Peroxynitrite-induced membrane lipid peroxidation: The cytotoxic potential of superoxide and nitric oxide
Abstract
Endothelial cells, macrophages, neutrophils, and neuronal cells generate superoxide (O2−) and nitric oxide (·NO) which can combine to form peroxynitrite anion (ONOO−). Peroxynitrite, known to oxidize sulfhydryls and to yield products indicative of hydroxyl radical (·OH) reaction with deoxyribose and dimethyl sulfoxide, is shown herein to induce membrane lipid peroxidation. Peroxynitrite addition to soybean phosphatidylcholine liposomes resulted in malondialdehyde and conjugated diene formation, as well as oxygen consumption. Lipid peroxidation was greater at acidic and neutral pH, with no significant lipid peroxidation occurring above pH 9.5. Addition of ferrous (Fe+2) or ferric (Fe+3) iron did not enhance lipid peroxide formation over that attributable to peroxynitrite alone. Diethylenetetraminepentacetic acid (DTPA) or iron removal from solutions by ion-exchange chromatography decreased conjugated diene formation by 25–50%. Iron did not play an essential role in initiating lipid peroxidation, since DTPA and iron depletion of reaction systems were only partially inhibitory. In contrast, desferrioxamine had an even greater concentration-dependent inhibitory effect, completely abolishing lipid peroxidation at 200 μm. The strong inhibitory effect of desferrioxamine on lipid peroxidation was due to direct reaction with peroxynitrous acid in addition to iron chelation. We conclude that the conjugate acid of peroxynitrite, peroxynitrous acid (ONOOH), and/or its decomposition products, i.e., ·OH and nitrogen dioxide (·NO2), initiate lipid peroxidation without the requirement of iron. These observations demonstrate a potential mechanism contributing to O2−- and ·NO-mediated cytotoxicity.
References (35)
- R. Radi et al.
J. Biol. Chem
(1991) - I. Fridovich
Arch. Biochem. Biophys
(1986) - P.R. Gardner et al.
J. Biol. Chem
(1991) - J.P. Barton et al.
Int. J. Radiat. Phys. Chem
(1970) - M.A. Marletta
TIBS
(1989) - A.C.F. Gorren et al.
Biochim. Biophys. Acta
(1987) - J.A. Buege et al.
- A.W. Girotti
J. Free Radicals Biol. Med
(1985) - B.H.J. Bielski et al.
J. Biol. Chem
(1983) - M. Tien et al.
Arch. Biochem. Biophys
(1982)
Fundam. Appl. Toxicol
J. Biol. Chem
Arch. Biochem. Biophys
Hypertension
Environ. Health Perspect
Free Radicals Res. Commun
Cited by (2099)
Silver nitroprusside as an efficient chemodynamic therapeutic agent and a peroxynitrite nanogenerator for targeted cancer therapies
2024, Journal of Advanced ResearchChemodynamic therapy (CDT) holds great promise in achieving cancer therapy through Fenton and Fenton-like reactions, which generate highly toxic reactive species. However, CDT is limited by the lower amount of catalyst ions that can decompose already existing intracellular H2O2 and produce reactive oxygen species (ROS) to attain a therapeutic outcome.
To overcome these limitations, a tailored approach, which utilizes dual metals cations (Ag+, Fe2+) based silver pentacyanonitrosylferrate or silver nitroprusside (AgNP) were developed for Fenton like reactions that can specifically kill cancer cells by taking advantage of tumor acidic environment without used of any external stimuli.
A simple solution mixing procedure was used to synthesize AgNP as CDT agent. AgNP were structurally and morphologically characterized, and it was observed that a minimal dose of AgNP is required to destroy cancer cells with limited effects on normal cells. Moreover, comprehensive in vitro studies were conducted to evaluate antitumoral mechanism.
AgNP have an effective ability to decompose endogenous H2O2 in cells. The decomposed endogenous H2O2 generates several different types of reactive species (•OH, O2•−) including peroxynitrite (ONOO−) species as apoptotic inducers that kill cancer cells, specifically. Cellular internalization data demonstrated that in short time, AgNP enters in lysosomes, avoid degradation and due to the acidic pH of lysosomes significantly generate high ROS levels. These data are further confirmed by the activation of different oxidative genes. Additionally, we demonstrated the biocompatibility of AgNP on mouse liver and ovarian organoids as an ex vivo model while AgNP showed the therapeutic efficacy on patient derived tumor organoids (PDTO).
This work demonstrates the therapeutic application of silver nitroprusside as a multiple ROS generator utilizing Fenton like reaction. Thereby, our study exhibits a potential application of CDT against HGSOC (High Grade Serous Ovarian Cancer), a deadly cancer through altering the redox homeostasis.
Vascular pathophysiology of sickle cell disease
2023, Presse MedicaleSickle cell disease (SCD) is an hereditary disorder characterized by the production of an abnormal hemoglobin called hemoglobin S (HbS). HbS may polymerize in deoxygenated conditions, which leads to red blood cell (RBC) sickling. Sickled RBCs are more rigid and fragile, and prone to lysis. SCD patients exhibit various acute and/or chronic complications, which may affect several organs. The clinical presentation of SCD is highly variable from one patient to another and cannot be only explained by RBC sickling. Increased blood viscosity, caused by the presence of RBCs with abnormal deformability and aggregation, may increase vascular resistance and increase the risk of acute and chronic vascular complications. Chronic hemolysis results in decreased nitric oxide (NO) bioavailability which may compromise vasodilation and participate to the development of chronic vasculopathy. Furthermore, chronic hemolysis is responsible for increased inflammation and oxidative stress, which affect the vascular system and may promote the adhesion of circulating cells to endothelial cells. Extracellular vesicles and especially RBC microparticles (massively released in the context of SCD) are also at the origin of vascular damages and increased white blood cells adhesion to the endothelium, which may trigger vaso-occlusive crisis and other vascular-related complications. This review highlights the fact that SCD should not only be considered as a hematological disorder but also as a vascular disease.
