Molecular Mechanisms Underlying Human Beta-defensin-2 Gene Expression in a Human Airway Cell Line (LC2/ad)

Respirology (Carlton, Vic.). Dec, 2002  |  Pubmed ID: 12421237

Recently, human beta-defensin-2 (hBD-2), an inducible defensin, has been reported to be involved in innate immunity and host defence. To examine the exact roles of hBD-2 in the respiratory system, we examined the molecular mechanisms of hBD-2 gene expression in vitro.

Estrogen Activates Cyclin-dependent Kinases 4 and 6 Through Induction of Cyclin D in Rat Primary Osteoblasts

Biochemical and Biophysical Research Communications. Nov, 2002  |  Pubmed ID: 12437973

Estrogen plays important roles in maintaining bone density and protecting against osteoporosis, but the underlying mechanisms of estrogen action via estrogen receptors (ERs) in bone remain to be clarified. In the present study, we isolated primary osteoblasts derived from transgenic rats harboring a dominant negative ER mutant, rat ERalpha (1-535) cDNA, and from their wild-type littermates. We observed that the rate of cell growth of osteoblasts from the transgenic rats was reduced compared to that of wild-type osteoblasts. Utilizing cDNA microarray analysis, we found that mRNA level of cyclin D2 was lower in the osteoblasts from the transgenic rats. D-type cyclins including cyclin D1, cyclin D2, and cyclin D3 are cell cycle regulators that promote progression through the early-to-mid G1 phase of the cell cycle. The protein levels of D-type cyclins including cyclin D2 and cyclin D3 but not cyclin D1 were elevated in wild-type osteoblasts with 17beta-estradiol treatment, resulting in the activation of cyclin-dependent kinases 4 and 6 (Cdk4/6) activities and the promotion of cell growth. Moreover, an anti-estrogen ICI 182,780 abolished the induction of the expression of D-type cyclins by 17beta-estradiol. Our findings indicate that estrogen and its receptors enhance Cdk4/6 activities through the induction of D-type cyclins, leading to the growth promotion of osteoblasts.

Nocturnal Gastroesophageal Reflux: Symptom of Obstructive Sleep Apnea Syndrome in Association with Impaired Swallowing

Chest. Dec, 2002  |  Pubmed ID: 12475880

Induction of Anti-metallothionein Antibody and Mercury Treatment Decreases Bone Mineral Density in Mice

Toxicology and Applied Pharmacology. Dec, 2002  |  Pubmed ID: 12490134

Mercuric chloride (HgCl2) is an industrial agent with toxic effects on the immune system, kidney, lung, and nervous tissue, but little is known about its effect on bone. Metallothionein (MT) is a cysteine-rich metal-binding protein that exerts cytoprotective effects against heavy metal toxins. It has been reported that the susceptibility of renal and pulmonary toxicity of mercury was markedly enhanced in MT-null mice compared to control mice. However, there is no report about the effects of anti-metallothionein (anti-MT) Ab induction on mercury toxicity. We investigated the effect of anti-MT Ab induction on mercury-induced bone injury. BALB/c mice were injected with MT (10 microg/mouse ic) five times to induce anti-MT Ab and then treated with HgCl2 (1 mg/kg sc) three times per week for 3 weeks. MT immunization plus HgCl2 treatment dramatically decreased bone mineral density (BMD), and the humoral bone formation indices, alkaline phosphatase (ALP) activity and osteocalcin. MT immunization or HgCl2 treatment alone did not affect either BMD or serum ALP activity and osteocalcin levels. MT immunization impeded HgCl2-induced increase of MT expression in the liver and led to an increase of mercury in serum and the liver but a decrease in the kidney. Furthermore, serum titers of IgE and IgG1 were significantly elevated in the MT-immunized plus HgCl2 treatment group compared with those in the HgCl2 treatment group. Similar results were also observed in splenic secretions of IL-4 and IL-10 based on anti-CD3 Ab stimulation. Taken together, our results indicate that anti-MT Ab induction causes mercury-induced bone injury in BALB/c mice and also enhances mercury-related immune disorders.

Airway Hyperresponsiveness in Transgenic Mice Overexpressing Platelet Activating Factor Receptor is Mediated by an Atropine-sensitive Pathway

American Journal of Respiratory and Critical Care Medicine. Jan, 2002  |  Pubmed ID: 11790655

Platelet activating factor (PAF) is a potent mediator potentially involved in the pathogenesis of inflammatory disorders, including bronchial asthma. Recently, transgenic mice overexpressing the PAF receptor (PAFR) gene have been established, and exhibit bronchial hyperresponsiveness, one of the cardinal features of asthma. To elucidate the molecular and pathophysiologic mechanisms underlying PAF-associated bronchial hyperreactivity, we studied airway responsiveness to methacholine (MCh) and serotonin (5-hydroxytryptamine; 5-HT) in PAFR-transgenic mice. In addition, we examined the role of the muscarinic receptor in PAF-induced responses and the binding activities of the muscarinic receptor. The PAFR-transgenic mice exhibited hyperresponsiveness to MCh and PAF; however, no significant differences in 5-HT responsiveness were observed between the control and PAFR-transgenic mice. The administration of atropine significantly blocked PAF-induced responses in PAFR-transgenic mice. There were no differences between the two phenotypes in the binding activities of muscarinic receptor. Morphometric analyses demonstrated that PAFR overexpression did not affect airway structure. These findings suggest that the muscarinic pathway may have a key role in airway hyperresponsiveness associated with PAFR gene overexpression. More generally, PAFR-transgenic mice may provide appropriate models for study of the molecular mechanisms underlying PAF-associated diseases.

Effects of Long-term and Reduced-dose Hormone Replacement Therapy on Endothelial Function and Intima-media Thickness in Postmenopausal Women

Menopause (New York, N.Y.). Jan-Feb, 2002  |  Pubmed ID: 11791087

Short-term estrogen therapy improves endothelial function in postmenopausal women. However, there are few reports on its long-term effects on endothelial function and carotid intima-media thickness. Further, we determined whether a reduced dosage of estrogen may maintain its beneficial effects.

Transient Left Ventricular Apical Ballooning Without Coronary Artery Stenosis: a Form of Stunning-like Phenomenon?

