Biological biomarkers of oral cancer.

The oral squamous cell carcinoma (OSCC) 5 year survival rate of 41% has marginally improved in the last few years, with less than a 1% improvement per year from 2005 to 2017, with higher survival rates when detected at early stages. Based on histopathological grading of oral dysplasia, it is estimated that severe dysplasia has a malignant transformation rate of 7%-50%. Despite these numbers, oral dysplasia grading does not reliably predict its clinical behavior. Thus, more accurate markers predicting oral dysplasia progression to cancer would enable better targeting of these lesions for closer follow-up, especially in the early stages of the disease. In this context, molecular biomarkers derived from genetics, proteins, and metabolites play key roles in clinical oncology. These molecular signatures can help predict the likelihood of OSCC development and/or progression and have the potential to detect the disease at an early stage and, support treatment decision-making and predict treatment responsiveness. Also, identifying reliable biomarkers for OSCC detection that can be obtained non-invasively would enhance management of OSCC. This review will discuss biomarkers for OSCC that have emerged from different biological areas, including genomics, transcriptomics, proteomics, metabolomics, immunomics, and microbiomics.

Nisin a probiotic bacteriocin mitigates brain microbiome dysbiosis and Alzheimer's disease-like neuroinflammation triggered by periodontal disease.

INTRODUCTION: Periodontitis-related oral microbial dysbiosis is thought to contribute to Alzheimer's disease (AD) neuroinflammation and brain amyloid production. Since probiotics can modulate periodontitis/oral dysbiosis, this study examined the effects of a probiotic/lantibiotic, nisin, in modulating brain pathology triggered by periodontitis. METHODS: A polymicrobial mouse model of periodontal disease was used to evaluate the effects of this disease on brain microbiome dysbiosis, neuroinflammation, Alzheimer's-related changes, and nisin's therapeutic potential in this context. RESULTS: 16S sequencing and real-time PCR data revealed that Nisin treatment mitigated the changes in the brain microbiome composition, diversity, and community structure, and reduced the levels of periodontal pathogen DNA in the brain induced by periodontal disease. Nisin treatment significantly decreased the mRNA expression of pro-inflammatory cytokines (Interleukin-1ß/IL-1 ß, Interleukin 6/IL-6, and Tumor Necrosis Factor α/TNF-α) in the brain that were elevated by periodontal infection. In addition, the concentrations of amyloid-ß 42 (Aß42), total Tau, and Tau (pS199) (445.69 ± 120.03, 1420.85 ± 331.40, 137.20 ± 36.01) were significantly higher in the infection group compared to the control group (193.01 ± 31.82, 384.27 ± 363.93, 6.09 ± 10.85), respectively. Nisin treatment markedly reduced the Aß42 (261.80 ± 52.50), total Tau (865.37 ± 304.93), and phosphorylated Tau (82.53 ± 15.77) deposition in the brain of the infection group. DISCUSSION: Nisin abrogation of brain microbiome dysbiosis induces beneficial effects on AD-like pathogenic changes and neuroinflammation, and thereby may serve as a potential therapeutic for periodontal-dysbiosis-related AD.

Specific Oral Microbial Differences in Proteobacteria and Bacteroidetes Are Associated with Distinct Sites When Moving from Healthy Mucosa to Oral Dysplasia-A Microbiome and Gene Profiling Study and Focused Review.

