ROS

Reactive Oxygen Species

The reactive oxygen species are the contributors of oxidative stress which lead to various diseases and disorders such as cardiovascular disease, cancer, aging, and various neurodegenerative diseases [14].

From: Toxicological Survey of African Medicinal Plants, 2014

Related terms:

Nitric Oxide

Enzymes

Apoptosis

Antioxidants

Mitochondrion

Oxidative Stress

Protein

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DNA

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Conceptual Background and Bioenergetic/Mitochondrial Aspects of Oncometabolism

Jing Chen, Clayton E. Mathews, in Methods in Enzymology, 2014

4 Concluding Remarks

ROS play essential roles for cell physiology and participate in many pathological processes. Mitochondria are an important source of cell ROS production. Here, we introduce techniques to detect mitochondrial-specific ROS production in several cell types using flow cytometry and spectrofluorometer plate reader. By selecting different ROS-detecting probes, it is possible to detect either total cellular ROS or mitochondrial-specific ROS. These techniques allow investigators to monitor basal ROS levels as well as dynamic ROS production in hours (using spectrofluorometer plate reader) or in days (using a flow cytometer). In addition to the detection of dynamic ROS production during long-term treatment, these flow cytometry methods also allow for the measurement of ROS in most specific types as well as in cells during different conditions or heterogeneous cell populations by costaining with cell surface markers.

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Cerebral Vascular Muscle

T.M. De Silva, F.M. Faraci, in Primer on Cerebrovascular Diseases (Second Edition), 2017

Reactive Oxygen Species

ROS have emerged as important regulators of vascular tone in the cerebral circulation [4]. While ROS can constrict cerebral arteries under some conditions, the majority of evidence suggests that physiological levels of ROS are vasodilators. However, during disease, ROS can have deleterious effects, especially on the bioavailability of NO (see earlier). Major sources of ROS include NADPH oxidases, cyclooxygenases, and mitochondria.

Both endogenous and exogenous ROS, via direct application or local generation using ROS-generating systems, have been shown to dilate large and small cerebral arteries. Endogenous ROS may be generated by application of enzyme substrates such as NADH/NADPH (NADPH oxidase) or arachidonic acid (cyclooxygenase). Dilation in response to ROS is generally mediated via activation of K+ channels, either KATP or BK channels.

Although less common, constriction of cerebral arteries to ROS has been described and may involve activation of PKC and stimulation of calcium entry into vascular muscle via L-type calcium channels.

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Molecular Pathways, Green Tea Extract, (−)-Epigallocatechin Gallate, and Ocular Tissue

Yao Jin, ... Ji Yong, in Handbook of Nutrition, Diet, and the Eye (Second Edition)�, 2019

Inhibition of Reactive Oxygen Species

Reactive oxygen species (ROS) include superoxide and hydroxyl radicals, nitric oxide, singlet oxygen, nitrogen dioxide, and peroxynitrite. Many reports have shown that EGCG inhibits the formation of or damage caused by ROS. For example, EGCG can block the reduced nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome P450 production of ROS.7 Besides, EGCG can effect AT1-ROS-ERK1/2 signal pathway to inhibit Ang II-induced C-reactive protein production in hepatocytes, which provides the new evidence and mechanism of EGCG by inhibition of ROS for the antiinflammatory action.8

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Endosome Signaling Part B

A. Paige Davis Volk, Jessica G. Moreland, in Methods in Enzymology, 2014

1 Introduction

ROS generated by the NOX in phagocytes are critical for innate immune defense against certain microbial pathogens. ROS for bacterial killing are generated into phagosomes, but there is accumulating evidence for ROS generation into endosomal compartments in both phagocytic and nonphagocytic cells. These ROS are generated in response to a wide variety of stimuli and function as intracellular signaling molecules. Regulation of phosphatase activity by oxidation of cysteines is the best-described ROS-based signaling modification (Janssen-Heininger et al., 2008), although a number of other mechanisms have been elucidated. In addition, ROS are implicated as metabolites initiating host cell damage under conditions leading to oxidative stress. Scientific investigation of the biological importance of these ROS signals requires sensitive and specific tools to allow spatial and quantitative analysis. However, by definition, these reactive species present a number of challenges to those who are investigating their effects. ROS have relatively short lifetimes and a number of antioxidants exist in vivo that may impair detection and measurement. These two facts suggest that signaling ROS are not likely to migrate a great distance from where they are generated. The spatial and temporal specificity of ROS generation is likely to provide highly relevant information about what are the physiological roles for those ROS.

As we select the best tools or probes to utilize in our investigations of endosomal ROS, there are several critical questions to be answered. What oxidant molecule(s) do we seek to measure? How stable is that molecule? For this chapter, we focus on ROS generated into endosomal or intracellular membrane-bound compartments; thus, the distribution of the probe is critical to what will be measured. Equally important questions include the following: What catalysts or cofactors are needed for the probe to detect the ROS under study? Which cellular antioxidants (enzymatic or nonenzymatic) will be in competition with the probe for reactivity with the ROS? What is the stability of the reaction product and can intermediates formed by the probe generate ROS themselves? Importantly, the available technology for the design and generation of probes for various ROS is advancing rapidly. Thus, the potential to analyze specific ROS in living cell systems continues to improve.

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Role of Autophagy in Cancer Development via Mitochondrial Reactive Oxygen Species

Bo Liu, Gu He, in Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging, 2016

ROS-Regulated Other Autophagic Signaling Pathways

ROS can regulate autophagy through transcription factor activity such as NF-κB leading to the induction of autophagy gene expression (Beclin-1 or p62) in cancer cells. In addition, mitogen-activated protein kinases (MAPKs) are downstream effectors of ROS in autophagy induction, as a novel compound was recently found to induce autophagic cell death by stimulating ROS production and activation of ERK and JNK. ROS-induced ATG gene upregulation in skeletal cells requires p38 activation, p38 and p53 also regulate ROS production in turn as positive-feedback responses. One p53-target gene encodes TP53-induced glycolysis and apoptosis regulator (TIGAR), whose inhibition can increase ROS production and enhance ROS-dependent autophagy (Hoshino et al., 2012). The pro-autophagic Ca2+ channel IP(3)R can be affected by ROS to increase the intracellular Ca2+ level, which has been reported to induce autophagy (Raina et al., 2013) (Figure 12.2).

Figure 12.2. ROS-regulated autophagic pathways.

Autophagy can be divided into five steps: induction, nucleation, elongation, docking and fusion, degradation and recycling. ROS may regulate these five steps through activating or inhibiting various signaling pathways and manipulate autophagy as a survival or programmed cell death role.

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Redox and Cancer Part A

Daohong Zhou, ... Douglas R. Spitz, in Advances in Cancer Research, 2014

Abstract

Reactive oxygen species (ROS) play an important role in determining the fate of normal stem cells. Low levels of ROS are required for stem cells to maintain quiescence and self-renewal. Increases in ROS production cause stem cell proliferation/differentiation, senescence, and apoptosis in a dose-dependent manner, leading to their exhaustion. Therefore, the production of ROS in stem cells is tightly regulated to ensure that they have the ability to maintain tissue homeostasis and repair damaged tissues for the life span of an organism. In this chapter, we discuss how the production of ROS in normal stem cells is regulated by various intrinsic and extrinsic factors and how the fate of these cells is altered by the dysregulation of ROS production under various pathological conditions. In addition, the implications of the aberrant production of ROS by tumor stem cells for tumor progression and treatment are also discussed.

