scholarly journals Nitric Oxide and Peroxynitrite in Health and Disease

2007 ◽  
Vol 87 (1) ◽  
pp. 315-424 ◽  
Author(s):  
Pál Pacher ◽  
Joseph S. Beckman ◽  
Lucas Liaudet
Keyword(s):  
Nitric Oxide ◽  
Free Radical ◽  
Mammalian Cells ◽  
Inflammatory Diseases ◽  
Cellular Damage ◽  
Diffusion Controlled ◽  
Wide Range ◽  
Health And Disease ◽  
Therapeutic Tools

The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

scholarly journals Antioxidant and Anti-Inflammatory Effects of Herbal Formula SC-E3 in Lipopolysaccharide-Stimulated RAW 264.7 Macrophages

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Soo Chil Lee ◽  
Young-Won Kwon ◽  
Ju-Yeon Park ◽  
Sung Yun Park ◽  
Ju-Hee Lee ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Free Radical ◽  
Inflammatory Diseases ◽  
Heme Oxygenase 1 ◽  
Prostaglandin E ◽  
Raw 264.7 ◽  
Herbal Formula ◽  
Raw 264.7 Macrophages ◽  
Wide Range ◽  
Anti Inflammatory

SC-E3 is a novel herbal formula composed of five oriental medicinal herbs that are used to treat a wide range of inflammatory diseases in Korean traditional medicine. In this study, we sought to determine the effects of SC-E3 on free radical generation and inflammatory response in lipopolysaccharide- (LPS-) treated RAW 264.7 macrophages and the molecular mechanism involved. The ethanol extract of SC-E3 showed good free radical scavenging activity and inhibited LPS-induced reactive oxygen species generation. SC-E3 significantly inhibited the production of the LPS-induced inflammatory mediators, nitric oxide and prostaglandin E2, by suppressing the expressions of inducible nitric oxide synthase and cyclooxygenase-2, respectively. SC-E3 also prevented the secretion of the proinflammatory cytokines, IL-1β, TNF-α, and IL-6, and inhibited LPS-induced NF-κB activation and the mitogen-activated protein kinase (MAPK) pathway. Furthermore, SC-E3 induced the expression of heme oxygenase-1 (HO-1) by promoting the nuclear translocation and transactivation of Nrf2. Taken together, these results suggest that SC-E3 has potent antioxidant and anti-inflammatory effects and that these effects are due to the inhibitions of NF-κB and MAPK and the induction of Nrf2-mediated HO-1 expression in macrophages. These findings provide scientific evidence supporting the potential use of SC-E3 for the treatment and prevention of various inflammatory diseases.

scholarly journals Autophagy Deficiency by Atg4B Loss Leads to Metabolomic Alterations in Mice

Metabolites ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 481
Author(s):  
Gemma G. Martínez-García ◽  
Raúl F. Pérez ◽  
Álvaro F. Fernández ◽  
Sylvere Durand ◽  
Guido Kroemer ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Mammalian Cells ◽  
Tissue Homeostasis ◽  
In Vivo Studies ◽  
Protective Mechanism ◽  
Cardiac Damage ◽  
Wide Range ◽  
First Time

Autophagy is an essential protective mechanism that allows mammalian cells to cope with a variety of stressors and contributes to maintaining cellular and tissue homeostasis. Due to these crucial roles and also to the fact that autophagy malfunction has been described in a wide range of pathologies, an increasing number of in vivo studies involving animal models targeting autophagy genes have been developed. In mammals, total autophagy inactivation is lethal, and constitutive knockout models lacking effectors of this route are not viable, which has hindered so far the analysis of the consequences of a systemic autophagy decline. Here, we take advantage of atg4b−/− mice, an autophagy-deficient model with only partial disruption of the process, to assess the effects of systemic reduction of autophagy on the metabolome. We describe for the first time the metabolic footprint of systemic autophagy decline, showing that impaired autophagy results in highly tissue-dependent alterations that are more accentuated in the skeletal muscle and plasma. These changes, which include changes in the levels of amino-acids, lipids, or nucleosides, sometimes resemble those that are frequently described in conditions like aging, obesity, or cardiac damage. We also discuss different hypotheses on how impaired autophagy may affect the metabolism of several tissues in mammals.

scholarly journals Oxygen radicals, nitric oxide, and peroxynitrite: Redox pathways in molecular medicine

2018 ◽  
Vol 115 (23) ◽  
pp. 5839-5848 ◽  
Author(s):  
Rafael Radi
Keyword(s):  
Nitric Oxide ◽  
Free Radical ◽  
Mammalian Cells ◽  
Oxygen Radicals ◽  
Biochemical Characterization ◽  
Cell Function ◽  
Molecular Medicine ◽  
Antioxidant Systems ◽  
Cellular Functions ◽  
Cell Degeneration