Oral potentially malignant disorders (OPMDs) are a group of conditions that carry a risk of oral squamous cell carcinoma (OSCC) development. Recent studies indicate that periodontal disease-associated pathogenic bacteria may play a role in the transition from healthy mucosa to dysplasia and to OSCC. Yet, the microbial signatures associated with the transition from healthy mucosa to dysplasia have not been established. To characterize oral microbial signatures at these different sites, we performed a 16S sequencing analysis of both oral swab and formalin-fixed, paraffin-embedded tissue (FFPE) samples. We collected oral swabs from healthy mucosa (from healthy patients), histologically normal mucosa adjacent to dysplasia, and low-grade oral dysplasia. Additionally, FFPE samples from histologically normal mucosa adjacent to OSCC, plus low grade and high-grade oral dysplasia samples were also collected. The collected data demonstrate significant differences in the alpha and beta microbial diversities of different sites in oral mucosa, dysplasia, and OSCC, as well as increased dissimilarities within these sites. We found that the Proteobacteria phyla abundance increased, concurrent with a progressive decrease in the Firmicutes phyla abundance, as well as altered levels of Enterococcus cecorum, Fusobacterium periodonticum, Prevotella melaninogenica, and Fusobacterium canifelinum when moving from healthy to diseased sites. Moreover, the swab sample analysis indicates that the oral microbiome may be altered in areas that are histologically normal, including in mucosa adjacent to dysplasia. Furthermore, trends in specific microbiome changes in oral swab samples preceded those in the tissues, signifying early detection opportunities for clinical diagnosis. In addition, we evaluated the gene expression profile of OSCC cells (HSC-3) infected with either P. gingivalis, T. denticola, F. nucelatum, or S. sanguinis and found that the three periodontopathogens enrich genetic processes related to cancer progression, including skin keratinization/cornification, while the commensal enriched processes related to RNA processing and adhesion. Finally, we reviewed the dysplasia microbiome literature and found a significant decrease in commensal bacteria, such as the Streptococci genus, and a simultaneous increase in pathogenic bacteria, mainly Bacteroidetes phyla and Fusobacterium genus. These findings suggest that features of the oral microbiome can serve as novel biomarkers for dysplasia and OSCC disease progression.

Periodontal treatment and microbiome-targeted therapy in management of periodontitis-related nonalcoholic fatty liver disease with oral and gut dysbiosis.

A growing body of evidence from multiple areas proposes that periodontal disease, accompanied by oral inflammation and pathological changes in the microbiome, induces gut dysbiosis and is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A subgroup of NAFLD patients have a severely progressive form, namely nonalcoholic steatohepatitis (NASH), which is characterized by histological findings that include inflammatory cell infiltration and fibrosis. NASH has a high risk of further progression to cirrhosis and hepatocellular carcinoma. The oral microbiota may serve as an endogenous reservoir for gut microbiota, and transport of oral bacteria through the gastro-intestinal tract can set up a gut microbiome dysbiosis. Gut dysbiosis increases the production of potential hepatotoxins, including lipopolysaccharide, ethanol, and other volatile organic compounds such as acetone, phenol and cyclopentane. Moreover, gut dysbiosis increases intestinal permeability by disrupting tight junctions in the intestinal wall, leading to enhanced translocation of these hepatotoxins and enteric bacteria into the liver through the portal circulation. In particular, many animal studies support that oral administration of Porphyromonas gingivalis, a typical periodontopathic bacterium, induces disturbances in glycolipid metabolism and inflammation in the liver with gut dysbiosis. NAFLD, also known as the hepatic phenotype of metabolic syndrome, is strongly associated with metabolic complications, such as obesity and diabetes. Periodontal disease also has a bidirectional relationship with metabolic syndrome, and both diseases may induce oral and gut microbiome dysbiosis with insulin resistance and systemic chronic inflammation cooperatively. In this review, we will describe the link between periodontal disease and NAFLD with a focus on basic, epidemiological, and clinical studies, and discuss potential mechanisms linking the two diseases and possible therapeutic approaches focused on the microbiome. In conclusion, it is presumed that the pathogenesis of NAFLD involves a complex crosstalk between periodontal disease, gut microbiota, and metabolic syndrome. Thus, the conventional periodontal treatment and novel microbiome-targeted therapies that include probiotics, prebiotics and bacteriocins would hold great promise for preventing the onset and progression of NAFLD and subsequent complications in patients with periodontal disease.

Incision-free, coronally advanced flap with subepithelial connective tissue graft placed by the molar or canine access (MOCA) technique: 13 case series.