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Molecular Mechanisms Underlying the Activation of Autophagy Pathways by Reactive Oxygen Species and their Relevance in Cancer Progression and Therapy

Noemí Rubio Romero, Patrizia Agostinis, in Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging, 2014

Reactive oxygen species (ROS) have emerged as signaling molecules in pathways regulating cell growth and differentiation, inflammation, immune responses, survival, and death. ROS have been shown to promote autophagy, a lysosomal pathway for degradation of dysfunctional unnecessary cellular components. In fact, recent works have revealed a complex cross-talk between these intertwined signals. Whereas ROS can modulate autophagy activation in response to different types of stimuli, autophagy, in turn, may modulate ROS production by degrading, for example, dysfunctional mitochondria that generate aberrant amounts of ROS. Autophagy pathways can act both as tumor-promoter and tumor-suppressor mechanisms, with involvement of ROS in both cases. Paradoxically, whereas ROS and autophagy regulation may contribute to cancer initiation and progression, many antineoplastic treatments are precisely based on the massive production of ROS and activation of autophagy to induce cell death and eradication of diseased tissue. Nevertheless, autophagy activation has also shown a cytoprotective role against the efficiency of the therapy, and the mechanism that controls the switch between these two cellular functions in still unknown. In this chapter we will review the molecular mechanisms by which ROS modulate autophagy, and those modulated by autophagy to control ROS production, in the context both of cancer development and of cancer treatment.

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Cardiac Metabolism in Health and Disease

Lionel H. Opie, in Cellular and Molecular Pathobiology of Cardiovascular Disease, 2014

Reactive Oxygen Species

Reactive oxygen species (ROS, also called oxygen free radicals) are a side-product of sites on mitochondrial complexes I and III of the electron transmitter chain (see later in text). In excess, ROS contribute to membrane damage by lipid peroxide formation and are part of the signaling sequence leading to apoptosis. Excess ROS are also derived from many complex sources besides damaged myocyte mitochondria, such as from uncoupled nitric oxide synthase in heart and endothelial cells, from xanthine oxidase and stimulation of membrane NADPH oxidase (by angiotensin II, endothelin, cytokines) and from neutrophils.24 Excess ROS are formed particularly during the reperfusion phase of ischemic damage.25

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Fermented Rice Bran Attenuates Oxidative Stress

Dongyeop Kim, Gi Dong Han, in Wheat and Rice in Disease Prevention and Health, 2014

Inhibitory Effects of Fermented Rice Bran Extract and Ferulic Acid on ROS Generation

ROS generation was evaluated in 3T3-L1 adipocytes following induction of oxidative stress by hydrogen peroxide (100 µM) for 12 hours. Treatment with FRB extract or ferulic acid significantly reduced ROS generation to 92.97–94.54% and 103.79–104.69%, respectively. However, there was no significant difference in ROS reduction between ferulic acid and FRB extract at all concentrations (Fig. 36.1).

FIGURE 36.1. Inhibitory effects of ferulic acid and fermented rice bran extract on ROS generation in 3T3-L1 adipocytes treated with hydrogen peroxide. Measurement of cellular redox status with rates of dichlorofluorescein (DCF) oxidation.

Two different concentrations of fermented rice bran extract (FRB) and ferulic acid (FA) were applied: 1FRB (10 μg/mL), 5FRB (50 μg/mL), 1FA (10 μM), and 5FA (50 μM). The results as mean values are shown with SD (n = 3) (∗∗∗P < 0.001). ROS generation was assessed by DCFDA oxidation (carboxy-H2DCFDA). Cells were plated onto 24-well plates at an initial density of 1 × 104 cells per well, followed by induction of differentiation. Cells were washed three times with 0.5 mL of HBSS per well. Following the addition of 20 μM DCFDA (final concentration), DCF fluorescence was followed continuously for 1 hour using a thermostatic plate reading spectrofluorometer (TECAN, infinite M200, Austria) at excitation and emission wavelengths of 495 and 525 nm, respectively. The amounts of cell proteins in each well were measured by bicinchoninic acid reaction, and DCF fluorescence levels were corrected for variations in total protein content between wells.

NIDDM is associated with increased oxidative stress caused by accelerated production or reduced scavenging of ROS. Some studies have indicated that treatment with antioxidants such as cysteine or N-acetylcystein (NAC) protects β cells from ROS-mediated damage.84 Other studies have found evidence that diabetes is associated with an antioxidant/pro-oxidant imbalance. In addition to impaired antioxidant defense, increased production of ROS has also been proposed.131

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Hordeiviruses (Virgaviridae)☆

Zhihao Jiang, ... Dawei Li, in Reference Module in Life Sciences, 2020

ROS bursts

Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) or superoxide anions (O2-) are amongst the earliest cellular responses against pathogen infection. BSMV infection reduces both H2O2 and O2- elevation by ~10 fold in inoculated leaves compared with the empty vector. The γb protein has a major role in reduction of ROS bursts by interacting directly with glycolate oxidase (GOX), which is localized in peroxisomes and is a key constitutive enzyme in the photorespiration pathway. These results demonstrate that γb interacts with GOX to suppress peroxisomal ROS production and facilitate virus infection, and contributes to an understanding of roles played by ROS and plant ROS-producing enzymes during viral infection.Skip to Main content

Reactive Oxygen Species

Reactive oxygen species (ROS) are oxygen-containing radicals that are capable of independent existence with one or more unpaired electrons.

From: Plant Metal Interaction, 2016

Related terms:

Oxidative Stress

Antioxidant

Inorganic Peroxide

Nanoparticles

Cadmium

DNA

Enzyme

Toxicity

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Selenium

Neha Handa, ... Nitika Kapoor, in Plant Metal Interaction, 2016

4.9 Protection against Oxidative Stress

Reactive oxygen species (ROS) are oxygen-containing radicals that are capable of independent existence with one or more unpaired electrons. However, the term ROS is most often expanded to include reactive oxygen-containing compounds without unpaired electrons, such as hydrogen peroxide (H2O2) and singlet oxygen (1O2) (Halliwell and Cross, 1994; Halliwell and Gutteridge, 1984). The consumption and utilization of oxygen in various physiological processes results in the generation of ROS. These ROS are then neutralized by the plant systems and when generation of ROS exceeds the system's ability to neutralize and eliminate them, stress conditions appear and these are defined as oxidative stress conditions (Sies, 1985, 1986; Sies and Cadenas, 1985). This unevenness in production and scavenging of ROS may occur because of lack of antioxidant capacity, which is further because of the disturbance in production, distribution, or because of excess ROS. Excess of ROS can damage cellular lipids, proteins, or DNA, thus inhibiting signal transduction pathways and normal cellular functions. Se has been demonstrated in much research (a detailed discussion appears in the following section) to promote antioxidant capacity in plants subjected to various types of stresses (Hartikainen and Xue, 1999; Djanaguiraman et al., 2005; Peng et al., 2002).

