N-Acetyl-Cysteine (NAC): A Powerful Health Aid

N-Acetyl-Cysteine (NAC) is the precursor (raw material) for the body to make glutathione (GSH). Glutathione is essential to protect your cells and is the most powerful antioxidant in your body. NAC has been used for several decades in clinical medicine as a mucolytic agent (clears up mucus), for respiratory infections and for the treatment of disorders associated with GSH deficiency.

N-Acetyl-Cysteine (NAC) is a supplement form of the amino acid cysteine and is not a drug.

Health benefits of NAC

  • Inhibition of inflammation
  • Nonantibiotic compound that exerts antimicrobial properties
  • Anticarcinogenic and antimutagenic effects against certain types of cancer
  • Improves oral and dental health
  • Helps replenish glutathione levels in the lungs and reduces inflammation in the bronchial tubes and lung tissue
  • Plays an important role in the body’s detoxification process
  • Helps to prevent side effects of drugs, drug overdose and environmental toxins
  • Can assist with rehabilitation and withdrawal therapy for drug addiction
  • Hospital emergency departments regularly give intravenous (IV) NAC to people with an acetaminophen overdose to prevent kidney and liver failure/damage
  • Has applications for many types of liver diseases

Therapeutic effects

N-Acetyl-Cysteine (NAC) possesses therapeutic effects over a wide range of disorders. These disorders include cystic fibrosis, acetaminophen poisoning, chronic obstructive pulmonary disease, chronic bronchitis, doxorubicin-induced cardiotoxicity, human immunodeficiency virus infection, heavy metal toxicity, and psychiatric/neurological disorders [1].

NAC is a cysteine pro-drug and glutathione (GSH) precursor that helps scavenge free radicals and bind metal ions into complexes [1]. Because NAC possesses anti-inflammatory activity via inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and modulation of proinflammatory cytokine synthesis [2], it has been used for modulating oxidative stress and inflammation-related diseases [3].

Antioxidants are effective in reducing the cumulative effects of oxidative stress caused by free radicals which are continually attacking the body. N-Acetyl-Cysteine is a direct antioxidant that interacts with the electrophilic groups of free radicals through its free thiol side-chain.  NAC reacts with the hydroxyl radical (·OH), nitrogen dioxide (·NO2), and carbon trioxide ion (CO3·−), and therefore detoxifies Reactive Oxygen Species (ROS) produced by white blood cells (leukocytes) [15]. NAC chelates transition metal ions such as Cu2+ and Fe3+, as well as heavy metal ions such as cadmium (Cd2+), mercury (Hg2+), and lead (Pb2+), through its thiol sidechain to produce complexes. This is called chelation and increases the removal of these toxic metal ions from the body [17].

Although NAC is not an antibiotic, it possesses antimicrobial properties and breaks down biofilms of medically relevant pathogens [4]. This makes NAC a potential candidate for managing oral diseases, especially gum disease.

NAC was shown to inactive Staphylococcus epidermidis biofilm formation in 1997 [47],  and many studies have demonstrated the efficacy of NAC in reducing biofilm formation induced by a broad array of medically significant microorganisms. One of those studies evaluated the antibacterial and biofilm eradication potential of NAC on Enterococcus faecalis [48], one of the most important bacterial pathogens responsible for chronic root canal infections [49]. This study showed that NAC was effective against both the planktonic and biofilm forms of E. faecalis. A more recent study reported that NAC has potent antibacterial effects against multiple planktonic endodontic pathogens (Actinomyces naeslundii, Lactobacillus salivarius, Streptococcus mutans, and E. faecalis) and effectively inhibits biofilm formation by all the monospecies and multispecies bacteria [50]. The biofilm disrupting activity of NAC is significantly better than that of calcium hydroxide or 2% chlorhexidine.

N-Acetyl-Cysteine has a long-established safety record in adults and children; the drug has been approved by the US Food and Drug Administration since 1963. The adverse effects experienced with the use of NAC are somewhat dependent on the route of administration. The clinical effects of NAC have been investigated in a phase I clinical study of 26 volunteers with a 6-month oral administration of NAC. The major reported side effects were gastrointestinal symptoms including intestinal gas, diarrhea, nausea, and fatigue with the highest nontoxic dose being 800 mg/m2/day [81]. In another clinical trial, oral administration of NAC at doses up to 8000 mg/day was reported to cause no significant adverse reactions in patients infected with the human immunodeficiency virus [82].

Absorption of NAC

Considering the poor oral absorption of dietary glutathione (GSH), orally administered NAC has been found to be more efficient than direct GSH administration and is as effective as intravenously administered NAC [83]. Compared with cysteine, the acetyl moiety of NAC reduces the reactivity of the thiol functionality, rendering NAC less toxic and less susceptible to oxidation to disulfide and easier for absorption and distribution [84]. N-Acetyl-Cysteine is rapidly and almost completely absorbed after oral administration in both animals and humans; only 3% of radioactive-labelled NAC is excreted in the feces [85]. Thus, NAC is a better source of cysteine compared with intravenous administration of cysteine.

Oral administration of NAC is preferred despite some clinical situations where other drug delivery routes are required.

Summary

The past decade has witnessed an explosion of data regarding the multifaceted biological activities of NAC, including antioxidant, anti-inflammatory, antimicrobial, and anticarcinogenic activities. The oral cavity is susceptible to oxidative stress from environmental factors which induce inflammation, and even initiate cancer. The actions of NAC and its ability to circumvent the mechanisms of disease progression make it a potential therapeutic agent for intervention in dental and oral disorders.

