Potent application of nitric oxide–releasing nanomaterials against toxigenic fungi and their mycotoxins

Chapter 20

Potent application of nitric oxideereleasing nanomaterials against toxigenic fungi and their mycotoxins Amedea B. Seabra, Wallace R. Rolim, Joana C. Pieretti Center for Natural and Human Sciences (CCNH), Federal University of ABC (UFABC), Santo Andre´, SP, Brazil

1. Introduction Fungi produce various secondary metabolites, including toxic molecules without any function in its metabolism [1]. There are around 400 metabolites, such as terpenoids, alkaloids, or polyketides, and mycotoxins produced by fungi [2]. Mycotoxigenic fungi represent a worldwide issue for pre- and postharvesting agricultural commodities, especially for products rich in carbohydrates, which are attractive sites for colonization of fungi, representing a contamination of 80% of the global agricultural supplies [3]. These mycotoxins are introduced into the food chain either by (1) livestock feeding, allowing the mycotoxins to be present in meat, milk, and other derivatives or (2) direct human or animal consume. These are stable secondary metabolites that withstand to a digestion process and to temperature treatments, such as cooking and freezing [4]. Among several fungi, Aspergillus, Fusarium, and Penicillium stand out for producing hazardous toxins, such as aflatoxins that present oncogenic properties and induce infections [5], fumonisins that has been related to cancer, and ochratoxin associated not only to nephropathy but also to hepatotoxic and carcinogenic behaviors [6]. In this context, there is an increasing need to develop new strategies to combat mycotoxins. Among the possible candidates for the control of mycotoxins, nitric oxide (NO) might find important applications because of its potent and great antimicrobial action [7]. NO donors have been successfully explored as antimicrobial agents against pathogenic bacteria [8,9], protozoa Nanomycotoxicology. https://doi.org/10.1016/B978-0-12-817998-7.00020-3 Copyright © 2020 Elsevier Inc. All rights reserved.

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[10], and fungi [11]. Interestingly, NO donors are not toxic to mammalian cells at concentration ranges suitable for antimicrobial applications [8]. Therefore, this chapter highlights the potent uses of NO donors, in particular NOreleasing nanomaterials, in the management of mycotoxins and toxicogenic fungi.

2. Chemistry and biology of NO Until the 1970s, NO was known to be carcinogenic and an air pollutant generated from the burning of fuel. In 1982, the journal Science referred NO as the “molecule of the year,” and, in 1998, Robert F. Furchgott, Louis J. Ignarro, and Ferid Murad were awarded the Nobel Prize in physiology for the discovery of the importance of NO in the biological system [12]. NO is a key molecule in the biological system that controls several important biological processes, including the control of the blood pressure, the inhibition of platelet adhesion and aggregation, the neurotransmission, and the defense against microbes (bacteria, virus, fungi, protozoa), in addition to anticancer and antioxidants activities [13,14]. NO is a diatomic and small gas molecule produced by numerous immune cells [13,15]. It is a paramagnetic molecule with 11 electrons in valence layer presenting an electron configuration (s1s)2(s1s*)2(s2s)2(s2s*)2(p2p)4(s2p)2(p2p*) with an unpaired electron located in an antibonding p-orbital, giving the character of a free radical [16]. Thus, NO is relatively unstable. In recent years, important reports have demonstrated the importance of NO in the control of several physiological and pathophysiological processes [12]. Indeed, NO acts as a signaling molecule [17] involved in several physiologic and pathophysiologic processes in mammals [18], including dilatation of blood vessels [19,20], neurotransmission [19], apoptosis [21], wound healing [22], tissue repair [23], and antibacterial, antifungal, and antiparasitic effects [15,17,24]. NO is conserved among organisms (plants and mammals) and also yeasts, bacteria, and fungi [25]. In vivo, NO is synthesized by the enzyme nitric oxide synthase (NOS), which has three isoforms: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS) forms [26]. As shown in Fig. 20.1, NOS catalyzes deoxidation of L-arginine to L-citrulline, producing NO [27]. The nNOS and eNOS isoforms are calcium dependent and produce small concentrations of NO (picomolarenanomolar range) for a short period, whereas iNOS is calcium-independent isoform and produces high concentrations of NO (micromolaremillimolar range) for prolonged periods [27,28]. Low concentrations of NO are related to cytoprotective effects, whereas higher concentrations are related to toxic effects, including antimicrobial activities [29]. As NO is a free radical, it has a half-life in the human body of 1e5 s. NO can rapidly react with other radical species, such as molecular oxygen, leading to the formation of NO2 (Eq. 20.1), which reacts with NO producing N2O3