Journal of the American College of Cardiology. Feb, 2002  |  Pubmed ID: 11849878

[Changes of Care Status Before and After the Introduction of the Long-term Care Insurance in Japan--results of Care Status Before the Long-term Care Insurance]

Nihon Ronen Igakkai Zasshi. Japanese Journal of Geriatrics. Jan, 2002  |  Pubmed ID: 11857965

Questionnaire Survey on the Japanese Guidelines for Treatment of Hypertension in the Elderly: 1999 Revised Version

Hypertension Research : Official Journal of the Japanese Society of Hypertension. Jan, 2002  |  Pubmed ID: 11924729

A questionnaire survey was administered to Japanese clinical specialists in hypertension in order to gauge their opinions on the 1999 revised version of the Guidelines for Hypertension in the Elderly prepared by the Comprehensive Research Project on Aging and Health of the Ministry of Health and Welfare. Out of 162 council members of the Japanese Society of Hypertension, 122 (75%) replied. The majority (93%) of respondents approved of the guidelines in general, and 72% of them approved of the age-related setting of a therapeutic goal for blood pressure. Sixty-five percent of respondents selected long-acting Ca antagonists, ACE inhibitors and low-dose diuretics as first-line agents for hypertension without complications in the elderly. The results of the questionnaire survey should be reflected in the next version of the guidelines.

[Chronic Obstructive Pulmonary Disease (COPD) in the Elderly: Analysis from Questionnaire About Attitudes to the COPD Guideline of the Japanese Respiratory Society and Actual Therapy for COPD Used by Physicians]

Nihon Kokyūki Gakkai Zasshi = the Journal of the Japanese Respiratory Society. Feb, 2002  |  Pubmed ID: 11974865

We have conducted a survey of attitudes to chronic obstructive pulmonary disease (COPD) in the elderly, a survey of attitudes to the COPD guideline prepared by the Japanese Respiratory Society, and a survey of the therapies actually used for this disease among physicians belonging to the Yokohama Medical Association. The results showed that most respondents thought that physicians, mainly except for respiratory physicians, miss the COPD patients because of failure to recognize COPD. The spread of the COPD guideline among physicians and the amount of therapy conducted according to this guideline were also insufficient. However, most physicians who know this guideline have used it well, and have also appreciated the contents. Thus, the results of our surveys suggested that this COPD guideline, with its step-by-step pharmacologic therapy, should be more widely disseminated, mainly among clinics and physicians that are not respiratory specialists. This would enable them to follow the guideline and improve their treatment of COPD. In addition, it was also supposed that the comprehensive respiratory rehabilitation should be more executed in the hospitals.

[Estrogen Receptor Gene Polymorphism]

Nihon Rinsho. Japanese Journal of Clinical Medicine. Mar, 2002  |  Pubmed ID: 11979896

A Pivotal Role of Cytosolic Phospholipase A(2) in Bleomycin-induced Pulmonary Fibrosis

Nature Medicine. May, 2002  |  Pubmed ID: 11984592

Pulmonary fibrosis is an interstitial disorder of the lung parenchyma whose mechanism is poorly understood. Potential mechanisms include the infiltration of inflammatory cells to the lungs and the generation of pro-inflammatory mediators. In particular, idiopathic pulmonary fibrosis is a progressive and fatal form of the disorder characterized by alveolar inflammation, fibroblast proliferation and collagen deposition. Here, we investigated the role of cytosolic phospholipase A(2) (cPLA(2)) in pulmonary fibrosis using cPLA(2)-null mutant mice, as cPLA(2) is a key enzyme in the generation of pro-inflammatory eicosanoids. Disruption of the gene encoding cPLA(2) (Pla2g4a) attenuated IPF and inflammation induced by bleomycin administration. Bleomycin-induced overproduction of thromboxanes and leukotrienes in lung was significantly reduced in cPLA(2)-null mice. Our data suggest that cPLA(2) has an important role in the pathogenesis of pulmonary fibrosis. The inhibition of cPLA(2)-initiated pathways might provide a novel therapeutic approach to pulmonary fibrosis, for which no pharmaceutical agents are currently available.

Red Wine Polyphenols Inhibit Vascular Smooth Muscle Cell Migration Through Two Distinct Signaling Pathways

Circulation. May, 2002  |  Pubmed ID: 12021228

Red wine polyphenols (RWPs) have been shown to have an antiatherogenic activity mainly through antioxidative effects on LDL oxidation. Although vascular smooth muscle cell (SMC) migration is critical to atherosclerosis formation, the effect of RWPs on SMC migration has not been elucidated. In this study, we investigated whether RWPs could affect the migration of cultured SMCs stimulated by growth factors.

Adverse Drug Reactions in Older People with Dementia

Journal of the American Geriatrics Society. Feb, 2002  |  Pubmed ID: 12028234

Effect of Red Wine Polyphenols on Vascular Smooth Muscle Cell Function--molecular Mechanism of the 'French Paradox'

Mechanisms of Ageing and Development. Apr, 2002  |  Pubmed ID: 12044952

Red wine polyphenols (RWP) have been shown to have an anti-atherogenic activity mainly through anti-oxidative effects on low-density lipoprotein (LDL) oxidation. Though proliferation of vascular smooth muscle cells (VSMC) is critical to atherosclerosis formation, the effect of RWP on VSMC proliferation has not been elucidated. In this study, we investigated whether RWP, which extracted from red wine using column chromatography, could affect the 10% serum-stimulated VSMC proliferation. Treatment with RWP showed a potent inhibitory effect on the proliferation and DNA syntheses is in cultured rat VSMC. In contrast, the inhibitory effect of RWP on the proliferation of bovine vascular endothelial cells (EC) was only observed at much higher doses. Moreover, RWP significantly inhibited the proliferation and DNA synthesis of human VSMC but no human vascular EC in a dose-dependent manner. To elucidate the molecular mechanisms of these anti-proliferative effects of RWP on VSMC, but not on vascular EC, we investigated the effects of RWP on the cell cycle regulation. RWP downregulated the expression and promoter activity of cyclin A gene, one of cell cycle regulators. In addition, RWP inhibited the binding of nuclear proteins to the activating transcription factor (ATF) site in the cyclin A promoter, and downregulated the expression of transcription factors, cyclic AMP-responsive element binding protein (CREB) and ATF-1. In conclusion, these results demonstrate one possible finding that the anti-proliferative effect of RWP on VSMC may be associated with the downregulation of cyclin A gene expression through the inhibition of transcription factor expression.