References:
1.   K. R. Atkuri, J. J. Mantovani, L. A. Herzenberg, and L. A. Herzenberg, “N-Acetylcysteine–a safe antidote for cysteine/glutathione deficiency,” Current Opinion in Pharmacology, vol. 7, no. 4, pp. 355–359, 2007.View at: Publisher Site | Google Scholar
2.   M. Berk, G. S. Malhi, L. J. Gray, and O. M. Dean, “The promise of N-acetylcysteine in neuropsychiatry,” Trends in Pharmacological Sciences, vol. 34, no. 3, pp. 167–177, 2013.View at: Publisher Site | Google Scholar
3.   G. F. Rushworth and I. L. Megson, “Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits,” Pharmacology & Therapeutics, vol. 141, no. 2, pp. 150–159, 2014.View at: Publisher Site | Google Scholar
4.   S. Dinicola, S. De Grazia, G. Carlomagno, and J. P. Pintucci, “N-acetylcysteine as powerful molecule to destroy bacterial biofilms: a systematic review,” European Review for Medical and Pharmacological Sciences, vol. 18, no. 19, pp. 2942–2948, 2014.View at: Google Scholar
5.   Y. Jiao, L. Niu, S. Ma, J. Li, F. R. Tay, and J. Chen, “Quaternary ammonium-based biomedical materials: state-of-the-art, toxicological aspects and antimicrobial resistance,” Progress in Polymer Science, vol. 71, pp. 53–90, 2017.View at: Publisher Site | Google Scholar
6.   S. Krifka, G. Spagnuolo, G. Schmalz, and H. Schweikl, “A review of adaptive mechanisms in cell responses towards oxidative stress caused by dental resin monomers,” Biomaterials, vol. 34, no. 19, pp. 4555–4563, 2013.View at: Publisher Site | Google Scholar
7.   P. A. Mouthuy, S. J. B. Snelling, S. G. Dakin et al., “Biocompatibility of implantable materials: an oxidative stress viewpoint,” Biomaterials, vol. 109, pp. 55–68, 2016.View at: Publisher Site | Google Scholar
8.   C. L. Hahn and F. R. Liewehr, “Innate immune responses of the dental pulp to caries,” Journal of Endodontics, vol. 33, no. 6, pp. 643–651, 2007.View at: Publisher Site | Google Scholar
9.   Y. C. Ko, Y. L. Huang, C. H. Lee, M. J. Chen, L. M. Lin, and C. C. Tsai, “Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan,” Journal of Oral Pathology & Medicine, vol. 24, no. 10, pp. 450–453, 1995.View at: Publisher Site | Google Scholar
10.   S. W. Chang, S. I. Lee, W. J. Bae et al., “Heat stress activates interleukin-8 and the antioxidant system via Nrf2 pathways in human dental pulp cells,” Journal of Endodontics, vol. 35, no. 9, pp. 1222–1228, 2009.View at: Publisher Site | Google Scholar
11.   S. K. Lee, K. S. Min, Y. Kim et al., “Mechanical stress activates proinflammatory cytokines and antioxidant defense enzymes in human dental pulp cells,” Journal of Endodontics, vol. 34, no. 11, pp. 1364–1369, 2008.View at: Publisher Site | Google Scholar
12.   Y. F. Feng, L. Wang, Y. Zhang et al., “Effect of reactive oxygen species overproduction on osteogenesis of porous titanium implant in the present of diabetes mellitus,” Biomaterials, vol. 34, no. 9, pp. 2234–2243, 2013.View at: Publisher Site | Google Scholar
13.   B. M. Hybertson, B. Gao, S. K. Bose, and J. M. McCord, “Oxidative stress in health and disease: the therapeutic potential of Nrf2 activation,” Molecular Aspects of Medicine, vol. 32, no. 4–6, pp. 234–246, 2011.View at: Publisher Site | Google Scholar
14.   A. H. Kesarwala, M. C. Krishna, and J. B. Mitchell, “Oxidative stress in oral diseases,” Oral Diseases, vol. 22, no. 1, pp. 9–18, 2016.View at: Publisher Site | Google Scholar
15.   T. Akca, H. Canbaz, C. Tataroglu et al., “The effect of N-acetylcysteine on pulmonary lipid peroxidation and tissue damage,” The Journal of Surgical Research, vol. 129, no. 1, pp. 38–45, 2005.View at: Publisher Site | Google Scholar
16.   N. Paolocci, M. I. Jackson, B. E. Lopez et al., “The pharmacology of nitroxyl (HNO) and its therapeutic potential: not just the janus face of NO,” Pharmacology & Therapeutics, vol. 113, no. 2, pp. 442–458, 2007.View at: Publisher Site | Google Scholar
17.   A. S. Koh, T. A. Simmons-Willis, J. B. Pritchard, S. M. Grassl, and N. Ballatori, “Identification of a mechanism by which the methylmercury antidotes N-acetylcysteine and dimercaptopropanesulfonate enhance urinary metal excretion: transport by the renal organic anion transporter-1,” Molecular Pharmacology, vol. 62, no. 4, pp. 921–926, 2002.View at: Publisher Site | Google Scholar
18.   H. Sies, “Glutathione and its role in cellular functions,” Free Radical Biology & Medicine, vol. 27, no. 9-10, pp. 916–921, 1999.View at: Publisher Site | Google Scholar
