Reactive oxygen and nitrogen intermediates in the relationship

of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates . AA Grover, HK Kim, EH Wiegeshaus, DW SmithHost-parasite relationships in. The participation of reactive oxygen intermediates (ROI) and reactive . earlier idea that persists in an uneasy relationship with its descendant. Abstract. This review summarizes recent evidence from knock-out mice on the role of reactive oxygen intermediates and reactive nitrogen.

Results showed that the rats performed better after receiving the metabolites, suggesting that the metabolites reduced oxidative damage and improved mitochondrial function. Additional experimental results suggest that oxidative damage is responsible for age-related decline in brain functioning.

Older gerbils were found to have higher levels of oxidized protein in comparison to younger gerbils. Treatment of old and young mice with a spin trapping compound caused a decrease in the level of oxidized proteins in older gerbils but did not have an effect on younger gerbils. In addition, older gerbils performed cognitive tasks better during treatment but ceased functional capacity when treatment was discontinued, causing oxidized protein levels to increase.

This led researchers to conclude that oxidation of cellular proteins is potentially important for brain function. While studies in invertebrate models indicate that animals genetically engineered to lack specific antioxidant enzymes such as SODin general, show a shortened lifespan as one would expect from the theorythe converse manipulation, increasing the levels of antioxidant enzymes, has yielded inconsistent effects on lifespan though some studies in Drosophila do show that lifespan can be increased by the overexpression of MnSOD or glutathione biosynthesizing enzymes.

Also contrary to this theory, deletion of mitochondrial SOD2 can extend lifespan in Caenorhabditis elegans. Deleting antioxidant enzymes, in general, yields shorter lifespan, though overexpression studies have not with some recent exceptions consistently extended lifespan. Numerous studies have shown that 8-OHdG increases in different mammalian organs with age [26] see DNA damage theory of aging.

Male infertility[ edit ] Exposure of spermatozoa to oxidative stress is a major causative agent of male infertility. But under oxidative stress conditions, excessive ROS can damage cellular proteins, lipids and DNA, leading to fatal lesions in cell that contribute to carcinogenesis.

Cancer cells exhibit greater ROS stress than normal cells do, partly due to oncogenic stimulation, increased metabolic activity and mitochondrial malfunction. ROS is a double-edged sword. On one hand, at low levels, ROS facilitates cancer cell survival since cell-cycle progression driven by growth factors and receptor tyrosine kinases RTK require ROS for activation [31] and chronic inflammation, a major mediator of cancer, is regulated by ROS.

On the other hand, a high level of ROS can suppress tumor growth through the sustained activation of cell-cycle inhibitor [32] [33] and induction of cell death as well as senescence by damaging macromolecules. In fact, most of the chemotherapeutic and radiotherapeutic agents kill cancer cells by augmenting ROS stress.

Modest levels of ROS are required for cancer cells to survive, whereas excessive levels kill them. Metabolic adaptation in tumours balances the cells' need for energy with equally important need for macromolecular building blocks and tighter control of redox balance. As a result, production of NADPH is greatly enhanced, which functions as a cofactor to provide reducing power in many enzymatic reactions for macromolecular biosynthesis and at the same time rescuing the cells from excessive ROS produced during rapid proliferation.

As matters stand, lists of examples do not add up to understanding, and facts accumulate without being incorporated into the thinking of many in the field. Specificity is the currency of cell signaling.

However, the very concept of second messengers suggests a lack of spatial resolution and target restriction that runs counter to contemporary notions of specificity in signaling. There is a second problem. Many years after the key facts were in, it still seems paradoxical that ROI and RNI participate in homeostatic regulation of physiologic processes, yet the same molecules kill cells foreign and self to protect the host from infection Killing is the end result of covalent modifications that lead to widespread malfunction.

Signaling reactions are generally reversible; death is not. If a molecule is reactive enough to be lethal, how can it be specific and reversible enough to participate in signaling? By it appeared that what separates signaling from killing by ROI and RNI is chiefly the tempo and extent of their production 1.

However, recent experiments have taught us that iNOS and phox can carry out signaling functions 25 Thus, the paradox is not dispelled by pigeonholing the enzymes that generate the products.

The present commentary suggests that the answer to the apparent paradox of homeostatic signaling by ROI and RNI lies, as is usual with paradoxes, in taking a less constrained view of its central concept. Below it is recounted how the paramount concept of specificity in intracellular signaling evolved from an earlier idea that persists in an uneasy relationship with its descendant.

