• Acetylcholine
• Blood flow
• Dose-dependent
• Endothelium-dependent vasodilation
• Gingiva

• Humans
• Male
• Acetylcholine/pharmacology
• Gingiva/blood supply
• Gingiva/drug effects
• Adult
• Dose-Response Relationship, Drug
• Regional Blood Flow/drug effects
• Vasodilator Agents/pharmacology
• Vasodilator Agents/administration & dosage
• Young Adult
• Vasodilation/drug effects

• EFOP-3.6.2-16-2017-00006 Hungarian Human Resources Development Operational Program
• EFOP-3.6.2-16-2017-00006 Hungarian Human Resources Development Operational Program
• EFOP-3.6.2-16-2017-00006 Hungarian Human Resources Development Operational Program
• EFOP-3.6.2-16-2017-00006 Hungarian Human Resources Development Operational Program

• diabetes
• oral health
• periodontal disease
• saliva
• xerostomia

• Glycogen synthesis
• Insulin resistance
• Oral microbiome
• Real-time PCR

• Humans
• Insulin Resistance
• MAP Kinase Signaling System
• Proto-Oncogene Proteins c-akt/metabolism
• Signal Transduction
• Glucose/metabolism
• Extracellular Signal-Regulated MAP Kinases/metabolism
• Diabetes Mellitus
• Microbiota
• Insulin/metabolism
• Glycogen Synthase Kinase 3 beta/metabolism
• Glycogen Synthase Kinase 3 beta/pharmacology
• Diabetes Mellitus, Type 2/metabolism

• bacteria
• diseases
• pathogens
• periodontitis
• systemic

Sex hormones influence circulation, periodontitis, and wound healing. The aim of the study was to compare the endothelium-dependent and independent vasodilation in human gingiva in men and women.

Gingival blood flow was evaluated in twelve male and twelve female subjects with healthy gingiva and no systemic conditions after acetylcholine or nitric oxide donor (NitroPOHL). Agonists were administered into the gingival sulcus at the right secondary incisor (test site). Regional gingival blood flow (GBF) was imaged by Laser Speckle Contrast Imager from the marginal gingiva to the mucogingival junction in four consecutive regions (coronal, midway1, midway2 and apical). Blood flow was expressed in Laser Speckle Perfusion Unit (LSPU). The absolute maximal blood flow change (Dmax), the area under the blood flow curve (AUC), and the time to peak (TTP) were calculated.

Males had higher baseline GBF than females (257 ± 18.2 vs. 225 ± 18.8 LSPU, p < 0.001). Acetylcholine and NitroPOHL significantly increased the GBF in all test regions. The Dmax after the acetylcholine was reduced apically compared to the coronal (90 ± 13 LSPU vs. 117 ± 7 LSPU, p < 0.01), but it was similar after NitroPOHL (78 ± 9 LSPU vs. 86 ± 6 LSPU, p = 0.398) in both sexes. The Dmax and AUC were higher, and the TTP was smaller in men in most regions after acetylcholine but not after NitroPOHL.

In the human gingiva, the endothelium-independent vasodilation propagates without attenuation in the line of the vascular supply in both sexes. At the same time, the endothelium-dependent ascending vasodilation attenuates similarly in men and women. However, men had more pronounced endothelium-dependent vasodilation than women. Therefore, it might contribute to the increased severity of periodontal disease in men.

The study was registered with ClinicalTrials.gov on 09.06.2021 (NCT04918563).

• Acetylcholine
• Endothelium
• Gingiva
• Microcirculation
• Nitric oxide
• Sex

• hypoxia
• inflammation
• periodontal disease
• vascular changes

• Dental caries
• Diabetes mellitus, Type 2
• Inflammation
• Microbiota
• Oral health
• Risk factors