INTRODUCTION: Root coverage procedures are not always predictable, and outcomes depend on several factors. This technique provides a predictable alternative to managing facial gingival recessions. CASE SERIES: A new grafting technique is introduced that requires no incisions at the recipient site, thereby preserving the integrity of the local blood supply to optimize the healing process. The graft is placed through the gingival sulcus via a molar or canine access (MOCA) approach, and there is minimal tension on the coronally advanced flap through use of suspension sutures. Thirteen non-smoking patients, between the ages of 27 and 57, with Cairo RT1 facial recession were studied, with a follow-up period of 1-60 weeks. This paper explains the step-by-step technique and highlights 13 cases. CONCLUSION: Complete root coverage was achieved in all 13 cases, although one case showed initial altered healing. While MOCA is technique sensitive, it provides optimal root coverage results. With no incisions at the recipient site, there is no uneven texture or scar formation, and healing proceeds with minimal interruption. Why is this case series new information? MOCA is a unique approach to introduce grafts into non-incised sites of recession that can be one, two, or three teeth away at molars or canines. Non-incised approach minimizes interruption to blood supply. Coronally advanced flaps are secured in place with composite-fastened suspension sutures for tension-free flap closure. What are the keys to successful management of these cases? Good quality and quantity of connective tissue graft Early diagnosis and treatment of recession Expert surgical technique What are the key limitations to the success of these cases? The quality of the donor site is variable among patients. A technique-sensitive approach Advanced recession might warrant a second surgery.

In vitro antiviral activity of stabilized chlorine dioxide containing oral care products.

OBJECTIVE: To determine the in vitro antiviral activity of oral care products containing stabilized chlorine dioxide toward infectious viruses that harbor in the oral cavity. Specfically, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), SARS-CoV, human coronavirus (HCoV) 229E, influenza A (H3N2), rhinovirus type 14, adenovirus type 5, and herpes simplex virus (HSV) type 1 and 2 were examined. METHODS: Validated in vitro suspension virucidal assays were used. Test product was mixed with the test virus for 30, 60, or 120 s, neutralized with sodium thiosulfate, serially diluted in dilution medium in a 96-well plate and incubated in a carbon dioxide incubator for 7 days. The 50% Tissue Culture Infectious Dose per milliliter was determined. RESULTS: Two rinses, one oral spray and one fluoride toothpaste showed log reduction of severe acute respiratory syndrome coronavirus-2 ranging from 1.81 to 2.98 and of influenza A from 2.58 to 4.13, respectively, within 30 s of contact time; similar results were obtained at 60 s. Further, the Ultra Sensitive rinse showed 0.19, 0.75, 1.58, 1.75, 2.66, and 3.24 log reduction of severe acute respiratory syndrome coronavirus, human coronavirus 229E, rhinovirus type 14, adenovirus type 5, and herpes simplex virus type 1 and type 2, respectively, within 30 s of contact time. CONCLUSION: Stabilized chlorine dioxide containing CloSYS® oral care products reduced the viral load of multiple viruses within 30 s. The results warrant further investigation for potential in vivo applications.

Use of the Probiotic Bifidobacterium animalis subsp. lactis HN019 in Oral Diseases.

The oral cavity is one of the environments on the human body with the highest concentrations of microorganisms that coexist harmoniously and maintain homeostasis related to oral health. Several local factors can shift the microbiome to a pathogenic state of dysbiosis. Existing treatments for infections caused by changes in the oral cavity aim to control biofilm dysbiosis and restore microbial balance. Studies have used probiotics as treatments for oral diseases, due to their ability to reduce the pathogenicity of the microbiota and immunoinflammatory changes. This review investigates the role of the probiotic Bifidobacterium animalis subsp. lactis (B. lactis) HN019 in oral health, and its mechanism of action in pre-clinical and clinical studies. This probiotic strain is a lactic acid bacterium that is safe for human consumption. It mediates bacterial co-aggregation with pathogens and modulates the immune response. Studies using B. lactis HN019 in periodontitis and peri-implant mucositis have shown it to be a potential adjuvant treatment with beneficial microbiological and immunological effects. Studies evaluating its oral effects and mechanism of action show that this probiotic strain has the potential to be used in several dental applications because of its benefit to the host.

Nisin and Nisin Probiotic Disrupt Oral Pathogenic Biofilms and Restore Their Microbiome Composition towards Healthy Control Levels in a Peri-Implantitis Setting.

