Biological Activities and Potential Oral Applications of N-Acetylcysteine: Progress and Prospects

Table 2

Representative studies on the protective effects of N-acetylcysteine against various oxidative insults in the oral cavity.

Insult	Cell model	Mode of action	NAC dose	NAC function	Reference
Co-Cr dental alloys	Human gingival fibroblasts, human osteoblasts	ROS ↑, TNF-α ↑, IL-1β ↑, IL-6 ↑, IL-8 ↑, iNOS ↑, NO ↑, COX-2 ↑, PGE2 ↑, Nrf2 ↑, NQO ↑, HO-1 ↑, GST ↑, GR ↑, GCL ↑, p-JAK2 ↑, p-STAT3 ↑, p-p38 MAPK ↑, p-ERK ↑, p-JNK ↑, NF-κB p65 ↑	20 mM	NAC pretreatment inhibited Co-Cr alloy-induced proinflammatory cytokine production and NF-κB activation	[99]
Dental resin monomers(e.g., HEMA, TEGDMA, MMA)	Human dental pulp cells	ROS ↑, GSH ↓, MDA ↑, SOD ↓, CAT ↑, GPx ↓, mitochondria dysfunction, intrinsic mitochondrial apoptosis	10 mM	NAC remarkably relieved dental resin monomer-induced oxidative stress and subsequently protected the cells against apoptosis	[25]
Dental quaternary ammonium monomer(e.g., DMAE-CB)	Human dental pulp cells, mouse fibroblasts	ROS ↑, cell cycle arrest, mitochondria dysfunction, intrinsic mitochondrial apoptosis	10 mM	NAC could reduce the cytotoxicity of quaternary ammonium monomers	[29, 100]
Dentin bonding agents	Human dental pulp cells	ALP ↓, DSPP ↓, OCN ↓, matrix, mineralization ↓	5 mM	NAC was useful for reversing cytotoxicity and antidifferentiation effects of dentin bonding agents on human dental pulp cells	[101]
Mineral trioxide aggregate (MTA)	Rat dental pulp cells	ROS ↑, GSH ↓	5 mM	The addition of NAC improved the number and spreading behavior, reduced ROS production, and increased the cellular antioxidant resources of rat dental pulp cells cultured on MTA	[102]
Root canal sealers	Mouse osteoblastic cell line	GSH ↓	10 mM	NAC prevented cytotoxicity and intracellular GSH depletion of root canal sealers	[103]
Photoinitiators(e.g., CQ)	Human dental pulp cells	ROS ↑, collagen I ↓, p21 ↑, HO-1 ↑, COX-2 ↑, p-ATM ↑, p-Chk2 ↑, p-p53 ↑, GADD45α ↑, 8-isoprostane ↑, PGE2 ↑, cell cycle arrest, apoptosis	2.5 mM,5 mM	NAC prevented CQ-induced cytotoxicity, cell cycle arrest, apoptosis and PGE2 production of pulp cells	[104]
Fluoride exposure	Rat hepatocytes	MDA ↑, SOD ↓, GPx ↓, GR ↑, GSH ↓, TAS ↓	1 mM	NAC pretreatment provided protection against fluoride-induced oxidative stress	[105]
Heat stress	Human dental pulp cells	ROS ↑, IL- 8↑, IL-8R ↑, HO-1 ↑, nuclear Nrf2 ↑, cytosolic Nrf2 ↓, SOD ↑, HO-1 ↑, GST ↑, GCL ↑, GR ↑	20 mM	The addition of NAC to cells blocked heat stress-activated proinflammatory chemokines and Nrf2-mediated antioxidant responses	[10]
Hydrogen peroxide (H2O2)	Rat palatal mucosal cells	Apoptosis, collagen I ↓, collagen III ↓, P4H ↓, GSH ↓, GSSG ↑	2.5 mM,5 mM,10 mM	NAC substantially reduced H2O2-induced elevation of cellular proliferation and collagen production associated with an increase in intracellular GSH reserves and decrease in GSSG	[22]
Lipopolysaccharide (LPS)	Human gingival fibroblasts	ROS ↑, GSH/GSSG ↓, IL-1β ↑, IL-6 ↑, IL-8 ↑, TNF-α ↑, MMP2 ↑	10 mM,20 mM	NAC prevented LPS-induced proinflammatory cytokines and MMP2 production	[41]
Mechanical stress	Human dental pulp cells	ROS ↑, IL-1β ↑, IL-6 ↑, IL-8 ↑, TNF-α ↑, HO-1 ↑, NQO-1 ↑, GPx ↑, SOD ↑, Nrf2 ↑	20 mM	NAC prevented the production of proinflammatory cytokines and ROS, as well as the activation of subsequent Nrf2-mediated gene transcription in response to mechanical strain	[11]
Nitric oxide (NO)	Human dental pulp cells	ROS ↑, intrinsic mitochondrial apoptosis	5 mM	NAC rescued the cell viability decreased by NO and downregulated NO-induced activation of proapoptotic mitochondria-dependent pathways	[23]

ALP: alkaline phosphatase; ATM: ataxia-telangiectasia mutated; CAT: catalase; Chk2: checkpoint kinase 2; Co: cobalt; COX-2: cyclooxygenase-2; CQ; camphorquinone; Cr: chromium; DSPP: dentin sialophosphoprotein; DMAE-CB: methacryloxylethyl cetyl ammonium chloride; ERK: extracellular signal-regulated kinase; GADD45α: growth arrest and DNA damage-inducible protein GADD45 alpha; GCL: γ-glutamylcysteine lygase; (GPx: glutathione peroxidase; GR: glutathione reductase; GSH: reduced glutathione; GSSG: oxidized form of glutathione; GST: glutathione S-transferase; HEMA: 2-hydroxyethyl methacrylate; HO-1: heme oxygenase 1; H₂O₂: hydrogen peroxide; IL-1β: interleukin-1beta; iNOS: inducible nitric oxide synthetase; JNK: c-Jun N-terminal kinase; LDH: lactate dehydrogenase; LPS: lipopolysaccharide; MDA: malondialdehyde; MMA: methyl methacrylate; MMP: matrix metalloproteinase; MTA: mineral trioxide aggregate; NAC: N-acetylcysteine; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NO: nitric oxide; NQO: nitroquinoline 1-oxide; Nrf2: NF-E2-related factor 2; OCN: osteocalcin; PGE2: prostaglandin E2; p21: cyclin-dependent kinase inhibitor 1; p38 MAPK: p38 mitogen-activated protein kinase; P4H: prolyl-4 hydroxylase; p-JAK2: phosphorylation of janus kinase 2; ROS: reactive oxygen species; SOD: superoxide dismutase; STAT3: signal transducer and activator of transcription 3; TAS: total antioxidant status; TEGDMA: triethylenglycol dimethacrylate; TNF-α: tumor necrosis factor-alpha.