**4. Conclusion**

Several clinical trials have shown their usefulness in the context of preventing thrombus formation [87]. NO-donating nanoparticle systems represent a new promising tumoricidal agents, thanks to their unique properties: (i) strengthening NO-donor stability, (ii) loading a

The modulation of NOS activity is another interesting strategy. In some pathologies inducing exacerbating inflammation (sepsis), a localized "nitrosative burst" occurs, and inhibition of NOS function is a crucial element. Thus, several l-arginine precursor analogs (N<sup>ω</sup>-substituted l-arginine) were developed and tested. However, since l-arginine is the common point between all NOS isoforms, these analogs represent nonselective drugs. Moreover, such therapy did not reach clinical studies on human stage despite its effects on canine vascular tone [89]. Thus, investigation on a more selective inhibition of iNOS, crucial for inflammation, was conducted through transgenic animals. Unfortunately, iNOS knockout mice exhibit an increase in mortality following polymicrobial sepsis [90]. More recently, researcher focused on increasing NO delivery within cancers. Thus, thanks to technical progress and scientific knowledge updating, iNOS-based suicide gene therapy was investigated through viral vector use. This treatment exhibits promising tumoricidal effects and appears interesting for its

The third strategy is the direct gaseous delivery of NO in the treatment of various infection diseases related to antibiotic resistant bacteria. Ghaffari et al. provided a considerable work on this topic. First, they developed an ingenious delivery system usefulness for the monitoring of gNO effects on microorganisms (bacteria and fungi) and eukaryotic cells [92]. Then, they reported an effective concentration of gNO up to 200 ppm in continuous 4 h delivery exhibiting bacteriostatic effects on a representative group of microorganisms (*Staphylococcus aureus*, *Pseudomonas aeruginosa*, *E. coli*, *Candida albicans*, and *Group B Streptococcus*). Moreover, no toxic effects were observed on representative mammalian cell lines (dermal fibroblasts) of wound-healing pathology such as leg ulcer or burn injuries [93]. Thus, these promising results placed gNO as a potential topical antibiotic agent [94]. Later, they also investigated the potential use of inhaled gNO in the treatment of pathogenic infection in the case of cystic fibrosis. Indeed, this pathology is a threatening pulmonary disease where microbial infection could be lethal. However, a continuous exposure of gNO at such concentration can lead to severe

large amount of NO, and (iii) possibility to trigger NO releasing [88].

34 Emerging Pollutants - Some Strategies for the Quality Preservation of Our Environment

**Table 1.** The different classes of NO donor (adapted from [86]).

specific and localized iNOS expression on animal models [91].

In summary, this review of the literature shows that NOx is ubiquitous and essential in our lives. We are exposed to these compounds through environmental contaminations, but they also result from physiological processes, infections, diseases, or even drugs. NO and derivatives are implicated in a large diversity of vital functions including brain functions; motricity; cardiac, vascular, and pulmonary functions; and immunity. For these reasons, NOx is key molecules of major biochemical interest. As all active substances, NOx can exert both beneficial and adverse effects with regard to the exposition dose. The physiological adaptation to NOx results from a fine-tuned equilibrium where detoxification plays crucial roles. Myriad of finely regulated processes has emerged in response to nitrosative stress. Our knowledge still remains incomplete, and future studies are necessary to finely precise the synergy of each NOx implemented in nitrosative stress, especially when they are presented in gaseous phase that remains less explored. However, in spite of all previously described mechanisms to counteract the nitrosative stress, abnormal NOx thresholds could trigger a wide range of pathologies and even death. These antagonists, positive and negative effects, of NOx are actually intriguing. So, many researches are now focusing on NOx producing pathways to find the most effective treatments and drugs. More investigations are still needed to better understand the real potential of NOx as antitumor, antibacterial agents, and their safe clinical use.
