Reiko Furugen

The relationship between periodontal condition and serum levels of resistin and adiponectin in elderly Japanese

BACKGROUND AND OBJECTIVE Diabetes and periodontitis are associated with each other. Adipokines, specifically adiponectin and resistin, are secreted from adipocytes and are thought to cause insulin resistance in rodents. Additionally, adiponectin and resistin may play a role in inflammation and immune responses. The aim of this study was to clarify the relationship between serum levels of adipokines and periodontal conditions in elderly Japanese people with and without periodontitis. MATERIAL AND METHODS A total of 158 Japanese men and women (76 years old) with or without periodontitis were selected for the study. Serum adiponectin, resistin, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) concentrations were compared between subjects with and without periodontitis. RESULTS Serum resistin levels and total leukocyte counts in subjects with periodontitis were higher than in control subjects. No significant differences were observed in adiponectin, IL-6 and TNF-alpha levels between subjects with and without periodontitis. Logistic regression analysis showed that periodontitis with at least one tooth that displayed a probing pocket depth of > or =6 mm was significantly associated with higher serum resistin levels (odds ratio, 2.0; 95% confidence interval, 1.0-4.0). When excluding periodontitis subjects with < or =10% of bleeding on probing and excluding control subjects with >10% bleeding on probing, differences between groups and odds ratio increased. Serum adiponectin tended to decrease in patients with periodontitis, albeit not significantly. CONCLUSION Increased serum resistin levels were significantly associated with periodontal condition, especially when considering bleeding on probing, in elderly Japanese people. There was also a trend, though non-significant, toward decreased levels of adiponectin in subjects with periodontitis.

A novel human HER2‐derived peptide homologous to the mouse Kd‐restricted tumor rejection antigen can induce HLA‐A24‐restricted cytotoxic T lymphocytes in ovarian cancer patients and healthy individuals

A mouse HER2‐derived peptide, HER2p63 (A) (TYLPANASL), can induce Kd‐restricted mouse cytotoxic T lymphocytes (CTL) and also function as a tumor rejection antigen in an in vivo assay. Since the anchor motif of mouse Kd for peptide binding has much similarity to that of human HLA‐A2402, we asked if human HER2p63 (T) (TYLPTNASL) could induce HER2‐specific CTL in HLA‐A2402‐positive individuals. Peripheral blood mononuclear cells (PBMC) of HLA‐A2402‐positive individuals were sensitized in vitro with HER2p63‐pulsed autologous dendritic cells prepared from PBMC. CTL clone derived from these specifically lysed HER2‐expressing cell lines bearing HLA‐A2402. Cytotoxic activity of the CTL clone against the HER2‐expressing cell line bearing HLA‐A2402 was blocked by antibodies against CD3, CD8, HLA‐A24 or MHC class I, and was also inhibited by the addition of excess HER2p63‐pulsed C1R bearing HLA‐A2402. Killer cells were generated from PBMC of seven healthy individuals and five ovarian cancer patients, all of HLA‐A2402 type, by in vitro sensitization with HER2p63‐pulsed autologous antigen presenting cells. These killer cells selectively lysed HER2‐expressing SKOV3 transfected with HLA‐A2402 cDNA, indicating high immunogenicity of HER2p63 in all 12 individuals examined.

A HER2/NEU‐derived peptide, a Kd‐restricted murine tumor rejection antigen, induces HER2‐specific HLA‐A2402‐restricted CD8+ cytotoxic T lymphocytes

We have identified an H‐2Kd‐binding peptide, HER2p780 (PYVSRLLGI), derived from murine HER2/neu (HER2), that can induce HER2‐specific murine cytotoxic T lymphocytes (CTL). Weekly vaccination of BALB/c mice by syngeneic dendritic cells pulsed with HER2p780 peptide, entirely common to murine and human HER2, suppressed growth of pretransplanted HER2‐expressing syngeneic tumors. A HER2‐expressing human cancer cell line SKOV3 transfected with murine H‐2Kd cDNA could also be lysed by HER2p780‐specific murine CTLs, indicating that human HER2‐expressing cancer cells can process and present the cognate peptide in the context of H‐2Kd. Since H‐2Kd and HLA‐A2402 molecules have similar anchor motifs, the possibility of inducing HER2‐specific CTL activity with HER2p780 in HLA‐A2402 individuals was examined. CD8+ CTL clones specific for HER2‐expressing cancer cell lines were established from peripheral blood lymphocytes with HLA‐A2402 by repeatedly sensitizing with peptide‐pulsed autologous dendritic cells as well as peripheral blood mononuclear cells. Detailed analysis of their specificity revealed that the cytotoxicity of CTL clones is specific for the cognate peptide with HLA‐A2402 restriction. The results suggest that HER2p780 is a unique peptide that may function as a tumor rejection antigen peptide in HLA‐A2402 individuals, as it was directly proven here to function in a murine tumor system. Int. J. Cancer 87:553–558, 2000.