Peri-implantitis is characterized by chronic inflammation of the peri-implant supporting tissues that progressively and irreversibly leads to bone loss and, consequently, implant loss. Similar to periodontal disease, oral dysbiosis is thought to be a driver of peri-implantitis. However, managing peri-implantitis with traditional treatment methods, such as nonsurgical debridement or surgery, is not always successful. Thus, novel strategies have been proposed to address these shortcomings. One strategy is the use of probiotics as antimicrobial agents since they are considered safe for humans and the environment. Specifically, the probiotic Lactococcus lactis produces nisin, which has been used worldwide for food preservation. The objective of this study was to determine whether nisin and the wild-type (WT) nisin-producing L. lactis probiotic can disrupt oral pathogenic biofilms and promote a healthier oral microbiome within these oral biofilms on titanium discs. Using confocal imaging and 16S rRNA sequencing, this study revealed that nisin and WT L. lactis probiotic disrupt oral pathogenic biofilms in a peri-implantitis setting in vitro. More specifically, nisin decreased the viability of the pathogen-spiked biofilms dose-dependently from 62.53 ± 3.69% to 54.26 ± 3.35% and 44.88 ± 2.98%, respectively. Similarly, 105 CFU/mL of WT L. lactis significantly decreased biofilm viability to 52.45 ± 3.41%. Further, both treatments shift the composition, relative abundance, and diversity levels of these biofilms towards healthy control levels. A total of 1 µg/mL of nisin and 103 CFU/mL of WT L. lactis were able to revert the pathogen-mediated changes in the Proteobacteria (from 80.5 ± 2.9% to 75.6 ± 2.0%, 78.0 ± 2.8%, and 75.1 ± 5.3%, respectively) and Firmicutes (from 11.6 ± 1.6% to 15.4 ± 1.3%, 13.8 ± 1.8%, and 13.7 ± 2.6%, respectively) phyla back towards control levels. Thus, nisin and its nisin-producing L. lactis probiotic may be useful in treating peri-implantitis by promoting healthier oral biofilms, which may be useful for improving patient oral health.

Solid Lipid Nanoparticles Loaded with Nisin (SLN-Nisin) are More Effective Than Free Nisin as Antimicrobial, Antibiofilm, and Anticancer Agents.

Bacteriocins are peptides produced by bacteria to inhibit the growth of other prokaryotes. Nisin is a bacteriocin widely used in the food industry and for biomedical applications. However, bacteriocins have some limitations, as they experience mechanisms of resistance, degradation by proteases, and suboptimal intracellular delivery. Combining bacteriocins with nanoscale drug delivery systems (nano-DDS) is an approach that can help overcome these limitations. Among the nano-DDS, solid lipid nanoparticles (SLN) have been described as promising candidates, because of their potential for industrial scale-up and lower toxicity. The objective of this proof-of-concept study was to investigate the use of nisin-loaded SLN (SLN-Nisin) as an antimicrobial and anticancer therapeutic. We show that SLN-Nisin can significantly inhibit the growth of the oral pathogen, Treponema denticola, disrupt oral biofilms, and decrease oral squamous cell carcinoma cell (OSCC) viability compared to free nisin. Further, analysis with scanning electron microscopy (SEM) revealed significant morphological changes in OSCC cells challenged with SLN-Nisin, compared to the empty-nanoparticle or free nisin, indicating that SLN-Nisin likely decreases cell viability by increasing pore formation. This data reveals that nano-DDS are robust tools that can enhance bacteriocin properties.

Phosphatidylserine-Gold Nanoparticles (PS-AuNP) Induce Prostate and Breast Cancer Cell Apoptosis.

Prostate and breast cancer are the current leading causes of new cancer cases in males and females, respectively. Phosphatidylserine (PS) is an essential lipid that mediates macrophage efferocytosis and is dysregulated in tumors. Therefore, developing therapies that selectively restore PS may be a potential therapeutic approach for carcinogenesis. Among the nanomedicine strategies for delivering PS, biocompatible gold nanoparticles (AuNPs) have an extensive track record in biomedical applications. In this study, we synthesized biomimetic phosphatidylserine-caped gold nanoparticles (PS-AuNPs) and tested their anticancer potential in breast and prostate cancer cells in vitro. We found that both cell lines exhibited changes in cell morphology indicative of apoptosis. After evaluating for histone-associated DNA fragments, a hallmark of apoptosis, we found significant increases in DNA fragmentation upon PS-AuNP treatment compared to the control treatment. These findings demonstrate the use of phosphatidylserine coupled with gold nanoparticles as a potential treatment for prostate and breast cancer. To the best of our knowledge, this is the first time that a phosphatidylserine-capped AuNP has been examined for its therapeutic potential in cancer therapy.