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FIGURE 20.1 Schematic representation of NO biosynthesis by NOS isoforms. eNOS, endothelial NOS; iNOS, inducible NOS; NO, nitric oxide; NOS, nitric oxide synthase; nNOS, neuronal NOS.

(Eq. 20.2), which is hydrolyzed in the cytosol and extracellular medium leading to the formation of nitrite (NO2) (Eq. 20.3) [30,31]. 2 NO• + O2

NO2• + NO•

2 NO2•

(20.1)

N2O3

(20.2)

N2 O3 þ H2 O/2NO2  þ 2Hþ

(20.3)

The reaction of NO with the superoxide radical anion (O2-•) is one of the most important reactions of NO in biological environment and generates the harmful peroxynitrite (ONOO), which can deteriorate cellular components such as proteins and DNA (Eq. 20.4) [32,33]. NO• + O2-•

ONOO-

(20.4)

The balance between NO synthesis and degradation controls NO homeostasis, which regulates the physiological actions of NO [25]. High concentrations of NO are responsible for nitrosation stress due to the formation of NO-derived compounds. In addition, NO can modify biological molecules via coordination of iron atoms (S-nitrosylation) or nitrosation of thiol groups (S-nitrosation). NO-modified proteins mediate cellular responses through NO signaling. In this sense, low concentrations of NO are important for signal transduction pathways, and higher NO levels produce toxic effects (such as antimicrobial activities) through the generation of nitrosative stress. This leads

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to cellular damage [25]. Most of the antimicrobial actions of NO are directly associated with its oxidized forms, such as N2O3 and ONOO. Thus, as NO is a free radical, in aerated biological systems, NO is oxidized leading to the formation of reactive oxygen and nitrogen species (ROS/RNS) that have cytotoxic effects, including antimicrobial actions against pathogenic microorganisms [13].

3. NO donors As NO is gas and a free radical, its biomedical applications are limited. To enable its use, NO donors have been synthesized to increase the stability of this molecule. NO donors are a heterogeneous group of molecules able to release NO or NO-related species, such as the nitroxyl anion (NO) or the nitrosonium cation (NOþ) [34]. Fig. 20.2 shows the most common classes of NO donors used in biomedical applications, namely S-nitrosothiols (RSNOs), nitroglycerin (NTG), sodium nitroprusside (SNP), and diazeniumdiolate (NONOates). In addition, there are many other classes of NO donors such as organic nitrates, organic nitrites, NOeamino complexes, and rutheniumenitrosyl complexes [35,36]. These NO donors/generators can significantly increase the bioavailability of NO because they act as NO carriers and donors.

4. S-nitrosothiols RSNOs are a class of compounds characterized by a nitroso group (-SNO) attached by a single chemical bond to the sulfur atom of a thiol [34]. S-nitrosoglutathione (GSNO) is an example of an endogenous found RSNO compound that can be chemically synthesized through one of the most abundant intracellular found thiol,

FIGURE 20.2 Main classes of NO donors: (A) S-nitrosothiol (RSNO); (B) nitroglycerin (GTN); (C) sodium nitroprusside (SNP); (D) diazeniumdiolate (NONOate).

