Atypical Antipsychotic Drug Ziprasidone Protects against Rotenone-Induced Neurotoxicity: An In Vitro Study.

Schizophrenia is a severe, chronic mental illness characterized by delusions, hallucinations, negative symptoms, and cognitive dysfunction. Recently, several studies have demonstrated that the pathogenesis of schizophrenia involves mitochondrial dysfunction and oxidative stress. However, the effect of antipsychotic drugs for these events has been poorly investigated. In the present study, we evaluated the neuroprotective effect of an atypical antipsychotic drug, ziprasidone (ZPD), on rotenone (ROT)-induced neurotoxicity involving oxidative stress in PC12 cells. Our data showed that ZPD treatment promoted the translocation of NF-E2-related factor-2 (Nrf2) from cytoplasm to nucleus and activated the expression of its target genes NAD(P)H quinone oxidoreductase (NQO-1), catalase (CAT), and heme oxygenase (HO-1). Additionally, ZPD prevented ROT-induced cell death and intracellular reactive oxygen species production. Interestingly, the use of serotonin 5-HT1A receptor antagonist 1-(2-methoxyphenyl)-4 (4-(2-phtalimido) butyl) piperazine (NAN-190) completely blocked the protective effect of ZPD against ROT-induced cell death. Our results demonstrate the neuroprotective effect of ZPD against ROT-induced neurotoxicity and suggest that ZPD may be a potential candidate for the prevention of mitochondrial dysfunction and oxidative stress in schizophrenia.

Up-regulation of NOX1/NADPH oxidase following drug-induced myocardial injury promotes cardiac dysfunction and fibrosis.

Cardiac fibrosis is a common feature in failing heart and therapeutic strategy to halt the progression of fibrosis is highly needed. We here report on NOX1, a non-phagocytic isoform of superoxide-producing NADPH oxidase, which promotes cardiac fibrosis in a drug-induced myocardial injury model. A single-dose administration of doxorubicin (DOX) elicited cardiac dysfunction accompanied by increased production of reactive oxygen species and marked elevation of NOX1 mRNA in the heart. In mice deficient in Nox1 (Nox1-/Y), cardiac functions were well retained and overall survival was significantly improved. However, increased level of serum creatine kinase was equivalent to that of wild-type mice (Nox1+/Y). At 4 days after DOX treatment, severe cardiac fibrosis accompanied by increased hydroxyproline content and activation of matrix metalloproteinase-9 was demonstrated in Nox1+/Y, but it was significantly attenuated in Nox1-/Y. When H9c2 cardiomyocytes were exposed to their homogenate, a dose-dependent increase in NOX1 mRNA was observed. Up-regulation of NOX1 mRNA in H9c2 co-incubated with their homogenate was abolished in the presence of TAK242, a TLR4 inhibitor. When isolated cardiac fibroblasts were exposed to H9c2 homogenates, increased proliferation and up-regulation of collagen 3a1 mRNA were demonstrated. These changes were significantly attenuated in cardiac fibroblasts exposed to homogenates from H9c2 harboring disrupted Nox1. These findings suggest that up-regulation of NOX1 following cellular damage promotes cardiac dysfunction and fibrosis by aggravating the pro-fibrotic response of cardiac fibroblasts. Modulation of the NOX1/NADPH oxidase signaling pathway may be a novel therapeutic strategy for preventing heart failure after myocardial injury.

Analysis of moment structures for assessing relationships among perceived chewing ability, dentition status, muscle strength, and balance in community-dwelling older adults.

OBJECTIVE: The aim of this study was to assess relationships among perceived chewing ability, dentition status, muscle strength and balance in community-dwelling older adults using analysis of moment structures (Amos). BACKGROUND: Physical performance parameters such as muscle strength and balance can predict the future onset of disabilities in activities of daily living among older adults. In this context, elucidation of the relationships among oral conditions and physical performance parameters is necessary. MATERIALS AND METHODS: Data on occlusal contact patterns of natural teeth (OPNT), self-assessed masticatory ability (mastication), body mass index (BMI), handgrip strength (HG) and one-leg standing time with eyes open (OLST) were collected from 501 independently living adults aged 65-74 years. The relationships among these parameters were analysed using Spearman's rank correlation coefficients and Amos. RESULTS: Subjects of both genders showed significant correlations among OPNT, mastication, HG and OLST, evaluated using Spearman's rank correlation coefficients. For each Amos model, the goodness-of-fit statistic indicated a good level of fit. In both men and women, OPNT was significantly related to mastication, and mastication was related to HG but not to OLST. OPNT was related to neither HG nor OLST in women and was related to OLST but not HG in men. CONCLUSION: The findings observed in this study present a possible importance of dental status and perceived chewing ability for the onset of disability by influencing physical performance in community-dwelling older adults.

Predictors of eligibility for long-term care funding for older people in Japan.

AIM: To determine the predictors of Japanese long-term care insurance system (LTCI) certification. METHODS: Care needs of 784 persons aged 65-84 were followed through LTCI over 5 years. Each participant's score was divided into quartiles according to handgrip strength and one-leg standing time with eyes open. Cox proportional hazard models were conducted for the onset of certification of LTCI. RESULTS: Over the 5-year period 64 women (14%) and 30 men (9%) were certified. Adjusted hazard ratios for certification were significantly higher for those of the lowest groups of one-leg standing time with eyes open at baseline than those in the highest groups, but no significance was found for handgrip strength. Other predictors were age and low social activity for women; and living alone and diabetes for men. CONCLUSIONS: One-leg standing time with eyes open predicts the onset of care-need certification in older people.

NOX1/NADPH oxidase is involved in endotoxin-induced cardiomyocyte apoptosis.

