ◽  
Stress Resistance ◽  
Mitochondrial Membrane ◽  
Reactive Oxygen ◽  
Ips Cells ◽  
Oxygen Species ◽  
Cd34 Cells ◽  
Human Ips Cells

Abstract Abstract 2349 In vitro differentiation of human induced pluripotent stem (iPS) cells is a new way to obtain donor material for blood transplantation. However, this is a long process in the course of which cells are exposed to alien environmental factors, capable to change cellular properties and decrease cellular viability. Indeed, cells in vitro are exposed to mechanical stress, artificial growth surface, unnatural gas composition etc. This fact could partially explain why cells obtained during directed iPS cells differentiation have different qualities in comparison with the analogous population from in vivo. It is supposed that oxidative stress is the major underlying mechanism of negative influence of various in vitro environmental factors on cells. N-acetylcysteine (NAC) is a powerful antioxidant. Due to free radical scavenging ability, the principal function of NAC is rendered to the inhibition of cellular damage and cell death in response to reactive oxygen species. Cytoprotective function of NAC is well demonstrated both in vitro and in vivo. We have established a protocol to obtain hematopoietic stem cell-like cells from human iPS cells with a pick of their production at three weeks of differentiation. We analyzed how intracellular accumulation of reactive oxygen species and NO, as well as cell viability, apoptosis, stress resistance, mitochondrial membrane potential were changed during this process by comparing status of cultures at 1 and at 3 weeks of differentiation. We found that during differentiation cells progressively accumulated intracellular reactive oxygen species and increased production of NO. The level of apoptosis in culture was significantly higher at 3 weeks of differentiation than at 1 week. Cell viability, on the contrary, decreased from 1 week till 3 weeks of differentiation. Stress resistance quantified through the amount of cells resistant to the H2O2 treatment was also decreased in 3 weeks old cultures. We also demonstrated that during in vitro culture the mitochondrial membrane potential of the cells under basal conditions and upon stimulation with carbonyl cyanide m-chlorophenylhydrazone was decreased at 3 weeks of differentiation in comparison with that at 1 week. All these phenomena were reversed by NAC supplementation. Remarkably, NAC administration also improved the hematopoietic differentiation of human iPS cells in terms of production of CD34, CD45, CD43 positive cells, that showed normal functionality in colony forming unit assay. CD34+ cells obtained from NAC treated cultures also increased their migration towards SDF1, therefore showing an increased ability of our CD34+ cells to home into bone marrow. Our results suggest that supplementation with NAC is beneficial for the improvement of hematopoietic differentiation of human iPS cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Targeting autophagy enhances atezolizumab-induced mitochondria-related apoptosis in osteosarcoma

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Zhuochao Liu ◽  
Hongyi Wang ◽  
Chuanzhen Hu ◽  
Chuanlong Wu ◽  
Jun Wang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Antitumor Immunity ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Specific Monoclonal Antibody ◽  
Osteosarcoma Cells ◽  
Jnk Pathway ◽  
In Vivo Experiments

AbstractIn this study, we identified the multifaceted effects of atezolizumab, a specific monoclonal antibody against PD-L1, in tumor suppression except for restoring antitumor immunity, and investigated the promising ways to improve its efficacy. Atezolizumab could inhibit the proliferation and induce immune-independent apoptosis of osteosarcoma cells. With further exploration, we found that atezolizumab could impair mitochondria of osteosarcoma cells, resulting in increased release of reactive oxygen species and cytochrome-c, eventually leading to mitochondrial-related apoptosis via activating JNK pathway. Nevertheless, the excessive release of reactive oxygen species also activated the protective autophagy of osteosarcoma cells. Therefore, when we combined atezolizumab with autophagy inhibitors, the cytotoxic effect of atezolizumab on osteosarcoma cells was significantly enhanced in vitro. Further in vivo experiments also confirmed that atezolizumab combined with chloroquine achieved the most significant antitumor effect. Taken together, our study indicates that atezolizumab can induce mitochondrial-related apoptosis and protective autophagy independently of the immune system, and targeting autophagy is a promising combinatorial approach to amplify its cytotoxicity.

scholarly journals Mitochondrion-Dependent Cell Death in TDP-43 Proteinopathies

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 376
Author(s):  
Chantal B. Lucini ◽  
Ralf J. Braun
Keyword(s):  
Cell Death ◽  
Oxygen Species ◽  
In Vivo Models ◽  
Dependent Cell ◽  
Cell Death Mechanisms ◽  
Sting Pathway ◽  
Mitochondrial Membrane Permeabilization

