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Nitric oxide--"double edged sword".

Introduction

Nitric oxide (NO) is synthesized by a complex family of enzymes called NO synthases (NOS) and thought to be one of the oldest molecules on earth, being formed in the primitive atmosphere of the cooling planet. It is a short-lived, highly reactive free radical. Its discovery in 1987 accounted for the bioactivity of endothelium derived relaxing factor (EDRF) which rapidly led to an explosion of information on the physiological and pathological roles of this molecule [1,2]. Since its discovery as a biological messenger, it has been implicated in many disease processes, ranging from septic shock to cancer, causing concentration dependent conformational changes in proteins, enzymes and DNA, predominantly by its reaction with transition metals and thiol residues. Although high concentrations of NO are cytotoxic, the levels produced in many human cancers possibly facilitate tumour growth and dissemination [3].

Basic Chemistry and Actions of NO

NO is an inorganic free radical formed as a byproduct of the stepwise conversion of L-arginine to citrulline by hydroxylation. It is a stable colorless gas, which is moderately soluble in [H.sub.2]O. In solution, it has a half life of less than 30 sec, undergoing oxidation to nitrite and nitrate.

In NO, the arrangement of one atom of nitrogen and one atom of oxygen leaves an unpaired electron, which makes the molecule a highly reactive free radical. NO readily reacts with superoxide, oxygen and thiol groups (-SH) to produce a number of other products, such as nitrosothiols (R-SNO), the toxic molecule peroxynitrite (ONOO-) and nitrites (NOx). All these molecules are also called as reactive nitrogen oxide species.

Peroxynitrite is very toxic, particularly to DNA and to enzymes involved in DNA repair. Reactive nitrogen oxide species react with transition metals (such as zinc and iron in heme containing proteins) and thiol groups in various enzymes and proteins. The resulting effects are concentration dependent, but can lead to inhibition of enzymes such as cytochrome c oxidase, resulting in decreased ATP production and cell death [4,5].

The physiological activities of NO are of two types

1. cGMP dependent

2. cGMP independent

cGMP dependent actions

NO interacts with the heme group in the enzyme guanylate cyclase in the presence of cGMP [6]. Effects following NO-induced guanylate cyclase activation include the regulation of vascular tone, and a complex role as a neuromodulator in the central nervous system. NO is implicated as a pain modulator in various conditions [7].

cGMP independent actions

NO actions that are cGMP independent include a pivotal role during the process of angiogenesis, [8] where it is thought to interact with many key molecules including the potent angiogenic factor, vascular endothelial growth factor (VEGF). NO acts as both an upstream activator and downstream effector molecule for VEGF [9]. It also has immunocytotoxicity against both pathogens and tumours [10,11] suggested that the NO concentrations found in human cancers are unlikely to be sufficient to produce tumour cell death or apoptosis, and instead are thought to be responsible for enhancing angiogenesis and tumour dissemination.

Biosynthesis of NO

NO is synthesized by a complex family of enzymes called NO syntheses (NOS) (figure 1). The amino acid L-arginine is the substrate for the NOS enzymes, generating NO and the by-product L-citrulline [12]. There are three NOS enzymes, each produced by distinct genes and named in order of discovery [13].

* NOS 1 was the first to be purified and cloned from neural tissue (nNOS).

* NOS2 is an inducible, calcium-independent isoform, also called (iNOS).

* NOS3 is the isoform first found in endothelial cells, also called (eNOS).

Bacterial NOS (bNOS) has been shown to protect bacteria against oxidative stress, diverse antibiotics, and host immune response (Table 1) [14].

The wide variety of roles described for NO can be placed into one of three categories:

* Intracellular signal.

* Transcellular messenger.

* A cytotoxic species.

Diseases and conditions that are associated with altered nitric oxide production are hypertension and hypotension, Thromboembolic disease, Septic shock, Bronchospasm, Acute respiratory distress syndrome (ARDS),Pulmonary hypertension, Renal failure, Immune deficiency HIV induced encephalopathy, Impotence, Depression, Malignancy. NOS 1 and NOS3 may themselves be induced under certain conditions (such as pregnancy) [15] and NOS2 is expressed constantly in certain sites (such as basal skin keratinocytes and salivary duct cells). Unlike NOS1 and NOS3, induction of NOS2 results in continuous production of NO because of tight calmodulin binding, which allow electrons to pass from the haem group to the flavin (FMN, FAD) and nicotinamide (NADPH) electron accepting co-factors [12].