[Questionnaire on the Attitude of the Physicians in Educating the Elderly Patients with Chronic Obstructive Pulmonary Disease About Smoking Cessation]

Nihon Ronen Igakkai Zasshi. Japanese Journal of Geriatrics. May, 2002  |  Pubmed ID: 12073594

Smoking status, the extent of recognition of the relationship between smoking and COPD, and actual nature of education for smoking cessation by physicians have not yet been fully elucidated. To investigate perceptions about education for smoking cessation in the elderly by physicians who work in the clinic, questionnaires were sent to the 1,012 physicians who belong to the Yokohama City Medical Association. Of these, 311 respond and their data (31%) were included in the analysis. The questionnaire included questions on the importance of smoking cessation in the elderly, on the perception about the relationship between smoking and various diseases, and actual education for smoking cessation. The smoking status of the physicians themselves was also investigated. The distribution of current smokers, ex-smokers, and non-smokers among the physicians was 13%, 33%, and 54%, respectively. Seventy-five percent of ex-smokers answered that their experience of smoking cessation influenced their patient education for smoking cessation, and 39% of smokers answered that their smoking status did not influence it. Only 53% of the physicians replied that they actually performed education for smoking cessation to the elderly, and 8% of them replied that they hardly perform any or do not perform it. Smoking cessation is thought to be the only way to prevent the development of COPD. However, only a half of physicians recognized the importance of smoking cessation for the treatment and control of COPD in the elderly. In addition, less than one third of physicians perform nicotine replacement therapy for smoking cessation. Enlightenment for physicians should be needed to make them perform education for smoking cessation more aggressively.

Efp Targets 14-3-3 Sigma for Proteolysis and Promotes Breast Tumour Growth

Nature. Jun, 2002  |  Pubmed ID: 12075357

Oestrogen exerts its influence on target organs through activating oestrogen receptors (ERs) and regulating downstream genes by means of their oestrogen-responsive elements. Efp, a target gene product of ER alpha, is a member of the RING-finger B-box coiled-coil (RBCC) motif family. Efp is predominantly expressed in various female organs as well as in breast cancers, and is thought to be essential for oestrogen-dependent cell proliferation and organ development Efp-disrupted mice display underdeveloped uteri and reduced oestrogen responsiveness. Here we show that Efp is a RING-finger-dependent ubiquitin ligase (E3) that targets proteolysis of 14-3-3 sigma, a negative cell cycle regulator that causes G2 arrest. We demonstrate that tumour growth of breast cancer MCF7 cells implanted in female athymic mice is reduced by treatment with antisense Efp oligonucleotide. Efp-overexpressing MCF7 cells in ovariectomized athymic mice generate tumours in the absence of oestrogen. Loss of Efp function in mouse embryonic fibroblasts results in an accumulation of 14-3-3 sigma, which is responsible for reduced cell growth. These data provide an insight into the cell-cycle machinery and tumorigenesis of breast cancer by identifying 14-3-3 sigma as a target for proteolysis by Efp, leading to cell proliferation.

Inhibitory Effects of Novel AP-1 Decoy Oligodeoxynucleotides on Vascular Smooth Muscle Cell Proliferation in Vitro and Neointimal Formation in Vivo

Circulation Research. Jun, 2002  |  Pubmed ID: 12089071

Excessive proliferation of vascular smooth muscle cells (VSMCs) and neointimal formation are critical steps in the pathogenesis of atherosclerosis and restenosis after percutaneous transluminal angioplasty. In this study, we investigated the hypothesis that the activator protein-1 (AP-1) plays an important role in neointimal formation after vascular injury. A circular dumbbell AP-1 decoy oligodeoxynucleotide (CDODN) was developed as a novel therapeutic strategy for restenosis after angioplasty. This CDODN was more stable than the conventional phosphorothioate linear decoy ODN (PSODN) and maintained structural integrity on exposure to exonuclease III or serum. Transfection with AP-1 decoy ODNs strongly inhibited VSMC proliferation and migration, as well as glucose- and serum-induced expression of PCNA and cyclin A genes. Administration of AP-1 decoy ODNs in vivo using the hemagglutinating virus of Japan (HVJ)-liposome method virtually abolished neointimal formation after balloon injury to the rat carotid artery. Compared with PSODN, CDODN was more effective in inhibiting the proliferation of VSMCs in vitro and neointimal formation in vivo. Our results collectively indicate that AP-1 activation is crucial for the mediation of VSMC proliferation in response to vascular injury. Moreover, the use of stable CDODN specific for AP-1 activity in combination with the highly effective HVJ-liposome method provides a novel potential therapeutic strategy for the prevention of restenosis after angioplasty in humans.

Augmentation of Immune Cell Activity Against Tumor Cells by Rauwolfia Radix

Journal of Ethnopharmacology. Aug, 2002  |  Pubmed ID: 12127238

In this study, we investigated the effect of Rauwolfia radix on heat shock protein (HSP) 70 expression and cytotoxicity against tumor cells in activated human T cells. When activated T cells were cultured with Rauwolfia radix for 18 h, HSP70 expression after heat shock was remarkably increased, and cytotoxicity against T98G tumor cells was augmented. Moreover, Rauwolfia radix also enhanced the cytotoxicity of heat shocked activated T cells against Molt-4 and T98G tumor cells. Secretions of interferon-gamma (IFN-gamma) and tumor necrosis alpha (TNF-alpha), due to Concanavalin A (Con A) stimulation, were increased by Rauwolfia radix in activated T cells. To investigate the antitumor effect in vivo, EL-4 tumor-bearing mice were administered with Rauwolfia radix in drinking water. The survival period of the Rauwolfia radix treatment group was significantly prolonged compared with that of the control group. Reserpine, the major active ingredient of Rauwolfia radix, also enhanced the cytotoxicity of activated T cells against Molt-4 and T98G tumor cells, and prolonged the survival period of EL-4 tumor-bearing mice. Taken together, our results suggest that Rauwolfia radix can enhance the activity of immune cells against tumor cells.