A nanocomposite competent to overcome cascade drug resistance in ovarian cancer via mitochondria dysfunction and NO gas synergistic therapy
2023, Asian Journal of Pharmaceutical SciencesOvarian cancer (OC) is one of the most common and recurring malignancies in gynecology. Patients with relapsed OC always develop "cascade drug resistance" (CDR) under repeated chemotherapy, leading to subsequent failure of chemotherapy. To overcome this challenge, amphiphiles (P1) carrying a nitric oxide (NO) donor (Isosorbide 5-mononitrate, ISMN) and high-density disulfide are synthesized for encapsulating mitochondria-targeted tetravalent platinum prodrug (TPt) to construct a nanocomposite (INP@TPt). Mechanism studies indicated that INP@TPt significantly inhibited drug-resistant cells by increasing cellular uptake and mitochondrial accumulation of platinum, depleting glutathione, and preventing apoptosis escape through generating highly toxic peroxynitrite anion (ONOO−). To better replicate the microenvironmental and histological characteristics of the drug resistant primary tumor, an OC patient-derived tumor xenograft (PDXOC) model in BALB/c nude mice was established. INP@TPt showed the best therapeutic effects in the PDXOC model. The corresponding tumor tissues contained high ONOO− levels, which were attributed to the simultaneous release of O2•− and NO in tumor tissues. Taken together, INP@TPt-based systematic strategy showed considerable potential and satisfactory biocompatibility in overcoming platinum CDR, providing practical applications for ovarian therapy.
In situ investigation of the oxidation of a phospholipid monolayer by reactive oxygen species
2023, Biophysical JournalThe oxidation of membrane lipids has been widely studied for several decades owing to its significance in biological systems. However, despite its damaging physiological impact and its known role in many diseases, relatively little is understood about the specific structural consequences of oxidative action, particularly in vivo. In this work, a combination of sum-frequency generation spectroscopy, surface tensiometry, and surface-selective infrared spectroscopies are used to gain deeper insight into the oxidation of phospholipids by reactive oxygen species generated in situ. Oxidation is achieved by employing the Fenton reaction to convert physiological levels of H2O2 into OH and HO2 radicals in proximity to the headgroups of lipid monolayers at the air-water interface. By temporally monitoring the surface tension and spectroscopic changes at the interface as the oxidation proceeds, the impact of oxidation on the structure, conformation, and intermolecular interactions within the membrane has been revealed.
Evaluation of oxidative stress markers in subtypes of preeclampsia: A systematic review and meta-analysis
2023, PlacentaStudies about oxidative stress biomarkers revealed different phenotypes between early and late preeclampsia (PE). Despite that, there is extensive evidence of oxidative stress in investigations that combinate forms different of preeclampsia. This study reviews the oxidative stress profile in the PE subtypes and evaluates which markers are altered in the blood and placental tissue. A search was conducted in databases such as MEDLINE, EMBASE, LILACS, and Web of Science without restricting the year and language of publication. The quality of the studies was evaluated by the Newcastle-Ottawa scale and Joanna Briggs Institute for analytical Cross-Sectional Studies. After 13,319 screened records, 65 were included in the systematic review. The markers of stress oxidative of damage and reactive species were those selected, such as malondialdehyde (MDA), lipid peroxide, advanced protein oxidation products, carbonyl protein, 8-hydroxy-2′-deoxyguanosine, total oxidant status, hydrogen peroxide, nitric oxide (NO). We described the antioxidant activity, including the superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase, free glutathione, and total antioxidant capacity (TAC). We results demonstrated that oxidative stress is related to pathophysiology of PE, there were increased lipid peroxidation in the blood and placenta, and in blood a reduction of NO levels and of TAC, like lower enzymatic activity of GPx, CAT in PE, and SOD in mild PE. In addition, altered levels of MDA in the placenta and blood show that placental changes have repercussions on the clinical syndrome and are related to the severity of the disease.
Nitric oxide strengthens defense system in plants
2023, Nitric Oxide in Developing Plant Stress ResilienceThe world is facing huge misfortune in the production of crops due to a stressful environment that is also not sufficient to fulfill the needs of the growing population. To overcome such problems, plants employ the use of a gaseous, bioactive molecule named nitric oxide (NO). NO is considered a small, reactive, lipid-soluble, and highly diffusive secondary messenger that is involved in various intracellular and physiological processes and brings about overall growth in plants. NO has the ability to freely roam inside the cell and interact with various biological entities and signaling molecules because of its high reactivity and short lifecycle. The two key methods for protection in plants shown by NO are either it can act as antioxidants or it signals different biomolecules that regulate several cascades of events to strengthen the defense system in combating various stresses. NO-related events help one to understand how plants adapt, function, and respond to stressful conditions. This chapter emphasizes the current knowledge about NO being a crucial multifunctional molecule that has a tendency to alter several metabolic and molecular processes in plants. The goal is to provide a comprehensive overview of its potential to work under abiotic stresses in plants that would help confer strategies in the development of climate-resilient crops of better quality and yield.
- 1
Permanent address: Department of Biochemistry, Faculty of Medicine, University of the Republic, Montevideo, Uruguay CP 11800.