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glutathione (GSH) [37]. RSNOs are degraded both enzymatically and nonenzymatically to release free NO, and most of the pharmacological actions of these compounds are a consequence of the nitrosation of cellular proteins [38]. As RSNOs are water-soluble compounds, they can be incorporated into hydrophilic vehicles to be topically applied to tissues allowing the local release of NO [39]. The decomposition of RSNOs can occur thermally, photochemically, or in the presence of copper ions, with NO release and formation of the dimmer RSSR. For example, in the case of GSNO decomposition, free NO is released in addition to formation of oxidized glutathione (GS-SG), according to the equation below [40]: 2GSNO/GS  SG þ 2NO

(20.5)

The cleavage of the SeNO bond occurs homolytically, although the possibility of the formation of NOþ and NO has already been suggested through the heterolytic cleavage of the RSNOs [41]. The antimicrobial actions of RSNOs have been already described against pathogenic bacteria [8,9], protozoa [10], and fungi [11].

5. Organic nitrates (nitroglycerin (glyceryl trinitrate) and isosorbide mononitrate) Organic nitrates such as nitroglycerin and isosorbide mononitrate are the most common NO donors utilized in artery disease; however, these classes of NO donor require enzymatic bioactivation to release NO [42]. Treatment with nitrovasodilators such as isosorbide-5-mononitrate (ISMN) and GTN is used as blood pressure lowering medications to treat cardiovascular disease [43]. GTN has been used for more than a century in medicine [44], and it enzymatically generates NO [45]. Thatcher and coauthors suggested that the NO3  derived from ISMN is rapidly biotransformed to NO2  by reaction with cysteine. The chemical conversion of NO3  into NO is a 3e reduction that can be achieved by a number of possible 2e plus 1e pathways, some of which can be drawn to involve initial liberation of NO2  (Eq. 20.6). Nitrite generates NO via nitrous acid (Eq. 20.7) [42]. RONO2 þ 2e þ Hþ /ROH þ NO2 

(20.6)

NO2  þ e þ Hþ /OH þ NO

(20.7)

The NO formed in aerated medium can react with thiol to generate an RSNO, which activates soluble guanylyl cyclase (sGC), an NO receptor [42].

6. Sodium nitroprusside SNP is an arterial and venous vasodilator used in clinical applications to lower blood pressure, and usually it is used to provide a rapid lowering of blood

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pressure in hypertensive emergencies [46,47]. SNP is a compound that has an iron core bonded with five cyanide groups (CN) and one group of the nitrosonium ion (NOþ) [34]. One concern of these NO donors is the potential to release cyanide group of the structure [47]. SNP does not liberate NO spontaneously in vitro, as it requires partial reduction by a variety of reducing agents present in membrane cells, such as GSH [47]. Grossi and coauthors proposed that the GSH reacts with the complex of Fe(III), reducing Fe(III) to Fe(II) and forming GSNO [48].

7. N-diazeniumdiolates NONOates (1-substituted diazen-l-ium-l,2-diolates) were first synthesized in 1960 [47]. NONOates are compounds that contain the [N(O)NO] functional group. This group is capable of release NO in vitro and in vivo. NONOates are synthesized by the reaction of nucleophilic species (X) to 5 atm of NO under anaerobic conditions and adding a base to stabilize the [N(O)NO] group (Eq. 20.8) [49]. Under physiological conditions, NONOates release 2 mols of NO per mol of NO donor (Eq. 20.9) [47,50]. X þ 2NO/X  ½NðOÞNO

(20.8)

X  ½NðOÞNO /X þ 2NO

(20.9)

The structure of the nucleophilic species influences the rate of decomposition, and it is not catalyzed by thiols or biological tissues [47]. NONOates have been widely utilized in biomedical research due to their ability to release NO spontaneously under physiological conditions [51]. This moiety is bonded to another atom or molecule (X) through a single bond at one of the nitrogens [51]. NONOates have proved to be a useful tool in pharmacological research applications [49].