Mouse Genetic Evidence That Tranilast Reduces Smooth Muscle Cell Hyperplasia Via a P21(WAF1)-dependent Pathway

Arteriosclerosis, Thrombosis, and Vascular Biology. Aug, 2002  |  Pubmed ID: 12171792

N-(3'4'-dimethoxycinnamoyl)-anthranilic acid (tranilast) is a drug that has been shown to reduce the incidence of restenosis after angioplasty in middle-scale clinical trials. Despite clinical interest in this drug, the pharmacological actions of tranilast remain relatively unexplored at a molecular level.

Identification of Multiple Novel Epididymis-specific Beta-defensin Isoforms in Humans and Mice

Journal of Immunology (Baltimore, Md. : 1950). Sep, 2002  |  Pubmed ID: 12193721

Defensins comprise a family of cationic antimicrobial peptides that are characterized by the presence of six conserved cysteine residues. We identified two novel human beta-defensin (hBD) isoforms by mining the public human genomic sequences. The predicted peptides conserve the six-cysteine motif identical with hBD-4, termed hBD-5 and hBD-6. We also evaluated the characteristics of the mouse homologs of hBD-5, hBD-6, and HE2beta1, termed mouse beta-defensin (mBD)-12, mBD-11, and mouse EP2e (mEP2e). The mBD-12 synthetic peptide showed salt-dependent antimicrobial activity. We demonstrate the epididymis-specific expression pattern of hBD-5, hBD-6, mBD-11, mBD-12, and mEP2e. In situ hybridization revealed mBD-11, mBD-12, and mEP2e expression in the columnar epithelium of the caput epididymis, contrasting with the predominant expression of mBD-3 in the capsule or septum of the whole epididymis. In addition, the regional specificity of mBD-11, mBD-12, and mEP2e was somewhat overlapping, but not identical, in the caput epididymis, suggesting that specific regulation may work for each member of the beta-defensin family. Our findings indicated that multiple beta-defensin isoforms specifically and cooperatively contribute to the innate immunity of the urogenital system.

Attenuation of Antigen-induced Airway Hyperresponsiveness in CGRP-deficient Mice

American Journal of Physiology. Lung Cellular and Molecular Physiology. Nov, 2002  |  Pubmed ID: 12376349

Bronchial hyperresponsiveness and eosinophilia are major characteristics of asthma. Calcitonin gene-related peptide (CGRP) is a neuropeptide that has various biological actions. In the present study, we questioned whether CGRP might have pathophysiological roles in airway hyperresponsiveness and eosinophilia in asthma. To determine the exact roles of endogenous CGRP in vivo, we chose to study antigen-induced airway responses using CGRP gene-disrupted mice. After ovalbumin sensitization and antigen challenge, we assessed airway responsiveness and measured proinflammatory mediators. In the sensitized CGRP gene-disrupted mice, antigen-induced bronchial hyperresponsiveness was significantly attenuated compared with the sensitized wild-type mice. Antigen challenge induced eosinophil infiltration in bronchoalveolar lavage fluid, whereas no differences were observed between the wild-type and CGRP-mutant mice. Antigen-induced increases in cysteinyl leukotriene production in the lung were significantly reduced in the CGRP-disrupted mice. These findings suggest that CGRP could be involved in the antigen-induced airway hyperresponsiveness, but not eosinophil infiltration, in mice. The CGRP-mutant mice may provide appropriate models to study molecular mechanisms underlying CGRP-related diseases.

Effects of Obstructive Sleep Apnea on Circulating ICAM-1, IL-8, and MCP-1

Journal of Applied Physiology (Bethesda, Md. : 1985). Jan, 2003  |  Pubmed ID: 12391099

Obstructive sleep apnea syndrome (OSAS) is one of the most important risk factors of cardiovascular disorders. In the treatment of OSAS, nasal continuous positive airway pressure (nCPAP) has been widely used and found to be effective. In the present study, we hypothesized that the hypoxic stress caused by obstructive sleep apnea would increase circulating intercellular adhesion molecule-1 (ICAM-1), interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1) in untreated OSAS patients compared with an age-matched control group. In addition, we hypothesized that nCPAP may decrease OSAS-induced hypoxic stress and mediators. To examine these hypotheses, we measured circulating ICAM-1 and IL-8 before and after nCPAP therapy in OSAS patients. We observed that nCPAP decreased apnea, desaturation, and the circulating ICAM-1 and IL-8 levels in OSAS patients. The circulating levels of ICAM-1, IL-8, and MCP-1 in untreated OSAS patients were significantly greater than those in the controls. These observations suggest that nCPAP therapy could reduce OSAS-induced hypoxia and generation of inflammatory mediators. Treatment of OSAS using nCPAP can be, therefore, a potential approach to decrease risk of the progression of OSAS-associated disorders.

A Potent Inhibitor of Cytosolic Phospholipase A2, Arachidonyl Trifluoromethyl Ketone, Attenuates LPS-induced Lung Injury in Mice

American Journal of Physiology. Lung Cellular and Molecular Physiology. May, 2003  |  Pubmed ID: 12505870

Acute respiratory distress syndrome (ARDS) is an acute lung injury of high mortality rate, and sepsis syndrome is one of the most frequent causes of ARDS. Metabolites of arachidonic acid, including thromboxanes and leukotrienes, are proinflammatory mediators and potentially involved in the development of ARDS. A key enzyme for the production of these inflammatory mediators is cytosolic phospholipase A(2) (cPLA(2)). Recently, it has been reported that arachidonyl trifluoromethyl ketone (ATK) is a potent inhibitor of cPLA(2). In the present study, we hypothesized that pharmacological intervention of cPLA(2) could affect acute lung injury. To test this hypothesis, we examined the effects of ATK in a murine model of acute lung injury induced by septic syndrome. The treatment with ATK significantly attenuated lung injury, polymorphonuclear neutrophil sequestration, and deterioration of gas exchange caused by lipopolysaccharide and zymosan administration. The current observations suggest that pharmacological intervention of cPLA(2) could be a novel therapeutic approach to acute lung injury caused by sepsis syndrome.

