Presence of periodontitis may synergistically contribute to cancer progression via Treg and IL-6.

A close causal relationship has been suggested to exist between cancer and periodontitis. We hypothesized that the immune surveillance system is impaired in patients with periodontitis, which contributes to cancer development and growth. Therefore, the present study investigated the relationship between immune surveillance mechanisms and periodontitis in cancer patients. The presence or absence of periodontitis was assessed and the peripheral blood (PB) concentrations of IL-6, immunosuppressive cytokines (VEGF, TGF-ß1, and CCL22) and proportion of T regulatory cells (Treg, CD3 + CD4 + CD25 + Foxp3 +) were measured. Subjects were classified into the following four groups: non-cancer patients without periodontitis (C - P -), non-cancer patients with periodontitis (C - P +), cancer patients without periodontitis (C + P -), and cancer patients with periodontitis (C + P +). The results of a multivariate analysis showed that the PB concentration of IL-6 was significantly higher in C + than in C- and higher in C + P + than in C + P -. The PB proportion of Treg was significantly higher in C + P + than in C + P -, C - P + , and C - P -. The results of this study suggested that the presence of periodontitis and cancer synergistically increased Treg in PB, which may be one of the underlying causes of immunosuppression and immune evasion in cancer. It was also suggested that the presence of periodontal disease and/or cancer also increases IL-6 in PB, which would be associated with cancer progression. These results suggest the possibility that the presence of periodontitis might synergistically contribute to cancer progression.

Exploration of correlation of oral hygiene and condition with influenza infection.

Influenza viruses are known to be infected through epithelial cells of the upper respiratory tract. The oral cavity is in close anatomical proximity to the upper respiratory tract, and it is conceivable that the viruses could pass through the oral cavity and infect to the upper respiratory tract. Several researchers have suggested that colonization of certain pathogenic bacteria such as Staphylococcus aureus or Streptococcus pneumoniae might affect the risk of influenza viral disease, indicating that oral hygiene and/or condition might play an important role in respiratory viral infection. Therefore, the purpose of this study was to investigate whether an oral hygiene/condition might impact influenza infection. We conducted a retrospective observational study of Japanese citizens' regional cohort (N = 2,904) consisting of National Health Insurance beneficiaries who underwent annual health/dental examination with data entries in the Kokuho database (KDB). Trained dentists checked the oral hygiene/condition, and saliva specimens were examined using the LION dental saliva multi-test (SMT) kit. Influenza infection was identified from the diagnosis recorded in the KDB. The correlations between influenza infection and oral hygiene, dryness of the mouth, or various salivary test results were examined by a multivariate analysis adjusting for confounding factors such as gender, age, recent smoking, alcohol drinking, BMI, HbA1c, RBC for influenza infection. The logistic regression model showed that age significantly correlated with influenza infection. In addition, oral hygiene status had a nearly significant impact on influenza infection (p = 0.061), whereby, the subjects with poor oral hygiene had a higher risk of influenza infection than those with good oral hygiene (odds ratio: 1.63, 95% confidence interval: 0.89-2.95). Further, the prevalence of influenza infection was lower in the subjects with saliva weakly acidic and/or containing higher protein level. The results of this study suggested that the maintenance of oral health conditions might be one of the pivotal factors for preventing and reducing influenza infection.

Relationship between dry mouth and hypertension.

OBJECTIVES: Salivary dysfunction, such as reduced salivary flow and an altered salivary composition, is caused by several diseases, medical conditions, and medications. The purpose of the present study was to clarify the relationship between hypertension and morphological changes in the submandibular glands. MATERIALS AND METHODS: An epidemiological study was conducted to elucidate the relationship between hypertension and dry mouth. The effects of hypertension on morphological changes and the intima thickness of arteries in the submandibular glands were histopathologically investigated. RESULTS: Among 1933 subjects in the epidemiological study, 155 (8.0%) had dry mouth. A multivariate analysis revealed that dry mouth correlated with age (p < 0.001), sex (p < 0.001), and hypertension (p < 0.05). No significant differences were observed in the size of the submandibular glands between patients with or without hypertension. The average area of acinar cells was smaller in patients with than in those without hypertension (0.366 ± 0.153 vs. 0.465 ± 0.178, p < 0.05). The arteriosclerotic index was significantly higher in patients with than in those without hypertension (0.304 ± 0.034 vs 0.475 ± 0.053, p < 0.05). CONCLUSIONS: Hypertension may contribute to the degeneration of the submandibular glands by decreasing the number of acinar cells and promoting fatty infiltration and stenosis of the arteries. CLINICAL RELEVANCE: There may be a correlation between hypertension and the degeneration of the submandibular glands by decreasing the number of acinar cells and promoting fatty infiltration and stenosis of the arteries.

Immunohistochemical Investigation of Predictive Biomarkers for Mandibular Bone Invasion in Oral Squamous Cell Carcinoma.