19.   K. R. Gibson, I. L. Neilson, F. Barrett et al., “Evaluation of the antioxidant properties of N-acetylcysteine in human platelets: prerequisite for bioconversion to glutathione for antioxidant and antiplatelet activity,” Journal of Cardiovascular Pharmacology, vol. 54, no. 4, pp. 319–326, 2009.View at: Publisher Site | Google Scholar
20.   A. Yoshida, Y. Shiotsu-Ogura, S. Wada-Takahashi, S. S. Takahashi, T. Toyama, and F. Yoshino, “Blue light irradiation-induced oxidative stress in vivo via ROS generation in rat gingival tissue,” Journal of Photochemistry and Photobiology B, vol. 151, no. 3, pp. 48–53, 2015.View at: Publisher Site | Google Scholar
21.   M. Suzuki, C. Bandoski, and J. D. Bartlett, “Fluoride induces oxidative damage and SIRT1/autophagy through ROS-mediated JNK signaling,” Free Radical Biology & Medicine, vol. 89, pp. 369–378, 2015.View at: Publisher Site | Google Scholar
22.   N. Sato, T. Ueno, K. Kubo et al., “N-Acetyl cysteine (NAC) inhibits proliferation, collagen gene transcription, and redox stress in rat palatal mucosal cells,” Dental Materials, vol. 25, no. 12, pp. 1532–1540, 2009.View at: Publisher Site | Google Scholar
23.   M. Y. Park, Y. J. Jeong, G. C. Kang et al., “Nitric oxide-induced apoptosis of human dental pulp cells is mediated by the mitochondria-dependent pathway,” The Korean Journal of Physiology & Pharmacology, vol. 18, no. 1, pp. 25–32, 2014.View at: Publisher Site | Google Scholar
24.   H. Schweikl, M. Widbiller, S. Krifka et al., “Interaction between LPS and a dental resin monomer on cell viability in mouse macrophages,” Dental Materials, vol. 32, no. 12, pp. 1492–1503, 2016.View at: Publisher Site | Google Scholar
25.   Y. Jiao, S. Ma, Y. Wang et al., “N-Acetyl cysteine depletes reactive oxygen species and prevents dental monomer-induced intrinsic mitochondrial apoptosis in vitro in human dental pulp cells,” PLoS One, vol. 11, no. 1, article e0147858, 2016.View at: Publisher Site | Google Scholar
26.   H. Schweikl, G. Spagnuolo, and G. Schmalz, “Genetic and cellular toxicology of dental resin monomers,” Journal of Dental Research, vol. 85, no. 10, pp. 870–877, 2016.View at: Publisher Site | Google Scholar
27.   Y. Jiao, S. Ma, Y. Wang, J. Li, L. Shan, and J. Chen, “Epigallocatechin-3-gallate reduces cytotoxic effects caused by dental monomers: a hypothesis,” Medical Science Monitor, vol. 21, pp. 3197–3202, 2015.View at: Publisher Site | Google Scholar
28.   G. Spagnuolo, V. D’Antò, C. Cosentino, G. Schmalz, H. Schweikl, and S. Rengo, “Effect of N-acetyl-L-cysteine on ROS production and cell death caused by HEMA in human primary gingival fibroblasts,” Biomaterials, vol. 27, no. 9, pp. 1803–9, 2006.View at: Publisher Site | Google Scholar
29.   Y. Jiao, S. Ma, J. Li et al., “N-Acetyl cysteine (NAC)-directed detoxification of methacryloxylethyl cetyl ammonium chloride (DMAE-CB),” PLoS One, vol. 10, no. 8, article e0135815, 2015.View at: Publisher Site | Google Scholar
30.   G. Nocca, V. D’Antò, C. Desiderio et al., “N-Acetyl cysteine directed detoxification of 2-hydroxyethyl methacrylate by adduct formation,” Biomaterials, vol. 31, no. 9, pp. 2508–2516, 2010.View at: Publisher Site | Google Scholar
31.   Y. Jiao, S. Ma, J. Li et al., “The influences of N-acetyl cysteine (NAC) on the cytotoxicity and mechanical properties of poly-methylmethacrylate (PMMA)-based dental resin,” PeerJ, vol. 3, article e868, 2015.View at: Publisher Site | Google Scholar
32.   M. Yamada, N. Tsukimura, T. Ikeda et al., “N-Acetyl cysteine as an osteogenesis-enhancing molecule for bone regeneration,” Biomaterials, vol. 34, no. 26, pp. 6147–6156, 2013.View at: Publisher Site | Google Scholar
33.   J. H. Jun, S. H. Lee, H. B. Kwak et al., “N-Acetylcysteine stimulates osteoblastic differentiation of mouse calvarial cells,” Journal of Cellular Biochemistry, vol. 103, no. 4, pp. 1246–1255, 2008.View at: Publisher Site | Google Scholar
34.   S. Batu, D. Ofluoglu, S. Ergun et al., “Evaluation of prolidase activity and oxidative stress in patients with oral lichen planus and oral lichenoid contact reactions,” Journal of Oral Pathology & Medicine, vol. 45, no. 4, pp. 281–288, 2016.View at: Publisher Site | Google Scholar
35.   Y. Yamamoto and R. B. Gaynor, “Therapeutic potential of inhibition of the NF-κB pathway in the treatment of inflammation and cancer,” The Journal of Clinical Investigation, vol. 107, no. 2, pp. 135–142, 2001.View at: Publisher Site | Google Scholar