Changing Spectrum of Infective Endocarditis: Review of 194 Episodes over 20 Years

Circulation Journal : Official Journal of the Japanese Circulation Society. Jan, 2003  |  Pubmed ID: 12520142

A review of admission records identified 194 episodes of infective endocarditis (IE) from January 1980 to December 1999 at a community hospital in Tokyo. The cases were divided into decades, and the clinical picture and short-term outcomes were compared and analyzed. The mean age of patients in the 1990s was older (45.5 +/-13.2 vs 55.1+/-12.6 years, p<0.001), and prosthetic valve endocarditis was significantly more frequently seen (14.4% vs 31.8%, p=0.004). None had a history of intravenous drug abuse (IVDA). Patients on chronic hemodialysis comprised 5.8% of IE cases in the 90s. Overall, dental procedure or caries still remained the main presumed source of infection. Staphylococcal IE showed a tendency to increase, and methicillin-resistant staphylococcal IE was significantly prominent in the 90s (0% vs 10.4%, p=0.0006). The overall in-hospital mortality was similar between the 2 groups (13.6% vs 18.8%, NS). Multivariate analysis found neurological abnormality, renal insufficiency and staphylococcal IE as predictors of in-hospital mortality. The characteristics of IE in Japan have changed, even among non-IVDA patients, and it appears to occur in a more high-risk patient population, which may warrant a more aggressive therapeutic approach to its management and treatment.

Increased C-reactive Protein and Increased Plasma Interleukin-6 May Synergistically Affect the Progression of Coronary Atherosclerosis in Obstructive Sleep Apnea Syndrome

Circulation. Feb, 2003  |  Pubmed ID: 12578892

Preventing Angiographic Progression of Coronary Atherosclerosis with Pravastatin

Journal of Atherosclerosis and Thrombosis. 2003  |  Pubmed ID: 12621161

We conducted a prospective study to investigate the relationship between the decrease of serum lipid levels during pravastatin therapy and changes of coronary angiography parameters in Japanese patients with coronary atherosclerosis. The patients were predominantly male, aged between 18 and 75 years (mean: 58 years), had at least 25% stenosis of one or more major coronary arteries, and had a serum total cholesterol ( TC) level > or = 200 mg/dl (5.18 mM/l). Treatment with pravastatin (10 mg/day) was continued for 3 years. Coronary angiography was performed before and 3 years after the start of pravastatin therapy to assess the relationship between the mean segment diameter (MSD), the minimal lumen diameter (MLD), and the annual changes of percent stenosis and TC levels. of 265 patients who were initially registered, 129 were followed for an average of 35 months. Consequently, second angiograms were only obtained in 68 patients for various reasons, so this group was used for analysis. During pravastatin therapy, the TC level significantly decreased from 239 mg/dl (6.19 mM/l) to 210 mg/dl (5.44 mM/l) (a 12% reduction; p<0.001). In addition, HDL-cholesterol increased by 5% (p=0.007), but the triglyceride level did not show a significant change. Both MSD and MLD were significantly improved on follow-up angiography, increasing from 2.67 mm to 2.76 mm and from 2.09 mm to 2.13 mm, respectively. However, no change of percent stenosis was observed. The mean TC level during treatment did not show any significant correlation with the changes of angiography parameters. However, a significant correlation was observed between the percent reduction of TC and the annual change of MSD (r=-0.272, p=0.027). A similar relationship was also found between the change of MLD and the percent reduction of TC (r=-0.260, p=0.035). In conclusion, the percent decrease of serum cholesterol may be a better indicator of clinical efficacy than the absolute cholesterol level during pravastatin therapy.

Guidelines for Treatment of Hypertension in the Elderly--2002 Revised Version

Hypertension Research : Official Journal of the Japanese Society of Hypertension. Jan, 2003  |  Pubmed ID: 12661910

Clinical Efficacy and Toxicity of Gefitinib in Patients with Lung Cancer

Lancet. Jun, 2003  |  Pubmed ID: 12801775

EBAG9/RCAS1 Expression and Its Prognostic Significance in Prostatic Cancer

International Journal of Cancer. Journal International Du Cancer. Sep, 2003  |  Pubmed ID: 12845666

Estrogen receptor-binding fragment-associated gene 9 (EBAG9) has been identified as a primary estrogen-responsive gene from MCF-7 human breast cancer cells (Watanabe T, et al., Mol Cell Biol 1998;18:442-9). EBAG9 is identical with RCAS1 (receptor-binding cancer antigen expressed on SiSo cells), which has been reported as a cancer cell surface antigen implicated in immune escape (Nakashima M, et al., Nat Med 1999;5:938-42). In our present study, we examined EBAG9 expression in human prostatic tissues and investigated its prognostic significance in patients with prostatic cancer. EBAG9 expression in normal prostatic epithelial cells and PC-3, DU145 and LNCaP cancer cells was determined by Western blot analysis. Immunohistochemic analysis was performed in 21 benign and 81 malignant prostatic specimens, and patients' charts were reviewed for clinical, pathologic and survival data. EBAG9 was abundantly expressed in the prostate cancer cells compared to the normal epithelial cells. Strong and diffuse immunostaining in the cytoplasm of EBAG9 was found in 44 of 81 (54%) cancerous tissue samples. EBAG9 expression significantly correlated with advanced pathologic stages and high Gleason score (p = 0.0305 and < 0.0001, respectively). EBAG9 was more frequently expressed at sites of capsular penetration (79%) and lymph node metastasis (100%) compared to intracapsular primary tumors (54%) (p = 0.0264 and 0.0048, respectively). Positive EBAG9 immunoreactivity significantly correlated with poor PSA failure-free survival (p = 0.0059). EBAG9/RCAS1 may play a significant role in cancer progression via an immune escape system. Immunodetection of EBAG9/RCAS1 expression can be a negative prognostic indicator for patients with prostatic cancer.

Gastroesophageal Reflux Common in Patients with Sleep Apnea Rather Than Snorers Without Sleep Apnea

Chest. Aug, 2003  |  Pubmed ID: 12907575

Effects of Oxygen Administration on the Circulating Vascular Endothelial Growth Factor (VEGF) Levels in Patients with Obstructive Sleep Apnea Syndrome

Internal Medicine (Tokyo, Japan). Aug, 2003  |  Pubmed ID: 12924491

Repeated nocturnal hypoxia is implicated in the pathogenesis of cardiovascular complications in obstructive sleep apnea syndrome (OSAS). We hypothesized that circulating vascular endothelial growth factor (VEGF) levels are affected by nocturnal hypoxemia in patients with OSAS.