The accurate preoperative determination of the extent of mandibular resection remains a challenge for the surgeons. The purpose of the present study was to immunohistochemically investigate predictive markers for histological bone invasion of oral squamous cell carcinoma (OSCC). The medical records of primary OSCC patients with mandibular bone contact in preoperative computed tomography scans between January 2003 and December 2017 were retrospectively reviewed and an immunohistochemical investigation was performed. Forty-five OSCC patients with mandibular bone contact radiographically were included in this study. Histopathologically, infiltrative bone invasion was observed in 19 patients (42.2%) and compressive bone invasion in 15 (33.3%). A correlation was noted between the histological pattern of bone invasion and mode of invasion (chi-squared test, p < 0.05). At the tumor surface, a correlation was observed between the expression of IL-6 and bone invasion (the Wilcoxon test, p < 0.05), although the expression was so weak. At the bone contact area, the expression of both ɑ-SMA and OPG correlated with infiltrative bone invasion (ɑ-SMA; the Wilcoxon test, p < 0.05, OPG; p < 0.05). These results suggest that predictive markers for aggressive (infiltrative) bone invasion in OSCC patients with a higher mode of invasion are the expression of ɑ-SMA and OPG.

Relationship Between the Quantity of Oral Candida and Systemic Condition/Diseases of the Host: Oral Candida Increases with Advancing Age and Anemia.

BACKGROUND: The impact of host systemic conditions/diseases on the prosperity of oral Candida colonies remains unclear. The aim of the present study was to investigate whether a relationship exists between the quantity of oral Candida and the systemic condition/diseases of the host. PATIENTS AND METHODS: The cross-sectional relationship between Candida mannan concentrations and health check-up results was analyzed in consideration of local conditions that influence the prevalence of oral Candida. RESULTS: Candida mannan concentrations correlated with age, the number of untreated decayed teeth, number of prosthetic teeth, salivary pH, HbA1c, and the red blood cell count in a univariate analysis. In a multivariate analysis, Candida mannan concentrations correlated with age, the number of untreated decayed teeth, number of prosthetic teeth, salivary pH, and the red blood cell count. Candida mannan concentrations were higher in subjects older than 80 years, with a higher number of either untreated or prosthetic teeth, with a lower salivary pH, and with a decreased red blood cell count. Mannan concentrations were slightly higher in subjects with elevated HbA1c. CONCLUSIONS: The present results suggest a close relationship between the quantity of oral Candida and the systemic condition/diseases of the host. Oral Candida may increase in immunocompromised hosts.

Synthetic studies of five-membered heteroaromatic derivatives as potassium-competitive acid blockers (P-CABs).

On the basis of a series of novel and potent potassium-competitive acid blockers represented by 1-sulfonylpyrrole derivative 7, we prepared several five-membered heterocyclic analogues (8) and evaluated their H(+),K(+)-ATPase activities in vitro. We also assessed the role of the methylaminomethyl side chain by comparison with methylamino and ethylamino derivatives. We observed that the five-membered core ring and its orientation affect inhibitory activity and that the methylaminomethyl moiety is the best side chain. On the basis of potency and ligand-lipophilicity efficiency, compound 7 remains the most drug-like of the compounds studied to date. This study revealed the factors necessary for potent H(+),K(+)-ATPase inhibition, such as differences in electron density, the properties of the lone pair at each apical position of the heteroaromatic ring, and the geometry of the substituents.

Molecular modeling, design, synthesis, and biological activity of 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives as potassium-competitive acid blockers.

A series of 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives were designed and synthesized based on our docking model as potassium-competitive acid blockers (P-CABs). Molecular modeling of these derivatives led us to introduce a substituent at the 1-position to access two lipophilic sites and polar residues. We identified potent P-CABs that exhibit excellent inhibitory activity in vitro and in vivo. These results indicate that the 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives are promising lead compounds as P-CABs.

Establishment and validation of a rabbit model for in vivo pharmacodynamic screening of tachykinin NK2 antagonists.

We attempted to establish and validate an in vivo pharmacodynamic (PD) rabbit model to screen tachykinin NK(2) receptor (NK(2)-R) antagonists using pharmacological and pharmacokinetic (PK)/PD analyses. Under urethane anesthesia, changes in intracolonic pressure associated with intravenous (i.v.) administration of a selective NK(2)-R agonist, ßAla(8)-neurokinin A(4-10) (ßA-NKA), was monitored as a PD marker. The analgesic effects of NK(2)-R antagonists were evaluated by monitoring visceromotor response (VMR) to colorectal distension in a rabbit model of visceral hypersensitivity induced by intracolonic treatment of acetic acid. Intravenous administration of ßA-NKA induced transient colonic contractions dose-dependently, which were inhibited by the selective NK(2)-R antagonists in dose- and/or plasma concentration-dependent manners. The correlation between PD inhibition and plasma concentration normalized with the corresponding in vitro binding affinity was relatively high (r(2) = 0.61). Furthermore, the minimum effective doses on the VMR and ID(50) values calculated in the PD model were highly correlated (r(2) = 0.74). In conclusion, we newly established and validated a rabbit model of agonist-induced colonic contractions as a screening tool for NK(2)-R antagonists. In a drug discovery process, this PD model could enhance the therapeutic candidate selection for irritable bowel syndrome, pharmacologically connecting in vitro affinity for NK(2)-R with in vivo therapeutic efficacy.