36.   S. Oka, H. Kamata, K. Kamata, H. Yagisawa, and H. Hirata, “N-Acetylcysteine suppresses TNF-induced NF-κB activation through inhibition of IκB kinases,” FEBS Letters, vol. 472, no. 2-3, pp. 196–202, 2000.View at: Publisher Site | Google Scholar
37.   F. Pajonk, K. Riess, A. Sommer, and W. H. McBride, “N-Acetyl-L-cysteine inhibits 26S proteasome function: implications for effects on NF-κB activation,” Free Radical Biology & Medicine, vol. 32, no. 6, pp. 536–543, 2002.View at: Publisher Site | Google Scholar
38.   H. Kim, J. Y. Seo, K. H. Roh, J. W. Lim, and K. H. Kim, “Suppression of NF-κB activation and cytokine production by N-acetylcysteine in pancreatic acinar cells,” Free Radical Biology & Medicine, vol. 29, no. 7, pp. 674–683, 2000.View at: Publisher Site | Google Scholar
39.   M. Zafarullah, W. Q. Li, J. Sylvester, and M. Ahmad, “Molecular mechanisms of N-acetylcysteine actions,” Cellular and Molecular Life Sciences, vol. 60, no. 1, pp. 6–20, 2003.View at: Publisher Site | Google Scholar
40.   S. P. Karapinar, Y. Z. A. Ulum, B. Ozcelik et al., “The effect of N-acetylcysteine and calcium hydroxide on TNF-α and TGF-β1 in lipopolysaccharide-activated macrophages,” Archives of Oral Biology, vol. 68, pp. 48–54, 2016.View at: Publisher Site | Google Scholar
41.   D. Y. Kim, J. H. Jun, H. L. Lee et al., “N-Acetylcysteine prevents LPS-induced pro-inflammatory cytokines and MMP2 production in gingival fibroblasts,” Archives of Pharmacal Research, vol. 30, no. 10, pp. 1283–1292, 2007.View at: Publisher Site | Google Scholar
42.   N. Celik, S. Askın, M. A. Gul, and N. Seven, “The effect of restorative materials on cytokines in gingival crevicular fluid,” Archives of Oral Biology, vol. 84, pp. 139–144, 2017.View at: Publisher Site | Google Scholar
43.   C. Di Nisio, S. Zara, A. Cataldi, and V. di Giacomo, “2-Hydroxyethyl methacrylate inflammatory effects in human gingival fibroblasts,” International Endodontic Journal, vol. 46, no. 5, pp. 466–476, 2013.View at: Publisher Site | Google Scholar
44.   H. Toker, H. Ozdemir, K. Eren, H. Ozer, and G. Sahin, “N-Acetylcysteine, a thiol antioxidant, decreases alveolar bone loss in experimental periodontitis in rats,” Journal of Periodontology, vol. 80, no. 4, pp. 672–678, 2009.View at: Publisher Site | Google Scholar
45.   Y. H. Lee, G. Bhattarai, I. S. Park et al., “Bone regeneration around N-acetyl cysteine-loaded nanotube titanium dental implant in rat mandible,” Biomaterials, vol. 34, no. 38, pp. 10199–10208, 2013.View at: Publisher Site | Google Scholar
46.   T. Ohnishi, K. Bandow, K. Kakimoto, J. Kusuyama, and T. Matsuguchi, “Long-time treatment by low-dose N-acetyl-L-cysteine enhances proinflammatory cytokine expressions in LPS-stimulated macrophages,” PLoS One, vol. 9, no. 2, article e87229, 2014.View at: Publisher Site | Google Scholar
47.   C. Pérez-Giraldo, A. Rodríguez-Benito, F. J. Morán, C. Hurtado, M. T. Blanco, and A. C. Gómez-García, “Influence of N-acetylcysteine on the formation of biofilm by Staphylococcus epidermidis,” The Journal of Antimicrobial Chemotherapy, vol. 39, no. 5, pp. 643–646, 1997.View at: Publisher Site | Google Scholar
48.   S. Y. Quah, S. Wu, J. N. Lui, C. P. Sum, and K. S. Tan, “N-Acetylcysteine inhibits growth and eradicates biofilm of Enterococcus faecalis,” Journal of Endodontics, vol. 38, no. 1, pp. 81–85, 2012.View at: Publisher Site | Google Scholar
49.   C. Stuart, S. Schwartz, T. Beeson, and C. Owatz, “Enterococcus faecalis: its role in root canal treatment failure and current concepts in retreatment,” Journal of Endodontics, vol. 32, no. 2, pp. 93–98, 2006.View at: Publisher Site | Google Scholar
50.   J. H. Moon, Y. S. Choi, H. W. Lee, J. S. Heo, S. W. Chang, and J. Y. Lee, “Antibacterial effects of N-acetylcysteine against endodontic pathogens,” Journal of Microbiology, vol. 54, no. 4, pp. 322–329, 2016.View at: Publisher Site | Google Scholar
51.   I. Portenier, H. Haapasalo, D. Orstavik, M. Yamauchi, and M. Haapasalo, “Inactivation of the antibacterial activity of iodine potassium iodide and chlorhexidine digluconate against Enterococcus faecalis by dentin, dentin matrix, type-I collagen, and heat-killed microbial whole cells,” Journal of Endodontics, vol. 28, no. 9, pp. 634–637, 2002.View at: Publisher Site | Google Scholar
52.   J. V. B. Barbizam, M. Trope, É. C. N. Teixeira, M. Tanomaru-Filho, and F. B. Teixeira, “Effect of calcium hydroxide intracanal dressing on the bond strength of a resin-based endodontic sealer,” Brazilian Dental Journal, vol. 19, no. 3, pp. 224–227, 2008.View at: Publisher Site | Google Scholar
