LACK of IRON Binding by Pixantrone IS ASSOCIATED with Reduced PRODUCTION of Reactive Oxygen SPECIES and Myoctye Cytotoxicity IN VITRO.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4806-4806 ◽  
Author(s):  
Miles Hacker ◽  
Marc McKennon ◽  
Jack W. Singer
Keyword(s):  
Reactive Oxygen Species ◽  
Animal Models ◽  
Secondary Alcohol ◽  
Reactive Oxygen ◽  
New Drugs ◽  
Visible Range ◽  
Oxygen Species ◽  
Aliphatic Ketone ◽  
Structural Element

Abstract Abstract 4806 Introduction Pixantrone (PIX), an aza-anthracenedione, which has successfully completed a phase 3 trial (J Clin Oncol 2009; 27:15s, No. 8523) was designed to enhance clinical efficacy while significantly decreasing cardiotoxicity compared to doxorubicin (DOX) and mitoxantrone (MIT). Multidose administration, in animal models of equitoxic doses of PIX, MIT, and DOX, with or without prior therapy with DOX, resulted in minimal evidence for PIX cardiotoxicity compared with the severe histologic lesions seen with these other agents (Cavaletti et al: Investigational New Drugs 2007; 3:187-95). Both DOX and MIT contain a dihydroquinone structural element known to interact with iron. Additionally, DOX contains an aliphatic ketone which, once metabolized to the corresponding secondary alcohol metabolite doxorubicinol, is implicated in release of free iron and the chronic cardiotoxicity observed with DOX. In contrast, PIX has a nitrogen containing heterocycle which replaces the dihydroquinone, forming an aza-anthracenedione structure. PIX also does not contain an aliphatic ketone and cannot form metabolites analogous to doxorubicinol. Methods To validate the proposed mechanisms underlying the observed differences in cardiotoxicity, we used established spectrophotometric techniques to quantify iron:drug interactions that are thought to be mechanistic for chronic doxorubicin cardiotoxicity (Menna et al: Cardiovasc Toxicol 2007; 7:80–85). Results Adding increasing amounts of iron to drug solution, we observed that DOX and MIT underwent changes in visible range absorbance patterns, characteristic of drug:iron complex formation, confirming the expected 1:3 Fe(II)-drug ratio for both DOX and MIT. In contrast, no spectrophotometric changes were observed with iron added to PIX, clearly demonstrating that PIX does not bind iron. In vitro studies using H2C9 rat myocardial cells indicate that PIX (ID50 >50 μg/ml) is far less toxic than DOX (ID50= 1 μ/ml). Moreover, PIX does not induce significant reactive oxygen species (ROS) production in the H2C9 cells compared to DOX. Conclusion These results demonstrate that PIX does not bind iron and that its inability to bind iron and its reduced propensity to generate ROS may be the mechanism for reduced PIX cardiotoxicity in animal models compared to DOX or MIT. Disclosures: McKennon: Cell Therapeutics, Inc: Employment. Singer:Cell Therapeutics, Inc: Employment.

scholarly journals The toxic effect of Vu-Defr, a defensin from Vigna unguiculata seeds, on Leishmania amazonensis is associated with reactive oxygen species production, mitochondrial dysfunction, and plasma membrane perturbation

2018 ◽  
Vol 64 (7) ◽  
pp. 455-464 ◽  
Author(s):  
Géssika Silva Souza ◽  
Lais Pessanha de Carvalho ◽  
Edésio José Tenório de Melo ◽  
Valdirene Moreira Gomes ◽  
André de Oliveira Carvalho
Keyword(s):  
Reactive Oxygen Species ◽  
Mitochondrial Membrane ◽  
Biological Activities ◽  
Reactive Oxygen ◽  
Leishmania Amazonensis ◽  
New Drugs ◽  
Oxygen Species ◽  
Membrane Perturbation ◽  
Plant Defensins