Paradigm shift in the pathogenesis and treatment of oral cancer and other cancers focused on the oralome and antimicrobial-based therapeutics.

The oral microbiome is a community of microorganisms, comprised of bacteria, fungi, viruses, archaea, and protozoa, that form a complex ecosystem within the oral cavity. Although minor perturbations in the environment are frequent and compensable, major shifts in the oral microbiome can promote an unbalanced state, known as dysbiosis. Dysbiosis can promote oral diseases, including periodontitis. In addition, oral dysbiosis has been associated with other systemic diseases, including cancer. The objective of this review is to evaluate the epidemiologic evidence linking periodontitis to oral, gastrointestinal, lung, breast, prostate, and uterine cancers, as well as describe new evidence and insights into the role of oral dysbiosis in the etiology and pathogenesis of the cancer types discussed. Finally, we discuss how antimicrobials, antimicrobial peptides, and probiotics may be promising tools to prevent and treat these cancers, targeting both the microbes and associated carcinogenesis processes. These findings represent a novel paradigm in the pathogenesis and treatment of cancer focused on the oral microbiome and antimicrobial-based therapies.

Oral health's inextricable connection to systemic health: Special populations bring to bear multimodal relationships and factors connecting periodontal disease to systemic diseases and conditions.

The landscape in dentistry is changing as emerging studies continue to reveal that periodontal health impacts systemic health, and vice versa. Population studies, clinical studies, and in vitro animal studies underscore the critical importance of oral health to systemic health. These inextricable relationships come to the forefront as oral diseases, such as periodontal disease, take root. Special populations bring to bear the multimodal relationships between oral and systemic health. Specifically, periodontal disease has been associated with diabetes, metabolic syndrome, obesity, eating disorders, liver disease, cardiovascular disease, Alzheimer disease, rheumatoid arthritis, adverse pregnancy outcomes, and cancer. Although bidirectional relationships are recognized, the potential for multiple comorbidities, relationships, and connections (multimodal relationships) also exists. Proposed mechanisms that mediate this connection between oral and systemic health include predisposing and precipitating factors, such as genetic factors (gene polymorphisms), environmental factors (stress, habits-such as smoking and high-fat diets/consumption of highly processed foods), medications, microbial dysbiosis and bacteremias/viremias/microbemias, and an altered host immune response. Thus, in a susceptible host, these predisposing and precipitating factors trigger the onset of periodontal disease and systemic disease/conditions. Further, high-throughput sequencing technologies are shedding light on the dark matter that comprises the oral microbiome. This has resulted in better characterization of the oral microbial dysbiosis, including putative bacterial periodontopathogens and shifts in oral virome composition during disease. Multiple laboratory and clinical studies have illustrated that both eukaryotic and prokaryotic viruses within subgingival plaque and periodontal tissues affect periodontal inflammation, putative periodontopathogens, and the host immune response. Although the association between herpesviruses and periodontitis and the degree to which these viruses directly aggravate periodontal tissue damage remain unclear, the benefits to periodontal health found from prolonged administration of antivirals in immunocompromised or immunodeficient individuals demonstrates that specific populations are possibly more susceptible to viral periodontopathogens. Thus, it may be important to further examine the implications of viral pathogen involvement in periodontitis and perhaps it is time to embrace the viral dark matter within the periodontal environment to fully comprehend the pathogenesis and systemic implications of periodontitis. Emerging data from the coronavirus disease 2019 pandemic further underscores the inextricable connection between oral and systemic health, with high levels of the severe acute respiratory syndrome coronavirus 2 angiotensin-converting enzyme 2 receptor noted on oral tissues (tongue) and an allostatic load or overload paradigm of chronic stress likely contributing to rapid breakdown of oral/dental, periodontal, and peri-implant tissues. These associations exist within a framework of viremias/bacteremias/microbemias, systemic inflammation, and/or disturbances of the immune system in a susceptible host. A thorough review of systemic and oral diseases and conditions and their mechanistic, predisposing, and precipitating factors are paramount to better addressing the oral and systemic health and needs of our patients.