Oxygen-derived free radicals and related oxidants are ubiquitous and short-lived intermediates formed in aerobic organisms throughout life. These reactive species participate in redox reactions leading to oxidative modifications in biomolecules, among which proteins and lipids are preferential targets. Despite a broad array of enzymatic and nonenzymatic antioxidant systems in mammalian cells and microbes, excess oxidant formation causes accumulation of new products that may compromise cell function and structure leading to cell degeneration and death. Oxidative events are associated with pathological conditions and the process of normal aging. Notably, physiological levels of oxidants also modulate cellular functions via homeostatic redox-sensitive cell signaling cascades. On the other hand, nitric oxide (•NO), a free radical and weak oxidant, represents a master physiological regulator via reversible interactions with heme proteins. The bioavailability and actions of •NO are modulated by its fast reaction with superoxide radical (O2•−), which yields an unusual and reactive peroxide, peroxynitrite, representing the merging of the oxygen radicals and •NO pathways. In this Inaugural Article, I summarize early and remarkable developments in free radical biochemistry and the later evolution of the field toward molecular medicine; this transition includes our contributions disclosing the relationship of •NO with redox intermediates and metabolism. The biochemical characterization, identification, and quantitation of peroxynitrite and its role in disease processes have concentrated much of our attention. Being a mediator of protein oxidation and nitration, lipid peroxidation, mitochondrial dysfunction, and cell death, peroxynitrite represents both a pathophysiologically relevant endogenous cytotoxin and a cytotoxic effector against invading pathogens.

scholarly journals Nitric oxide interactions with cobalamins: biochemical and functional consequences

Blood ◽  
1996 ◽  
Vol 88 (5) ◽  
pp. 1857-1864 ◽  
Author(s):  
M Brouwer ◽  
W Chamulitrat ◽  
G Ferruzzi ◽  
DL Sauls ◽  
JB Weinberg
Keyword(s):  
Nitric Oxide ◽  
Electron Paramagnetic Resonance Spectroscopy ◽  
Resonance Spectroscopy ◽  
Paramagnetic Resonance ◽  
No Formation ◽  
Iron Nitrosyl ◽  
Wide Range ◽  
Functional Consequences

Abstract Nitric oxide (NO) is a paramagnetic gas that has been implicated in a wide range of biologic functions. The common pathway to evoke the functional response frequently involves the formation of an iron- nitrosyl complex in a target (heme) protein. In this study, we report on the interactions between NO and cobalt-containing vitamin B12 derivatives. Absorption spectroscopy showed that of the four Co(III) derivatives (cyanocobalamin [CN-Cbl], aquocobalamin [H2O-Cbl], adenosylcobalamin [Ado-Cbl], and methylcobalamin [MeCbl]), only the H2O- Cbl combined with NO. In addition, electron paramagnetic resonance spectroscopy of H2O-Cbl preparations showed the presence of a small amount of Cob-(II)alamin that was capable of combining with NO. The Co(III)-NO complex was very stable, but could transfer its NO moiety to hemoglobin (Hb). The transfer was accompanied by a reduction of the Co(III) to Co(II), indicating that NO+ (nitrosonium) was the leaving group. In accordance with this, the NO did not combine with the Hb Fe(II)-heme, but most likely with the Hb cysteine-thiolate. Similarly, the Co(III)-NO complex was capable of transferring its NO to glutathione. Ado-Cbl and Me-Cbl were susceptible to photolysis, but CN- Cbl and H2O-Cbl were not. The homolytic cleavage of the Co(III)-Ado or Co(III)-Me bond resulted in the reduction of the metal. When photolysis was performed in the presence of NO, formation of NO-Co(II) was observed. Co(II)-nitrosyl oxidized slowly to form Co(III)-nitrosyl. The capability of aquocobalamin to combine with NO had functional consequences. We found that nitrosylcobalamin had diminished ability to serve as a cofactor for the enzyme methionine synthase, and that aquocobalamin could quench NO-mediated inhibition of cell proliferation. Our in vitro studies therefore suggest that interactions between NO and cobalamins may have important consequences in vivo.

scholarly journals Tunneling Nanotubes and the Eye: Intercellular Communication and Implications for Ocular Health and Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-15 ◽  
Author(s):  
Holly R. Chinnery ◽  
Kate E. Keller
Keyword(s):  
Eye Diseases ◽  
Cellular Communication ◽  
Tunneling Nanotubes ◽  
Extracellular Milieu ◽  
Wide Range ◽  
Aqueous Environments ◽  
Health And Disease ◽  
Ocular Health

