Ir-Catalyzed Remote Functionalization by the Combination of Deconjugative Chain-Walking and C-H Activation Using a Transient Directing Group.

An Ir-catalyzed reaction of N-benzylideneanilines with functionalized alkenes such as α,ß-unsaturated esters gave ortho-substituted benzaldehyde derivatives with a functional group at the remote position after acidic treatment. The present transformation involves deconjugative long-range isomerization (chain-walking) up to 11 times and C-H activation using an imino group as a transient directing group.

Ameliorative effects of telmisartan on the inflammatory response and impaired spatial memory in a rat model of Alzheimer's disease incorporating additional cerebrovascular disease factors.

Telmisartan, an angiotensin type 1 receptor blocker, is used in the management of hypertension to control blood pressure. In addition, telmisartan has a partial agonistic effect on peroxisome proliferator activated receptor γ (PPARγ). Recently, the effects of telmisartan on spatial memory or the inflammatory response were monitored in a mouse model of Alzheimer's disease (AD). However, to date, no studies have investigated the ameliorative effects of telmisartan on impaired spatial memory and the inflammatory response in an AD animal model incorporating additional cerebrovascular disease factors. In this study, we examined the effect of telmisartan on spatial memory impairment and the inflammatory response in a rat model of AD incorporating additional cerebrovascular disease factors. Rats were subjected to cerebral ischemia and an intracerebroventricular injection of oligomeric or aggregated amyloid-ß (Aß). Oral administration of telmisartan (0.3, 1, 3 mg/kg/d) seven days after ischemia and Aß treatment resulted in better performance in the eight arm radial maze task in a dose-dependent manner. Telmisartan also reduced tumor necrosis factor α mRNA expression in the hippocampal region of rats with impaired spatial memory. These effects of telmisartan were antagonized by GW9662, an antagonist of PPARγ. These results suggest that telmisartan has ameliorative effects on the impairment of spatial memory in a rat model of AD incorporating additional cerebrovascular disease factors via its anti-inflammatory effect.

Neuroprotective effects of citidine-5-diphosphocholine on impaired spatial memory in a rat model of cerebrovascular dementia.

Citidine-5-diphosphocholine or citicoline (CDP-choline) is used as a neuroprotective and memory-enhancing drug in cerebral stroke, Alzheimer's disease, and other neurovascular diseases. Non-clinical studies have demonstrated the neuroprotective effects of CDP-choline in ischemic animal models. However, the relationship between the neuroprotective effect and the memory enhancing effect of CDP-choline is still unknown. No studies have demonstrated the ameliorative effect on impaired spatial memory and the suppressive effect on neuronal cell death of CDP-choline in the same model. In this study, we examined the effect of CDP-choline on impaired spatial memory and hippocampal CA1 neuronal death in rats subjected to repeated cerebral ischemia, and we compared the mechanism of CDP-choline to that of donepezil. Seven days post administration of CDP-choline (100, 300, 1000 mg/kg per day, p.o.) or donepezil increased correct choices and reduced error choices in an eight-arm radial maze task in a dose-dependent manner. Neuronal cell death of caspase-3 protein-positive neurons in the hippocampus were reduced by repeated administration of CDP-choline at the highest dose. These results suggest that CDP-choline has ameliorative effects on the impairment of spatial memory via hippocampal neuronal cell death in a rat model of cerebral ischemia.

Effects of positive and negative affect and emotional suppression on short-term life satisfaction.

Relationships between emotional experiences and health and adjustment are influenced by many variables, with emotional suppression (ES) being one of the most influential factors. In the current study, we examined the effects of affect and ES on short-term life satisfaction (LS) measured over the previous week. We also considered the dimension of activation status for both positive affect (PA) and negative affect (NA). The final sample included data collected from 398 undergraduates (184 men and 214 women). Participants answered six questionnaires, two of which were used for another study. All of the tests were of Japanese versions and were answered with regard to the previous week's experiences. Results showed that LS was positively associated with PA and negatively with NA, but that the positive association was stronger for activated PA than deactivated PA, while the negative association was stronger for deactivated NA than activated NA. Furthermore, an interactive effect between deactivated NA and ES on LS was significant in men, where post hoc tests demonstrated that deactivated NA was more negatively associated with LS when ES was higher. This study suggests that activated and deactivated affect differ in their effects on LS. In addition, it is likely that the detrimental effect of deactivated NA on LS is larger when NA is more strongly suppressed. The necessity of interventional research along with the limitations of this study is discussed for future research.

Telmisartan, a partial agonist of peroxisome proliferator-activated receptor gamma, improves impairment of spatial memory and hippocampal apoptosis in rats treated with repeated cerebral ischemia.