The discord is eased by the concept that there are several individually essential and mutually complementary kinds of specificity in intracellular signaling. Specificity of three kinds When most of us think about cell signaling, we envision oligomolecular interactions among signaling intermediates. A given signaling intermediate reacts with a small number of other intermediates to which it binds transiently and noncovalently as a ligand, receptor, adapter, enzyme, cosubstrate, or cofactor by virtue of complementarity of shape.

Shape in this context includes not just the disposition of mass in space but also the accompanying distribution of charge and hydrophobicity. Complementarity of shape can be defined as the set of properties that determine that two distinct types of molecules will approach each other significantly more closely and for a significantly longer time than the average for all pairwise combinations of molecules in the system under consideration here, a cell.

Most of the signaling intermediates with this type of specificity are macromolecules. The great diversity of macromolecular shapes and the highly restricted distribution of any given shape dictate that this type of specificity is oligomolecular in its range. Binding may lead to a covalent modification, as when a protein kinase attaches a phosphate to its substrate, but the associations that precede covalent modification are determined by the fit between enzyme and substrate.

Similarly, when signaling paths involve dephosphorylation or proteolysis, the breaking of a covalent bond is preceded by a specific handshake between two or more molecules based on shape. Related to this notion of specificity is a view of information flow in signaling as being linear continuouswhether the lines are simple, branched, or webbed The information is relayed privately, that is, shielded from most other signaling pathways in the same cell. Progress in genomics and proteomics, along with discoveries that many signaling pathways are conserved among disparate organisms, makes it reasonable to anticipate that most oligomolecular signaling pathways will soon be identified.

It is already apparent that a list of such pathways will not add up to understanding physiology within a cell. Oligomolecular networks link pathways together However, it is difficult to imagine that a cell could coordinate all its responses solely by relying on the linkage of each of several hundred pathways to a subset of the others.

If the pass-through of a signal from path 1 to path 3 depended on simultaneous activity in path 2, the linkage between 1 and 3 would be erratic.

Signal strength would fade and error would mount as the number of relays increased. A signal perceived nearly simultaneously by individually distinct signaling pathways across a cell can be described as public. As illustrated in Figure 1 and Table 1macromolecular signaling intermediates such as kinases and phosphatases act with oligomolecular specificity to signal locally in a cell in a linear, private manner. Diffusion enables these mediators to activate several pathways at once that are not themselves spatially linked, in which case information can flow in a discontinuous manner.

Reactive oxygen species - Wikipedia

They can act both locally and distantly to tune responses to agonists, a role for which they are suited not only by their small size and diffusibility but also by their reactive chemistry. In fact, chemical reactivity is their distinctive feature as signaling molecules, because it imparts submolecular atomic specificity and therewith multimolecular specificity. The combination of diffusibility and multimolecular reactivity suits ROI and RNI to the role of public mediators of intracellular signaling.

Figure 1 Distinct types of specificity in intracellular signaling. Two first messengers, A and B, each initiate a separate, private, linear signaling pathway that proceeds with type I specificity via oligomolecular handshakes.

A or B may also arise intracellularly and activate a pathway that is entirely intracellular. A micromolecular first messenger, C, may originate outside or inside the cell.

C is shown arising from mitochondria, but there may be other intracellular origins, including type I pathways. C diffuses to various locations in the cell and initiates several signaling pathways. Where C is bicarbonate and the next component of the pathway is bicarbonate-activated adenylyl cyclase, cAMP diffuses a short distance to the next mediator, such as protein kinase A. Panels II and III illustrate ways in which information can be shared publicly via discontinuous pathways.

Table 1 Types of specificity in intracellular signaling When a cell responds to an agonist, it commits resources to a particular program of gene expression and posttranslational behavior with distinct metabolic consequences.

Multiple incoming signals call for multiple resource commitments. A cell will collapse in chaos if it fails to prioritize its commitments and balance them with its resources. Thus, a major homeostatic role of ROI and RNI may be to link the behavioral and differentiative commitments of a cell to its metabolic budget.

It is only the exaggerated production of ROI and RNI that leads to maladaptive signaling in the producing cell or a neighboring or ingested target cell, resulting in disease or defense, depending on the context. Terms of discourse Some scientists write as if the terms ROI and RNI lack precise definitions, or conversely, as if all members of each class fit one definition.

ROI and RNI are sets of related molecules with individually distinct chemical and biological properties. ROI refers to all oxidation and excitation states of O2, from superoxide O2. Their distinctive properties arise from differences in such features as reactivity, half-life, and lipid solubility. Oxidative reactions include carbonylations, hydroxylations, peroxidations, or oxidation of sulfhydryls to disulfides or sulfenic, sulfinic, or sulfonic acids.