High-throughput screening of potassium-competitive acid blockers.

H(+),K(+)-ATPase is a key enzyme in the process of gastric acid secretion, and proton pump inhibitors (PPIs) have been accepted as one of the most effective treatments for peptic ulcer and gastroesophageal reflux disease. To discover a novel class of PPIs, the authors screened a low-molecular-weight compound library and identified two prospective acid blockers that were pyrrole derivatives. Both compounds inhibited H(+),K(+)-ATPase in a reversible and potassium-competitive manner. These compounds led to the development of TAK-438 (1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate), which is currently undergoing clinical trials as a novel potassium-competitive acid blocker for the treatment of acid-related diseases.

Novel 3-phenylpiperidine-4-carboxamides as highly potent and orally long-acting neurokinin-1 receptor antagonists with reduced CYP3A induction.

The synthesis and biological evaluation of a series of novel 3-phenylpiperidine-4-carboxamide derivatives are described. These compounds are generated by hybridization of the substructures from two types of tachykinin NK(1) receptor antagonists. Compound 42 showed high metabolic stability and excellent efficacy in the guinea-pig GR-73637-induced locomotive activity assay at 1 and 24h after oral administration. It also exhibited good pharmacokinetic profiles in four animal species, and a low potential in a pregnane X receptor induction assay.

Bidirectional regulation of human colonic smooth muscle contractility by tachykinin NK(2) receptors.

In this study, we attempted to clarify the mechanism of tachykinin-induced motor response in isolated smooth muscle preparations of the human colon. Fresh specimens of normal colon were obtained from patients suffering from colonic cancer. Using mucosa-free smooth muscle strips, smooth muscle tension with circular direction was monitored isometrically. Substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) produced marked contraction. All of these contractions were inhibited by saredutant, a selective NK(2)-R antagonist, but not by CP122721, a selective NK(1)-R antagonist or talnetant, a selective NK(3)-R antagonist. ßAla(8)-NKA(4-10) induced concentration-dependent contraction similar to NKA, but Sar(9)-Met(11)-SP and Met-Phe(7)-NKB did not cause marked contraction. Colonic contraction induced by ßAla(8)-NKA(4-10) was completely blocked by saredutant, but not by atropine. Tetrodotoxin or N(G)-nitro-L-arginine methyl ester pretreatment significantly enhanced ßAla(8)-NKA(4-10)-induced contraction. Immunohistochemical analysis showed that the NK(2)-R was expressed on the smooth muscle layers and myenteric plexus where it was also co-expressed with neuronal nitric oxide synthase in the myenteric plexus. These results suggest that the NK(2)-R is a major contributor to tachykinin-induced smooth muscle contraction in human colon and that the NK(2)-R-mediated response consists of an excitatory component via direct action on the smooth muscle and an inhibitory component possibly via nitric oxide neurons.

Design, structure-activity relationship, and highly efficient asymmetric synthesis of 3-phenyl-4-benzylaminopiperidine derivatives as novel neurokinin-1 receptor antagonists.

We synthesized a series of novel 3-phenyl-4-benzylaminopiperidine derivatives that were identified as potent tachykinin NK(1) receptor antagonists by structural modification of the 3-benzhydrylpiperidone derivative through high-throughput screening. N-{2-[(3R,4S)-4-({2-Methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl}amino)-3-phenyl-1-piperidinyl]-2-oxoethyl}acetamide ((+)-39) was found to be one of the most potent tachykinin NK(1) receptor antagonists with high metabolic stability. Highly efficient asymmetric synthesis of (+)-39 was achieved via dynamic kinetic resolution.

A noncompetitive BACE1 inhibitor TAK-070 ameliorates Abeta pathology and behavioral deficits in a mouse model of Alzheimer's disease.

We discovered a nonpeptidic compound, TAK-070, that inhibited BACE1, a rate-limiting protease for the generation of Abeta peptides that are considered causative for Alzheimer's disease (AD), in a noncompetitive manner. TAK-070 bound to full-length BACE1, but not to truncated BACE1 lacking the transmembrane domain. Short-term oral administration of TAK-070 decreased the brain levels of soluble Abeta, increased that of neurotrophic sAPPalpha by approximately 20%, and normalized the behavioral impairments in cognitive tests in Tg2576 mice, an APP transgenic mouse model of AD. Six-month chronic treatment decreased cerebral Abeta deposition by approximately 60%, preserving the pharmacological efficacy on soluble Abeta and sAPPalpha levels. These results support the feasibility of BACE1 inhibition with a noncompetitive inhibitor as disease-modifying as well as symptomatic therapy for AD.