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Environmental Geochemistry

G.S. Plumlee, T.L. Ziegler, in Treatise on Geochemistry, 2007

9.07.4.4 ROS Generated by Earth Materials—An Important Source of Toxicity

ROS are intermediate oxidation-state species formed by the incomplete reduction of molecular oxygen. Although the body utilizes ROS to its advantage in a variety of physiological processes (i.e., macrophages release ROS as a potent microbicide), there is widespread recognition in the literature that ROS can also serve as important triggers of toxicity and carcinogenesis (Kawanishi, 1995; Schoonen et al., 2006). For example, ROS are thought to trigger oxidative damage to DNA, proteins, and lipids.

Earth materials may generate ROS by a variety of mechanisms (Schoonen et al., 2006). Metals dissolved or desorbed from Earth materials into the body's fluids can participate in redox reactions that produce ROS. For example, although iron is tightly regulated by a variety of physiological processes, excess iron released from inhaled particulates is thought to participate in the generation of ROS (ultimately including highly reactive hydroxyl radicals) via a series of reactions (Schoonen et al., 2006; Aust et al., 2002):

Other transition metals can also participate in similar reactions.

Catalytic reactions of the body's fluids with particle surfaces can generate ROS, both through reactions with metals bound to the particle surfaces and through reactions with defects on the particle surfaces (including defects generated by grinding or crushing). The same series of reactions written previously for aqueous iron can also be written for iron and other metals structurally bound to particle surfaces. In fact, reaction rates involving structurally bound metals can be considerably faster than those involving dissolved metals, because coordination of the metals with anionic species on the particle surface shifts the metal redox couples to effectively lower Eh values, making them more effective electron donors (Schoonen et al., 2006). A variety of studies have demonstrated that oxidation of pyrite can be highly effective at production of hydrogen peroxide and ROS, and breakdown of RNA (Schoonen et al., 2006; Cohn et al., 2006; Borda et al., 2004). Grinding-induced surface structural defects, particularly on freshly ground mineral particles, can generate a variety of ROS; although crystalline silica is best known for this effect, a variety of other minerals have also been investigated, such as metal oxides, sulfides, asbestos, and zeolites (see references in Schoonen et al., 2006).

ROS can also be generated when the body's clearance mechanisms fail to clear inert particles from the lungs. AMs activated by foreign particles produce and release into the surrounding alveolar environment a variety of ROS and chemicals that recruit additional macrophages to the site. Macrophages that fail to clear particles also release a variety of cytotoxic chemicals into their surrounding environment. All these activities contribute to inflammation and can, in the case of biodurable or biopersistent particles, lead to long-term opportunities for DNA damage and resulting toxicity.

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Impact of Nanoparticles on Abiotic Stress Responses in Plants

Zesmin Khan, Hrishikesh Upadhyaya, in Nanomaterials in Plants, Algae and Microorganisms, 2019

15.3 Impact of Nanoparticles on ROS and Antioxidant System

ROS are very harmful for plant cells; examples of ROS include alkoxy radical (RO˙), singlet oxygen (1O2), hydroxyl radical (OH), superoxide radical (O2·−), and peroxy radical (ROO) (Dismukes et al., 2001; Karuppanapandian et al., 2006a,b,c; 2009, 2011; Karuppanapandian and Manoharan, 2008; Vellosillo et al., 2010). Cellular metabolism or respiration produces ROS, and in normal conditions various antioxidative defense systems composed of enzymic and nonenzymic molecules scavenge the ROS (Navrot et al., 2007). But ROS production is increased under stress, so they are not properly eliminated in a stress condition which disturbs the plant cell (Apel and Hirt, 2004; Foyer and Noctor, 2005; Munne-Bosch and Alegre, 2004; Karuppanapandian et al., 2006a,b,c, 2008, 2009, 2011; Karuppanapandian and Manoharan, 2008; Vellosillo et al., 2010). All the macromolecules present in the cell are attacked by ROS, which results in dysfunction of the metabolic system and death of the cell (Karuppanapandian et al., 2011). ROS are overproduced by the abiotic stresses which cause serious cell damage (Torres et al., 2002; Mittler, 2002, 2006; Karuppanapandian et al., 2006a,b,c; 2009, 2011; Karuppanapandian and Manoharan, 2008; Mafakheri et al., 2010; Vellosillo et al., 2010; Tripathi et al., 2016a,b). Oxidation of proteins, lipids, carbohydrates, and DNA takes place by accumulation of ROS (Arora et al., 2002; Demidchik, 2015), but activities of antioxidant enzymes are increased by NPs. Nanoceria (cerium oxide NPs) were shown to scavenge ROS in isolated chloroplasts (Giraldo et al., 2014 and protect plant photosynthesis from the detrimental effects of ROS accumulation during abiotic stress. Silicon is well documented to provide significant protection against abiotic stresses to plants (Tripathi et al., 2014, 2017g,h), and silicon NPs have been reported to enhance abiotic stress tolerance by activation of antioxidant enzymes, enhancing uptake processes within plants (Tripathi et al., 2015b, 2016a, 2017a). Thus various abiotic stresses can be withstood by plants (Liang et al., 2007). By increasing the activities of antioxidant enzymes, TiO2 NPs protect chloroplast from strong light (Hong et al., 2005). Nanosize TiO2 is known to have prooxidant and antioxidant properties. They also reported that Growth-promoting effects were reported to be simultaneous with increased levels of chlorophyll b, soluble sugars, and proline and enhanced activities of antioxidant enzymes in spinach. Latef et al. (2017b) reported that broad beans can tolerate saline soil and enjoy improved growth in these adverse conditions after application of TiO2 NPs. Lei et al. (2008) reported that abiotic stress in Spinacia oleracea can be mitigated by TiO2 NPs, which lower the activities of various ROS and increase the activities of antioxidant enzymes. NPs affect ROS and antioxidant metabolism, and this effect is dependent on NP type and concentration (Table 15.2).

Table 15.2. Impact of Some Nanoparticles on ROS and Antioxidant System in Plants

Serial NoType of NanoparticleImpact on ROS and Antioxidant SystemReferences1Nanoceria (cerium oxide NPs)Scavenge ROS in isolated chloroplasts and protect plant photosynthesis from detrimental effects of ROS accumulation during abiotic stressGiraldo et al. (2014).2SiEnhance antioxidant enzyme activation and increase plant capabilities to withstand abiotic stresses (salinity, drought, etc.)Liang et al. (2007)3TiO2Enhance antioxidant stress tolerance

Increased antioxidant enzyme activities contribute to reduction in hydrogen peroxide and malondialdehyde contents under salinityLei et al. (2008)

Latef et al. (2017b)4AgInduce ROS (up to 10 mg/L); significant increase in activity of SOD, CAT, and POD; significant increase in content of nonenzymatic antioxidants GSH (Glutathione) and MDA (Malondialdehyde)Jiang et al. (2014)5ZnODecreased MDA content and increased SOD, CAT, POD, and APX activities when applied under salinity stressLatef et al. (2017a)

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Recent Progress of Nanotoxicology in Plants

Muhammad Zia-ur-Rehman, ... Muhammad Azhar, in Nanomaterials in Plants, Algae, and Microorganisms, 2018

