[Research Progress in Niacinamide in the Prevention and Treatment of Mouth and Systemic Diseases].

Nicotinamide (NAM) is the amide form of niacin and one of the precursors of nicotinamide adenine dinucleotide (NAD +). NAM can be used as a dietary supplement or clinical therapeutic drug to replenish NAD + levels in the human body and participate in key bodily functions such as cellular metabolism and DNA repair. NAM has the advantage of low cost, wide availability, and sound biosafety. It also has multiple biological functions, including antibacterial effect, anti-inflammatory effect, and modulation of cellular immunity, producing significant ameliorative effects on skin and neurodegenerative diseases. However, most studies on NAM are still at the laboratory stage. Herein we reviewed the role and mechanism of NAM in the prevention and treatment of oral and systemic diseases, explored its potential as clinical therapeutic medication, provided some basis and references for the clinical application of nicotinamide in the prevention and treatment of various diseases, and discussed its prospects for future research and application.

Glucosyltransferase-modulated Streptococcus mutans adhesion to different surfaces involved in biofilm formation by atomic force microscopy.

Biofilm on dental restorative materials is an important determinant in the etiology of secondary caries development. Formation of biofilm involves adhesion of bacteria onto substrate, bacterial cell, and biofilm surfaces. Glucosyltransferase B and C (GtfB and GtfC) are essential factors for regulation of Streptococcus mutans biofilm formation, but the mechanisms involving different kinds of bacterial adhesion still lack detailed description. In this study, nanoscale adhesion force measurement was performed using atomic force microscopy. Bacteria-coated cantilevers were used to probe S. mutans adhesion to substrates, bacterial cells, and early biofilms. Two representative dental materials, glass ionomer cement (GIC) and composite resin, served as substrates. It was found that deletion of gtfB and gtfC genes both reduced adhesion forces of S. mutans toward substrate and bacterial cell surfaces (P < 0.05). Notably, reduction of the gtfB gene remarkably decreased bacterial adhesion to biofilm surfaces (P < 0.05), while gtfC showed no obvious effect during this stage. Biofilms cultured on GIG further decreased cell-biofilm adhesion, compared with those on resin (P < 0.05). Confocal fluorescence images and scanning electron microscopy images showed that deletion of gtfB lead to reduced microcolony formation and less production of exopolysaccharides (EPSs) in the biofilm, and after bacterial culturing on GIC, the EPS content was further decreased. Our findings suggest that EPSs mainly mediate bacterial adhesion to early biofilm surface. Deletion of gtfB and coculture with GIC could significantly reduce the cell-biofilm adhesion, which is probably through decreasing of EPS production. gtfB exerts a critical role in the bacterial adhesion for the whole process of biofilm development, while gtfC possibly works only in the early stages.

Nicotinamide employs a starvation strategy against Porphyromonas gingivalis virulence by inhibiting the heme uptake system and gingipain activities.

Periodontitis is a common oral bacterial infection characterized by inflammatory responses. Its high prevalence lowers the quality of life for individuals and increases the global economic and disease burden. As microorganisms in dental plaque are responsible for this oral disease, antibacterial drug treatments are effective strategies for preventing and treating periodontitis. In this study, we investigated the inhibitory effect of nicotinamide (NAM), a vitamin B3 derivative, on the growth and virulence of Porphyromonas gingivalis, a key member of the red complex. Our findings revealed that NAM inhibited bacterial growth and gingipain activities, which played a dominant role in protein hydrolysis and heme acquisition. NAM decreased hemagglutination and hemolysis abilities and changed hemin and hemoglobin binding capacities, controlling bacterial infection through a starvation strategy by blocking access to growth-essential nutrients from the outside and reducing bacterial virulence. Several experiments in an animal model showed the effectiveness of NAM in preventing alveolar bone loss and reducing inflammatory cell infiltration, shedding light on its potential therapeutic applicability.

Inhibition of Streptococcus mutans growth and biofilm formation through protein acetylation.

Numerous cellular processes are regulated in response to the metabolic state of the cell, and one such regulatory mechanism involves lysine acetylation. Lysine acetylation has been proven to play an important role in the virulence of Streptococcus mutans, a major cariogenic bacterial species. S. mutans' glucosyltransferases (Gtfs) are responsible for synthesizing extracellular polysaccharides (EPS) and contributing to biofilm formation. One of the most common nonsteroidal anti-inflammatory drugs is acetylsalicylic acid (ASA), which can acetylate proteins through a nonenzymatic transacetylation reaction. Herein, we investigated the inhibitory effects of ASA on S. mutans. ASA treatment was observed to impede the growth of S. mutans, leading to a reduction in the production of water-insoluble EPS and the formation of biofilm. Moreover, ASA decreased the enzyme activity of Gtfs while increasing the protein acetylation level. The in vivo anticaries efficacy of ASA has further been proved using the rat caries model. In conclusion, ASA as an acetylation agent attenuated the cariogenic virulence of S. mutans, suggesting the potential value of protein acetylation on antimicrobial and anti-biofilm applications to S. mutans.

A GntR family transcription factor in Porphyromonas gingivalis regulates bacterial growth, acylpeptidyl oligopeptidase, and gingipains activity.