53.   Z. Mohammadi and P. M. H. Dummer, “Properties and applications of calcium hydroxide in endodontics and dental traumatology,” International Endodontic Journal, vol. 44, no. 8, pp. 697–730, 2011.View at: Publisher Site | Google Scholar
54.   M. Ehsani, A.-A. Moghadamnia, S. Zahedpasha et al., “The role of prophylactic ibuprofen and N-acetylcysteine on the level of cytokines in periapical exudates and the post-treatment pain,” Daru, vol. 20, no. 1, p. 30, 2012.View at: Publisher Site | Google Scholar
55.   L. F. M. Silveira, P. Baca, M. T. Arias-Moliz, A. Rodríguez-Archilla, and C. M. Ferrer-Luque, “Antimicrobial activity of alexidine alone and associated with N-acetylcysteine against Enterococcus faecalis biofilm,” International Journal of Oral Science, vol. 5, no. 3, pp. 146–149, 2013.View at: Publisher Site | Google Scholar
56.   U. Palaniswamy, S. R. Lakkam, S. Arya, and S. Aravelli, “Effectiveness of N-acetyl cysteine, 2% chlorhexidine, and their combination as intracanal medicaments on Enterococcus faecalis biofilm,” Journal of Conservative Dentistry, vol. 19, no. 1, pp. 17–20, 2016.View at: Publisher Site | Google Scholar
57.   A. T. Ulusoy, E. Kalyoncuoglu, A. Reis, and Z. C. Cehreli, “Antibacterial effect of N-acetylcysteine and taurolidine on planktonic and biofilm forms of Enterococcus faecalis,” Dental Traumatology, vol. 32, no. 3, pp. 212–218, 2016.View at: Publisher Site | Google Scholar
58.   J. H. Moon, E. Y. Jang, K. S. Shim, and J. Y. Lee, “In vitro effects of N-acetyl cysteine alone and in combination with antibiotics on Prevotella intermedia,” Journal of Microbiology, vol. 53, no. 5, pp. 321–329, 2015.View at: Publisher Site | Google Scholar
59.    J. Alam, K. J. Baek, Y. S. Choi, Y. C. Kim, and Y. Choi, “N-acetylcysteine and the human serum components that inhibit bacterial invasion of gingival epithelial cells prevent experimental periodontitis in mice,” Journal of Periodontal & Implant Science, vol. 44, no. 6, pp. 266–273, 2014.View at: Publisher Site | Google Scholar
60.   L. Van Aelst and C. D’Souza-Schorey, “Rho GTPases and signaling networks,” Genes & Development, vol. 11, no. 18, pp. 2295–2322, 1997.View at: Publisher Site | Google Scholar
61.   F. Blasi, C. Page, G. M. Rossolini et al., “The effect of N-acetylcysteine on biofilms: implications for the treatment of respiratory tract infections,” Respiratory Medicine, vol. 117, pp. 190–197, 2016.View at: Publisher Site | Google Scholar
62.   A. C. Olofsson, M. Hermansson, and H. Elwing, “N-Acetyl-L-cysteine affects growth, extracellular polysaccharide production, and bacterial biofilm formation on solid surfaces,” Applied and Environmental Microbiology, vol. 69, no. 8, pp. 4814–4822, 2003.View at: Publisher Site | Google Scholar
63.   M. Yamada, K. Ishihara, T. Ogawa, and K. Sakurai, “The inhibition of infection by wound pathogens on scaffold in tissue-forming process using N-acetyl cysteine,” Biomaterials, vol. 32, no. 33, pp. 8474–8485, 2011.View at: Publisher Site | Google Scholar
64.   M. AlMatar, T. Batool, and E. A. Makky, “Therapeutic potential of N-acetylcysteine for wound healing, acute bronchiolitis, and congenital heart defects,” Current Drug Metabolism, vol. 17, no. 2, pp. 156–167, 2016.View at: Publisher Site | Google Scholar
65.   M. Deniz, H. Borman, T. Seyhan, and M. Haberal, “An effective antioxidant drug on prevention of the necrosis of zone of stasis: N-acetylcysteine,” Burns, vol. 39, no. 2, pp. 320–325, 2013.View at: Publisher Site | Google Scholar
66.   B. Yilmaz, G. Turkcu, E. Sengul, A. Gul, F. E. Ozkurt, and M. Akdag, “Efficacy of N-acetylcysteine on wound healing of nasal mucosa,” The Journal of Craniofacial Surgery, vol. 26, no. 5, pp. e422–e426, 2015.View at: Publisher Site | Google Scholar
67.   A. Oguz, O. Uslukaya, U. Alabalik, A. Turkoglu, M. Kapan, and Z. Bozdag, “Topical N-acetylcysteine improves wound healing comparable to dexpanthenol: an experimental study,” International Surgery, vol. 100, no. 4, pp. 656–661, 2015.View at: Publisher Site | Google Scholar
68.   C. Fischak, R. Klaus, R. M. Werkmeister et al., “Effect of topically administered chitosan-N-acetylcysteine on corneal wound healing in a rabbit model,” Journal of Ophthalmology, vol. 2017, Article ID 5192924, 6 pages, 2017.View at: Publisher Site | Google Scholar