Nosocomial Infections in Adult Intensive-care Units

Lancet. Aug, 2003  |  Pubmed ID: 12927442

Estrogen Receptor Beta Mediates the Inhibitory Effect of Estradiol on Vascular Smooth Muscle Cell Proliferation

Cardiovascular Research. Sep, 2003  |  Pubmed ID: 14499875

It has been demonstrated that 17beta-estradiol (E2) has an inhibitory effect on the proliferation of vascular smooth muscle cells (VSMCs) through an estrogen receptor (ER)-dependent pathway. Both ER subtypes, classical ER (ERalpha) and the newly identified ER subtype (ERbeta), are expressed in VSMCs. However, it remains unknown which receptor plays the critical role in the inhibitory effect on VSMC proliferation.

Clinical Insignificance of (1-->3)-beta-D-glucan in Early Diagnosis of Invasive Pulmonary Aspergillosis in a Patient with Chronic Obstructive Pulmonary Disease

Journal of Medical Microbiology. Nov, 2003  |  Pubmed ID: 14532351

Oxygen Administration Improves the Serum Level of Nitric Oxide Metabolites in Patients with Obstructive Sleep Apnea Syndrome

Sleep Medicine. Sep, 2003  |  Pubmed ID: 14592281

Nocturnal apnea and hypoxia are implicated in the pathogenesis of pulmonary and systemic hypertension in obstructive sleep apnea syndrome (OSAS). We have hypothesized that vasodilating factors including nitric oxide (NO) are affected by nocturnal apnea and hypoxia in patients with OSAS.

17 Beta-estradiol Inhibits Cardiac Fibroblast Growth Through Both Subtypes of Estrogen Receptor

Biochemical and Biophysical Research Communications. Nov, 2003  |  Pubmed ID: 14592435

The effect of 17 beta-estradiol (E2) on the proliferation of cardiac fibroblasts (CFs) remains controversial. This study investigated which subtype of estrogen receptor (ER), ER alpha or ER beta, mediated the effect of E2 on CF growth by the gain of function analysis using an adenovirus vector. One hundred nanomoles per liter of E2 attenuated DNA synthesis by up to 10%, and transactivated the estrogen-responsive element determined by luciferase assay in rat neonatal CFs. We constructed replication-deficient adenoviruses bearing the coding region of human ER alpha, ER beta, or the dominant-negative form of ER beta (designated AxCAER alpha, AxCAER beta, and AxCADNER beta, respectively). When CFs were infected with AxCAER alpha or AxCAER beta at multiplicity of infection of 20 or higher, DNA synthesis was decreased by 50% in response to E2 and the effect was abolished by co-infection with AxCADNER beta. Similarly, transcriptional activity of ER in CFs infected with AxCAER alpha or AxCAER beta was markedly enhanced and co-infection with AxCADNER beta abolished the effects. These results suggest that E2 inhibits CF growth and that both ER subtypes mediate the effect comparably and redundantly.

Global Burden of COPD in Japan and Asia

Lancet. Nov, 2003  |  Pubmed ID: 14643136

Depletion of Glutathione S-transferase P1 Induces Apoptosis in Human Lung Fibroblasts

Experimental Lung Research. Oct-Nov, 2003  |  Pubmed ID: 14710442

Glutathione S-transferase P1 (GSTP1) is one of the xenobiotic-metabolizing and antioxidant enzymes, identified in the peripheral lungs. Recently, the authors reported the association between GSTP1 gene polymorphism and susceptibility to chronic obstructive pulmonary disease (COPD), and protective effect of GSTP1 against cigarette smoke in human lung fibroblasts in vitro. In this study, the authors investigated that depletion of GSTP1 by itself could induce cell death, including apoptosis, in human lung fibroblast-derived HFL-1 cells. The level of apoptosis and necrosis was increased significantly with GSTP1 antisense vector transfection. It was also observed that the transfection efficiency and the expression level of the vector were weaker in the transfectant of the antisense vector than in those of the sense and control vectors, which is also thought to indicate that inhibition of GSTP1 expression by the antisense vector alone affects cellular viability. However, there was no difference among these transfectants neither on glutathione (GSH) level nor on c-Jun NH2-terminal kinase (JNK) activation. Therefore, the authors report here that underexpression of GSTP1 appeared to induce apoptosis on lung fibroblasts, which suggests that GSTP1 may have protective effects against apoptosis in the airway cells, though the mechanism of this apoptotic pathway is still to be elucidated.

Reduced Endothelial Vasomotor Function and Enhanced Neointimal Formation After Vascular Injury in a Rat Model of Blood Pressure Lability

Hypertension Research : Official Journal of the Japanese Society of Hypertension. Dec, 2003  |  Pubmed ID: 14717342

Increased short-term blood pressure variability is known to be associated with hypertensive target organ damage. Sinoaortic denervation (SAD) induces a marked increase in blood pressure lability without affecting the average blood pressure level. The aim of this study was to investigate the effects of blood pressure lability on endothelial vasomotor function and neointimal formation after balloon injury in SAD rats. Direct longterm measurement of mean arterial pressure showed no significant difference in the average of mean arterial pressure between the SAD group and sham-operated control group. In contrast, the standard deviation of mean arterial pressure, as an index of blood pressure lability, was 3-fold greater in SAD rats. To study endothelial function, isometric tension of aortic rings was measured 4 weeks after SAD or sham operation. Endothelium-dependent vasorelaxation induced by acetylcholine was significantly reduced in the SAD group (20% reduction at maximum relaxation). Endothelium-independent vasorelaxation induced by sodium nitroprusside was similar in each group. Acetylcholine-induced NO release from aortic rings was significantly reduced in the SAD group. Next, we examined neointimal formation in carotid arteries in SAD and sham-operated rats at 2 weeks after balloon injury. The neointimal-to-medial area ratio in the SAD group was 50% higher than that in the sham-operated group. The percentage of proliferating cell nuclear antigen-positive cells in the intima was significantly higher in the SAD group. These findings suggest that increased blood pressure lability, independently of average blood pressure level, impairs endothelial function by inhibiting NO production, enhances neointimal formation after balloon injury, and may thereby contribute to atherogenesis.