Nitrosative reactions include nitrosylation of sulfhydryls or metals and nitrations of tyrosine residues. It is critical that many of these reactions are reversible, such as formation of methionine sulfoxides and cysteinyl nitrosyls, disulfides, and sulfenic acids. With respect to the biologic actions of ROI and RNI, some authors use the terms oxidative stress or nitrosative stress in a neutral sense indistinguishable from perturbation.

However, most use it to mean reactions that threaten or cause harm. The frame of reference of the present discussion is that ROI and RNI are routinely produced throughout the aerobic biome.

Evolution has capitalized on their properties to put them to use as signaling molecules, including in the special case of host defense. From this perspective, the molecules usually referred to as antioxidant and antinitrosative defenses spend most of their time acting as integral parts of homeostatic signaling systems.

Formation of reactive oxygen species in mitochondria in hindi .

As with any aspect of physiology, production of ROI and RNI can become excessive to the point that it is maladaptive, if not for the producing cell, then for a target cell. Second messengers and second thoughts The modern era of cell signaling had its beginnings in work that Earl Sutherland summarized in his Nobel address over 30 years ago Sutherland brought the study of hormone action from the level of the organism or organ to the level of the individual cell, thereby helping to open the field of signal transduction.

Free radical generation in neutrophils and macrophages during phagocytosis. Reactive species are released during phagocytosis. Host defense is a primary function of the NOX family, facilitating the killing of microorganisms by the release of ROS.

Oxidative Medicine and Cellular Longevity

They are also known to play a role in cellular signaling and induce a calcium release from intracellular stores. Purified endothelial nitric oxide synthase can also generate superoxide during the process of cell signaling using nitric oxide NO [ 10 ]. The direct killing of microorganisms is not solely done by oxidants, as other mechanisms such as phagocytosis and the release of antimicrobial products also facilitate this process.

Inside phagosomes, bacteria are ingested and killed by neutrophils. Cytoplasmic granules, for example, myeloperoxidases, are also released within these phagosomes, forming strong acids with a decrease in pH and causing microbial destruction [ 12 ].

Other sources of intracellular ROS are the cytochrome P enzymes. The cytochrome P enzymes CYPpresent in the liver, produce free radicals as a result of metabolizing xenobiotics crucial in endogenous functions.

CYP enzymes convert some xenobiotics into toxic quinones and semiquinones, which generate H2O2 and superoxide anions [ 13 ]. Cytochrome P enzymes heme-thiolate enzymes are also responsible for the oxidation of lipophilic compounds. If there is poor coupling of the P catalytic cycle, it can cause the continuous production of ROS.

This continuous generation can cause lipid peroxidation, cell toxicity, and death [ 14 ].

reactive oxygen and nitrogen intermediates in the relationship

However, various antioxidant systems such as catalases, GSH-Px glutathione peroxidasesand the SODs superoxide dismutases are present to counteract the effect of elevated ROS levels and are activated under oxidative stress [ 15 ].

SODs are not an antioxidant per se, as they remove the superoxide, but they cause the generation of hydrogen peroxide. As a result of the interaction of reactive species with various signaling molecules due to oxidative stress or reductiona number of processes, such as differentiation, iron hemostasis, and DNA and nucleic acid cycles, are affected [ 17 ] Table 1.

ROS regulation of pathways. MAPKs are protein kinases involved in a variety of cellular functions which are activated by ROS, but the mechanism of action is unclear [ 18 ]. There may be modifications in the amino acid sequence of related proteins, resulting in the activation of MAPKs, or certain oxidative changes in intracellular kinases.

The KeapNrf2-ARE pathway is important for maintaining the cellular redox, balance, and metabolism. At low levels of Akt, ROS can be removed from the cells, with normal growth then taking place [ 19 ] Figure 4. ROS and major signaling pathways. ROS activates signaling molecules within various pathways, such as MAPKs mitogen-activated protein kinase the major pathway for cell cycles and apoptosisKeapNrf2-ARE a regulator of the cellular redox balance and metabolismand PI3K-Akt a regulator of protein synthesis, cell proliferation, and drug resistance.

Sources of ROS in Dentistry Reactive oxygen species are known to have effects on wound healing, immunological response generation, and antibacterial properties, all of which have made them popular during dental treatments. However, ROS may also be a byproduct of resin cements, photosensitizers, and lasers, used often in dentistry, which may be harmful to cell survival in the long run Table 2.