Telmisartan, an angiotensin type 1 receptor blocker (ARB), is used for hypertension to control blood pressure and has been shown to have a partial agonistic effect on peroxisome proliferator-activated receptor gamma (PPARgamma). Recently, the ligand of PPARgamma has been implicated in cerebroprotection due to its anti-inflammatory effect. In this study, we investigated whether telmisartan has a cerebroprotective effect on memory impairment and neuronal cell death induced by repeated cerebral ischemia. Repeated cerebral ischemia (RI: 10 min x 2) significantly induced impairment of spatial memory and hippocampal apoptosis in rats. Fourteen-day pre- and post-ischemic administration of telmisartan (0.3, 1, 3mg/kg/day, p.o.) increased the number of correct choices and reduced the number of errors made in the eight-arm radial maze task in a dose-dependent manner in RI treated rats. TUNEL-positive cells in the hippocampus CA1 areas were also reduced following 14-day administration of telmisartan (3mg/kg/day, p.o.). Seven-day post-ischemic administration of telmisartan improved spatial memory and reduced TUNEL-positive cells while 7-day pre-ischemic administration of telmisartan did not. These effects of telmisartan were inhibited by the PPARgamma antagonist, GW9662. On further experiment, 7-day post-ischemic administration of telmisartan reduced the expression of caspase-3 in the hippocampus, and this effect was also inhibited by GW9662. These results suggest that telmisartan improves memory impairment and reduces neuronal apoptosis via a PPARgamma-dependent caspase-3 inhibiting mechanism. Telmisartan, which has the unique character of having both ARB and PPARgamma agonistic effect, will be useful for preventing memory impairment after cerebrovascular disease.

An intervention study of the effects of the coping strategy of "finding positive meaning" on positive affect and health.

Previous research has shown that positive affect (PA) is associated with the coping strategies of "searching for and finding positive meaning." The purpose of this study was to investigate the relationship between the coping strategy of "finding positive meaning" and PA using an intervention method. Additionally, inasmuch as previous research has revealed that PA is associated with physical and mental health status, the current study measured health status in order to carry out a preliminary test as to whether PA increased by the intervention can also improve health. Participants in the intervention group (Japanese graduate students; 13 men and 16 women) reported the most stressful event during the past 3 days and its positive meaning, while those in the control group (13 men and 15 women) reported the most stressful event alone. Both groups reported twice a week for 5 successive weeks using e-mails. Three questionnaires, the Japanese version of the Positive and Negative Affect Schedule scales for measuring positive and negative affects (NA), the situational version of the General Coping Questionnaire for coping strategies, and the Japanese version of the General Health Questionnaire for health status, were administered to all participants just before the start of the intervention, after the conclusion of the intervention, and at the 5-week follow-up session. Results revealed that the "finding positive meaning" coping strategy and PA were enhanced by the intervention in the follow-up for men and women with no changes in NA. For the health scales of the General Health Questionnaire, no significant group-related effects were observed. Thus, the intervention had no significant influence on NA or health status. Implications of these findings for future research are discussed along with a few limitations in this study.

An intervention study of the relations of positive affect to the coping strategy of 'finding positive meaning' and health.

This study examined the relations of positive affect (PA) to the coping strategy of 'finding positive meaning' and to health. Participants in the intervention group (29 university students) wrote about a happy event once a week in an experimental room and noted happy events each day as homework for four consecutive weeks. In addition, they received a small present each time they left the room after writing. Participants in the control group (29 university students) wrote about and noted trivial neutral events instead of happy events, and they did not receive any small presents. Results showed that PA induced by this manipulation did not significantly enhance coping but did significantly improve health status on several self-report scales.

Social support mediating between coping by emotional expression and depression.

The present purpose was to investigate the effects of social support on the relationship between coping by expressing emotions and depression in women. Japanese undergraduate students (N = 218) completed four self-report questionnaires: the dispositional and situational versions of the Emotional Coping Questionnaire which measures the mode of expression as being either to self as in a diary or to others as in telling a friend, the Social Support Scale to evaluate received support, and the Center for Epidemiologic Studies-Depression Scale. Analysis showed that expression of emotions to self in both dispositional and situational coping had significant positive correlations with depression, especially for women who scored high on depression, and expression of emotions to others in both dispositional and situational coping were significantly positively correlated with social support. However, no significant mediation effects of social support in emotional expression and depression were found. Limitations and topics for research are discussed.

Methylation status of breast cancer resistance protein detected by methylation-specific polymerase chain reaction analysis is correlated inversely with its expression in drug-resistant lung cancer cells.

BACKGROUND: Breast cancer resistance protein (BCRP) functions as a drug efflux transporter that mediates drug resistance. Topoisomerase I inhibitors, including 7-ethyl-10-hydroxycamptothecin (SN-38), are substrates effluxed by BCRP. However, it remains unclear whether the overexpression of BCRP induces drug resistance during chemotherapy. The objectives of the current study were to examine a correlation of altered promoter methylation of BCRP with BCRP expression and to investigate the correlation between methylation status according to methylation-specific polymerase chain reaction (MSP) analysis and BCRP expression levels in several small cell and nonsmall cell lung cancer cells. METHODS: Non-BCRP-expressing PC-6 cells, which were sensitive to SN-38, were treated with DNA methyltransferase inhibitor to induce BCRP re-expression by means of reverse transcriptase-polymersae chain reaction, Western blot, and flow cytometric analyses. Subsequently, bisulfite sequencing analysis in both PC-6 cells and SN-38-resistant PC-6/SN2-5H, highly expressing BCRP cells was performed to identify the methylated region in the BCRP promoter. Finally, the authors established an MSP method on the basis of methylated and unmethylated DNA sequences. RESULTS: DNA methyltransferase inhibitor treatment of PC-6 cells induced BCRP re-expression at the messenger RNA and protein levels. Bisulfite sequencing analysis revealed that both alleles at all CpG sites were methylated completely in PC-6 cells, whereas alleles at portions of CpG sites in PC-6/SN2-5H cells were unmethylated. There was an inverse correlation between promoter methylation of BCRP determined by MSP and BCRP expression in both small cell and nonsmall cell lung cancer cells. CONCLUSIONS: The current results indicated that demethylation of at least 1 allele is necessary for BCRP re-expression and that promoter demethylation of BCRP may be a mechanism of BCRP expression in lung cancer cells.