Plant defensins are plant antimicrobial peptides that present diverse biological activities in vitro, including the elimination of Leishmania amazonensis. Plant defensins are considered promising candidates for the development of new drugs. This protozoan genus has great epidemiological importance and the mechanism behind the protozoan death by defensins is unknown, thus, we chose L. amazonensis for this study. The aim of the work was to analyze the possible toxic mechanisms of Vu-Defr against L. amazonensis. For analyses, the antimicrobial assay was repeated as previously described, and after 24 h, an aliquot of the culture was tested for viability, membrane perturbation, mitochondrial membrane potential, reactive oxygen species (ROS) and nitric oxide (NO) inductions. The results of these analyses indicated that after interaction with L. amazonensis, the Vu-Defr causes elimination of promastigotes from culture, membrane perturbation, mitochondrial membrane collapse, and ROS induction. Our analysis demonstrated that NO is not produced after Vu-Defr and L. amazonensis interaction. In conclusion, our work strives to help to fill the gap relating to effects caused by plant defensins on protozoan and thus better understand the mechanism of action of this peptide against L. amazonensis.

scholarly journals 2337

2017 ◽  
Vol 1 (S1) ◽  
pp. 7-7
Author(s):  
Trevi A. Mancilla ◽  
Gregory J. Aune
Keyword(s):  
Reactive Oxygen Species ◽  
Animal Models ◽  
Cardiac Fibroblasts ◽  
Reactive Oxygen Species Generation ◽  
Reactive Oxygen ◽  
Alternative Therapies ◽  
Cardiac Cells ◽  
Oxygen Species ◽  
Doxorubicin Cardiotoxicity

OBJECTIVES/SPECIFIC AIMS: Our research strives to understand the pathophysiology of doxorubicin cardiotoxicity, focusing on the understudied nonmyocyte cardiac cells. Our understanding will enable researchers to develop protective or alternative therapies for cancer patients and treatments for cancer survivors. METHODS/STUDY POPULATION: Early studies have been carried out in isolated primary cardiac fibroblasts. Cells were treated with varying doses of doxorubicin. Cell viability, proliferation, and reactive oxygen species generation have all been studied. Future studies will focus on mitochondrial assessment in treated cells and confirmation of findings in animal models. Potential therapies discovered in these studies will also be conducted in animal models. RESULTS/ANTICIPATED RESULTS: Our results show a direct effect of doxorubicin on cardiac fibroblasts in vitro. Treated cells show a decreased rate of proliferation and increased production of reactive oxygen species. Similarly to cardiomyocytes, we hypothesize that reactive oxygen species damage the mitochondria of cardiac fibroblasts thereby altering their function and playing a role in doxorubicin cardiotoxicity. DISCUSSION/SIGNIFICANCE OF IMPACT: Current therapies have not been able to adequately protect patients from the cardiotoxicity of doxorubicin and other anthracyclines. A complete understanding of how doxorubicin damages cardiac tissue will only be possible by studying all cell types of the heart. With a better understanding, alternative therapies can be developed to prevent or treat doxorubicin cardiotoxicity without sacrificing the efficacy of doxorubicin in treating cancer.

scholarly journals The Effects of Bioactive Compounds from Blueberry and Blackcurrant Powder on Oat Bran Pastes: Enhancing In Vitro Antioxidant Activity and Reducing Reactive Oxygen Species in Lipopolysaccharide-Stimulated Raw264.7 Macrophages

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 388
Author(s):  
Xiao Dan Hui ◽  
Gang Wu ◽  
Duo Han ◽  
Xi Gong ◽  
Xi Yang Wu ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Antioxidant Activity ◽  
Phenolic Compounds ◽  
Antioxidant Capacity ◽  
Bioactive Compounds ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Raw264.7 Macrophages ◽  
Oat Bran

In this study, blueberry and blackcurrant powder were chosen as the phenolic-rich enrichments for oat bran. A Rapid Visco Analyser was used to form blueberry and blackcurrant enriched oat pastes. An in vitro digestion process evaluated the changes of phenolic compounds and the in vitro antioxidant potential of extracts of pastes. The anthocyanidin profiles in the extracts were characterised by the pH differential method. The results showed that blueberry and blackcurrant powder significantly increased the content of phenolic compounds and the in vitro antioxidant capacity of pastes, while the total flavonoid content decreased after digestion compared to the undigested samples. Strong correlations between these bioactive compounds and antioxidant values were observed. Lipopolysaccharide-stimulated RAW264.7 macrophages were used to investigate the intracellular antioxidant activity of the extracts from the digested oat bran paste with 25% enrichment of blueberry or blackcurrant powder. The results indicated that the extracts of digested pastes prevented the macrophages from experiencing lipopolysaccharide (LPS)-stimulated intracellular reactive oxygen species accumulation, mainly by the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) signalling pathway. These findings suggest that the bioactive ingredients from blueberry and blackcurrant powder enhanced the in vitro and intracellular antioxidant capacity of oat bran pastes, and these enriched pastes have the potential to be utilised in the development of the functional foods.