Sources of ROS in dentistry. Nonthermal Atmospheric Pressure Plasma Applications Plasma medicine has emerged as a field of research combining the aspects of physics and life sciences [ 2021 ].

reactive oxygen and nitrogen intermediates in the relationship

Cold atmospheric pressure plasma CAP has been used extensively for biomedical applications. They demonstrated that plasma-activated media PAM can have antitumor effects on chemoresistant cells both in vitro and in vivo. They noted accelerated cell proliferation and keratinocyte migration. These findings may be beneficial for future treatments of diabetes mellitus. Studies are being done to identify plasma applications in microsurgery. Such evaluations can be utilized in future studies of cell manipulation in tissues [ 25 ].

The plasma needle has also emerged as a nonaggressive plasma source which can be used on mammalian cells and tissues without damaging the cells or causing cell necrosis. Nonthermal plasma has been used in dermatology [ 26 ] and wound healing applications in the medical field and in research; however, its use in dentistry is relatively new, with studies being carried out for sterilization in vitro of the root surfaces of the teeth, bleaching, or the removal of caries from the tooth.

A user-friendly RC-plasma jet device capable of generating plasma within the root canal has been developed by Lu et al.

The jet can be directly placed in the root canal, facilitating painless plasma disinfection. The device is currently undergoing clinical trials [ 28 ].

Additionally, Pierdzioch et al. Nonthermal Plasma as a Source of ROS Generation for Biomedical Applications Plasma jets, corona discharges [ 30 ], and barrier discharges have been applied therapeutically [ 31 ].

Plasma jets can generate a column of plasma outside of electrodes into the surrounding area in a highly controlled manner, thus playing a crucial role in applications in the medical field. The ability of the plasma jet to penetrate into small structures via a direct or indirect mode as well as the small size and lightweight of this device makes it ideal for use during medical and dental treatments. The jet is operated such that there is a constant high voltage supply followed by the cutting off of the supply plasma on and plasma off.

Nonthermal plasma NTP consists of partially ionized gases such as oxygen, helium, and argon. Low-pressure plasmas are known to generate very high concentrations of reactive species. Nonthermal plasma involves mostly electrons that are energized with no significant heating of ions or the constituent gases within [ 30 ]. NTP has been used for the sterilization of instruments [ 32 ] and bacteria [ 33 ], in wound healing, and in other procedures Figure 5.

The argon plasma jet kINPen a commercially available device has been used successfully for wound healing procedures.

When applied, the device generates ROS, ions, UV rays, magnetic fields, neutral particles, and others. However, if used correctly, these types of radiation are not harmful to humans. Components of a plasma jet and DBD dielectric barrier discharge plasma. A plasma jet can penetrate into small structures and it has a small size and lightweight, making it ideal for use in dental treatments.

DBB plasma device consists of a carrier gas, which moves between two electrodes and is ionized to create plasma. The introduction of nonthermal plasma in dentistry, due to its ease of use and painless characteristic, may eventually help to eliminate fear of dentistry in patients [ 35 ]. Nonthermal plasma can be used to treat various dental problems, such as the elimination of caries, root canal sterilization, and bleaching.

The application of this type of plasma can be done by both direct and indirect means. O3, NO, and OH radicals are released, in biosolutions, as a result of interaction between plasma and liquid [ 36 ], which further act on cells and tissues. The use of nonthermal plasma for experimental [ 16 ] as well as clinical trials [ 34 ] has been done on a large scale in the medical field; however, in dentistry, clinical applications of nonthermal plasma are still in the nascent stage.

Dental biofilms are a major source of stress to clinicians, as they contain various types of bacteria, such as Streptococcus and E. A plasma application in conjunction with sprayed water has been used for the successful elimination of biofilms.

Several researchers have confirmed that the use of a plasma device was superior to chlorhexidine for biofilm removal. The biofilm removal outcomes in both cases were comparable, but the nonthermal plasma treatment resulted in additional chemical cleansing, leading to a significant plaque reduction.

Porphyromonas gingivalis, a major periodontal pathogen, can be eliminated successfully with an intermittent plasma dose according to work by Mahasneh et al. Atmospheric plasma sources have also been used for alterations of surfaces for cell attachment for dental treatments such as the installation of titanium and poly-lactonic surfaces [ 41 ] and on dental biomaterials.

Using plasma can increase the wettability of the implant surface, which facilitates the spreading of cells such as fibroblasts and osteoblasts, thereby enabling better osseointegration [ 42 ].

The effect of a plasma treatment on the wettability of elastomeric impression materials was also investigated. Increased wettability results in a better impression of the tooth surface. Different materials such as addition silicones, condensation silicones, and polyether impression materials were used. It was concluded that the plasma treatment resulted in the formation of a high-energy impression surface on the tested materials [ 44 ].