8. NO and nanomaterials Recently, to optimize the uses of NO in biomedical applications, NO donors have been incorporated into nanomaterials [13]. The combination of NO donors with nanomaterials has been successfully employed in several biomedical applications, including antimicrobial activity [9,13]. Indeed, the incorporation of NO donors in nanomaterials has enabled a sustained and localized release of therapeutic amounts of NO for antimicrobial activities [52], with great potential to combat myotoxicity. Nanotechnology and its application in medicine has shown great potential to improve human health. Considering the uses of nanomaterials in drug delivery, nanoparticles may increase the drug stability, providing an increased drug circulation time and a drug-targeted delivery, contributing to lower doses, reducing drug toxicity and side effects [53]. Despite NO donors potentiate the

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FIGURE 20.3 Main classes of NO-releasing nanoparticles: (A) functionalized metallic nanoparticles; (B) porous silica nanoparticles; (C) polymeric nanoparticles; (D) dendrimers and (E) micelles.

application of NO, their utility is still limited due to storage instability and the lack of delivery and dose controls. Thus, the incorporation of NO donors into nanoparticles (so-called NO nanocarriers) might improve the NO stability, the targeted delivery, and a controlled and long-term NO release [54]. To date, various nanoparticles have been prepared to deliver exogenous NO. In this section, different NO-releasing nanomaterials with potent antimicrobial activity will be discussed, categorized as follows: (A) functionalized metallic nanoparticles; (B) porous silica nanoparticles; (C) polymeric nanoparticles; (D) dendrimers; and (E) micelles (Fig. 20.3). It should be noted that these NO-releasing nanomaterials might find important application in the combat of mycotoxins.

9. Functionalized metallic nanoparticles Metal and metal oxide nanoparticles with a functionalized surface recently attracted great attention as most of them are considered biosafe and have been

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extensively used as drug nanocarriers [55]. Schoenfisch’s group functionalized gold nanoparticles (AuNPs) with NONOate as NO carrier [56]. To this end, the surface of AuNPs was functionalized with ethylenediamine, butylamine, hexanediamine, or diethylenetriamine, followed by exposition to NO gas. The resulting NO-AuNPs presented a size of 2.1 nm, and the NO release was measured, presenting a release from 9750 to 87,000 pmol of NO per mg of nanoparticles and a duration from 200 to 600 min [56]. Similarly, Duong and coworkers described the preparation of functionalized AuNPs for storage and controlled NO release [57]. AuNPs were synthesized by using tetrachloroauric acid as a precursor and trisodium citrate as reducing and stabilizer agent. After, these nanoparticles were functionalized with a previously modified poly(oligoethylene glycol methyl ether methacrylate)-b-poly(vinyl benzyl chloride) (P(OEGMA)-b-P(VBHA)) polymer, followed by an NO gas purge, incorporating a NONOate donor on the surface of AuNPs. This nanomaterial presented a slow NO release at pH 6.8, and it showed great potential for biomedical applications, such as biofilm dispersion and cancer cell cytotoxicity [57]. Likewise, silver nanoparticles (AgNPs) are well known as an antimicrobial agent [58]. Seabra et al. reported the functionalization of the surface of biogenic synthesized catechin-AgNPs with an RSNO group [59]. RSNOcatechin-AgNPs was able to release 346 mmol of NO per gram of nanoparticle and demonstrated potent antibacterial effects against resistant bacteria, indicating the potential uses of NO-releasing AgNPs in antimicrobial applications. Pant et al. reported the functionalization of copper nanoparticles (CuNPs), which have antimicrobial effects, with the NO donor S-nitroso-N-acetylpenicillamine (SNAP) [60]. The authors demonstrated that the NO-releasing mechanism is related to the reduction of Cu0 nanoparticles to Cu2þ. Cu2þ ions are reduced to Cuþ ions, which catalyzes the generation of NO from RSNOs. The use of CuNPs potentiates the controlled release of NO and presented nontoxicity to mammalians cell, being safe for clinical use and showing great potential to be applied in multiple antimicrobial applications [60]. Similarly, NO-releasing hybrid metal oxide/metal nanoparticles combine both particle properties, generating a well-stabilized hybrid nanoparticle with desired properties as a nanocarrier. A superparamagnetic iron oxide@gold (Fe3O4@Au) core shell nanoparticle, conjugated to N-nitrosothiolproline (NO donor) was reported [17]. To obtain the hybrid material, Fe3O4 was firstly prepared by the chemical coprecipitation method and added into the Au nanoparticle synthesis, using sodium citrate as a reducing and a capping agent. The Au-coated Fe3O4 nanoparticles were functionalized with thioproline by self-assembly method and sodium nitrite was posteriorly added to the functionalized material leading to N-nitrosothioproline. As N-nitrosothioproline is a natural and nontoxic molecule, it has high biocompatibility. The material provided an excellent NO release under dark conditions and under irradiation

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with different wavelengths of light and showed efficient cellular uptake and good cytotoxicity against HeLa cancerous cells [17].