Cellular communication is an essential process for the development and maintenance of all tissues including the eye. Recently, a new method of cellular communication has been described, which relies on formation of tubules, called tunneling nanotubes (TNTs). These structures connect the cytoplasm of adjacent cells and allow the direct transport of cellular cargo between cells without the need for secretion into the extracellular milieu. TNTs may be an important mechanism for signaling between cells that reside long distances from each other or for cells in aqueous environments, where diffusion-based signaling is challenging. Given the wide range of cargoes transported, such as lysosomes, endosomes, mitochondria, viruses, and miRNAs, TNTs may play a role in normal homeostatic processes in the eye as well as function in ocular disease. This review will describe TNT cellular communication in ocular cell cultures and the mammalian eye in vivo, the role of TNTs in mitochondrial transport with an emphasis on mitochondrial eye diseases, and molecules involved in TNT biogenesis and their function in eyes, and finally, we will describe TNT formation in inflammation, cancer, and stem cells, focusing on pathological processes of particular interest to vision scientists.

Responses of Free Radicals to Subcutaneous Implantation of Alginate-Chitosan-Alginate (ACA) Microcapsules in Mice

2009 ◽  
Vol 32 (4) ◽  
pp. 224-231 ◽  
Author(s):  
Haibao Zhu ◽  
Zhaofang Xi ◽  
Shijin Yang ◽  
Yanhong Zhang ◽  
Hong Wang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Superoxide Dismutase ◽  
Free Radicals ◽  
Cell Viability ◽  
Cellular Damage ◽  
Specific Response ◽  
Saline Injection ◽  
Encapsulated Cells ◽  
Post Implantation

The objective of this study was to characterize the levels of free radicals in serum and antioxidase activity after microcapsules were implanted into the subcutaneous space of mice. Cell viability was evaluated using AO/EB staining. Serum free radicals, malondialdehyde and superoxide dismutase levels were evaluated by colorimetry analysis. The mice were divided into three groups: saline injection group (n=15), empty microcapsules injected group (n=21), encapsulated cells injected group (n=21). Cell viability and serum analysis were executed at 1, 4 and 7 days post-implantation. Hydrogen peroxide and malondialdehyde levels initially increased in the recipients of the empty microcapsules, before decreasing to the basal level. However, in mice receiving the encapsulated cells, the levels were higher at the end of study. Nitric oxide and superoxide dismutase increased after the implantation of microcapsules with or without the BHK-21 cells, but were not changed in response to the saline injection. The viability of the encapsulated cells was high in vivo, although some microcapsules had broken by 7 days post-implantation. These results suggest that nitric oxide plays a role in the specific response to microcapsules. The levels of free radicals rapidly increased immediately following microcapsule transplantation, but they caused only slight cellular damage before the microencapsulated cells were exposed.

scholarly journals Achieving tight control of a photoactivatable Cre recombinase gene switch: new design strategies and functional characterization in mammalian cells and rodent

2019 ◽  
Vol 47 (17) ◽  
pp. e97-e97 ◽  
Author(s):  
Kyle Meador ◽  
Christina L Wysoczynski ◽  
Aaron J Norris ◽  
Jason Aoto ◽  
Michael R Bruchas ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Cultured Cells ◽  
Functional Characterization ◽  
Cre Recombinase ◽  
Common Mechanism ◽  
Protein Fragments ◽  
Low Background ◽  
Wide Range ◽  
Split Protein

AbstractA common mechanism for inducibly controlling protein function relies on reconstitution of split protein fragments using chemical or light-induced dimerization domains. A protein is split into fragments that are inactive on their own, but can be reconstituted after dimerization. As many split proteins retain affinity for their complementary half, maintaining low activity in the absence of an inducer remains a challenge. Here, we systematically explore methods to achieve tight regulation of inducible proteins that are effective despite variation in protein expression level. We characterize a previously developed split Cre recombinase (PA-Cre2.0) that is reconstituted upon light-induced CRY2-CIB1 dimerization, in cultured cells and in vivo in rodent brain. In culture, PA-Cre2.0 shows low background and high induced activity over a wide range of expression levels, while in vivo the system also shows low background and sensitive response to brief light inputs. The consistent activity stems from fragment compartmentalization that shifts localization toward the cytosol. Extending this work, we exploit nuclear compartmentalization to generate light-and-chemical regulated versions of Cre recombinase. This work demonstrates in vivo functionality of PA-Cre2.0, describes new approaches to achieve tight inducible control of Cre DNA recombinase, and provides general guidelines for further engineering and application of split protein fragments.

Free radical biology and medicine: it's a gas, man!