• Dental Caries/epidemiology
• Humans

Diabetes and periodontitis are two of the most prevalent diseases worldwide that negatively impact the quality of life of the individual suffering from them. They are part of the chronic inflammatory disease group or, as recently mentioned, non-communicable diseases, with inflammation being the meeting point among them. Inflammation hitherto includes vascular and tissue changes, but new technologies provide data at the intracellular level that could explain how the cells respond to the aggression more clearly. This review aims to emphasize the molecular pathophysiological mechanisms in patients with type 2 diabetes mellitus and periodontitis, which are marked by different impaired central regulators including mitochondrial dysfunction, impaired immune system and autophagy pathways, oxidative stress, and the crosstalk between adenosine monophosphate-activated protein kinase (AMPK) and the renin-angiotensin system (RAS). All of them are the shared background behind both diseases that could explain its relationship. These should be taken in consideration if we would like to improve the treatment outcomes. Currently, the main treatment strategies in diabetes try to reduce glycemia index as the most important aspect, and in periodontitis try to reduce the presence of oral bacteria. We propose to add to the therapeutic guidelines the handling of all the intracellular disorders to try to obtain better treatment success.

• AMPK
• autophagy
• diabetes
• mitochondrial dysfunction
• oxidative stress
• periodontal disease

• Animals
• Diabetes Mellitus/physiopathology
• Humans
• Inflammation/physiopathology
• Oxidative Stress
• Periodontitis/physiopathology

• Diabetes mellitus
• Gut microbiota
• Lactobacillus
• Metformin
• Montelukast
• Testes

• Microcirculation
• Peri-implantitis
• Scanning electron microscopy
• Vascular resin cast

• bleeding on probing
• diabetes
• diabetic retinopathy
• fasting blood sugar
• periodontal disease
• probing pocket depth

• N/A Kanagawa Dental University Research Fund

• animal study
• experimental periodontitis
• gingival blood flow
• mouth gag

• Diabetes
• Orthodontic movement
• Oxidative stress
• Periodontal ligament

Proline-rich proteins are associated with the formation of an acquired protein layer overlying the tooth enamel surface. Previous studies have described the antioxidant activity of salivary histatin against the hydroxyl radical from Fenton’s reaction, acting as the critical reactive oxygen species. However, the role of proline-rich proteins in mitigating the oxidative stress caused by reactive oxygen species in the oral cavity remains unclear. In this study, we investigated the antioxidant effects of proline-rich proteins 2 on direct reactive oxygen species using electron spin resonance spectroscopy. For the first time, we demonstrated that proline-rich proteins 2 exhibits antioxidant activity directly against the hydroxyl radical produced by hydrogen peroxide with ultraviolet. Considering that identical results were obtained when assaying 30 residues of proline-rich proteins 2, the direct antioxidant effects against the hydroxyl radical by proline-rich proteins 2 may be related to these specific 30 residues.

• antioxidant
• oxidative stress
• proline-rich proteins
• reactive oxygen species
• saliva

• Aging
• Animals
• Gingiva/blood supply
• Gingiva/physiology
• Male
• Microcirculation
• Physical Stimulation/methods
• Rats
• Rats, Wistar

• Japan Society for the Promotion of Science
• Major Course Field Integrated Fundamental Research 1, Graduate School of Dentistry, Kanagawa Dental University

Pancreatic cancer is a highly lethal disease, and most patients remain asymptomatic until the disease enters advanced stages. There is lack of knowledge in the pathogenesis, effective prevention and early diagnosis of pancreatic cancer. Recently, bacteria were found in pancreatic tissue that has been considered sterile before. The distribution of flora in pancreatic cancer tissue was reported to be different from normal pancreatic tissue. These abnormally distributed bacteria may be the risk factors for inducing pancreatic cancer. Therefore, studies on combined effect of multi-bacterial and multi-virulence factors may add to the knowledge of pancreatic cancer pathogenesis and aid in designing new preventive and therapeutic strategies. In this review, we outlined three oral bacteria associated with pancreatic cancer and their virulence factors linked with cancer.