10. Porous silica nanoparticles Kafshgari et al. studied the ability of porous silicon nanoparticles (Psi NPs) to entrap and deliver NO [61]. NO was entrapped inside silicon pores by a glucose layer, and it is only released when the pores are exposed to moisture, which conferred a high capacity for sustained NO release, at therapeutic levels. These NPs were effective at killing pathogenic Pseudomonas aeruginosa (P. aeruginosa), Escherichia coli (E. coli), and Staphylococcus aureus (S. aureus) and in addition to inhibit the growth of biofilm-based microbes, as a 47% reduction in Staphylococcus epidermis (S. epidermis) biofilm [61]. Schoenfisch and coworkers presented various studies onto NO-releasing silica nanoparticles. The synthesis of NO-releasing silica nanoparticles was firstly reported in 2009 by Schoenfisch’s group, where the material was prepared via cocondensation of tetrahydroxy- (TEOS) and tetramethoxysilane (TMOS) and aminoalkoxysilane. The amino functional groups present in the obtained silica nanoparticles were converted into N-diazeniumdiolate (NO donor) via NO gas exposure. The size of the silica nanoparticles was widely varied (20e500 nm of diameter) and the NO loading varied from 10 to 5500 ppb/mg, which led to a 30 h maximum release [62]. Afterward, varied surface hydrophobicity onto amine-containing silica nanoparticles was prepared for tuning NO release [63]. As NO therapeutic activity depends on the concentration, controlling this parameter is important to fit specific applications. This study indicated an improvement on the stability of these NO donors and a tunable NO-release kinetics [63]. One of the most recent studies on NOreleasing silica nanoparticles of Schoenfisch’s group presented a controlled scaffold design [64]. The synthesis produced different sizes of nanoparticles (30e1100 nm) with different architectural properties, which NO release exhibited dependence. Thus, the modification with different aminosilanes enabled tuning the NO release kinetics without losing the nanoparticles size control and, unlike the previously shown study, without sacrificing the NO storage [64].

11. Polymeric nanoparticles Polymeric nanoparticles present great potential especially for their high biocompatibility and low cytotoxicity. Nurhasni et al. presented a poly(lacticco-glycolic acid)-polyethylenimine (PLGA-PEI) nanoparticles (PPNPs) with NONOate as NO donor resulting in a 6-day release of NO [22]. The nanomaterial presented an outstanding NO prolonged release, being able to sustain the release on 6 days without any NO burst release. This NO nanocarrier is considered a promising approach for antimicrobial applications [22]. Similarly,

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a gelatin-siloxane nanoparticle with NO donor (RSNO) enhanced the NO stability, being able to sustainably release 0.12 mmol/mg for 7 days [65]. This concentration is suitable for antifungal applications. Chitosan is a biocompatible, biodegradable, antioxidant, and mucoadhesion polymer [66]. Chitosan has antimicrobial activities. In fact, cross-linked chitosan was used for adsorption of multiple mycotoxins, including aflatoxin B1 (AFB1), ochratoxin A (OTA), zearalenone (ZEN), fumonisin B1 (FB1), deoxynivalenol (DON), and T-2 toxin (T2) [67]. NO donors (RSNOs) were incorporated into chitosan nanoparticles and used as potent antimicrobial agent against pathogenic bacteria [9] and protozoa that causes Chagas’s disease [10] and cutaneous leishmaniasis [68]. The combination of NO donors and chitosan enhances the antimicrobial effect of the engineered NO-releasing chitosan nanoparticles, suggesting their potential uses in the management control of mycotoxins.