7.6.4 Increase in Reactive Oxygen Species

ROS are derivatives of oxygen that arise in oxygenated conditions and comprise hydrogen peroxide (H2O2), hydroxyl ions (OH−), and superoxide anions (O2−) (Yang et al., 2009). ROS production and oxidative stress initiation is the crucial biomarker of NP toxicity (Rizwan et al., 2016a,b) and is measured by direct ROS quantification or antienzyme activities such as catalase (CAT) and SOD (Thwala et al., 2013; Shaw and Hossain, 2013; Perreault et al., 2014; Oukarroum et al., 2012; Lin et al., 2012; Faisal et al., 2013; Begum and Fugetsu, 2012; Chang et al., 2012). Large quantities of ROS might be generated even at very low exposure of NPs to plants (Toduka et al., 2012). NPs are capable of reacting with biomolecules because of their high specific area, which provides NPs with high electronic density and reactive activity (Pisanic et al., 2009). Throughout this process, chemical reactions that enhance the formation of radicals (O2−, OH−1, etc.) interact with various protein groups, leading to accumulation of ROS and oxidative stress (Shaw et al., 2014a,b; Wang et al., 2011; Gorczyca et al., 2015; Mohammadi et al., 2013; Rao and Shekhawat, 2014).

7.6.4.1 Factors

ROS stress results in programmed cell death and this oxidative stress depends upon the dose of NPs rather than bulk metal material (Rajeshwari et al., 2015; Wang et al., 2011; Cui et al., 2014a,b). The time period of stress applied, e.g., stress of CuO NPs, does not change the chlorophyll contents of barley leaves after 10 days of growth, but after 20 days there was a sudden decrease in chlorophyll contents, regardless of NP concentrations (Shaw et al., 2014a,b). Plants can tolerate the toxicity of NPs up to a certain period, whereas extended exposure of NPs to plants imparts toxic effects because of the harmful effects of NPs on the plant defense mechanism, such as antioxidant enzymes (Zhao et al., 2015).

7.6.4.2 Interaction of Reactive Oxygen Species with Nanoparticles

NPs stimulate ROS production and release NP ions on exposure to acidic conditions of lysosomes (Nohl and Gille, 2013) or interaction with oxidative organelles such as mitochondria and redox active proteins in cells (Chang et al., 2012). ROS, after interacting with biomolecules, instigate an imbalance between reactive oxygen productions and the ability of biological systems to heal, resulting in damage and decontamination of reactive intermediates (Yang et al., 2009). NP-stimulated production of ROS leads to a variety of biological responses, which are dependent upon cellular pathway types, comparative abundance of ROS, and antioxidant response components, which belong to oxidative stress (Xia et al., 2015).

OH−1 is included in the category of highly toxic ROS species; it is capable of oxidizing nearly all the components of cells (Yamakoshi et al., 2003). Metal oxide NPs generate extracellular OH−1 that might stimulate oxidative damage of the plasma membrane, which exhibits toxic impacts in organisms because NP-induced oxidative stress is an authenticating cell-damaging mechanism (Pulskamp, 2007; Yang et al., 2009).

7.6.4.3 Effect of Reactive Oxygen Species

Extreme oxidative stress modifies nucleic acid, lipids, and proteins, which may lead to cell death or excite antioxidant defense mechanisms. In the interim, with enhanced production of ROS, NPs induce DNA damage by point mutations or breaking its strands and enhances expression of death receptor genes (Singh and Lillard, 2009; Yang et al., 2009). Furthermore, NP ions inactivate the functional proteins by dislodging metal ions in precise metalloproteins or chelating with biomolecules (Material et al., 2012). Another response of oxidative stress damage is the release of intracellular Ca2+ ions, leading to perturbation of mitochondria and cell death (Xia et al., 2015), Various diseases including autoimmune diseases, cardiovascular disease, lung disease, and aging are connected to oxidative stress (Yamakoshi et al., 2003).

In plants, oxidative stress interrupts biochemical reactions and decreases gas exchange and photosynthetic rate probably because of increased ROS production (Adrees et al., 2015; Das et al., 2015), and the impact on photosynthesis is extensively reported (Shaw et al., 2014a,b; Mirzajani et al., 2013; Abou-Zeid and Baraka, 2014; Rao and Shekhawat, 2014; Das et al., 2015). Seed priming of barley, soybean, and wheat with Ag NPs quenched photosynthetic pigments and killed chlorophyll fluorescence (Gorczyca et al., 2015; Zhao et al., 2013a,b; Abou-Zeid and Baraka, 2014). In a similar manner, CeO2 NPs affected cucumber and radish plants (Zhao et al., 2013a,b; Corral-Diaz et al., 2014).

7.6.4.3.1 Examples

Ag NPs enhance electrolyte leakage in wheat and reduce viable algal cells and chlorophyll contents in green algae (Oukarroum et al., 2012). CeO2 NPs increase lipid peroxidation and H2O2 production in rice and maize (Zhao et al., 2012a,b; Rico et al., 2013a,b). Similarly, CuO NPs enhance MDA contents in barley, chickpea, and rice leading to oxidative damage (Shaw and Hossain, 2013). ZnO and CuO NPs simulate oxidative stress by glutathione oxidation and lipid peroxidation in wheat (Dimkpa et al., 2012a,b). NiO NPs significantly induce cellular toxicity by increasing production of ROS in tomato roots (Faisal et al., 2013). Al2O3 NPs revealed phytotoxicity in tobacco only by reactive oxygen generation in a time- and concentration-dependent manner (Poborilova et al., 2013). CNT-induced phytotoxicity also endorsed ROS production leading to oxidative stress (Begum and Fugetsu, 2012).

From these studies it is obvious that NPs cause oxidative stress in plants in the form of increased production of ROS. Defense systems in plants can scavenge the production of ROS when stress is low to mild. However, at higher stress, ROS generation by plants is unavoidable. Similarly, the increase or decrease in the production of antioxidant enzymes in plants upon exposure to NPs is evident depending on certain factors such as size and type of NPs, time, and conditions of exposure.

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DEVELOPMENTAL, CYTOGENETIC AND BIOCHEMICAL EFFECTS OF SPIKED OR ENVIRONMENTALLY POLLUTED SEDIMENTS IN SEA URCHIN BIOASSAYS

G. Pagano, ... M. Warnau, in Biomarkers in Marine Organisms, 2001

Oxidative Activity: LDCL and GSH

ROS formation in embryos and gametes was determined by: a) luminol-dependent chemiluminescence (LDCL), and b) measuring glutathione (GSH) levels (Cossu et al, 1997; Foerder et al, 1978; Gyllenhammar, 1987; Korkina et al, 1984; 1992). Thus, three series of experiments were devoted to investigate this hypothesis, by testing LDCL following exposure to a ROS catalyst, as Fe(III), and Al(III), promoting prooxidant activity (Pagano et al, 1996), or to sediment samples, e.g. from Kiel Fjord. Further details are described in Appendix.