Relationship Between Periodontal Status and HbA1c in Nondiabetics

OBJECTIVES Many studies have reported an association between diabetes and periodontitis. We analyzed the periodontal status and glycosylated hemoglobin (HbA1c) level in nondiabetic subjects to investigate the relationship between periodontitis and glucose control in nondiabetics. METHODS Periodontal status, HbA1c, serum cholesterol, triglyceride, body mass index (BMI), and demographic variables were assessed in 141 Japanese adults. The difference in the HbA1c level was evaluated among subjects according to periodontal status. RESULTS After adjusting for age, gender, BMI, and smoking, alcohol, and exercise habits as covariates, the mean HbA1c was significantly elevated with periodontal deterioration (P = 0.023). CONCLUSIONS There was a significant relationship between periodontal status and HbA1c levels in nondiabetics.

Association of periodontitis with carotid artery intima–media thickness and arterial stiffness in community-dwelling people in Japan: The Nagasaki Islands study

OBJECTIVE Recent studies have suggested an association between periodontitis and atherosclerosis; however, the relationship between periodontal status and arterial alterations should be clarified. The purpose of this study was to examine associations between periodontal status and carotid intima-media thickness (cIMT) and arterial stiffness using the cardio-ankle vascular index (CAVI) in community dwellers. METHODS A community-based cross-sectional study of 1053 subjects ≥40 years with 10 teeth or more was conducted in Goto, Japan from 2008 to 2010. RESULTS In a multiple linear regression analysis adjusted for age, sex, number of present teeth, and other confounders, each 1-mm increase in mean periodontal pocket depth corresponded to a 0.02-mm increase in maximal cIMT (β = 0.018; P = 0.049) and also to a 0.1 increase in mean CAVI (β = 0.133; P = 0.040). In addition, each 1-mm increase in the mean periodontal attachment loss corresponded to a 0.01-mm increase in maximal cIMT (β = 0.013; P = 0.040). A multiple logistic regression analysis revealed that each 1-mm increase in mean periodontal pocket depth was associated with an increased risk of a maximal cIMT >1 mm (adjusted odds ratio [OR], 1.430; 95% confidence interval [CI], 1.067-1.918; P = 0.017) and mean CAVI of ≥8 (OR, 1.323; 95% CI, 1.003-1.743; P = 0.047). Furthermore, each 1-mm increase in mean periodontal attachment loss was associated with an increased risk of a maximal cIMT >1 mm (OR, 1.251; 95% CI, 1.032-1.516; P = 0.022). CONCLUSION A linear, dose-dependent relationship was found between periodontal pocket depth, cIMT, and arterial stiffness.

Porphyromonas gingivalis and Escherichia coli lipopolysaccharide causes resistin release from neutrophils

OBJECTIVES It was reported that periodontitis is associated with increased serum resistin levels. We examined whether there was a difference between the release of resistin from neutrophils incubated lipopolysaccharide (LPS) from Porphyromonas gingivalis and with LPS from Escherichia coli, and which cell-surface receptors and intracellular kinases were involved in this process. METHODS Several concentrations of P. gingivalis-LPS and E. coli-LPS were added to neutrophils, supernatant from cultured neutrophils was collected, and resistin levels were measured by ELISA. To examine signaling pathways, neutrophils were pretreated with monoclonal antibodies against CD14, CD18, TLR2, and TLR4, and specific inhibitors of PI3K and MAPKs. RESULTS Resistin release from neutrophils was induced both by P. gingivalis-LPS and E. coli-LPS, but resistin release by P. gingivalis-LPS was weaker than E. coli-LPS in low concentrations. Resistin release was decreased by pretreatment with monoclonal antibodies against CD14, CD18, and TLR4, but not by TLR2. Moreover, it was decreased by inhibitors of PI3K, JNK, and p38 MAPK, but not by ERK1/2. CONCLUSIONS Resistin release from neutrophils was induced by both P. gingivalis-LPS and E. coli-LPS. This was decreased by CD14, CD18, and TLR4 and was dependent on PI3K, JNK, and p38 MAPK, but not on ERK1/2 in intracellular pathways of neutrophils.