2006 ◽  
Vol 291 (3) ◽  
pp. R491-R511 ◽  
Author(s):  
William A. Pryor ◽  
Kendall N. Houk ◽  
Christopher S. Foote ◽  
Jon M. Fukuto ◽  
Louis J. Ignarro ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Free Radical ◽  
Cell Signaling ◽  
Adaptive Responses ◽  
Adaptive Mechanisms ◽  
Low Levels ◽  
Very High ◽  
Ozone Reactions

We review gases that can affect oxidative stress and that themselves may be radicals. We discuss O2 toxicity, invoking superoxide, hydrogen peroxide, and the hydroxyl radical. We also discuss superoxide dismutase (SOD) and both ground-state, triplet oxygen (3O2), and the more energetic, reactive singlet oxygen (1O2). Nitric oxide (·NO) is a free radical with cell signaling functions. Besides its role as a vasorelaxant, ·NO and related species have other functions. Other endogenously produced gases include carbon monoxide (CO), carbon dioxide (CO2), and hydrogen sulfide (H2S). Like ·NO, these species impact free radical biochemistry. The coordinated regulation of these species suggests that they all are used in cell signaling. Nitric oxide, nitrogen dioxide, and the carbonate radical (CO3·−) react selectively at moderate rates with nonradicals, but react fast with a second radical. These reactions establish “cross talk” between reactive oxygen (ROS) and reactive nitrogen species (RNS). Some of these species can react to produce nitrated proteins and nitrolipids. It has been suggested that ozone is formed in vivo. However, the biomarkers that were used to probe for ozone reactions may be formed by non-ozone-dependent reactions. We discuss this fascinating problem in the section on ozone. Very low levels of ROS or RNS may be mitogenic, but very high levels cause an oxidative stress that can result in growth arrest (transient or permanent), apoptosis, or necrosis. Between these extremes, many of the gasses discussed in this review will induce transient adaptive responses in gene expression that enable cells and tissues to survive. Such adaptive mechanisms are thought to be of evolutionary importance.

scholarly journals T cell lineage choice and differentiation in the absence of the RNase III enzyme Dicer

2005 ◽  
Vol 201 (9) ◽  
pp. 1367-1373 ◽  
Author(s):  
Bradley S. Cobb ◽  
Tatyana B. Nesterova ◽  
Elizabeth Thompson ◽  
Arnulf Hertweck ◽  
Eric O'Connor ◽  
...  
Keyword(s):  
T Cell ◽  
Mammalian Cells ◽  
Early Stage ◽  
Early Embryo ◽  
Specific Gene ◽  
Small Interfering Rnas ◽  
Developmentally Regulated ◽  
Micro Rnas ◽  
Wide Range

The ribonuclease III enzyme Dicer is essential for the processing of micro-RNAs (miRNAs) and small interfering RNAs (siRNAs) from double-stranded RNA precursors. miRNAs and siRNAs regulate chromatin structure, gene transcription, mRNA stability, and translation in a wide range of organisms. To provide a model system to explore the role of Dicer-generated RNAs in the differentiation of mammalian cells in vivo, we have generated a conditional Dicer allele. Deletion of Dicer at an early stage of T cell development compromised the survival of αβ lineage cells, whereas the numbers of γδ-expressing thymocytes were not affected. In developing thymocytes, Dicer was not required for the maintenance of transcriptional silencing at pericentromeric satellite sequences (constitutive heterochromatin), the maintenance of DNA methylation and X chromosome inactivation in female cells (facultative heterochromatin), and the stable shutdown of a developmentally regulated gene (developmentally regulated gene silencing). Most remarkably, given that one third of mammalian mRNAs are putative miRNA targets, Dicer seems to be dispensable for CD4/8 lineage commitment, a process in which epigenetic regulation of lineage choice has been well documented. Thus, although Dicer seems to be critical for the development of the early embryo, it may have limited impact on the implementation of some lineage-specific gene expression programs.

The occurrence of a stable quinone radical accumulating in vivo during natural and induced senescence in a range of plants

1994 ◽  
Vol 102 ◽  
pp. 501-503 ◽  
Author(s):  
George A. F. Hendry ◽  
N. M. Atherton ◽  
Wendy Seel ◽  
Olivier Leprince
Keyword(s):  
Free Radical ◽  
Seed Viability ◽  
Biochemical Processes ◽  
Organic Free Radical ◽  
W Band ◽  
Wide Range ◽  
Electron Transport Chains ◽  
Long Term Studies

SynopsisA correlation has been firmly established, in a wide range of plants, between environmental stress, the onset of senescence, loss of viability in seeds and the development and accumulation of a stable organic free radical. On the basis of the EPR response obtained at 95 GHz (W-band) and ENDOR spectra, and comparisons with quinone radical anions, we present evidence from contrasted plant species, plant tissues and sub-cellular fractions that this stable radical originates from one or more quinones possibly, though perhaps not exclusively, associated with stressed or age-impaired photosynthetic and respiratory electron transport chains. The radical appears to be ubiquitously associated with sub-lethal stress-induced damage and with senescence and arises during the sub-cellular structural and biochemical processes associated with the final phases of metabolism prior to death. As the free radical persists for some considerable time after death, it may have value in long-term studies of seed viability and in broader areas of plant pathology and stress physiology.

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