It is recognized that NO and related compounds have a complex role in cancer biology, been implicated in both tumour progression and inhibition [16]. Despite some 33000 research papers written to date on NO, few have concentrated on head and neck pathosis.

Recent investigations on NOS expression in tumor tissue indicate that, at least for certain tumors, NO may mediate one or more of these roles during the growth of human [17]. Multifaceted biological effects of nitric oxide [18] are discussed in chart 1.

Chemical Biology of NO

During the mid-1990s, the concept of the chemical biology of NO was introduced to explain this complexity in the context of biological conditions. For instance, various reactions of nitrogen oxides occur over many days at elevated temperature and pressure, which makes them kinetically and thermodynamically unlikely and incompatible with human physiology [18]. On the other hand, some reactions are sufficiently fast to occur under achievable biological conditions.

The chemical biology of NO divides these potential reactions into two categories : direct and indirect [19]. One advantage of dividing the chemistry of NO in these two categories is that direct effects generally occur at low concentrations, whereas indirect effects occur at much higher concentrations.

Direct effects of NO are those chemical reactions that occur fast enough to allow NO to react directly with a biological target molecule [20].

Direct effects of NO

Three major types of NO reactions are seen with metals

1. The direct reactions of NO to metal centre.

2. NO redox reaction to dioxygen metal complexes.

3. Reaction of NO with high valent metals to form metal nitrosyls.

NO reacts with metalloproteins containing heme moieties such as guanylate cyclase and Cytochrome p450. The reaction of NO on guanylate cyclase has profound effects on vascular tone, platelet function, neurotransmission and a variety of other intercellular functions. Cytochrome p450 are a family of enzymes involved in synthesis and catabolism of numerous biomolecules such as fatty acids, steroids, and prostaglandins. Cytochrome p450 activity is inhibited by NO in either reversible or irreversible. Reversible inhibition is direct one in which NO binds to heme to prevent the oxygen binding, thus inhibiting its catalysis. Irreversible inhibition is mediated by the formation of superoxide formed by the autoxidation of NO. Superoxide binds to the cysteine ligand of heme present in CP450 enzyme and prevents the reattachment of cysteine ligand to heme [20,21].

An important direct effect of NO is the reaction between NO and oxyhemoglobulin to form methemoglobulin and nitrate. The reaction between oxyhemoglobulin and NO is one of the primary metabolic fates as well as primary detoxification mechanism for NO. NO also converts high valent metals which abuses tissue damage to low valent metals by their reduction. NO reacts with catalase, which protects cells from hydrogen peroxide and inhibits its function, which can cause cytotoxicity [22].

Indirect effects

1. NO forms RNOS (Peroxynitrite) which are injurious to biological tissues[23].

2. Activities of RNOS includes.

3. Lipid peroxidation.

4. Glutathione depletion by oxidation.

5. DNA damage by nitrosation, deamination and oxidation.

6. High concentration cause cellular necrosis.

7. Law concentration cause apoptosis.

8. Mutation of cells.

There are three potential chemical mechanisms by which NO can damage DNA. The first is the direct reaction of peroxy nitrite with the DNA structure. The second is through inhibition of repair process. The third is the increased production of genotoxic species [23]. DNA when exposed to NO results in the deamination of cytosine, adenine and guanine unit present in DNA. Deamination results in the conversion of cytosine to uracil, guanine to xanthine and adenine to hypoxanthine [24,25]. The chemical biology of NO is discussed in chart 2.

Protective Mechanism of NO

1. NO protects cells from hydrogen peroxide mediated toxicity. When peroxide enters cell, it quickly reacts with heme proteins present in the cell to form hypervalent complexes, which can lead to lipid peroxidation. These hypervalent complexes can damage DNA. NO can react with these hypervalent complexes, restoring these oxidized species to ferric form, thereby limiting intracellular damage [26,27].

2. NO can protect proteins against oxidative stress. NO also provides cellular signals for the up regulation of variety of protective genes [28,29].