12. Dendrimers Dendrimers present a well-defined molecular architecture, seen in Fig. 20.4, which permits a great control of the particle size and the number of functional groups. Poly(amidoamine) (PAMAM) dendrimers changed modified with NOreleasing alkyl chains were described [69]. The nanomaterials stand out presenting a 10 h NO release and a maximum concentration of 1.07 mmol/mg, and it also presented an antibiofilm efficacy. A more recent work describes NOreleasing dendrimes obtained from electrospun polyurethane fibers [70]. Firstly, dendrimer nanoparticles were prepared and modified with N-diazeniumdiolate, as NO donors. Secondly, fibers of polyurethane containing

FIGURE 20.4 Representation of dendrimers highlighting their well-defined structure.

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NO-releasing dendrimers were prepared. The final material presents great potential as a wound dressing, with adequate porosity, water absorption properties, and gas and fluid exchange. Regarding NO release, this matrix presented a total amount of 80 mg/mg of dendrimer release and 0.072 mmol/mg of NO up to 24 h [70]. Roveda et al. reported the preparation of dendrimer nanoparticle functionalized with ruthenium nitrosyl complexes, as NO donors. As the compounds are robust, it is possible to store a high payload of NO and the release could be controlled or triggered by light irradiation [71]. These NO-releasing nanomaterials might find important applications in the control of pathogenic fungi.

13. Micelles The use of micelles increases aqueous solubility of drugs and present an advantage of allowing a large amount of hydrophobic drugs, keeping low toxicity and small size [54]. Jo and coauthors synthesized a micelle using a block copolymer of Nacryloylmorpholine and N-acryloyl-2,5-dimethylpiperazine for long-term NO release [72]. Spherical micelles with 50 nm diameter and hydrophobic core protected the loaded NONOate from the water, required for NO liberation, delaying NO release to a remarkable 7-day half-life [72]. Shishido et al. synthesized a micelle using the triblock copolymer F127 [73]. This copolymer is a commercially available nonionic that has the symmetrical structure poly(ethylene oxide)99epoly(propylene oxide)65e poly(ethylene oxide)99. The release of the NO donor GSNO was modulated thermally and photochemically. Besides, the copolymer F127 demonstrates a high potential for drug-delivery systems [73]. Kanayama and coauthors prepared a PEGylated polymer micelle based to protect the NO donor 4-nitro-3-trifluoromethylphenyl with a hydrodynamic size of 42.3 nm and a low polydispersive index of 0.15 [74]. The NO release from the micelles was trigged by exposure to UV light (330e385 nm). These micelles demonstrated antitumoral effects against HeLa cell line. However, the wavelength used in this work was a limitation for in vivo applications [74]. As reported in this section, several different classes of nanomaterials (composed by polymers and/or metals) have been synthesized to carry NO donors. These NO nanocarriers are able to sustain release therapeutic amounts of NO for biomedical applications. Although the combination of NO donors with nanomaterials have been extensively explored in different biomedical applications, including antimicrobial properties, NO-releasing nanomaterials have been not appropriated explore in the combat of pathogenic fungi. Because of the ability and versatility of NO-releasing nanomaterials, this approach might find important application in the management of mycotoxicity. In this direction, the next sections present and discuss the applicability of NO donors and NO-releasing nanomaterials against pathogenic fungi.