The oralome and its dysbiosis: New insights into oral microbiome-host interactions.

The oralome is the summary of the dynamic interactions orchestrated between the ecological community of oral microorganisms (comprised of up to approximately 1000 species of bacteria, fungi, viruses, archaea and protozoa - the oral microbiome) that live in the oral cavity and the host. These microorganisms form a complex ecosystem that thrive in the dynamic oral environment in a symbiotic relationship with the human host. However, the microbial composition is significantly affected by interspecies and host-microbial interactions, which in turn, can impact the health and disease status of the host. In this review, we discuss the composition of the oralome and inter-species and host-microbial interactions that take place in the oral cavity and examine how these interactions change from healthy (eubiotic) to disease (dysbiotic) states. We further discuss the dysbiotic signatures associated with periodontitis and caries and their sequalae, (e.g., tooth/bone loss and pulpitis), and the systemic diseases associated with these oral diseases, such as infective endocarditis, atherosclerosis, diabetes, Alzheimer's disease and head and neck/oral cancer. We then discuss current computational techniques to assess dysbiotic oral microbiome changes. Lastly, we discuss current and novel techniques for modulation of the dysbiotic oral microbiome that may help in disease prevention and treatment, including standard hygiene methods, prebiotics, probiotics, use of nano-sized drug delivery systems (nano-DDS), extracellular polymeric matrix (EPM) disruption, and host response modulators.

Poor Oral Health and Inflammatory, Hemostatic, and Cardiac Biomarkers in Older Age: Results From Two Studies in the UK and USA.

BACKGROUND: We examined the association of objective and subjective oral health markers with inflammatory, hemostatic, and cardiac biomarkers in older age. METHODS: Cross-sectional analyses were based on the British Regional Heart Study (BRHS) comprising British men aged 71-92 years (n = 2,147), and the Health, Aging and Body Composition (HABC) Study comprising American men and women aged 71-80 years (n = 3,075). Oral health markers included periodontal disease, tooth count, dry mouth. Inflammatory biomarkers included C-reactive protein (CRP), interleukin-6 (IL-6) in both studies, and tissue plasminogen activator (t-PA), von Willebrand Factor (vWF), fibrin D-dimer, high-sensitivity Troponin T (hsTnT), and N-terminal pro-brain natriuretic peptide (NTproBNP) only in the BRHS. RESULTS: In both studies, tooth loss, was associated with the top tertile of CRP-odds ratios (ORs) (95% confidence interval [CI]) are 1.31 (1.02-1.68) in BRHS; and 1.40 (1.13-1.75) in the HABC Study, after adjusting for confounders. In the HABC Study, cumulative (≥3) oral health problems were associated with higher levels of CRP (OR [95% CI] =1.42 [1.01-1.99]). In the BRHS, complete and partial tooth loss was associated with hemostatic factors, in particular with the top tertile of fibrin D-dimer (OR [95% CI] = 1.64 [1.16-2.30] and 1.37 [1.05-1.77], respectively). Tooth loss and periodontal disease were associated with increased levels of hsTnT. CONCLUSIONS: Poor oral health in older age, particularly tooth loss, was consistently associated with some inflammatory, hemostatic, and cardiac biomarkers. Prospective studies and intervention trials could help understand better if poor oral health is causally linked to inflammatory, hemostatic, and cardiac biomarkers.

Rebuilding the Interproximal Papilla: Description of "Tube" Technique and Two Case Reports.

