Yasuyoshi Ouchi

Background: Higher cholesterol absorption has been reported to be related to a higher incidence of cardiovascular events (CVEs). The KEEP (Kyushu Elderly Ezetimibe Phytosterol) study, a substudy of the EWTOPIA 75 (Ezetimibe Lipid‐Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older) study, investigated the relationships of cholesterol absorption and synthesis markers with CVEs in older old individuals with hypercholesterolemia, particularly in relation to ezetimibe treatment. Methods and Results: Eligible patients were those aged ≥75 years who had low‐density lipoprotein cholesterol ≥140 mg/dL, no history of coronary artery disease, and no recent use of lipid‐lowering drugs. Participants were randomly assigned into a diet‐only or diet‐plus‐ezetimibe group. Baseline and 24‐week follow‐up blood samples were analyzed for cholesterol absorption (eg, campesterol) and synthesis markers (eg, lathosterol). Of 1287 patients, 1061 patients with baseline measurement were analyzed. Over a median follow‐up of 4.0 years, 64 CVEs occurred. Higher campesterol levels at baseline were significantly associated with a lower risk of CVEs. After adjustment for sex, age, and treatment, the hazard ratios for the lowest to highest quartile categories of baseline campesterol were 1.00 (reference), 0.59 (95% CI, 0.30–1.17), 0.44 (95% CI, 0.21–0.94), and 0.44 (95% CI, 0.21–0.93), respectively (trend P =0.01). This association persisted after further adjustment for hypertension, diabetes, and other cardiovascular risk factors. Neither interactions with ezetimibe treatment nor mediating effects of the changes in cholesterol absorption markers were observed. Conclusions: The KEEP study indicated that higher campesterol levels without lipid‐lowering drugs were associated with a lower incidence of CVEs in older old individuals with hypercholesterolemia who were subsequently treated with diet or ezetimibe. Registration: URL: https://www.umin.ac.jp ; unique identifier: UMIN000017769.

Aim Elevation of homocysteine is associated with an increased risk for bone fractures. We previously reported that the methylenetetrahydrofolate reductase (MTHFR) gene polymorphism is associated with homocysteine levels and fracture. The association between the fracture and folate levels or their related gene polymorphisms is not completely clear. We speculated that the SLC25A32 gene, the mitochondrial inner membrane folate transporter, also could be implicated in the regulation of folate metabolism and fracture. Methods A total of 851 Japanese postmenopausal women participated in the association study between the single nucleotide polymorphism genotype and plasma homocysteine or folate. We also tested the association between the candidate single nucleotide polymorphism and 663 postmenopausal women. Results The AA genotype of rs2241777 single nucleotide polymorphism at the 3′UTR region in the SLC25A32 gene was associated with lower plasma folate concentration compared with the other genotypes in 851 postmenopausal women. A total of 674 postmenopausal ambulatory Japanese women were followed up for 5.5 ± 0.1 years (mean ± SE). The AA genotype groups also showed an apparently higher rate and earlier onset of incident fractures than the other genotypes. A total of 407 participants had >70% young‐adult mean bone mineral density at the start of the observation. Conclusions These results show that the SLC25A32 gene polymorphism could be a risk factor for lower folate concentration and future fracture. Geriatr Gerontol Int 2014; 14: 942–946.