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14. NO and fungi NO is an important molecule that has been successfully applied as antimicrobial agent, especially against fungi and bacteria, mostly when it is combined to nanoparticles, that enhances the NO stability and improves the targeted NO delivery [35]. As NO is a potent antimicrobial agent [7], NOreleasing nanomaterials might find important applications against mycotoxigenic fungi. NO has shown significant action against Penicillium expansum (P. expansum), an important fungal pathogen that causes blue mold, mostly in fruits, and produces patulin, a mycotoxin with potential damage to human health. Lai et al. demonstrated the toxicity of the NO donor SNP at different concentrations (0e6 mmol/L) against P. expansum [75]. The authors demonstrated a concentration-dependent toxicity, and an effective action with NO concentration of 6 mmol/L. At this concentration, germination rate was below 25% after a 10-h incubation against 85% germination without SNP treatment [75]. In situ NO release from NOx has also shown great potential against Candida albicans (C. albicans), Candida krusei (C. krusei), and Candida tropicalis (C. tropicalis) biofilms [76]. NOx addition in the biofilms resulted in median population reduction of a maximum 3.9 log fold when compared with control, indicating that NO can penetrate the biofilms, inducing their dispersion [76]. Heilman and his coauthors tested the antifungal propriety of (MneNO) @Al-MCM-41, an NO complex of manganese, against the hyphal and the yeast form of C. albicans [77]. The opportunist fungal pathogen, C. albicans, leads to severe to life-threatening infections in immunocompromised hosts (such as burn victims and HIV patients). The NO complex released NO under light exposure at low power (10e100 mW). Authors verified that 16 mg of the complex (MneNO)@Al-MCM-41 in powder form was able to eradicate C. albicans after 1 h of irradiation. In addition, the authors verified that yeast form is less susceptive to cell death than hyphal form. Moreover, the cells that were treated with NO exhibited a limited budding during the next 12 h of incubation. This work indicates that a moderate dose of NO could avoid the spread of hyphal form of C. albicans and demonstrated that NO can treat C. albicans infections [77]. Recently, the use of the green light to trigger NO release from N-nitroso group on a rhodamine dye (NOD565) for antifungal activity was reported [78]. Light irradiation (LED source, 532 nm, 16 W) significantly promoted NO release and suppressed Aspergillus nidulans (A. nidulans) growth [78]. Similarly, the NO-releasing organometallic ruthenium complexes were prepared, and their antifungal activity was demonstrated against pathogenic fungi (Aspergillus niger (A. niger) and C. albicans) [79]. In this direction, the antifungal action of NO generated from ruthenium nitrosyl complex was evaluated in vivo in

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BALB/c mice infected intravenously with Paracoccidioides brasiliensis (Pb), a dimorphic fungus that causes Paracoccidioidomycosis, a deep mycosis [11]. Animals treated with NO donor were more resistant to fungal infection compared with the control group. In addition, treated animals showed a decrease in the inflammatory cells in the liver and lung tissues, due to a minor reduction in fungal cell numbers. Treated animals showed high levels of NO after 40 days of infection. These results demonstrated that NO donor is involved in the regulation of immune response in lung of Pb-infected mice [11]. Besides the ruthenium nitrosyl complexes, a series of NONOates, with different chemical structure, were synthesized and their antifungal efficacy was evaluated against Fusarium oxysporum f. sp. lycopersici, causing opportunistic infections in immunocompromised patients [80]. It should be highlighted that exogenous NO, generated from NO donor (free NO donor, nonencapsulated into a nanomaterial), itself showed a potential antifungal activity, being able to eradicate the pathogens, disperse biofilms, and limit fungus germinability. These effects might be enhanced by the combination of NO donor and nanomaterials, because nanocarriers are reported to improve NO stability, bioavailability, and, as a consequence, result in superior activity against pathogenic fungi. An example of NO nanocarriers against fungi was accomplished by Mordorski and coworkers. The authors synthesized a solegel matrix based on either tetraethyl orthosilicate (TEOS) or tetramethyl orthosilicate (TMOS), where NO was released through the thermal degradation of nitrite ions. These nanoparticles were able to promote a sustained release of NO. Minimum inhibitory concentration values of 10 and 5 mg/mL for reference strains and clinical isolated Trichophyton rubrum (T. rubrum), respectively, were obtained. The obtained nanoparticles demonstrated a fungistatic activity via DNA damage, lipid peroxidation, and enzyme inactivation. Besides, NO-releasing nanoparticle activity was associated with the downregulation of IL-2, 6, 10 and TNFa, disfavoring fungal growth and reducing T. rubrum virulence [34,81]. Schoenfisch’s group presented an NO-releasing silica nanoparticle against bacteria and fungi biofilm, more specifically C. albicans biofilms [82]. The nanoparticles were obtained as previously reported in section “NO and nanomaterials” of this chapter and presented a maximum NO release of 7.6 mmol/mg. Fungi biofilm was treated with this nanoparticle in a range of 0e8 mg/mL, and the authors reported a 99.9% of biofilm reduction in the maximum concentration of NO nanoparticle, achieving three logs of biofilm fold, compared with the control, which confirms the efficacy of the proposed material against fungi using low concentrations of the nanoparticles (Fig. 20.5). The uses of NO nanocarriers against mycotoxigenic fungi are still scarce in literature; nevertheless, it is well known that NO donors already demonstrated potent toxic effects against fungi. Although NO donors have been explored as potent antimicrobial agents, and although NO-releasing nanomaterials have