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Cardiovascular Toxicology

A.K. Lund, in Comprehensive Toxicology, 2010

6.14.4.1.3 Other redox-sensitive enzymes

ROS have been shown to regulate expression and/or activity of several other key signaling molecules in the vasculature. One such example is the serine/threonine kinase Akt, which plays a key role in cell survival and protein synthesis, as well as activates transcription factors activator protein (AP)-1 and E2F (Coffer et al. 1998). Similar to what has been reported with tyrosine kinase and MAPK family members, exogenous H2O2 has been reported to activate Akt in the vasculature (Ushio-Fukai et al. 1999b). Additionally, NAD(P)H oxidase-derived ROS have also been demonstrated to play a role in Akt activation in nonvascular cell types (Shaw et al. 1998; Wang et al. 2000a). Other redox-sensitive signaling proteins include, but are not limited to, phospholipase D, JAK2, STAT, Fyn, and proline-rich tyrosine kinase (Pyk), based on their activation in the presence of exogenous ROS (Abe and Berk 1999; Natarajan et al. 1993; Simon et al. 1998).

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Cellular and Molecular Toxicology

A.R. Parrish, in Comprehensive Toxicology, 2010

2.27.2 Reactive Oxygen Species

ROS are highly reactive and involved in numerous biochemical reactions, both in normal physiology (Cave et al. 2005; Griendling et al. 2000; Moslen 1994; Touyz 2005; Voeikov 2006) and pathophysiology (Gao et al. 2008; Griendling et al. 2000; Touyz 2005). Donation of a single electron to O2 produces the superoxide radical (O2−), while a second electron forms peroxide (O22−), which is then protonated to H2O2. A third electron produces the highly reactive hydroxyl radical (OH). Given that ROS are cytotoxic, cells have developed antioxidant mechanisms, which include enzymes that dismutate O2− into H2O2 (superoxide dismutases) or degrade H2O2 (catalase, glutathione peroxidases, and peroxiredoxins). At low concentrations, ROS can act as second messengers in signal transduction and gene regulation (Forman et al. 2004; Gorlach and Kietmann 2007; Lyle and Griendling 2006; McCubrey et al. 2006; Ushio-Fukai and Alexander 2004). However, when ROS levels exceed cellular antioxidant capacity, a condition termed oxidative stress is reached; oxidative stress is implicated in the pathogenesis of a number of diseases including aging (Droge and Schipper 2007; Kregel and Zhang 2007), diabetes (Kaneto et al. 2007; Maiese et al. 2007), hypertension (Ceriello 2008; Vaziri and Rodriguez-Iturbe 2006; Ward and Croft 2006), and cancer (Pugh et al. 2001; Valko et al. 2006), as well as in the toxic response to chemical insult (Gonzalez 2005; Kappus 1987; Parke and Sapota 1996; Sies and de Groot 1992).

ROS are rapidly increased following IR; they can cause cell injury and death via reactions with lipids, protein, and DNA (Goswami et al. 2007; Jaeschke 2003; Ovechkin et al. 2007; Toledo-Pereyra et al. 2004; Wong and Crack 2008). Specific interactions of ROS with signaling pathways in hypoxia and/or ischemia will be discussed in detail below (Figure 1). Although not discussed in detail in this chapter, it is important to note that nitric oxide and reactive nitrogen species are increasingly implicated in IR injury (Inglott and Mathie 2000; Nonami 1997; Schulz et al. 2004).

Figure 1. A schematic depiction of the pathways impacted by hypoxia and/or IR-induced ROS generation. ROS can activate PERK and AMPK, kinases associated with initiating UPR and subsequent inhibition of protein synthesis and increasing glucose uptake and enhancing glycolysis, respectively. In addition, ROS increase the activity of the NF-κB and HIF-1 transcription factors. Finally, prolonged insult is associated with cell damage and eventual death, which is mediated by the targeting of lipids, proteins, and DNA.

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Natural and Nature-Inspired Synthetic Small Molecule Antioxidants in the Context of Green Chemistry

William Horton, Marianna Török, in Green Chemistry, 2018

3.27.1 Introduction

Reactive oxygen species (ROS) are produced by enzymatic/nonenzymatic metabolic redox reactions starting with the partial reduction of oxygen to superoxide (O2−) or hydrogen peroxide (H2O2) followed by further secondary reactions of the products.1 Often, transition metal ions, such as Cu2+, Co2+, Ni2+, or Fe2+, are also involved in these reactions.1 Similarly, reactive nitrogen species (RNS) are derived from various reactions of the free radical nitrogen oxide (NO) that is synthetized from arginine by nitrogen oxide synthases.1 The ROS/RNS family includes both free radicals and nonradical species, with superoxide (O2−), hydroxyl (OH) radicals, hydroperoxyl (HOO) radicals, the peroxynitrite (OONO−) ion, the paramagnetic singlet oxygen (1O2), nitrogen oxide (NO) radical, hydrogen peroxide (H2O2), ozone (O3), and hypochlorous acid (HOCl) molecules being the most frequently mentioned members.1–4 The production of ROS/RNS can be both harmful and beneficial in living systems. At physiological concentration, they play significant roles in cell survival by regulating signaling pathways or fighting infections.3,4 At high concentrations, however, they react with proteins, lipids, and nucleic acids and may modify their biological function.4 It is a consequence of an imbalance in the redox homeostasis due to the overproduction of ROS/RNS or inadequate activity of the cellular antioxidant defenses and is referred to as oxidative (or sometimes nitrosative) stress. The cellular damage caused by superoxide and other ROS/RNS has been implicated in the aging process and numerous diseases including cancer, cardiovascular diseases, neurodegenerative diseases (e.g., Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, multiple sclerosis), macular degeneration, rheumatoid arthritis, and diabetes.1,4,5 The collective term "antioxidants" refers to a diverse group of bioactive molecules that protect against the cellular damage caused by oxidative stress through various mechanisms (e.g., scavenging free radicals, regenerating other antioxidants, chelating metal ions, regulating enzyme activities, repairing oxidative damage).3–5 Endogenous antioxidants (Table 3.27.1) include protective enzymes (e.g., superoxide dismutase, catalase, glutathione peroxidase), nonenzymatic peptides/proteins (e.g., glutathione, ferritin, transferrin, ceruloplasmin, albumin), enzyme cofactors (e.g., coenzyme Q, lipoic acid), and metabolites (e.g., bilirubin, uric acid, melatonin).4,5 A diet rich in fruits and vegetables usually contains low-molecular-weight exogenous antioxidants (Table 3.27.1), (e.g., vitamin C, vitamin E, β-carotene, resveratrol, curcumin), contributing to the cellular antioxidant defense.4,5

Table 3.27.1. Endogenous and Exogenous Antioxidants

SourceAntioxidantsExamplesEndogenousProtective enzymesSuperoxide dismutase, catalase, glutathione peroxidaseNonenzymatic peptides/proteinsGlutathione, ferritin, transferrin, ceruloplasmin, albuminEnzyme cofactorsCoenzyme Q, lipoic acidMetabolitesBilirubin, uric acid, melatoninExogenousDietary small molecule antioxidantsVitamin C, vitamin E, β-carotene, resveratrol, curcumin

Beside the age and state of health of a person, lifestyle issues and environmental factors may contribute to oxidative stress and result in different pathological conditions.6–8 A 2016 study in China warns of the increasing cases of lung, colorectal and breast cancers, blaming rapid industrialization and urbanization combined with unhealthy lifestyle changes (heavy smoking, poor diet and obesity) in an aging population.9

As mentioned earlier, excessive ROS/RNS can form not only as natural by-products of metabolic redox reactions but also in response to environmental stress (e.g., pollution or radiation). We have less control over the amount and activity of endogenous antioxidants in our body than those of the exogenous antioxidants in our daily diet. Therefore, the dietary natural antioxidants and their synthetic analogs garner extensive attention, as these compounds are potential candidates for preventing and/or treating many diseases.10

From the viewpoint of green chemistry, small molecule antioxidants have been the focus of interest for several reasons. The investigation of their protective/repairing role against oxidative damage triggered by environmental exposures,6–10 design and preferably green synthesis of novel antioxidants,11 the extraction of natural antioxidants from inexpensive sustainable resources,12–17 and the development of environment-friendly technologies to do so18–21 are all active current topics in this research area.