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Aim:  There is little evidence that dehydroepiandrosterone (DHEA) has beneficial effects on physical and psychological functions in older women. We investigated the effect of DHEA supplementation on cognitive function and ADL in older women with cognitive impairment.Methods:  A total of 27 women aged 65–90 years (mean ± standard deviation, 83 ± 6) with mild to moderate cognitive impairment (Mini‐Mental State Examination, MMSE; 10–28/30 points), receiving long‐term care at a facility in Japan were enrolled. Twelve women were assigned to receive DHEA 25 mg/day p.o. for 6 months. The control group (n = 15) matched for age and cognitive function was followed without hormone replacement. Cognitive function was assessed by MMSE and Hasegawa Dementia Scale‐Revised (HDS‐R), and basic activities of daily living (ADL) by Barthel Index at baseline, 3 and 6 months. Plasma hormone levels including testosterone, DHEA, DHEA‐sulfate and estradiol were also followed up.Results:  After 6 months, DHEA treatment significantly increased plasma testosterone, DHEA and DHEA‐sulfate levels by 2–3‐fold but not estradiol level compared to baseline. DHEA administration increased cognitive scores and maintained basic ADL score, while cognition and basic ADL deteriorated in the control group (6‐month change in DHEA group vs control group; MMSE, +0.6 ± 3.2 vs −2.1 ± 2.2, P < 0.05; HDS‐R, +2.8 ± 2.8 vs −0.3 ± 4.1, P < 0.05; Barthel Index, +3.7 ± 7.1 vs −2.7 ± 4.6, P = 0.05). Among the cognitive domains, DHEA treatment improved verbal fluency (P < 0.05).Conclusion:  DHEA supplementation in older women with cognitive impairment may have beneficial effects on cognitive function and ADL. Geriatr Gerontol Int 2010; 10: 280–287.

Estrogen receptor α (ERα) is a nuclear receptor that functions as a ligand-activated transcription factor. Besides its genomic action in nuclei, ERα could exert nongenomic actions at the plasma membrane. To investigate the mechanism underlying the nongenomic action of ERα in breast cancer cells, we generated a construct of membrane-targeted ERα (memER), an expression vector of ERα without the nuclear localizing signal and including instead the membrane-targeting sequence of Src kinase. MemER was stably expressed in human breast cancer MCF-7 cells. Cell migration test and tumorigenic assay in nude mice revealed that the in vitro motility and the in vivo proliferation activity of MCF-7 cells expressing memER were significantly enhanced compared with those of vector-transfected cells. Interestingly, the acetylation level of tubulin in memER-overexpressing cells was lower than that in control cells. We found that histone deacetylase (HDAC) 6 translocated to the plasma membrane shortly after estrogen stimulation, and rapid tubulin deacetylation subsequently occurred. We also showed that memER associated with HDAC6 in a ligand-dependent manner. Although tamoxifen is known for its antagonistic role in the ERα genomic action in MCF-7 cells, the agent showed an agonistic function in the memER-HDAC6 association and tubulin deacetylation. These findings suggest that ERα ligand dependently forms a complex with HDAC6 and tubulin at the plasma membrane. Estrogen-dependent tubulin deacetylation could provide new evidence for the nongenomic action of estrogen, which potentially contributes to the aggressiveness of ERα-positive breast cancer cells. [Cancer Res 2009;69(7):2935–40]

Cerebral monoamine systems play important pathogenic roles in various psychiatric and neurologic diseases, such as depression, anxiety and swallowing disturbance. Hange-koboku-to, a Kampo (Japanese herbal) medicine, has been successfully used for the treatment of these disorders. To elucidate the mechanisms underlying its clinical efficacy for these disorders, the effects of Hange-koboku-to (500 mg/kg, p.o.) on the cerebral monoamine systems were examined. Regional levels of 5-HT (5-hydroxytryptamine), NA (noradrenaline), DA (dopamine) and their metabolites in mouse brain were measured using a high-performance liquid chromatography system. Hange-koboku-to increased the 5-HT and NA levels and decreased 5-HIAA (5-hydroxyindole-3-acetic acid), thus decreasing 5-HT and NA turnover (metabolites/monoamine ratio) in the hypothalamus. The levels of DA, DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (4-hydroxy-3-methoxy-phenylacetic acid) were all increased, resulting in a decreased DA turnover in the striatum. Since decreased 5-HT turnover has been observed after administration of various antidepressants, Hange-koboku-to-mediated reduction of 5-HT turnover may be related to the clinical efficacy of this Kampo medicine on certain psychiatric disorders. Furthermore, the beneficial therapeutic effects of Hange-koboku-to on swallowing disturbance may be related to the increased cerebral DA level brought about by this Kampo medicine. Copyright © 2005 John Wiley & Sons, Ltd.