Diffuse Aspiration Bronchiolitis Due to Achalasia

Chest. Jan, 2004  |  Pubmed ID: 14718468

Protein Phosphatase 5 is a Negative Regulator of Estrogen Receptor-mediated Transcription

Molecular Endocrinology (Baltimore, Md.). May, 2004  |  Pubmed ID: 14764652

Estrogen receptors (ERs) are transcription factors that can be modulated by both estrogen-dependent and growth factor-dependent phosphorylation. A yeast two-hybrid screening identified a serine/threonine protein phosphatase (PP5) as an interactant of ERbeta (1-481), a dominant negative ERbeta mutant. Glutathione S-transferase pull-down assays, mammalian two-hybrid assays, and immunoprecipitation studies showed that PP5 directly binds to both ERalpha and ERbeta via its tetratricopeptide repeat domain. E domains of ERalpha and ERbeta, without containing activation domain core regions in transcription activation function 2, were required for the binding to PP5. In ERalpha-positive breast cancer MCF7 cells, estrogen- and epidermal growth factor-dependent phosphorylation of ERalpha on serine residue 118, a major phosphorylation site of the receptor, was reduced by expressing PP5 but enhanced by PP5 antisense oligonucleotide. Estrogen-induced transcriptional activities of both ERalpha and ERbeta and mRNA expression of estrogen-responsive genes, including pS2, c-myc, and cyclin D1, were suppressed by PP5 but enhanced by PP5 antisense oligonucleotide. A truncated PP5 mutant consisting only of its tetratricopeptide repeat domain acted as a dominant negative PP5 that enhanced serine residue 118 phosphorylation of ERalpha and transactivations by ERalpha and ERbeta. We present the first evidence that PP5 functions as an inhibitory regulator of ER phosphorylation and transcriptional activation in vivo.

A Novel Diagnostic Test for the Risk of Aspiration Pneumonia in the Elderly

Chest. Feb, 2004  |  Pubmed ID: 14769774

[TGF-beta]

Nihon Rinsho. Japanese Journal of Clinical Medicine. Feb, 2004  |  Pubmed ID: 15035099

[Tumor Necrosis Factor Receptor(TNFR) Gene Polymorphism]

Nihon Rinsho. Japanese Journal of Clinical Medicine. Feb, 2004  |  Pubmed ID: 15035120

Increased Plasma Interleukin-6 is Associated with the Pathogenesis of Obstructive Sleep Apnea Syndrome

Chest. May, 2004  |  Pubmed ID: 15136420

Platelet-activating Factor Receptor Develops Airway Hyperresponsiveness Independently of Airway Inflammation in a Murine Asthma Model

Journal of Immunology (Baltimore, Md. : 1950). Jun, 2004  |  Pubmed ID: 15153532

Lipid mediators play an important role in modulating inflammatory responses. Platelet-activating factor (PAF) is a potent proinflammatory phospholipid with eosinophil chemotactic activity in vitro and in vivo. We show in this study that mice deficient in PAF receptor exhibited significantly reduced airway hyperresponsiveness to muscarinic cholinergic stimulation in an asthma model. However, PAF receptor-deficient mice developed an eosinophilic inflammatory response at a comparable level to that of wild-type mice. These results indicate an important role for PAF receptor, downstream of the eosinophilic inflammatory cascade, in regulating airway responsiveness after sensitization and aeroallergen challenge.

14-3-3sigma is Down-regulated in Human Prostate Cancer

Biochemical and Biophysical Research Communications. Jul, 2004  |  Pubmed ID: 15184053

The 14-3-3sigma is a negative regulator of the cell cycle, which is induced by p53 in response to DNA damage. It has been characterized as an epithelium-specific marker and down-regulation of the protein has been shown in breast cancers, suggesting its tumor-suppressive activity in epithelial cells. Here we demonstrate that 14-3-3sigma protein is down-regulated in human prostate cancer cell lines, LNCaP, PC3, and DU145 compared with normal prostate epithelial cells. Immunohistochemical analysis of primary prostate cells shows that the expression of 14-3-3sigma protein is epithelial cell-specific. Among prostate pathological specimens, > 95% of benign hyperplasia samples show significant and diffuse immunostaining of 14-3-3sigma in the cytoplasm whereas < 20% of carcinoma samples show positive staining. In terms of mechanisms for the down-regulation of 14-3-3sigma in prostate cancer cells, hypermethylation of the gene promoter plays a causal role in LNCaP cells as 14-3-3sigma mRNA level was elevated by 5-aza-2'-deoxycytidine demethylating treatment. Intriguingly, the proteasome-mediated proteolysis is responsible for 14-3-3sigma reduction in DU145 and PC3 cells, as 14-3-3sigma protein expression was increased by treatment with a proteasome inhibitor MG132. Furthermore, tumor necrosis factor-related apoptosis-inducing ligand enhances 14-3-3sigma gene and protein expression in DU145 and PC3 cells. These data suggest that 14-3-3sigma expression is down-regulated during the neoplastic transition of prostate epithelial cells.

Caveolin-1, Id3a and Two LIM Protein Genes Are Upregulated by Estrogen in Vascular Smooth Muscle Cells

Life Sciences. Jul, 2004  |  Pubmed ID: 15219810

Estrogen has diverse effects on the vasculature, such as vasodilation, endothelial growth and inhibition of vascular smooth muscle cell (VSMC) proliferation and migration. However, little is known about the genes that are regulated by estrogen in the vascular wall. Wistar rats were ovariectomized or sham-operated (Sham group), and 2 weeks after the operation, were subjected to subcutaneous implantation of placebo pellets (OVX + V group) or estradiol pellets (OVX + E group). Endothelium-denuded aortic tissue was examined 2 weeks after implantation. By applying high-density oligonucleotide microarray analysis, the expression of approximately 7000 genes was analyzed. Among the genes with different expression levels between the OVX + E group and the OVX + V group, those that have been reported to be expressed in the vasculature or muscle tissue, were chosen. Finally, four genes, caveolin-1, two LIM proteins (enigma and SmLIM) and Id3a, were identified. Microarray as well as real-time polymerase chain reaction showed that the expression levels of these genes were significantly higher in the OVX + E group than in the OVX + V group. To clarify whether estrogen directly upregulates these genes in the vascular wall, Northern blot analysis was performed using cultured rat VSMC. Addition of 100 nmol/L estradiol for 24 hours increased the mRNA levels of all four genes. Although the precise mechanism remains unclear, regulation of these genes by estrogen might contribute to its effect on VSMC.