• CDT
• FadA
• Gingipains
• NDK
• oral bacteria
• pancreatic cancer
• virulence factors

• antioxidant
• histatin
• oxidative stress
• reactive oxygen species
• saliva

• (MeSH) dendritic cells
• Porphyromonas gingivalis
• apoptosis
• autophagy
• periodontitis

A growing body of literature suggests that there is a link between periodontitis and systemic diseases. These diseases include cardiovascular disease, gastrointestinal and colorectal cancer, diabetes and insulin resistance, and Alzheimer's disease, as well as respiratory tract infection and adverse pregnancy outcomes. The presence of periodontal pathogens and their metabolic by-products in the mouth may in fact modulate the immune response beyond the oral cavity, thus promoting the development of systemic conditions. A cause-and-effect relationship has not been established yet for most of the diseases, and the mediators of the association are still being identified. A better understanding of the systemic effects of oral microorganisms will contribute to the goal of using the oral cavity to diagnose and possibly treat non-oral systemic disease.

• Chronic disease
• Dentistry
• Inflammation
• Oral pathogens
• Periodontal disease
• Systemic disease

• gingival blood flow
• human
• laser speckle contrast imaging
• postocclusive hyperemia
• transient compression

• diabetes mellitus
• dyslipidemia
• hyperglycemia
• hypertension
• immune dysfunction
• insulin resistance
• oral complications

• Laser Speckle Contrast Imaging
• coefficient of variation
• gingival blood flow
• reliability
• reproducibility

Periodontal disease is of established etiology in which polymicrobial synergistic ecology has become dysbiotic under the influence of Porphyromonas gingivalis. Following breakdown of the host's protective oral tissue barriers, P. gingivalis migrates to developing inflammatory pathologies that associate with Alzheimer's disease (AD). Periodontal disease is a risk factor for cardiovascular disorders (CVD), type II diabetes mellitus (T2DM), AD and other chronic diseases, whilst T2DM exacerbates periodontitis. This study analyzed the relationship between the P. gingivalis/host interactome and the genes identified in genome-wide association studies (GWAS) for the aforementioned conditions using data from GWASdb (P < 1E-03) and, in some cases, from the NCBI/EBI GWAS database (P < 1E-05). Gene expression data from periodontitis or P. gingivalis microarray was compared to microarray datasets from the AD hippocampus and/or from carotid artery plaques. The results demonstrated that the host genes of the P. gingivalis interactome were significantly enriched in genes deposited in GWASdb genes related to cognitive disorders, AD and dementia, and its co-morbid conditions T2DM, obesity, and CVD. The P. gingivalis/host interactome was also enriched in GWAS genes from the more stringent NCBI-EBI database for AD, atherosclerosis and T2DM. The misregulated genes in periodontitis tissue or P. gingivalis infected macrophages also matched those in the AD hippocampus or atherosclerotic plaques. Together, these data suggest important gene/environment interactions between P. gingivalis and susceptibility genes or gene expression changes in conditions where periodontal disease is a contributory factor.

• Alzheimer's disease
• Porphyromonas gingivalis
• cardiovascular
• diabetes
• interactome

• Adipocytes
• coculture techniques
• endothelial cells
• pericytes
• periodontal diseases
• regeneration

Periodontitis is the commonest oral disease affecting population worldwide. This disease is notorious for the devastation of tooth supporting structures, ensuing in the loss of dentition. The etiology for this disease is bacterial biofilm, which accumulates on the teeth as dental plaque. In addition to the biofilm microorganisms, other factors such as environmental, systemic and genetic are also responsible in progression of periodontitis. Diabetes mellitus (DM) is metabolic disorder which has an impact on the global health. DM plays a crucial role in the pathogenesis of periodontitis. Periodontitis is declared as the “sixth” major complication of DM. Evidence based literature has depicted an enhanced incidence and severity of periodontitis in subjects with DM. A “two way” relationship has been purported between periodontitis and DM. Mutual management of both conditions is necessary. Periodontal therapy (PT) may assist to diminish the progression of DM and improve glycemic control. Various advanced technological facilities may be utilized for the purpose of patient education and disease management. The present paper clarifies the etio-pathogenesis of periodontitis, establishing it as a complication of DM and elaborating the various mechanisms involved in the pathogenesis. The role of PT in amelioration of DM and application of digital communication will be discussed. Overall, it is judicious to create an increased patient cognizance of the periodontitis-DM relationship. Conjunctive efforts must be undertaken by the medical and oral health care professionals for the management of periodontitis affected DM patients.