Porphyromonas gingivalis is a keystone pathogen for periodontitis. The function of the GntR family transcription factor is poorly studied in P. gingivalis. Numerous processes govern bacterial growth. The survival and pathogenicity of P. gingivalis depend heavily on its capacity to acquire amino acids as nutritional sources. In this investigation, a GntR transcription factor, pg1007, was identified in P. gingivalis, the deletion of which significantly inhibited bacterial growth. The mutant strain also exhibited an increased extracellular activity of gingipains and acylpeptidyl oligopeptidase (AOP). Global gene expression profiling revealed that the expression levels of 59 genes were significantly altered in the Δpg1007 mutant, with an upregulation in gene expression for AOP, ABC transporters, and some membrane proteins. In addition, His-PG1007 protein was purified as a recombinant protein from Escherichia coli, and the conserved DNA sequence bound by it was determined using electrophoretic mobility shift assays and DNase I footprinting assays. Consequently, this study demonstrated that pg1007 is a crucial transcription factor in P. gingivalis and regulates the bacterial growth and activity of gingipains and AOP. These findings may enhance our understanding of the regulation of bacterial proliferation and protease activity in P. gingivalis.

Upconversion Nanoplatform Enables Multimodal Imaging and Combinatorial Immunotherapy for Synergistic Tumor Treatment and Monitoring.

Designing a novel nanoplatform that integrates multimodal imaging and synergistic therapy for precision tumor nanomedicines is challenging. Herein, we prepared rare-earth ion-doped upconversion hydroxyapatite (FYH) nanoparticles as nanocarriers coated and loaded respectively with polydopamine (PDA) and doxorubicin (DOX), i.e., FYH-PDA-DOX, for tumor theranostics. The developed FYH-PDA-DOX complexes exhibited desirable photothermal conversion, pH/near-infrared-irradiation-responsive DOX release, and multimodal upconversion luminescence/computed tomography/magnetic resonance imaging performance and helped monitor the metabolic distribution process of the complexes and provided feedback to the therapeutic effect. Upon 808 nm laser irradiation, the fast release of DOX facilitated the photothermal-chemotherapy effect, immunogenic cell death, and antitumor immune response. On combining with the anti-programmed cell death 1 ligand 1 antibody, an enhanced tri-mode photothermal-chemo-immunotherapy synergistic treatment against tumors can be realized. Thus, this treatment elicited potent antitumor immunity, producing appreciable T-cell cytotoxicity against tumors, amplifying tumor suppression, and extending the survival of mice. Therefore, the FYH-PDA-DOX complexes are promising as a smart nanoplatform for imaging-guided synergistic cancer treatment.

A novel theranostic nanoplatform for imaging-guided chemo-photothermal therapy in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is highly malignant and invasive, and current treatments are limited due to serious side effects and unsatisfactory outcomes. Here, we reported the terbium ion-doped hydroxyapatite (HATb) nanoparticle as a luminescent probe to encapsulate both the near-infrared (NIR) photothermal agent polydopamine (PDA) and anticancer doxorubicin (DOX) for imaging-guided chemo-photothermal therapy. The morphology, crystal structure, fluorescence, and composition of HATb-PDA-DOX were characterized. HATb-PDA showed a high DOX loading capacity. A theranostic nanoplatform showed pH/NIR responsive release properties and better antitumor outcomes in OSCC cells than monomodal chemotherapy or photothermal therapy, while keeping side effects at a minimum. Also, the luminescence signal was confirmed to be tracked and the increase of the red/green (R/G) ratio caused by the DOX release could be used to monitor the DOX release content. Furthermore, HATb-PDA-DOX plus NIR treatment synergistically promoted in vitro cell death through the overproduction of reactive oxygen species (ROS), cell cycle arrest, and increased cell apoptosis. Overall, this work presents an innovative strategy in designing a multifunctional nano-system for imaging-guided cancer treatment.

Nanoscale adhesion forces of glucosyltransferase B and C genes regulated Streptococcal mutans probed by AFM.

Glucosyltransferases (Gtfs), represented by GtfB and GtfC, are important virulence factors of Streptococcus mutans and the major etiologic pathogens of tooth decay. However, the individual roles of gtfB and gtfC in the initial attachment of S. mutans are not known. We used atomic force microscopy to explore the contribution of gtfB and gtfC, as well as enamel-surface roughness, on the initial attachment of S. mutans. Adhesion forces of four S. mutans strains (wild-type, ΔgtfB, ΔgtfC, and ΔgtfBC), onto etched enamel surfaces, were determined. Force curves showed that, with increasing etching time from 0 to 10 s, the forces of all strains increased accordingly with acid-exposure time, the adhesion forces of wild-type strains were significantly greater than those of mutant strains (p < .05), and the forces of the three mutants were similar (p < .05). When the etching time was increased from 10 to 30 s, difference in force between 20 and 30 s was not observed, and adhesion forces among ΔgtfB, ΔgtfC, and wild-type strains were not significantly different when the etching time was >20 s (p > .05). These data suggest that the roughness and morphology of enamel surfaces may have a significant influence upon the initial attachment of bacteria, and that gtfB and gtfC are essential for the adhesion activity of bacteria. Furthermore, gtfB seems to be more important than gtfC for bacterial-biofilm formation, and gtfB inactivation is an effective strategy to inhibit the virulence of cariogenic biofilms.