Neutrophil-derived resistin release induced by Aggregatibacter actinomycetemcomitans

Resistin is an adipokine that induces insulin resistance in mice. In humans, resistin is not produced in adipocytes, but in various leukocytes instead, and it acts as a proinflammatory molecule. The present investigation demonstrated high levels of resistin in culture supernatants of neutrophils that are stimulated by a highly leukotoxic strain of Aggregatibacter actinomycetemcomitans. In contrast, the level of resistin was remarkably low when neutrophils were exposed to two other strains that produce minimal levels of leukotoxin and a further isogenic mutant strain incapable of producing leukotoxin. Pretreatment of neutrophils with a monoclonal antibody to CD18, β chain of lymphocyte function-associated molecule 1 (LFA-1), or an Src family tyrosine kinase inhibitor before incubation with the highly leukotoxic strain inhibited the release of resistin. These results show that A. actinomycetemcomitans-expressed leukotoxin induces extracellular release of human neutrophil-derived resistin by interacting with LFA-1 on the surface of neutrophils and, consequently, activating Src family tyrosine kinases.

Comment on: Cani et al. (2007) Metabolic Endotoxemia Initiates Obesity and Insulin Resistance: Diabetes 56:1761–1772

The recent article by Cani et al. (1) interests us very much. We have reported that obesity and periodontitis were associated for the first time in 1998 (2). Further study revealed that hepatic impairment was more strongly associated with periodontitis than obesity indexes (3). Our results showed that periodontitis increased with elevated serum …

Relationship among salivary antioxidant activity, cytokines, and periodontitis: The Nagasaki Island study

AIM Antioxidant activities and cytokine levels in human body fluids are considered to be strongly associated with periodontitis. The aim of this study was to elucidate the relationship between salivary antioxidant activities against superoxide or hydroxyl radical, cytokines, and periodontal conditions through a community-based cross-sectional study conducted in Goto city, Japan. MATERIALS AND METHODS Saliva samples were analysed for superoxide or hydroxyl radical scavenging activities and cytokine levels from 160 participants. We demonstrated that saliva contained superoxide and hydroxyl radical scavenging activities by using electron spin resonance with a spin-trapping agent. The concentrations of eight cytokines were measured using multiplex bead assays. RESULTS There were significant differences in salivary superoxide or hydroxyl radical scavenging activity, and the levels of Interleukin-1β, Interleukin-6, and Interleukin-8 between periodontitis classifications. Multivariate stepwise logistic regression model showed that salivary superoxide and hydroxyl radical scavenging activities were significantly associated with the classification of periodontitis. In addition, salivary superoxide scavenging activity was found to have significant association with all periodontal parameters using multiple linear regression analysis. CONCLUSIONS These findings suggest that the evaluation of salivary antioxidant activities, as assessed by electron spin resonance, are associated with periodontitis and various clinical variables in community-dwelling participants (ClinicalTrials.gov number NCT01742728).

Periodontal Host Response in Subjects with Obesity

Purpose of ReviewThis review focuses on recent advances in understanding the periodontal host response in obese subjects.Recent FindingsIncreased pro-inflammatory adipokines such as leptin, progranulin, resistin, and visfatin and decreased anti-inflammatory adipokines such as adiponectin, exacerbated inflammatory response, alveolar bone resorption, and inhibition of tissue regeneration have been observed in the periodontal tissue in obese subjects. Elevated oxidative stress also affects progression of periodontitis. Obesity may affect the expression of microRNAs related to inflammatory and metabolic mRNA targets in periodontal tissue.SummaryAlthough obesity may promote the progression of periodontitis in multiple manners, additional studies are needed to clarify the periodontal host response in obesity.