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Viable Biofilm Cells (CFU)

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106

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103 0

2

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6

8

MAP3 Nanoparticles (mg/mL) FIGURE 20.5 Broad spectrum antibiofilm properties of silica nanoparticles (70 mol% MAP3) against C. albicans (pathogenic fungus) biofilms. Reproduced with modification from E.M. Hetrick, J.H. Shin, H.S. Paul, M.H. Schoenfisch, Anti-biofilm efficacy of nitric oxide-releasing silica nanoparticles. Biomaterials 30 (14) (2009) 2782e2789, with permissions from Elsevier.

been extensively explored in the combat of bacteria and protozoa; few publications report the uses of NO-releasing nanomaterials against mycotoxigenic fungi.

15. How does NO exert its antifungal activity? Although several important publications demonstrated the efficacy of NO against pathogen fungi, the antifungal mechanism of NO is still not completely elucidated. In this sense, more studies are required. NO can exert antifungal activity by eliminating the pathogen-protective effects of the inhibitors of NADPH oxidase. In this sense, ROS is involved in fungi death via NO [83]. As represented in Fig. 20.6, when fungi are exposed to an exogenous source of NO (NO donor), NO can regulate nitric oxide dioxygenase (NOD), the enzyme responsible to catalyze the conversion of NO into nitrate (NO3  ), consuming NADPH [73]. The consumption of NADPH is connected to glycolysis, and it influences the catalytic activity of glutamine synthase (GS) [84]. This enzyme catalyzes the condensation of ammonia and glutamate to form glutamine, by the consumption of ATP. Thus, NO stress stimulates the enzymes NOD and GS, stimulating the glutamine production, which results in an excessive ATP consume and a disturbance in Krebs cycle, leading to the limitation of spore’s germinability of fungal pathogens [74].

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FIGURE 20.6 Proposed mechanism of exogenous NO against mycotoxigenic fungi.

In addition, NO might induce fungi sexual development and affect the morphogenesis of fungi. In fact, NO and ROS are considered key players in host defense against fungal infection [83]. As stated in this chapter, peroxynitrite is formed on the reaction of NO with ROS (Eq. 20.4), which is a potent oxidant molecule. However, even after the removal of ROS with special scavengers, NO can still have antifungal activity. This effect might be assigned to the signaling pathways of NO causing cell death through S-nitrosation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), leading to the specific binding and stabilization of E3 ubiquitin ligase, Siah1, a protein mediator of apoptosis [85]. More studies are required to deeply understand the antifungal actions of NO. We hope that this chapter opens new avenues in this exciting and promising field where nanoparticles with different architectures and composition might be applied as NO donors to enhance NO efficacy against mycotoxigenic fungi.

16. Conclusions NO is a recognized antimicrobial agent that displays potent toxicity against several pathogenic microorganisms, including fungi. Several important papers describe the uses of exogenous NO donors in vitro and in vivo applications against plant pathogenic fungi. In addition, the combined NO donors and nanomaterials have been extensively explored to promote a sustained NO release direct to the target site of applications, with minimum side effects, where NO can have its therapeutic effects. In fact, NO-releasing nanomaterials have been explored in several biomedical applications. Although NO donors have potent antifungal activity and in despite that NO-releasing nanomaterials enhance the antimicrobial effects of NO, the

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combination of NO donors and nanomaterials has been poorly explored for antifungal applications. In this context, this chapter highlights that NO-releasing nanomaterials might find important applications in the management of pathogenic fungi. We hope to inspire new avenues in this promising field.

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