INTRODUCTION: Papilla reconstruction relies on similar principles as those applied to soft tissue grafting for recession defects; however, it is uniquely challenging from a surgical perspective because of the small size and lack of a blood supply. Several techniques have been used to reconstruct lost papilla; however, there are no prescribed techniques for this specific application. CASE PRESENTATION: This report describes a novel technique, herein called, the "tube technique" for treating interproximal recession and reconstructing the interproximal papilla, and documents two cases using the tube technique. An increase in attachment levels was observed in Case 1 (5 mm) and in Case 2 (4 mm) after using this surgical technique for papilla reconstruction. CONCLUSION: The tube grafting technique requires technical precision. Although when executed carefully, it results in predictable reconstruction of the interproximal papilla. Use of the tube technique helps mitigate issues associated with inadequate flap thickness, blood supply, and flap retraction.

Periodontal pathogens promote cancer aggressivity via TLR/MyD88 triggered activation of Integrin/FAK signaling that is therapeutically reversible by a probiotic bacteriocin.

Epidemiological studies reveal significant associations between periodontitis and oral cancer. However, knowledge about the contribution of periodontal pathogens to oral cancer and potential regulatory mechanisms involved is limited. Previously, we showed that nisin, a bacteriocin and commonly used food preservative, reduced oral cancer tumorigenesis and extended the life expectancy in tumor-bearing mice. In addition, nisin has antimicrobial effects on key periodontal pathogens. Thus, the purpose of this study was to test the hypothesis that key periodontal pathogens (Porphyromonas gingivalis, Treponema denticola, and Fusobacterium nucleatum) promote oral cancer via specific host-bacterial interactions, and that bacteriocin/nisin therapy may modulate these responses. All three periodontal pathogens enhanced oral squamous cell carcinoma (OSCC) cell migration, invasion, tumorsphere formation, and tumorigenesis in vivo, without significantly affecting cell proliferation or apoptosis. In contrast, oral commensal bacteria did not affect OSCC cell migration. Pathogen-enhanced OSCC cell migration was mediated via integrin alpha V and FAK activation, since stably blocking alpha V or FAK expression abrogated these effects. Nisin inhibited these pathogen-mediated processes. Further, Treponema denticola induced TLR2 and 4 and MyD88 expression. Stable suppression of MyD88 significantly inhibited Treponema denticola-induced FAK activation and abrogated pathogen-induced migration. Together, these data demonstrate that periodontal pathogens contribute to a highly aggressive cancer phenotype via crosstalk between TLR/MyD88 and integrin/FAK signaling. Nisin can modulate these pathogen-mediated effects, and thus has therapeutic potential as an antimicrobial and anti-tumorigenic agent.

Modulation of pathogenic oral biofilms towards health with nisin probiotic.

BACKGROUND: Oral dysbiosis is an imbalance in the oral microbiome and is associated with a variety of oral and systemic diseases, including periodontal disease, caries, and head and neck/oral cancer. Although antibiotics can be used to control this dysbiosis, they can lead to adverse side effects and superinfections. Thus, novel strategies have been proposed to address these shortcomings. One strategy is the use of probiotics as antimicrobial agents, since they are considered safe for humans and the environment. Specifically, the Gram-positive Lactococcus lactis, a species present in the oral and gut microbiota, is able to produce nisin, which has been used worldwide for food preservation. OBJECTIVE: The objective of this study was to test whether a nisin probiotic can promote a healthier oral microbiome in pathogen-spiked oral biofilms. RESULTS: We found that L. lactis can prevent oral biofilm formation and disrupt 24-h and 48-h pre-formed biofilms. Finally, we demonstrate that both treatments, a nisin-producing L. lactis probiotic and nisin can decrease the levels of pathogens in the biofilms and return the diversity levels back to control or 'healthy' levels. CONCLUSION: A nisin-producing probiotic, can be used to treat 'disease-altered' biofilms and promote healthier oral biofilms, which may be useful for improving patient oral health.

Bacterial anti-microbial peptides and nano-sized drug delivery systems: The state of the art toward improved bacteriocins.