The functional significance of NOX1/NADPH oxidase in the heart has not been explored due to its low expression relative to other NOX homologs identified so far. We aimed to clarify the role of NOX1/NADPH oxidase in the septic heart by utilizing mice deficient in the Nox1 gene (Nox1(-/Y)). Sepsis was induced by intraperitoneal administration of lipopolysaccharides (LPS: 25mg/kg) or cecal ligation and puncture (CLP) surgery. A marked elevation of NOX1 mRNA was demonstrated in cardiac tissue, which was accompanied by increased production of reactive oxygen species (ROS). In Nox1(-/Y) treated with LPS, cardiac dysfunction and survival were significantly improved compared with wild-type mice (Nox1(+/Y)) treated with LPS. Concomitantly, LPS-induced cardiomyocyte apoptosis and activation of caspase-3 were alleviated in Nox1(-/Y). The level of phosphorylated Akt in cardiac tissue was significantly lowered in Nox1(+/Y) but not in Nox1(-/Y) treated with LPS or that underwent CLP surgery. Increased oxidation of cysteine residues of Akt and enhanced interaction of Akt with protein phosphatase 2A (PP2A), a major phosphatase implicated in the dephosphorylation of Akt, were demonstrated in LPS-treated Nox1(+/Y). These responses to LPS were significantly attenuated in Nox1(-/Y). Taken together, ROS derived from NOX1/NADPH oxidase play a pivotal role in endotoxin-induced cardiomyocyte apoptosis by increasing oxidation of Akt and subsequent dephosphorylation by PP2A. Marked up-regulation of NOX1 may affect the risk of mortality under systemic inflammatory conditions.

Relationship between subjective assessment of oral health and medical expenses in community-dwelling elderly persons.

OBJECTIVES: The increasing medical expenses of elderly persons in Japan's rapidly ageing society have become a major concern. It is therefore important to elucidate the factors associated with such escalation. Here, we focused on the relationship between subjective self-assessment of oral health, as an index of general health, and medical expenses (excluding dental repair) under the hypothesis that oral health contributes to general medical expenses. Several studies have shown that oral health status is correlated with general health status among elderly persons. We speculated that oral health status might show a relation with medical costs among elderly persons. However, few studies have investigated this relationship to date. MATERIALS AND METHODS: Participants were 259 elderly subjects (range: 65-84 years; 120 men, 139 women) residing independently. Subjective assessment of oral health was evaluated by their responses ('Good', 'Not good' and 'Not at all good') on a survey questionnaire. The correlation between subjective assessment of oral health and medical expenditure was analysed using Spearman's rank method, the Mann-Whitney U-test and the Kruskal-Wallis test. Medical expenses were used as the dependent variable in multinomial logistic regression analysis with background and intraoral factors as independent variables. RESULTS: A slight yet statistically significant correlation was observed between subjective assessment of oral health and outpatient treatment fees. CONCLUSION: The findings revealed that subjective assessment of oral health is significantly and independently related to the medical expenses of community-dwelling elderly persons after adjusting for social background, living environment and physical factors.

Influence of dental treatment on physical performance in community-dwelling elderly persons.

OBJECTIVE: The aim of the study was to investigate the influence of dental treatment on physical performance (muscle strength and balance function) among the elderly. BACKGROUND: Oral conditions have been associated with physical performance. We hypothesised that improved oral conditions by dental treatment would lead to improved physical performance. METHODS: A total of 154 persons aged 65 years or over were judged to be in need of dental treatment as a result of dental examination; of these, 121 persons underwent dental treatment. After 1 year, differences in each parameter of physical performance before and after the intervention were evaluated using the Wilcoxon signed rank sum test. The Spearman rank correlation coefficient was calculated to examine correlations between changes in self-assessed masticatory ability (masticatory ability) and each parameter of physical performance, and multivariate logistic regression analysis was performed using changes in each parameter of physical performance as the dependent variable and changes in masticatory ability as the principal independent variable. RESULTS: Improved physical performance was not observed for the total study population with dental treatment; however, in subjects with improved masticatory ability, one-leg standing times with eyes open increased significantly. A significant correlation was established between changes in masticatory ability and each parameter of physical performance. These relationships were not found in those without dental treatment. A significant relationship was also established for one-leg standing time after adjusting for age, gender, dentition status and needs of dental treatments. CONCLUSION: Chewing ability may be a positive contributing factor to balance function among the elderly.

Relationships between Geriatric Oral Health Assessment Index scores and general physical status in community-dwelling older adults.

OBJECTIVE: The aim of this study was to investigate the relationships between Geriatric Oral Health Assessment Index (GOHAI) and general physical status among community-dwelling older adults. BACKGROUND: Geriatric Oral Health Assessment Index is a patient-centred assessment of oral health for older adults. We hypothesised that GOHAI is a significant indicator of general physical status of older adults. METHODS: This study included 354 adults (age, ≥65 years) living independently. Body mass index, handgrip strength and one-leg standing time with eyes open were used to evaluate the general physical status. Spearman's rank correlation coefficients were calculated to examine the relationships between the GOHAI scores, its three subdivided categories (physical function, psychological function and pain and discomfort) and each physical status measurement. A stepwise linear regression model was applied with each physical status measurement as the dependent variable and the GOHAI scores and its subdivisions as the principal independent variable. RESULTS: Positive correlations were found between the GOHAI scores, its three subdivided categories and handgrip strength. The physical function category positively correlated with one-leg standing time. The GOHAI and the pain and discomfort category scores were retained in the final models of stepwise regression for handgrip strength, and significant relationships persisted after adjustments for demographic, psychosocial, medical and dental status. CONCLUSION: The GOHAI scores and its pain and discomfort category score may be significant indicators of body muscle strength.