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Renal Toxicology

J.L. Koyner, ... G.L. Bakris, in Comprehensive Toxicology, 2010

7.15.4.3.1 The role of reactive oxygen species

Reactive oxygen species (ROS) include the superoxide anion, hydrogen peroxide, hydroxyl radical, and single oxygen. These molecules are released from renal cells in response to various stimuli, and act as paraCRIne and autoCRIne stimuli (Baud and Ardaillou 1986; Baud et al. 1983; Cross et al. 1987; Messana et al. 1988b; Shah 1989).

ROS are released by a variety of different cells, including polymorphonuclear leukocytes, macrophages, and glomerular mesangial cells (Baud and Ardaillou 1986; Baud et al. 1983; Cross et al. 1987; Shah 1989). This group of molecules has many functions, including antimicrobial activity. Their production can be inhibited by glucocorticoids and their effects reduced by specific scavengers, such as superoxide dismutase (SOD), glutathione, and dimethyl sulfoxide (Baud et al. 1983; Messana et al. 1988b; Scaduto et al. 1988; Shah 1989). Renal biopsies performed within 3 h of intrarenal RCM administration confirmed a large influx of polymorphonuclear leukocytes and macrophages in both the glomerular and tubular areas (Arakawa et al. 1996). It is hypothesized that these cells, in addition to mesangial cells, release ROS, which in turn contributes to the tubular injury initially induced by the hyperosmotic properties of RCM (Figure 2).

In vitro investigations utilizing electron spin resonance techniques demonstrated that exposure of human mesangial cells to anionic RCM (diatrizoate sodium) produced an increase in ROS (Figure 6), including both superoxide and hydroxyl radical species. Both types of RCM increased the intracellular peroxide levels produced by mesangial cells; however, d-alpha-tocopherol attenuated only the effect of the hyperosmolar RCM diatrizoate. This suggests that oxidative stress may contribute to injury under hyperosmolar conditions.

Figure 6. The electron spin resonance spectra following a hyperosmolar radiocontrast media (RCM), sodium diatrizoate, administered to human mesangial cells. Arrows indicate generation of hydroxyl radicals. Reproduced from Baud, L.; Hagege, J.; Sraer, J.; Rondeau, E.; Perez, J.; Ardaillou, R. J. Exp. Med. 1983, 158, 1836–1852.

Direct tubular toxicity is difficult to measure in a clinical setting. Direct tubule toxicity is reflected by increased urinary excretion of lysosomal enzymes and low-molecular-weight proteins. It is therefore difficult to differentiate between direct toxicity and tubular injury caused by renal ischemia (Katholi et al. 1998). In normal, mildly volume-depleted dogs, the oxygen-free radical scavenger SOD partially blocked the fall in GFR following hyperosmolar RCM treatment, but it had no effect on RBF (Arakawa et al. 1996). Yoshioka et al. (1992) found that the proximal tubular content of SOD was much lower in volume-depleted rats when compared with euvolemic animals. As expected, this group showed the greatest declines in GFR following ionic RCM administration.

It has also been argued that injection of RCM causes ischemia that decreases pO2.In a separate study, Liss et al. (1997) measured oxygen tension in the rat kidney following intravenous injection of a high-osmolar RCM. They reported a small decrease in pO2 in the renal cortex with a profound decrease (to nearly 45%) in the medulla.

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Biotransformation

J.F. Turrens, in Comprehensive Toxicology, 2010

4.12.5 Future Directions

The formation of ROS may impact cell homeostasis at many levels, which may or may not involve gene expression. On one hand, minor fluctuations in the intracellular steady state concentration of ROS may modify certain molecules involved in the intracellular signaling and gene expression. In addition, their indiscriminate reactivity may either protect the cell or exacerbate cell damage depending on whether they annihilate a harmful oxidant or form stronger oxidant species such as peroxynitrite.

From a pharmacological standpoint, learning more about the role of ROS in cell signaling will open new fields and targets toward the development of new chemotherapies. Cell permeable ROS scavengers or enzyme mimetics could be useful in modulating the intracellular steady state concentration of ROS. Quite a few of them have been used in experimental settings but their application in clinical scenarios is still in the early stages (Sampayo et al. 2003).

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Recommended publications:

Ecotoxicology and Environmental Safety

Journal

Journal of Plant Physiology

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Chemosphere

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Mutation Research/Genetic Toxicology and Environmental Mutagenesis

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Reactive Oxygen Metabolite

ROMs are of special importance in inflammatory states, hypersensitivity responses, and in the conditions that result in diminished mucosal blood flow.

From: Comprehensive Toxicology, 2010

Related terms:

Oxidative Stress

Protein

Superoxide

Nitric Oxide

Nanoparticle

Cell Death

Antioxidant Agent

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Oxidation State as a Bioresponsive Trigger

John R. Martin, Craig L. Duvall, in Oxidative Stress and Biomaterials, 2016

Abstract

Reactive oxygen species (ROS) serve as important mediators and signaling molecules in many biological processes, but their overproduction can cause or exacerbate disease. This has motivated the development of biomaterials that can interact with ROS in a therapeutic capacity. These ROS-sensitive materials have been primarily used in three broad biomedical applications: (1) ROS-mediated intracellular drug release for targeted delivery to highly oxidative phagocytic or cancerous cells, (2) extracellular drug delivery targeted to tissues with elevated levels of ROS, and (3) the formation of ROS-degradable tissue engineering scaffolds. This chapter outlines the chemistry and function of the different oxidatively responsive polymers currently being researched and describes their functionality in various biomedical applications.

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Hydrocyanines

Kousik Kundu, Niren Murthy, in Oxidative Stress and Biomaterials, 2016

8.2.11 ROS Signaling Pathways in Cardiovascular Disease Elucidated with the Hydrocyanines

ROS plays a central role in both atherosclerosis and a variety of pulmonary diseases. For example, ROS has been implicated in the development of atherosclerosis and vascular inflammation. However, the biological mechanisms that cause inflammation and ROS production in the vasculature have been difficult to identify in vivo. Low shear stress in the lumen of the blood vessels has been implicated as an important contributor in the pathogenesis of atherosclerosis, however, their role in generating vascular inflammation and ROS had never been clearly understood. Willett et al. developed a murine aortic coarctation model to create regions of low magnitude oscillatory wall shear stress in vivo and used hydro-Cy3 to analyze if regions of low shear stress generate high levels of ROS and inflammation [58]. To determine ROS production in vivo, Willet et al. injected hydro-Cy3 into the aorta of these mice, before sacrificing them. The mice were then sacrificed and analyzed via histology to determine ROS production and vascular inflammation. Willet et al. observed that regions of low shear stress had high levels of ROS production and vascular markers of inflammation, such as VCAM1. Thus the hydrocyanines can measure ROS at a cellular level in diverse tissues [58] (Fig. 8.7).