69.   S. De Flora, C. Bennicelli, P. Zanacchi, A. Camoirano, A. Morelli, and A. De Flora, “In vitro effects of N-acetylcysteine on the mutagenicity of direct-acting compounds and procarcinogens,” Carcinogenesis, vol. 5, no. 4, pp. 505–510, 1984.View at: Publisher Site | Google Scholar
70.   S. De Flora, A. Izzotti, F. D’Agostini, and R. M. Balansky, “Mechanisms of N-acetylcysteine in the prevention of DNA damage and cancer, with special reference to smoking-related end-points,” Carcinogenesis, vol. 22, no. 7, pp. 999–1013, 2001.View at: Publisher Site | Google Scholar
71.   R. L. Siegel, K. D. Miller, and A. Jemal, “Cancer statistics, 2015,” CA: a Cancer Journal for Clinicians, vol. 65, no. 1, pp. 5–29, 2015.View at: Publisher Site | Google Scholar
72.   H. Schliephake, “Prognostic relevance of molecular markers of oral cancer–a review,” International Journal of Oral and Maxillofacial Surgery, vol. 32, no. 3, pp. 233–245, 2003.View at: Publisher Site | Google Scholar
73.   N. van Zandwijk, O. Dalesio, U. Pastorino, N. de Vries, and H. van Tinteren, “EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the EUropean Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups,” Journal of the National Cancer Institute, vol. 92, no. 12, pp. 977–986, 2000.View at: Publisher Site | Google Scholar
74.   S. De Flora, G. Ganchev, M. Iltcheva et al., “Pharmacological modulation of lung carcinogenesis in smokers: preclinical and clinical evidence,” Trends in Pharmacological Sciences, vol. 37, no. 2, pp. 120–142, 2016.View at: Publisher Site | Google Scholar
75.   F. J. Van Schooten, A. Besaratinia, S. De Flora et al., “Effects of oral administration of N-acetyl-L-cysteine: a multi-biomarker study in smokers,” Cancer Epidemiology and Prevention Biomarkers, vol. 11, no. 2, pp. 167–175, 2002.View at: Google Scholar
76.   S. Temam, H. Kawaguchi, A. K. El-Naggar et al., “Epidermal growth factor receptor copy number alterations correlate with poor clinical outcome in patients with head and neck squamous cancer,” Journal of Clinical Oncology, vol. 25, no. 16, pp. 2164–2170, 2007.View at: Publisher Site | Google Scholar
77.   H. Kamata, Y. Shibukawa, S. I. Oka, and H. Hirata, “Epidermal growth factor receptor is modulated by redox through multiple mechanisms. Effects of reductants and H2O2,” European Journal of Biochemistry, vol. 267, no. 7, pp. 1933–1944, 2000.View at: Publisher Site | Google Scholar
78.   M. F. Lee, C. Y. Chan, H. C. Hung, I. T. Chou, A. S. Yee, and C. Y. Huang, “N-Acetylcysteine (NAC) inhibits cell growth by mediating the EGFR/Akt/HMG box-containing protein 1 (HBP1) signaling pathway in invasive oral cancer,” Oral Oncology, vol. 49, no. 2, pp. 129–135, 2013.View at: Publisher Site | Google Scholar
79.   J. Luo, T. Tsuji, H. Yasuda, Y. Sun, Y. Fujigaki, and A. Hishida, “The molecular mechanisms of the attenuation of cisplatin-induced acute renal failure by N-acetylcysteine in rats,” Nephrology, Dialysis, Transplantation, vol. 23, no. 7, pp. 2198–2205, 2008.View at: Publisher Site | Google Scholar
80.   J. Yoo, S. J. Hamilton, D. Angel et al., “Cisplatin otoprotection using transtympanic L-N-acetylcysteine: a pilot randomized study in head and neck cancer patients,” The Laryngoscope, vol. 124, no. 3, pp. E87–E94, 2014.View at: Publisher Site | Google Scholar
81.   L. Pendyala and P. J. Creaven, “Pharmacokinetic and pharmacodynamic studies of N-acetylcysteine, a potential chemopreventive agent during a phase I trial,” Cancer Epidemiology, Biomarkers & Prevention, vol. 4, no. 3, pp. 245–251, 1995.View at: Google Scholar
82.   S. C. De Rosa, M. D. Zaretsky, J. G. Dubs et al., “N-Acetylcysteine replenishes glutathione in HIV infection,” European Journal of Clinical Investigation, vol. 30, no. 10, pp. 915–929, 2000.View at: Publisher Site | Google Scholar
83.   A. Witschi, S. Reddy, B. Stofer, and B. H. Lauterburg, “The systemic availability of oral glutathione,” European Journal of Clinical Pharmacology, vol. 43, no. 6, pp. 667–669, 1992.View at: Publisher Site | Google Scholar
84.   L. Bonanomi and A. Gazzaniga, “Toxicological, pharmacokinetic and metabolic studies on acetylcysteine,” European Journal of Respiratory Diseases Supplement, vol. 111, pp. 45–51, 1980.View at: Google Scholar
85.   L. Borgstrom, B. Kagedal, and O. Paulsen, “Pharmacokinetics of N-acetylcysteine in man,” European Journal of Clinical Pharmacology, vol. 31, no. 2, pp. 217–222, 1986.View at: Publisher Site | Google Scholar