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 The Effect of the Clenbuterol—β2-Adrenergic Receptor Agonist on the Peripheral Blood Mononuclear Cells Proliferation, Phenotype, Functions, and Reactive Oxygen Species Production in Race Horses In Vitro

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 936
Author(s):  
Olga Witkowska-Piłaszewicz ◽  
Rafał Pingwara ◽  
Jarosław Szczepaniak ◽  
Anna Winnicka
Keyword(s):  
Reactive Oxygen Species ◽  
Acute Exercise ◽  
Mononuclear Cells ◽  
Anabolic Steroids ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Peripheral Blood Mononuclear ◽  
Adrenoceptor Agonist ◽  
Race Horses

Clenbuterol, the β2-adrenoceptor agonist, is gaining growing popularity because of its effects on weight loss (i.e., chemical liposuction). It is also popular in bodybuilding and professional sports, due to its effects that are similar to anabolic steroids. However, it is prohibited by anti-doping control. On the other hand, it is suggested that clenbuterol can inhibit the inflammatory process. The cells from 14 untrained and 14 well-trained race horses were collected after acute exercise and cultured with clenbuterol. The expressions of CD4, CD8, FoxP3, CD14, MHCII, and CD5 in PBMC, and reactive oxygen species (ROS) production, as well as cell proliferation, were evaluated by flow cytometry. In addition, IL-1β, IL-4, IL-6, IL-10, IL-17, INF-γ and TNF-α concentrations were evaluated by ELISA. β2-adrenoceptor stimulation leads to enhanced anti-inflammatory properties in well-trained horses, as do low doses in untrained animals. In contrast, higher clenbuterol doses create a pro-inflammatory environment in inexperienced horses. In conclusion, β2-adrenoceptor stimulation leads to a biphasic response. In addition, the immune cells are more sensitive to drug abuse in inexperienced individuals under physical training.

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.

Reactive Oxygen Species-Mediated Apoptosis and Cytotoxicity of Newly Synthesized Pyridazin-3-Ones In P815 (Murin Mastocytoma) Cell Line

Drug Research ◽  
2019 ◽  
Vol 69 (10) ◽  
pp. 528-536
Author(s):  
Najat Bouchmaa ◽  
Reda Ben Mrid ◽  
Youness Boukharsa ◽  
Youssef Bouargalne ◽  
Mohamed Nhiri ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Anticancer Activity ◽  
Cell Line ◽  
Cytotoxic Effect ◽  
Redox Homeostasis ◽  
Reactive Oxygen ◽  
Cytotoxic Activities ◽  
Oxygen Species ◽  
P815 Cell

Abstract Background In cancer cells, the intracellular antioxidant capacity and the redox homeostasis are mainly maintained by the glutathione- and thioredoxin-dependent systems which are considered as promising targets for anticancer drugs. Pyridazinones constitute an interesting source of heterocyclic compounds for drug discovery. The present investigation focused on studying the in-vitro antitumor activity of newly synthesized Pyridazin-3(2h)-ones derivatives against P815 (Murin mastocytoma) cell line. Methods The in-vitro cytotoxic activities were investigated toward the P815 cell line using tetrazolium-based MTT assay. Lipid peroxidation and the specific activities of antioxidant enzymes were also determined. Results The newly compounds had a selective dose-dependent cytotoxic effect without affecting normal cells (PBMCs). Apoptosis was further confirmed through the characteristic apoptotic morphological changes and DNA fragmentation. Two compounds (6f and 7h) were highly cytotoxic and were submitted to extend biological testing to determine the likely mechanisms of their cytotoxicity. Results showed that these molecules may induce cytotoxicity via disturbing the redox homeostasis. Importantly, the anticancer activity of 6f and 7h could be due to the intracellular reactive oxygen species hypergeneration through significant loss of glutathione reductase and thioredoxin reductase activities. This eventually leads to oxidative stress-mediated P815 cell apoptosis. Furthermore, the co-administration of 6f or 7h with Methotrexate exhibited a synergistic cytotoxic effect. Conclusions considering their significant anticancer activity and chemosensitivity, 6f and 7h may improve the therapeutic efficacy of the current treatment for cancer.

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