Figure 8.7. A novel murine aortic coarctation model to acutely create a region of low magnitude oscillatory WSS in vivo to test the hypothesis that acute changes in WSS in vivo induce upregulation of inflammatory proteins (VCAM-1), mediated by ROS. ROS was imaged by hydro-Cy3.

ROS also plays a critical role in a variety of pulmonary diseases. Although the role of ROS in generating pulmonary inflammation and tissue damage is well known, ROS are also involved in a variety of physiologic processes that are essential for healthy tissue function. For example, the Helms laboratory was able to use hydro-Cy7 to demonstrate that ROS generated by NADPH oxidases regulate alveolar epithelial sodium channel activity and lung fluid balance in vivo, and thus plays a critical role in protecting the lung against edema [59].

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Fluorescent Sensors and Imaging Agents

C.X. Yin, in Comprehensive Supramolecular Chemistry II, 2017

Abstract

Reactive oxygen species (ROS) are the most abundant intracellular oxidizing substances, produced by metabolic processes. ROS can cause biomacromolecule damage and are associated with or result in many diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Wilson's disease, and asthma. To elucidate and visualize the physiology and pathology of ROS, fluorescent probes can be used to evaluate the concentration of ROS and image their distribution in biological systems. In this article, the recent developments of fluorescent probes for ROS detection are comprehensively discussed. The article is structured by the fluorophores of the probes. The optical properties, detection mechanisms, and biological applications are highlighted.

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Antibacterial Nanoparticles

Gemma C. Cotton, ... Carla J. Meledandri, in Comprehensive Nanoscience and Nanotechnology (Second Edition), 2019

3.04 2.1 ROS-Induced Oxidative Stress

ROS produced from NP surfaces has been widely recognised as a source of NP-induced antimicrobial action [31,38–41]. ROS is a collective term for multiple oxygen free radicals, where the oxygen species contains one or more unpaired electrons. The inherent instability of ROS has been linked to cellular damage caused by their covalent binding with DNA, lipids, proteins, and enzymes [42,43]. ROS are continuously generated and eliminated in biological systems and play important roles in a variety of normal biochemical functions. Cells contain antioxidant defense mechanisms to mitigate elevated levels of ROS; if ROS levels exceed antioxidant capacity, oxidative stress and apoptosis can result, a form of programmed cell death due to the severe damage caused to fundamental biological components, including DNA, proteins, and lipids [44–46]. One of the cellular structures most sensitive to the damaging impact of oxidative stress and lipid peroxidation by ROS is the inner or cytoplasmic membrane. ROS interact with polyunsaturated fatty acids which are a major constituent of the phospholipids of biological membranes. The resulting lipid peroxidation products, typically diene conjugates and hydroperoxides of fatty acids, cause conformational changes of the phospholipids, which in turn alters the structural behaviour of the biological membrane and causes impairment of membrane function. Lipid peroxidation is not limited to the cellular membrane, however, and also occurs within cells via internal ROS generation.

NP treatment has been attributed to a concentration- and time-dependent increase in proportions of apoptotic cells. Thus, to investigate whether NP-mediated antibacterial effects are ROS-derived, treated bacterial cells may be examined for characteristic signals of apoptosis and oxidative stress [47].

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Inorganic Reaction Mechanisms

Janusz M. Dąbrowski, in Advances in Inorganic Chemistry, 2017

Abstract

Reactive oxygen species (ROS) play key roles in cell signaling systems and homeostasis, and they are also fundamental to photodynamic therapy (PDT). PDT efficacy can be affected by the nature and persistence of ROS. A comprehensive understanding of ROS generation pathways greatly facilitates the analysis of photodynamic mechanisms and enables potentiation of PDT efficacy. Diverse methods exist to distinguish between Type I and Type II mechanisms of ROS generation. The direct monitoring of 1O2 formation involves the detection of its phosphorescence at 1270 nm. Electron spin resonance is also used in conjunction with appropriate spin traps for detection of oxygen-centered radical species. Moreover, a variety of more or less specific fluorescent probes are frequently used to detect both singlet oxygen and free radicals. This chapter summarizes our recent efforts in the design and characterization of new ROS-generating systems for PDT. Special attention is given to bacteriochlorins because they absorb in the NIR, generate ROS via both Type I and Type II mechanisms, and are very efficient in the PDT treatment of several types of tumors including pigmented melanoma. The current status and possible opportunities of ROS generation and potentiation in PDT are highlighted. Particular emphasis is placed on the elucidation of the ROS-mediated photochemical and molecular mechanisms that give rise to the establishment of PDT as a first-line systemic treatment of highly resistant diseases, especially invasive and metastatic tumors.

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Plant-Derived Prooxidants as Potential Anticancer Therapeutics

Alak Manna, ... Mitali Chatterjee, in Studies in Natural Products Chemistry, 2016

Sources of Cellular Reactive Oxygen Species

ROS are constantly produced by cellular enzymatic and nonenzymatic reactions. The enzyme-catalyzed reactions include NADPH oxidase, xanthine oxidase, and uncoupled endothelial NOS along with metabolic enzymes such as the cytochrome P450, lipoxygenases, and cyclooxygenases. The major nonenzymatic source of ROS includes the mitochondrial respiratory chain wherein about 2% of the oxygen consumed by the mitochondria is reduced to form superoxide (O2·−) [8,9]. Other exogenous sources of ROS include pollutants, tobacco smoke, iron salts, and radiation.

In cancers, high levels of ROS are generated following an upscaling of metabolic activity, eg, mitochondrial and endoplasmic reticulum (ER) dysfunctions, peroxisome activity, increased cellular receptor signaling, oncogene activity, increased activity of oxidases, cyclooxygenases, lipoxygenases, and thymidine phosphorylase or even following cross talk with infiltrating immune cells [10].

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Environmental Geochemistry

G.S. Plumlee, T.L. Ziegler, in Treatise on Geochemistry, 2007

9.07.4.4 ROS Generated by Earth Materials—An Important Source of Toxicity

Other transition metals can also participate in similar reactions.

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Oxidative stress of Cr(III) and carcinogenesis

James T.F. Wise, ... Xianglin Shi, in The Nutritional Biochemistry of Chromium (III) (Second Edition), 2019

Role of Cr(III) in Cr(VI) Carcinogenesis

ROS has a dual role in Cr(VI)-induced carcinogenesis. It is very like that Cr(III) would follow a similar mechanism if exposure duration and level of Cr(III) were long and high enough. In brief, Cr(VI)-induced carcinogenesis can be divided into two parts early and late stage. In the early stage ROS generated by Cr(VI) reduction is high and causes a variety of issues that drive the carcinogenesis process. These include genomic instability, impaired DNA repair, epigenetic modifications, and redox imbalances (10,14). During Cr(VI)-induced carcinogenesis and after reduction of Cr(VI) to Cr(III), Cr(III) is able to interact with DNA and with proteins. These interactions have been shown to be key to Cr(VI) carcinogenic mechanism (3,5,16,17). Cr(III) can also produce ROS through the Haber–Weiss-like reaction, as discussed in more details earlier, and this ROS can produce the same dysfunctions as ROS produced by Cr(VI). Then during the late stage, the role of ROS changes and it becomes used as a survival mechanism by the cells/tumor, where ROS levels are lower and drive the survival advantages and other changes (autophagy deficiency, oncogenic protein accumulation, angiogenesis, and chronic inflammation) in the cells/tumor (14). These outcomes clearly demonstrate a role for Cr(III) in Cr(VI)-induced carcinogenesis.