• Cost-effectiveness
• Advanced glycation end products
• Complications
• Glycated hemoglobin
• Inflammation
• Mobile health
• Periodontitis
• Periodontal therapy
• Scaling and root planing
• Type 2 diabetes mellitus

• Blood flow
• Gingivitis
• Microcirculation
• Resin cast
• SEM

We herein investigated the regulatory mechanism in the circulation responsible for rat gingival reactive hyperemia (RH) associated with ischemia/reperfusion (I/R). RH was analyzed using a laser Doppler flowmeter. RH and I/R were elicited by gingival compression and release with a laser Doppler probe. RH increased in a time-dependent manner when the duration of compression was between 30 s and 20 min. This increase was significantly suppressed by N^ω-nitro-l-arginine-methyl-ester (l-NAME), 7-nitroindazole (7-NI), and 2,4-diamino-6-hydroxypyrimidine (DAHP). However, RH was markedly inhibited following 60 min of compression. This inhibition was significantly decreased by treatments with superoxide dismutase (SOD), (6R)-5,6,7,8-tetrahydro-l-biopterin (BH₄), and sepiapterin. The luminescent intensity of superoxide anion (O₂^•−)-induced 2-methyl-6-(4-methoxyphenyl)-3,7-dihydroimidazo-[1,2-a] pyrazine-3-one (MCLA) was markedly decreased by SOD and BH₄, but only slightly by sepiapterin. BH₄ significantly decreased O₂^•− scavenging activity in a time-dependent manner. These results suggested that nitric oxide (NO) secreted by the nitrergic nerve played a role in regulating local circulation in rat gingiva. This NO-related regulation of local circulation was temporarily inhibited in the gingiva by the I/R treatment. The decrease observed in the production of NO, which was caused by suppression of NO synthase (NOS) activity subsequent to depletion of the NOS co-factor BH₄ by O₂^•−, played a partial role in this inhibition.

• BH4
• gingiva
• nitric oxide synthases
• reactive hyperemia
• reperfusion

• Animals
• Apolipoproteins E/genetics
• Apolipoproteins E/metabolism
• Bacteroidaceae Infections/metabolism
• Bacteroidaceae Infections/microbiology
• Biopterins/analogs & derivatives
• Biopterins/metabolism
• Gastrointestinal Tract/metabolism
• Gastrointestinal Tract/microbiology
• Male
• Mesenteric Arteries/metabolism
• Mesenteric Arteries/microbiology
• Mice
• Mice, Knockout
• NF-E2-Related Factor 2/metabolism
• Nitric Oxide Synthase Type I/metabolism
• Periodontal Diseases/metabolism
• Periodontal Diseases/microbiology
• Porphyromonas gingivalis
• Treponema denticola

• R01DE020820 NIDCR NIH HHS
• R21DKO76704 PHS HHS
• G12 MD007586 NIMHD NIH HHS
• RG/12/5/29576 British Heart Foundation
• 1 U54RR026140-01 NCRR NIH HHS
• R21 DK076704 NIDDK NIH HHS
• U54 RR026140 NCRR NIH HHS
• R01 DE020820 NIDCR NIH HHS
• U54 MD007593 NIMHD NIH HHS

Reactive hyperemia reflects a compensatory vasodilation response of the local vasculature in ischemic tissue. The purpose of this study is to clarify the mechanism of regulation of this response in gingival circulation by using pharmacological analysis of reactive hyperemia and histochemical analysis of gingival tissue. Application of pressure to the gingiva was used to create temporary ischemia, and gingival blood flow was measured after pressure release. Reactive hyperemia increased in proportion to the duration of pressure. Systemic hemodynamics remained unaffected by the stimulus; therefore, the gingival reactive hyperemia reflected a local adjustment in circulation. Gingival reactive hyperemia was significantly suppressed by nitric oxide (NO) synthase inhibitors, especially the neural NO synthase-selective antagonist 7-nitroindazole, but not by anticholinergic drugs, β-blockers, or antihistaminergic drugs. Moreover, immunohistochemical staining for neural NO synthase and histochemical staining for NADPH diaphorase activity were both positive in the gingival perivascular region. These histochemical and pharmacological analyses show that reactive hyperemia following pressure release is mediated by NO-induced vasodilation. Furthermore, histochemical analysis strongly suggests that NO originates from nitrergic nerves. Therefore, NO may play an important role in the neural regulation of local circulation in gingival tissue ischemia.