Different epidermal growth factor receptor gene mutations in a patient with 2 synchronous lung cancers.

Recently, the frequency of lung adenocarcinoma has been increasing among nonsmokers, though the etiology remains unclear. Mutations of the epidermal growth factor receptor (EGFR) gene are frequently detected in the lung adenocarcinomas seen in nonsmokers. Thus, EGFR mutations can be implicated in carcinogenesis of lung adenocarcinoma. Herein, we report a case of 2 synchronous lung adenocarcinomas composed of 2 distinct pathological subtypes with different EGFR mutations: homozygous deletion in exon 19 in the papillary subtype of adenocarcinoma and a point mutation of L858R in exon 21 in the tubular adenocarcinoma. These findings suggest that specific mutations can occur randomly in the EGFR hot spot, and that these EGFR mutations can contribute to the distinct carcinogenic process of each adenocarcinoma.

Relation of positive affect with emotion-focused coping in Japanese undergraduates.

This study examined the relationships between coping and positive affect and sex differences in those relationships, focusing on emotional expression as an emotion-focused coping strategy. Undergraduates (193 men and 225 women) completed the Center for Epidemiologic Studies-Depression to assess positive affect by using the Positive Affect subscale and the General Coping Questionnaire for measurement of coping. Analysis showed a positive relationship between positive affect and both problem-solving and cognitive reinterpretation, but only for men, while a positive relation between positive affect and emotional expression was found only for women. Also there were no interactions of emotional expression and other coping strategies, such as problem-solving, cognitive reinterpretation, and emotional support-seeking, on positive affect. These findings provide evidence to suggest that the relationship between positive affect and coping should be examined by sex.

Long-term survival in three patients with metastatic non-small cell lung cancer treated with gefitinib.

Gefitinib, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), produces radiographic regression and symptom relief in patients with refractory advanced non-small cell lung cancer. However, it remains controversial whether gefitinib improves patient survival. We report three cases of refractory metastatic non-small cell lung cancer who have survived approximately 3 years since they first started gefitinib. These long-term survivors were Japanese female non-smokers with adenocarcinoma, who often had multiple lung metastases and were effectively re-treated with gefitinib. One patient had a surgical specimen available for DNA extraction and showed deletions in exon 19 of EGFR. Our experience suggests that gefitinib may improve long-term survival in selected patients. Further studies are required to identify biomarkers downstream of the EGFR mutations that are involved in multiple lung metastases and which could identify those patients who may benefit from gefitinib re-treatment.

Use of human liver S9 in the Ames test: assay of three procarcinogens using human S9 derived from multiple donors.

The purpose of the present study was to examine the inter-individual variation in the mutagenicity of chemicals using a variety of human S9 fractions. For this purpose, three procarcinogens, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), benzo[a]pyrene (BP), and dimethylnitrosamine (DMN), were selected for the Ames test and their mutagenicity was examined using human liver S9 fractions prepared from 18 different donors and one pooled liver S9 fraction prepared from 15 different donors. In addition, rat S9 fraction prepared from male rats pretreated with phenobarbital and 5,6-benzoflavone (PB/BF) was used as reference in order to examine the mutagenic differences between human and rat (PB/BF) S9 fractions. The data demonstrate a large inter-individual diversity in the mutagenic response to procarcinogens. The mutagenicity of IQ and BP in the presence of a human liver S9 fraction (lot HLS-014) was equal to that observed in the presence of rat (PB/BF) S9 fraction. The mutagenicity of IQ and BP in the presence of a pooled human liver S9 fraction was lower (90 and 95%, respectively) than that observed in the presence of rat (PB/BF) S9. On the contrary, the mutagenicity of DMN in the presence of either a selected human liver S9 fraction (lot HLS-014) or pooled fraction was 8-fold higher than that found in the presence of rat (PB/BF) S9 fraction. Human liver S9 fraction (lot HLS-014) had one of the highest cytochrome P450 enzyme activities among the 18 different donors and higher than the pooled human liver S9 fraction. These results suggest that the use of both selected human liver S9 fractions with high metabolic activity (e.g., lot HLS-014 as used in this study) and a pooled S9 fraction with moderate metabolic activity could be used as a means to evaluate the inter-individual variability in mutagenic response to chemicals and to confirm positive responses from studies completed with rodent S9.