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Imaging biomaterial-associated inflammation

S. Selvam, in Monitoring and Evaluation of Biomaterials and their Performance In Vivo, 2017

3.2.3 Small molecule imaging

Reactive oxygen species (ROS), small molecules comprising oxygen radicals and peroxides, released by activated inflammatory cells, play a crucial role in the inflammatory response to implanted biomaterials (Hooper et al., 2000; Tsaryk et al., 2007). Numerous biomaterials induce activated macrophages and neutrophils to produce ROS (Tsaryk et al., 2007; Karlsson and Tang, 2006; Serrano et al., 2005). Elevated levels of ROS induce stress cracking and oxidative damage that alter the microarchitecture of the implant surface, ultimately leading to implant failure (Anderson et al., 2008). Consequently, methods to image ROS near the vicinity of an implant could greatly improve the diagnosis of inflammatory responses to implanted biomaterials.

Small molecule ROS imaging probes, termed the hydrocyanines, were synthesized via a one-step reduction of commercially available cyanine dyes, such as indocyanine green (ICG), Cy5, and Cy7, with sodium borohydride (Kundu et al., 2009). The hydrocyanines demonstrated excellent stability to auto-oxidation, tunable emission wavelengths, and most importantly, displayed high selectivity, specificity, and nanomolar sensitivity to ROS (Kundu et al., 2009). To evaluate the ability of hydrocyanines to detect ROS in vivo, hydro-ICG was used to detect extracellular ROS released in response to PET disks implanted under the skin in the back of mice (Selvam et al., 2011) (Fig. 3.5(a)). Fluorescence data showed that signals from PET implants were 2.5-fold greater than surgical sham controls at days 7 and 14 postimplantation, while nonsurgical dye-only controls demonstrated two-fold lower signal intensities compared to surgical sham controls at all time points during the two-week time period (Fig. 3.5(b)). Histological analysis on implant-associated tissues revealed that the thickness of collagenous fibrous capsules formed around implants correlated strongly with corresponding ROS fluorescence values (Fig. 3.5(c)). Furthermore, costaining analysis for inflammatory cell markers and ROS activity demonstrated that activated macrophages and neutrophils were primarily responsible for the upregulation of ROS at PET implant sites (Fig. 3.5(d)). This imaging strategy was also able to detect attenuation in inflammatory responses in response to delivery of anti-inflammatory agents (Fig. 3.5(e)). Intravenous injections of hydro-Cy7 showed a significant decrease in fluorescence intensities around dexamethasone-loaded poly(lactic-co-glycolyic acid) (PLGA) microparticles compared to blank PLGA microparticles at day 14 postimplantation (Fig. 3.5(f)). These results correlated directly with significant presence of inflammatory cells around empty PLGA compared to PLGA microparticles releasing dexamethasone (Fig. 3.5(g)). Viewed comprehensively, these results prove that ROS is a reliable indicator and an excellent diagnostic marker for evaluating biomaterial-related inflammation around implanted devices.

Figure 3.5. Reactive oxygen species (ROS) imaging of implant-associated inflammation using hydrocyanine dyes. (a) In vivo fluorescence imaging of ROS in surgical sham and PET implant groups after subcutaneous delivery of H-ICG. (b) Quantification of fluorescence signals (mean ± SE, n ≥ 5) of implant, sham, and dye-only control groups over a period of two weeks. ∗∗ denotes p < .01, significant difference in fluorescence signals between implant and sham groups. (c) Correlation of implant fibrous capsule thickness to corresponding implant-associated ROS fluorescence values (mean ± SE, n = 3). (d) Representative colocalization images of macrophages (CD68+, green) and neutrophils (NIMP-R14+, green) with intracellular ROS (H-Cy5+, red) in 14-day implants. Scale bar, 50 μm. (e) Representative images of the ROS imaging of animals injected with saline, empty poly(lactic-co-glycolyic acid) (PLGA), and dexamethasone-loaded PLGA microparticles using H-Cy7. (f) Quantification of ROS signals (mean ± SE, n ≥ 5) from saline, empty PLGA, and dexamethasone-loaded PLGA injected groups on days 7 and 14 postinjection. (g) Histological tissue sections from mice injected with empty PLGA and dexamethasone-loaded PLGA microparticles in 14-day explants. Scale bars, 100 μm.

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Electrochemical Biosensors for DNA–Drug Interactions

S.C.B. de Oliveira, ... A.M. Oliveira-Brett, in Encyclopedia of Interfacial Chemistry, 2018

Oxygen reactive species

Reactive oxygen species (ROS) are generated inside cells as products of metabolism, by leakage from mitochondrial respiration and also under the influence of exogenous agents, such as ionizing radiation, quinones, peroxides, and transition metal ions. The biological function of ROS in the organism so far is ambiguous. Excess ROS are responsible for causing DNA and cellular damage, which can contribute to development of tumors.61 However, ROS can assist the immune system, mediates cell signaling, and is essential in apoptosis. The treatment of cancer cells by ROS-inducing antineoplastic drugs exceeds the threshold for ROS causing the activation of multiple cell death programs.61 The ROS–dsDNA interaction mechanism has been investigated, using various methods with great sensitivity and specificity; however, for different reasons, conflicting results have been reported.61

The dsDNA oxidative damage caused by hydroxyl radicals electrogenerated (by water discharge), in situ at a dsDNA-electrochemical biosensor, using a boron-doped diamond electrode (BDDE) surface,61 was investigated. A large increase in the oxidation peak currents of dGuo and dAdo was observed, three new oxidation peaks, corresponding to the oxidation of 8-oxoG, and free purine bases Gua and Ade, occurred (Fig. 14), and were confirmed by nondenaturing agarose gel electrophoresis.61

Fig. 14. DP voltammograms, at a thick multi-layer dsDNA-BDDE-electrochemical biosensor, in acetate buffer pH = 4.5: () control and () first and (–) second to fourth scans after applying + 3.0 V during 2 h to the BDDE surface, causing electrogeneration of hydroxyl radicals.

[Adapted from Oliveira, S. C. B.; Oliveira-Brett, A. M. In Situ DNA Oxidative Damage by Electrochemically Generated Hydroxyl Free Radicals on a Boron-Doped Diamond Electrode Surface. Langmuir 2012, 28, 4896–4901, with permission.]

The dsDNA-BDDE-electrochemical biosensors enabled, for the first time, a direct and fast detection procedure to follow the interaction of dsDNA with hydroxyl free radicals, and the BDDE surface played a dual role being the source of the electrochemically generated hydroxyl radicals and also the transducer for the detection of dsDNA oxidative damage (Fig. 14).

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