3. NO can protect cells against apoptosis under different conditions. NO protects hepatocytes from TNF- a induced apoptosis. NO causes the apoptosis of certain tumour cells indirectly. NO increase P53 expression in response to DNA damage, which leads to apoptosis [30]. At high concentration of NO, P53 may be inactivated because of the formation of super oxide. It is suggested that the cells which are present from a significant distance from iNOS source may undergo apoptosis, while cells close to iNOS source may degrade the p53 protein formed resulting in protection from apoptosis, which suggest a special relationship in cells with regard to the effect of NO on apoptosis [31,32].

iNOS (inducible Nitric Oxide Synthase)

The role of nitric oxide (NO) generated by the inducible isoform of nitric oxide synthase (iNOS) is very complex. Induction of iNOS expression and hence NO production has been described to have beneficial and detrimental consequences and seems to be involved in the pathophysiology of different human diseases.

iNOS is rarely expressed in normal tissue and its expression occurs in response to cytotoxin, endotoxin, tumour cells or inflammatory cells participating in pathologic procedures. Prolonged NO production by iNOS has been implicated in tumour progression, angiogenesis and metastasis in human cancer [13, 3234].

An important regulator of iNOS is the tumour suppressor gene P53, which senses raised cellular NO and inhibits iNOS by a negative feedback loop. This relationship has important implications in oral cancer. At a post transcription level, transforming growth factor-a (TGF-a) and NO can destabilize mRNA. In chronic inflammatory conditions, iNOS expression is also dependent on the overall cytokine balance. iNOS is found in various cells including macrophages and natural killer cells in the immune system [20,35].

iNOS can modulate the expression of matrix metalloproteins (MMP) [36]. MMP are a family of highly homologous proteolytic enzymes involved in the degradation of basement membrane and other extracellular components. iNOS can also down regulate the synthesis of Tissue Inhibitors of Matrix Metalloproteases (TIMP). The invasion stimulating effects of NO are mediated by the down regulation of TIMP and up-regulation of MMP [36].

iNOS gene is under the transcriptional control of variety of inflammatory mediators like cytokines and lipopolysaccharides (LPS). iNOS gene is 37Kb in length and is in chromosome 17. Human iNOS has Hypoxia responsive element (HRE). HRE present in iNOS helps for the iNOS induction at decreased oxygen level. Induction of hypoxia inducible factor by hypoxia and binding of iNOS-HRE in cooperation with INF-a leads to iNOS induction [37,38].

NO, produced by iNOS, may cause DNA damage which may occur through several mechanisms including nitrosative deamination, DNA strand breakage by iNOS, oxidative damage by peroxynitrite, and DNA modification by metabolically activated N-nitrosamines. The iNOS isoform can produce high, persistent concentrations of NO upon induction with cytokines in many cell types and is expressed in the resting state in other cells, potentially resulting in cytotoxicity, tissue damage, or DNA damage [23].

The pathways regulating iNOS expression seem to vary in different cells or different species. In general, activation of the transcription factors nuclear factor (NF) kB and signal transducer and activator of transcription (STAT) 1a and thereby activation of the iNOS promoter seems to be an essential step in the regulation of iNOS expression in most cells. Also, post transcriptional mechanisms are critically involved in the regulation of iNOS expression [39]. However, it is believed generally that modulation of iNOS expression is the most important component of iNOS regulation.

Pathways of iNOS Induction in Human Cells

Maximal induction of the iNOS gene necessitates signals such as:

* IFN - a

* Endotoxins

* TNF-a

* IL-1a

TNF-a or IL- 1a stimulate iNOS transcription by activation of the transcription factor NF-eB which binds to a eB element in the NOS promoter [40]. IFN- a activates the transcription factor IRF-1 (interferon regulatory factor-1), which also binds to elements in the NOS promoter [41,42]. Synergism between NF-eB and IRF-1 is believed to be achieved partly through the interaction between these two transcription factors while bound to the NOS promoter, leading to modifications in the physical structure of the NOS 5' flanking region [40]. This pathway is important in cases of microbial infection where NO-mediated cytotoxicity may be essential in fighting the infection but not in cancer because endotoxins or TNF-a are not normally present in tumors [43].

In tumors, however, hypoxia which is often present in the central areas that are not well-vascularized synergistically interacts with IFN-a to induce iNOS expression through the physical interaction between HIF1 and IRF-1. It is believed that the requirement for IFN-a and HIF-1(hypoxia-inducible factor) co-stimulation in the induction of iNOS may be crucial to the prevention of iNOS expression during non-inflammatory hypoxic conditions, such as anemia [43-46].