In the last decade, pieces of evidence for TDP-43-mediated mitochondrial dysfunction in neurodegenerative diseases have accumulated. In patient samples, in vitro and in vivo models have shown mitochondrial accumulation of TDP-43, concomitantly with hallmarks of mitochondrial destabilization, such as increased production of reactive oxygen species (ROS), reduced level of oxidative phosphorylation (OXPHOS), and mitochondrial membrane permeabilization. Incidences of TDP-43-dependent cell death, which depends on mitochondrial DNA (mtDNA) content, is increased upon ageing. However, the molecular pathways behind mitochondrion-dependent cell death in TDP-43 proteinopathies remained unclear. In this review, we discuss the role of TDP-43 in mitochondria, as well as in mitochondrion-dependent cell death. This review includes the recent discovery of the TDP-43-dependent activation of the innate immunity cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway. Unravelling cell death mechanisms upon TDP-43 accumulation in mitochondria may open up new opportunities in TDP-43 proteinopathy research.

scholarly journals Plant Extracts and Reactive Oxygen Species as Two Counteracting Agents with Anti- and Pro-Obesity Properties

2019 ◽  
Vol 20 (18) ◽  
pp. 4556 ◽  
Author(s):  
Hanna Zielinska-Blizniewska ◽  
Przemyslaw Sitarek ◽  
Anna Merecz-Sadowska ◽  
Katarzyna Malinowska ◽  
Karolina Zajdel ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Plant Extracts ◽  
Complex Disease ◽  
Reactive Oxygen ◽  
Complementary Therapy ◽  
Biologically Active ◽  
Mitochondrial Activity ◽  
Oxygen Species

Obesity is a complex disease of great public health significance worldwide: It entails several complications including diabetes mellitus type 2, cardiovascular dysfunction and hypertension, and its prevalence is increasing around the world. The pathogenesis of obesity is closely related to reactive oxygen species. The role of reactive oxygen species as regulatory factors in mitochondrial activity in obese subjects, molecules taking part in inflammation processes linked to excessive size and number of adipocytes, and as agents governing the energy balance in hypothalamus neurons has been examined. Phytotherapy is the traditional form of treating health problems using plant-derived medications. Some plant extracts are known to act as anti-obesity agents and have been screened in in vitro models based on the inhibition of lipid accumulation in 3T3-L1 cells and activity of pancreatic lipase methods and in in vivo high-fat diet-induced obesity rat/mouse models and human models. Plant products may be a good natural alternative for weight management and a source of numerous biologically-active chemicals, including antioxidant polyphenols that can counteract the oxidative stress associated with obesity. This review presents polyphenols as natural complementary therapy, and a good nutritional strategy, for treating obesity without serious side effects.

scholarly journals Effects of Ubiquinol-10 on MicroRNA-146a Expression In Vitro and In Vivo

2009 ◽  
Vol 2009 ◽  
pp. 1-7 ◽  
Author(s):  
Constance Schmelzer ◽  
Mitsuaki Kitano ◽  
Gerald Rimbach ◽  
Petra Niklowitz ◽  
Thomas Menke ◽  
...  
Keyword(s):  
Gene Expression ◽  
Reactive Oxygen Species ◽  
Biological Processes ◽  
Oxygen Species ◽  
Moderate Reduction ◽  
Suppression Of Gene Expression ◽  
Fine Tune ◽  
Dependent Pathway

MicroRNAs (miRs) are involved in key biological processes via suppression of gene expression at posttranscriptional levels. According to their superior functions, subtle modulation of miR expression by certain compounds or nutrients is desirable under particular conditions. Bacterial lipopolysaccharide (LPS) induces a reactive oxygen species-/NF-κB-dependent pathway which increases the expression of the anti-inflammatory miR-146a. We hypothesized that this induction could be modulated by the antioxidant ubiquinol-10. Preincubation of human monocytic THP-1 cells with ubiquinol-10 reduced the LPS-induced expression level of miR-146a to 78.9±13.22%. In liver samples of mice injected with LPS, supplementation with ubiquinol-10 leads to a reduction of LPS-induced miR-146a expression to 78.12±21.25%. From these consistent in vitro and in vivo data, we conclude that ubiquinol-10 may fine-tune the inflammatory response via moderate reduction of miR-146a expression.

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