Antimicrobial peptides (AMP) are molecules consisting of 12-100 amino acids synthesized by certain microbes and released extracellularly to inhibit the growth of other microbes. Among the AMP molecules, bacteriocins are produced by both gram-positive and gram-negative bacterial species and are used to kill or inhibit other prokaryotes in the environment. Due to their broad-spectrum antimicrobial activity, some bacteriocins have the potential of becoming the next generation of antibiotics for use in the crisis of multi antibiotic-resistant bacteria. Recently, bacteriocins have even been used to treat cancer. However, bacteriocins present a few drawbacks, such as sensitivity to proteases, immunogenicity issues, and the development of bacteriocin resistance by pathogenic bacteria. In this regard, nanoscale drug delivery systems (Nano-DDS) have led to the expectation that they will eventually improve the treatment of many diseases by addressing these limitations and improving bacteriocin pharmacokinetics and pharmacodynamics. Thus, combining bacteriocins with nano-DDS may be useful in overcoming these drawbacks and thereby reveal the full potential of bacteriocins. In this review article, we highlight the importance of tailoring nano-DDS to address bacteriocin limitations, the successes and failures of this technology thus far, the challenges that this technology still has to overcome before reaching the market, and future perspectives. Therefore, the purpose of this review is to highlight, categorize, compare and contrast the different nano-DDS described in the literature so far, and compare their effectiveness in order to improve the next generation of bacteriocin nano-sized drug delivery systems (Nano-DDS).

Antibiotic prescribing practices in periodontal surgeries with and without bone grafting.

BACKGROUND: The prevention of postoperative infection is often the basis for antibiotic prescription; however, the risks of unwarranted antibiotics and lack of guidelines for procedures involving bone grafts creates additional difficulty in decision making for practitioners. This study aims to evaluate practices in antibiotics prescribed for periodontal surgeries with and without bone grafting and acceptability of guidelines. METHODS: An anonymous survey was distributed to periodontists via the California Society of Periodontists e-mail listserv. The survey questioned prescribing practices for periodontal procedures, prescribing rationale, demographic and dental practice information, and acceptability of guidelines. Results were analyzed using McNemar tests and logistic regression. RESULTS: Practitioners were significantly less likely to prescribe antibiotics for traditional periodontal surgeries without bone grafting compared with socket preservation, guided tissue regeneration, guided bone regeneration, and sinus augmentation (P < 0.0001). Practitioners were significantly more likely to prescribe antibiotics with more complex bone grafting such as guided bone regeneration and sinus augmentation compared with socket preservation (P < 0.0001). The most common rationale for prescribing antibiotics with bone grafting was to decrease the chances of developing an infection. Seventy-five percent of practitioners reported they would follow guidelines for antibiotic prescription if they were developed by the American Academy of Periodontology. CONCLUSIONS: Practitioners are more likely to prescribe antibiotics with bone grafting and as complexity of the bone grafting procedure increases. Based on these results, the low incidence of infection in periodontal surgery cited in the literature, and willingness of practitioners to adopt guidelines, the establishment of evidence-based guidelines would be of benefit to the periodontal practicing community.

Microbial Communities Associated with Primary and Metastatic Head and Neck Squamous Cell Carcinoma - A High Fusobacterial and Low Streptococcal Signature.

Given the potential relationship between head and neck squamous cell carcinoma (HNSCC) and microbial dysbiosis, we profiled the microbiome within healthy normal and tumorous (primary and metastatic) human tissues from the oral cavity, larynx-pharynx, and lymph nodes using 16S rRNA sequencing. Alpha and beta diversity analyses revealed that normal tissues had the greatest richness in community diversity, while the metastatic populations were most closely related to one another. Compared to the normal, the microbiota associated with tumors supported altered abundances in the phyla Fusobacteria, Firmicutes, Actinobacteria and Proteobacteria. Most notably, the relative abundance of Fusobacterium increased whereas Streptococcus decreased in both primary and metastatic samples. Principal coordinate analysis indicated a separation and clustering of samples by tissue status. However, random forest analysis revealed that the microbial profiles alone were a poor predictor for primary and metastatic HNSCC samples. Here, we report that the microbial communities residing in the tumorous tissues are compositionally distinct compared to the normal adjacent tissues. However, likely due to the smaller sample size and sample-to-sample heterogeneity, our prediction models were not able to distinguish by sample types. This work provides a foundation for future studies aimed at understanding the role of the dysbiotic tissue microbiome in HNSCC.