86.   M. E. Ullian, A. K. Gelasco, W. R. Fitzgibbon, C. N. Beck, and T. A. Morinelli, “N-Acetylcysteine decreases angiotensin II receptor binding in vascular smooth muscle cells,” Journal of the American Society of Nephrology, vol. 16, no. 8, pp. 2346–2353, 2005.View at: Publisher Site | Google Scholar
87.   M. Hayakawa, H. Miyashita, I. Sakamoto et al., “Evidence that reactive oxygen species do not mediate NF-κB activation,” The EMBO Journal, vol. 22, no. 13, pp. 3356–3366, 2003.View at: Publisher Site | Google Scholar
88.   B. Sarnstrand, A. H. Jansson, G. Matuseviciene, A. Scheynius, S. Pierrou, and H. Bergstrand, “N,N’-Diacetyl-L-cystine-the disulfide dimer of N-acetylcysteine-is a potent modulator of contact sensitivity/delayed type hypersensitivity reactions in rodents,” The Journal of Pharmacology and Experimental Therapeutics, vol. 288, no. 3, pp. 1174–1184, 1999.View at: Google Scholar
89.   E. M. Grandjean, P. H. Berthet, R. Ruffmann, and P. H. Leuenberger, “Cost-effectiveness analysis of oral N-acetylcysteine as a preventive treatment in chronic bronchitis,” Pharmacological Research, vol. 42, no. 1, pp. 39–50, 2000.View at: Publisher Site | Google Scholar
90.   S. N. Chen and M. Z. Hoffman, “Effect of pH on the reactivity of the carbonate radical in aqueous solution,” Radiation Research, vol. 62, no. 1, pp. 18–27, 1975.View at: Publisher Site | Google Scholar
91.   K. M. Miranda, N. Paolocci, T. Katori et al., “A biochemical rationale for the discrete behavior of nitroxyl and nitric oxide in the cardiovascular system,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 16, pp. 9196–9201, 2011.View at: Publisher Site | Google Scholar
92.   A. V. Peskin and C. C. Winterbourn, “Kinetics of the reactions of hypochlorous acid and amino acid chloramines with thiols, methionine, and ascorbate,” Free Radical Biology & Medicine, vol. 30, no. 5, pp. 572–579, 2001.View at: Publisher Site | Google Scholar
93.   O. Skaff, D. I. Pattison, and M. J. Davies, “Hypothiocyanous acid reactivity with low-molecular-mass and protein thiols: absolute rate constants and assessment of biological relevance,” The Biochemical Journal, vol. 422, no. 1, pp. 111–117, 2009.View at: Publisher Site | Google Scholar
94.   C. C. Winterbourn and D. Metodiewa, “Reactivity of biologically important thiol compounds with superoxide and hydrogen peroxide,” Free Radical Biology & Medicine, vol. 27, no. 3-4, pp. 322–328, 1999.View at: Publisher Site | Google Scholar
95.   O. I. Aruoma, B. Halliwell, B. M. Hoey, and J. Butler, “The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid,” Free Radical Biology & Medicine, vol. 6, no. 6, pp. 593–597, 1989.View at: Publisher Site | Google Scholar
96.   W. A. Prutz, H. Monig, J. Butler, and E. J. Land, “Reactions of nitrogen dioxide in aqueous model systems: oxidation of tyrosine units in peptides and proteins,” Archives of Biochemistry and Biophysics, vol. 243, no. 1, pp. 125–134, 1985.View at: Publisher Site | Google Scholar
97.   M. Benrahmoune, P. Therond, and Z. Abedinzadeh, “The reaction of superoxide radical with N-acetylcysteine,” Free Radical Biology & Medicine, vol. 29, no. 8, pp. 775–782, 2000.View at: Publisher Site | Google Scholar
98.   M. Trujillo and R. Radi, “Peroxynitrite reaction with the reduced and the oxidized forms of lipoic acid: new insights into the reaction of peroxynitrite with thiols,” Archives of Biochemistry and Biophysics, vol. 397, no. 1, pp. 91–98, 2002.View at: Publisher Site | Google Scholar
99.   E. C. Kim, M. K. Kim, R. Leesungbok, S. W. Lee, and S. J. Ahn, “Co-Cr dental alloys induces cytotoxicity and inflammatory responses via activation of Nrf2/antioxidant signaling pathways in human gingival fibroblasts and osteoblasts,” Dental Materials, vol. 32, no. 11, pp. 1394–1405, 2016.View at: Publisher Site | Google Scholar
100.   S. Ma, L. Shan, Y. H. Xiao et al., “The cytotoxicity of methacryloxylethyl cetyl ammonium chloride, a cationic antibacterial monomer, is related to oxidative stress and the intrinsic mitochondrial apoptotic pathway,” Brazilian Journal of Medical and Biological Research, vol. 44, no. 11, pp. 1125–1133, 2011.View at: Google Scholar
101.   N. R. Kim, H. C. Park, I. Kim, B. S. Lim, and H. C. Yang, “In vitro cytocompatibility of N-acetylcysteine-supplemented dentin bonding agents,” Journal of Endodontics, vol. 36, no. 11, pp. 1844–1850, 2010.View at: Publisher Site | Google Scholar
102.   H. Minamikawa, M. Yamada, Y. Deyama et al., “Effect of N-acetylcysteine on rat dental pulp cells cultured on mineral trioxide aggregate,” Journal of Endodontics, vol. 37, no. 5, pp. 637–641, 2011.View at: Publisher Site | Google Scholar