• gingiva
• nitrergic nerve
• nitric oxide
• reactive hyperemia

• angigenesis
• bone remodeling
• diabetes complications
• immune responses
• inflammation
• microvascular disease

• Animals
• Antioxidants/therapeutic use
• Catalase/physiology
• Cytokines/metabolism
• Humans
• Life Style
• Lipid Peroxidation
• Membrane Glycoproteins/physiology
• NADPH Oxidase 2
• NADPH Oxidases/physiology
• Neutrophils/physiology
• Oxidative Stress/genetics
• Oxidative Stress/physiology
• Periodontal Diseases/drug therapy
• Periodontal Diseases/etiology
• Periodontal Diseases/metabolism
• Reactive Oxygen Species
• Superoxide Dismutase/physiology

Oral mucositis is often induced in patients receiving cancer chemotherapy treatment. It has been reported that oral mucositis can reduce quality of life, as well as increasing the incidence of mortality. The participation of reactive oxygen species (ROS) in the pathogenesis of oral mucositis is well known, but no report has actually demonstrated the presence of ROS. Thus, the purpose of this study was thus to demonstrate the involvement of ROS and the alteration of the redox state in oral mucositis using an in vivo L-band electron spin resonance (ESR) technique. An oral mucositis animal model induced by treatment of 5-fluorouracil with 10% acetic acid in hamster cheek pouch was used. Lipid peroxidation was measured as the level of malondialdehyde determined by the thiobarbituric acid reaction. The rate constants of the signal decay of nitroxyl compounds using in vivo L-band ESR were calculated from the signal decay curves. Firstly, we established the oral mucositis animal model induced by treatment of 5-fluorouracil with acetic acid in hamster cheek pouch. An increased level of lipid peroxidation in oral mucositis was found by measuring malondialdehyde using isolated hamster cheek pouch ulcer. In addition, as a result of in vivo L-band ESR measurements using our model animals, the decay rate constants of carbamoyl-PROXYL, which is a reagent for detecting the redox balance in tissue, were decreased. These results suggest that a redox imbalance might occur by excessive generation of ROS at an early stage of oral mucositis and the consumption of large quantities of antioxidants including glutathione in the locality of oral mucositis. These findings support the presence of ROS involved in the pathogenesis of oral mucositis with anti-cancer therapy, and is useful for the development of novel therapies drugs for oral mucositis.

The present study has two aims; firstly, it attempts to verify the presence of oxidative stress by estimating the reactive oxygen species (ROS) levels in periodontal pockets ≥5 mm as compared to controls. The second aim is to evaluate the effect of lycopene as a locally delivered antioxidant gel on periodontal health and on the gingival crevicular fluid (GCF) levels of 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative injury.

Thirty-one subjects participated in this study. In the pretreatment phase, the ROS levels in pockets ≥5 mm were measured by flow cytometry. Three sites in each subject were randomly assigned into each of the following experimental groups: sham group, only scaling and root planing (SRP) was done; placebo group, local delivery of placebo gel after SRP; and lycopene group, local delivery of lycopene gel after SRP. Clinical parameters included recording site-specific measures of GCF 8-OHdG, plaque, gingivitis, probing depth, and clinical attachment level.

The gel, when delivered to the sites with oxidative stress, was effective in increasing clinical attachment and in reducing gingival inflammation, probing depth, and 8-OHdG levels as compared to the placebo and sham sites.

From this trial conducted over a period of 6 months, it was found that locally delivered lycopene seems to be effective in reducing the measures of oxidative stress and periodontal disease.

• Antioxidants
• Oxidative stress
• Periodontitis