Chemosensitization of oral squamous cell carcinoma cells to cisplatin by histone deacetylase inhibitor, suberoylanilide hydroxamic acid

In the present study, the precise mechanism of the enhancing action of histone deacetylase (HDAC) inhibitors on cisplatin (CDDP)-induced apoptosis was investigated using suberoylanilide hydroxamic acid (SAHA) in human oral squamous cell carcinoma cells (HSC-3). HDAC inhibitors are promising novel compounds for the treatment of cancer, which cooperate with chemotherapeutic agents to induce apoptosis. Apoptosis enhancement of HSC-3 cells by SAHA was accompanied by the activation of caspase-3, -8 and -9, suggesting a mitochondrial-dependent amplification loop. Concomitant treatment (CDDP/SAHA) of cells resulted in the most effective enhancement of apoptosis compared to other timing combinations. By means of cell-cycle synchronization, G0/G1-phase cells proved to be a more sensitive fraction to SAHA action than their synchronized counterparts in other phases. Furthermore, cells treated with SAHA revealed a decrease in intracellular reduced glutathione (GSH) contents. Of importance, the GSH synthesis inhibitor, diethyl maleate, decreased intracellular GSH and enhanced CDDP-induced apoptosis in a similar pattern of timing to SAHA. Thus, SAHA appears to disrupt the intracellular redox balance, which causes maximal apoptosis at the G0/G1 phase arrested by CDDP in HSC-3 cells. These results demonstrate that HDAC inhibitors not only cause a change in the histone acetylation status, but are also able to influence the apoptotic process at several levels, and GSH plays a key role in governing SAHA-dependent enhancement of CDDP-induced apoptosis.     

Yi-gan san for the treatment of neuroleptic-induced tardive dyskinesia: an open-label study

BACKGROUND: Recent studies indicate that the traditional Japanese herbal medicine yi-gan san (YGS, yokukan-san in Japanese), a serotonin modulator, may be safe and useful in treating behavioral and psychological symptoms in dementia and borderline personality disorder patients. The authors examined the efficacy, tolerability, and safety of YGS in patients with tardive dyskinesia. METHODS: Twenty-two patients with schizophrenia who had neuroleptic-induced tardive dyskinesia were given 7.5 g/day of YGS for 12 weeks in an open-label study. RESULTS: Administration of YGS resulted in a statistically significant improvement in tardive dyskinesia and psychotic symptoms. CONCLUSIONS: YGS may be an effective and safe therapy to control tardive dyskinesia and psychosis in patients with schizophrenia, that should be further tested in double-blind, placebo-controlled trials.     

Phenylimidazole derivatives of 4-pyridone as dual inhibitors of bacterial enoyl-acyl carrier protein reductases FabI and FabK

FabI and FabK are bacterial enoyl-acyl carrier protein (ACP) reductases that catalyze the final and rate-limiting step of bacterial fatty acid biosynthesis (FAS) and are potential targets of novel antibacterial agents. We have reported 4-pyridone derivative 3 as a FabI inhibitor and phenylimidazole derivative 5 as a FabK inhibitor. Here, we will report phenylimidazole derivatives of 4-pyridone as FabI and FabK dual inhibitors based on an iterative medicinal chemistry and crystallographic study of FabK from Streptococcus pneumoniae/compound 26. A representative compound 6 showed strong FabI inhibitory (IC50 = 0.38 microM) and FabK inhibitory (IC50 = 0.0045 microM) activities with potent antibacterial activity against S. pneumoniae (MIC = 0.5 microg/mL). Since elevated MIC value was observed against S. pneumoniae mutant possessing one amino acid substitution in FabK, the antibacterial activity of the compound was considered to be due to the inhibition of FabK. Moreover, this compound showed no significant cytotoxicity (IC50 > 69 microM). These results support compound 6 as a novel agent for the treatment of bacterial infections.     

Social capital and psychological distress of elderly in Japanese rural communities

The growing recognition of the social determinants of health has stimulated research on social capital and mental health. We explored new empirical evidence regarding whether social capital was a determinant of psychological distress. Baseline surveys examining psychological distress were conducted in two towns in 2006–2007 (participation rates for those aged 20 or over were 27.6 per cent, 6.1 per cent). We also conducted follow‐up surveys in 2008 to capture the social capital measured by trust. By linking these data and excluding the missing data, 141 males and 234 females remained as the subjects of our study. Results showed that the odds ratios of psychological distress was higher in groups with low social capital measured by trust (odds ratio 2.17; 95 per cent CI, 1.40–3.36), than those in groups with high social capital. Further, we examined the interaction effect of social capital and social support. The odds ratios of psychological distress was higher in groups with some social support/lower trust (odds ratio 2.21; 95 per cent CI, 1.36–3.58) or no social support/lower trust (odds ratio 2.07; 95 per cent CI, 1.06–4.05), than those in groups with some social support/higher trust. These findings reinforce the hypothesized discussion regarding pathways from social capital to psychological distress via supportive relationships. Copyright © 2010 John Wiley & Sons, Ltd.