103.   D. H. Lee, B. S. Lim, Y. K. Lee, and H. C. Yang, “Mechanisms of root canal sealers cytotoxicity on osteoblastic cell line MC3T3-E1,” Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics, vol. 104, no. 5, pp. 717–721, 2007.View at: Publisher Site | Google Scholar
104.   M. C. Chang, L. D. Lin, M. T. Wu et al., “Effects of camphorquinone on cytotoxicity, cell cycle regulation and prostaglandin E2 production of dental pulp cells: role of ROS, ATM/Chk2, MEK/ERK and hemeoxygenase-1,” PLoS One, vol. 10, no. 12, article e0143663, 2015.View at: Publisher Site | Google Scholar
105.   K. Pawlowska-Goral, E. Kurzeja, and M. Stec, “N-Acetylcysteine protects against fluoride-induced oxidative damage in primary rat hepatocytes,” Toxicology In Vitro, vol. 27, no. 8, pp. 2279–2282, 2013.View at: Publisher Site | Google Scholar
106.   A. Mohsen, A. Gomaa, F. Mohamed et al., “Antibacterial, anti-biofilm activity of some non-steroidal anti-inflammatory drugs and N-acetyl cysteine against some biofilm producing uropathogens,” American Journal of Epidemiology and Infectious Disease, vol. 3, no. 1, pp. 1–9, 2015.View at: Publisher Site | Google Scholar
107.   L. Drago, E. De Vecchi, R. Mattina, and C. L. Romano, “Activity of N-acetyl-L-cysteine against biofilm of Staphylococcus aureus and Pseudomonas aeruginosa on orthopedic prosthetic materials,” The International Journal of Artificial Organs, vol. 36, no. 1, pp. 39–46, 2018.View at: Publisher Site | Google Scholar
108.   S. Aslam and R. O. Darouiche, “Role of antibiofilm-antimicrobial agents in controlling device-related infections,” The International Journal of Artificial Organs, vol. 34, no. 9, pp. 752–758, 2011.View at: Publisher Site | Google Scholar
109.   M. A. El-Feky, M. S. El-Rehewy, M. A. Hassan, H. A. Abolella, R. M. Abd El-Baky, and G. F. Gad, “Effect of ciprofloxacin and N-acetylcysteine on bacterial adherence and biofilm formation on ureteral stent surfaces,” Polish Journal of Microbiology, vol. 58, no. 3, pp. 261–267, 2009.View at: Google Scholar
110.   S. Aslam, B. W. Trautner, V. Ramanathan, and R. O. Darouiche, “Combination of tigecycline and N-acetylcysteine reduces biofilm-embedded bacteria on vascular catheters,” Antimicrobial Agents and Chemotherapy, vol. 51, no. 4, pp. 1556–1558, 2007.View at: Publisher Site | Google Scholar
111.   B. Leite, F. Gomes, P. Teixeira, C. Souza, E. Pizzolitto, and R. Oliveira, “Combined effect of linezolid and N-acetylcysteine against Staphylococcus epidermidis biofilms,” Enfermedades Infecciosas y Microbiología Clínica, vol. 31, no. 10, pp. 655–659, 2013.View at: Publisher Site | Google Scholar
112.   S. Kirmusaoǧlu, S. Yurdugül, and M. Esra Koçoǧlu, “The effect of N-acetylcysteine on growth and biofilm formation in Staphylococcus epidermidis strains,” Turkish Journal of Medical Sciences, vol. 42, no. 4, pp. 689–694, 2012.View at: Google Scholar
113.   F. Gomes, B. Leite, P. Teixeira, J. Azeredo, and R. Oliveira, “Farnesol in combination with N-acetylcysteine against Staphylococcus epidermidis planktonic and biofilm cells,” Brazilian Journal of Microbiology, vol. 43, no. 1, pp. 235–242, 2012.View at: Publisher Site | Google Scholar
114.   M. Venkatesh, L. Rong, I. Raad, and J. Versalovic, “Novel synergistic antibiofilm combinations for salvage of infected catheters,” Journal of Medical Microbiology, vol. 58, no. 7, pp. 936–944, 2009.View at: Publisher Site | Google Scholar
115.   A. Marchese, M. Bozzolasco, L. Gualco, E. A. Debbia, G. C. Schito, and A. M. Schito, “Effect of fosfomycin alone and in combination with N-acetylcysteine on E. coli biofilms,” International Journal of Antimicrobial Agents, vol. 22, pp. 95–100, 2003.View at: Publisher Site | Google Scholar
116.   J. Lea, A. Conlin, I. Sekirov et al., “In vitro efficacy of N-acetylcysteine on bacteria associated with chronic suppurative otitis media,” Journal of Otolaryngology – Head & Neck Surgery, vol. 43, no. 1, p. 20, 2014.View at: Publisher Site | Google Scholar
117.   T. Zhao and Y. Liu, “N-acetylcysteine inhibit biofilms produced by Pseudomonas aeruginosa,” BMC Microbiology, vol. 10, no. 1, p. 140, 2010.View at: Publisher Site | Google Scholar
118.    R. M. A. el-Baky, D. M. M. A. el Ela, and G. F. M. Gad, “N-acetylcysteine inhibits and eradicates candida albicans biofilms,” American Journal of Infectious Diseases and Microbiology, vol. 2, no. 5, pp. 122–130, 2014.View at: Publisher Site | Google Scholar