Various Transcription factors involved in the iNOS expression includes

* NF-eB(Nuclear factor eB)

* IRF(Interferon Regulatory Factor)

* STAT-1a (Signal Transducer and activator of transcription factor 1-a)

* Activating Protein- 1(AP-1)

The bacterial lipopolysaccharide (LPS) and interferon-a (IFN-a), numerous other factors induce the production of the enzyme iNOS. These include the cytokines IFN a, TNF-a, IL-1, IL-10, IL-12, Platelet activating factor (PAF) and NF-eB once induced the enzyme continues to produce much higher NO concentrations than the other two NOS isoforms, for many hours or even days until the protein is eventually inactivated, probably as a result of NO-induced protein modification [47].

Influence of iNOS on Cancer Biology

NO appears to play a key role in tumour angiogenesis and spread in patients with head and neck cancer [48]. It plays a significant role in angiogenesis by cGMP dependent mechanism and was shown to modulate the activity of angiogenic VEGF Importantly, NF-eB and iNOS are the key components of the angiogenic cascade, which contribute to VEGF induced angiogenesis through up regulation of VEGF in many tumours and believed to be the upstream regulators of iNOS, which induces NO generation, which further activate angiogenic factor[49,50].

Interestingly, lymph node metastasis of OSCC has shown with increase in iNOS leads to increase in microvessel counts [51] and also 6-35 fold elevated levels of NO oxidation product such as nitrite in synovial fluid of rheumatoid arthritis [52].

Effects of iNOS in oral lesions

With all the possible cytotoxic effects of NO against the proliferation of stem cells in oral premalignant lesions and conditions like oral submucous fibrosis, oral lichen planus including the periodontal disease it is mandatory to conduct further studies on this naked molecule [53,54,55].

NO on Biomaterial Implants-does it have an impact?

Eventhough NO exhibits an exceptional promise for the forthcoming generations; its use in the field of medicine as well in dentistry is still questionable. Few authors had explained when this NO is impregnated on the medical devices like implants they exhibited promising results with its potent ability towards the inhibiting nature on platelet activation, adhesion and smooth muscle cell proliferation [56]. Few studies have revealed that the use of NO subcutaneously demonstrated the reduction in biomaterial associated infection [57].

Conclusion

Depending on the overall cytokine balance, NO is found in various cells including macrophages and natural killer cells in the immune system. NO, being an important indicator of mediating the inflammation, controlling it may enhance the treatment as well; development of a target drug to this molecule may be useful. Hence, regulation of this highly free radical may definitely aid in controlling the disease progression and multiple trials of its application are mandatory.

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Ramesh KSV (1) *, Swetha P (2), Madahavan Nirnmal (3), Rama Krishna Alla (4)

(1) Department of Periodontics, (2) Department of Oral & Maxillofacial Pathology, (4) Department of Dental Materials, Vishnu Dental College, Bhimavaram, Andhra Pradesh, India

(3) Department of Oral and Maxillofacial Pathology, Rajah Muthaiah Dental College & Hospital, Annamalai University, Chidambaram, Tamilnadu, India

* Corresponding author: Ramesh KSV; ksv006@yahoo.com

Received 19 September 2013; Accepted 1 December 2013; Available online 1 March 2014

Table 1: Different forms of NO synthase have been
classified as follows (14)

Name               Genes       Location

Neuronal NOS       NOS1        Nervous Tissue
(nNOS or NOS1)                 Skeletal Muscle Type Ii

Inducible NOS      NOS2        Immune System
(iNOS or NOS2)                 Cardiovascular System

Endothelial NOS    NOS3        Endothelium
(eNOS or NOS3
or cNOS)

Bacterial NOS      multiple    Various Gram(+) Species
(bNOS)

Name               Function

Neuronal NOS       Cell communication
(nNOS or NOS1)

Inducible NOS      Immune defense against
(iNOS or NOS2)     pathogens

Endothelial NOS    Vasodilation
(eNOS or NOS3
or cNOS)

Bacterial NOS      Defense Against Oxidative
(bNOS)             Stress, Antibiotics,
                   Immune Attack
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Date:Jan 1, 2014
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