Association of a Single-nucleotide Polymorphism in Low-density Lipoprotein Receptor-related Protein 5 Gene with Bone Mineral Density

Journal of Bone and Mineral Metabolism. 2004  |  Pubmed ID: 15221492

Low-density lipoprotein receptor-related protein 5 (LRP5) is an important regulator of osteoblast growth and differentiation, affecting peak bone mass in vertebrates. Here, we analyzed whether the LRP5 gene was involved in the etiology of postmenopausal osteoporosis, using association analysis between bone mineral density (BMD) and an LRP5 gene single-nucleotide polymorphism (SNP). Association of an SNP in the LRP5 gene at IVS17-1677C > A (intron 17) with BMD was examined in 308 postmenopausal Japanese women (65.2 +/- 9.6 years; mean +/- SD). The subjects bearing at least one variant A allele (CA + AA; n = 142) had significantly lower Z scores for total body and lumbar BMD than the subjects with no A allele (CC; n = 166) (total body, 0.08 +/- 1.09 versus 0.50 +/- 1.03; P = 0.0022; lumbar spine, -0.42 +/- 1.43 versus -0.02 +/- 1.42; P = 0.013). These findings suggest that the LRP5 gene is a candidate for the genetic determinants of BMD in postmenopausal women, and this SNP could be useful as a genetic marker for predicting the risk of osteoporosis.

Inhibitory Effect of Low-dose Estrogen on Neointimal Formation After Balloon Injury of Rat Carotid Artery

European Journal of Pharmacology. Oct, 2004  |  Pubmed ID: 15476753

The current regimens of hormone replacement therapy for postmenopausal women, estrogen combined with progestogen, have failed to show beneficial effects for the prevention of atherosclerotic disease. Although the relatively higher dose of estrogen contained in those regimens exerted adverse effects, there are few data examining a lower dose of estrogen in an atherosclerosis model. Therefore, we investigated experimentally whether lower doses of estrogen could inhibit neointimal formation after balloon injury of the rat carotid artery. Ten-week-old Wistar rats were subjected to ovariectomy or sham-operation (n=7). Four days after ovariectomy, rats were implanted with an osmotic mini-pump containing 17-beta estradiol (0.2, 1, 2, 10 and 20 microg/kg/day; n=6, 4, 8, 6 and 5, respectively) or placebo (n=10). After 3 days of hormone therapy, balloon injury was performed in the left common carotid artery. Neointimal formation was histologically evaluated 2 weeks after injury. Cross-sectional intimal area and the ratio of intimal area to medial area were dose-dependently reduced by estrogen replacement compared with those in ovariectomized rats without estrogen replacement. The effects of estrogen replacement were identical to those of an angiotensin II type 1 receptor blocker, candesartan. Interestingly, the effect was significant even in rats receiving lower doses of estrogen, in which plasma estradiol concentrations were not increased and the hyperplastic response of the uterus was minimal. These results suggest the efficacy of low-dose estrogen therapy for the protection of atherosclerosis.

Analysis of Estrogen Receptor Alpha Signaling Complex at the Plasma Membrane

FEBS Letters. Nov, 2004  |  Pubmed ID: 15556606

There is accumulating evidence that the estrogen receptor (ER) can transduce specific signals at the plasma membrane. We tried to clarify the biological function of ER as a signaling molecule by identifying proteins that interact with the membrane-localized ER. The activation function 1 and 2 (AF-1 and AF-2) domains of ERalpha with or without the membrane-targeting sequence were stably expressed in the breast cancer cell line, MCF-7. The level of tyrosine phosphorylation of AF-2 was significantly elevated by the membrane localization. By mass-spectrometry analysis, alpha- and beta-tubulins and heat shock protein 70 were identified as the AF-1-associated proteins. Of these, tubulins are associated only with membrane-targeted AF-1.

[Right or Wrong of the Hormone Replacement Therapy Involving Osteoporosis]

Clinical Calcium. Nov, 2004  |  Pubmed ID: 15577164

Hormone Replacement Therapy (HRT) is replacement of depleted endogenous estrogen for postmenopausal women. Usually progestin is used in combination to avoid endometrial proliferation. As for bone metabolism, estrogens exert bone protective effect through inhibition of bone absorption. HRT has been shown to improve bone mineral density and to lower the risk of osteoporotic bone fracture. However, recent clinical studies proved that HRT not only raise the risk of breast cancer, but also increase the incidence of atherosclerotic cardiovascular diseases. Other than the treatment of postmenopausal vasomotor symptoms, the benefit of HRT is thought to be hard to outweigh its risk. To resolve this problem, low dose HRT and SERM (Selective Estrogen Receptor Modulator) regimens are under investigation. The evidences of androgen replacement for aged men are not accumulated enough to verify its effects and long term safety.

[Necessity and Role of Geriatric Health Services]

Nihon Naika Gakkai Zasshi. The Journal of the Japanese Society of Internal Medicine. Dec, 2004  |  Pubmed ID: 15658475

Amelioration of Vascular Endothelial Dysfunction in Obstructive Sleep Apnea Syndrome by Nasal Continuous Positive Airway Pressure--possible Involvement of Nitric Oxide and Asymmetric NG, NG-dimethylarginine

Circulation Journal : Official Journal of the Japanese Circulation Society. Feb, 2005  |  Pubmed ID: 15671617

Asymmetric NG,NG-dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide (NO) synthase and its plasma concentration is elevated in patients with cardiovascular risk factors, including hyperlipidemia, hypertension, diabetes, and hyperhomocysteinemia. Obstructive sleep apnea syndrome (OSAS) has been attracting attention as a risk factor for cardiovascular disorders because it often accompanies hypertension, obesity, glucose impairment, and dyslipidemia, all of which are factors in metabolic syndrome and risk factors for cardiovascular disease.

Obstructive Sleep Apnea Causes Systemic Inflammation and Metabolic Syndrome

Chest. Mar, 2005  |  Pubmed ID: 15764798

Apoptosis of Circulating Neutrophils and Alveolar Macrophages in COPD

Chest. Mar, 2005  |  Pubmed ID: 15764803

[The Role of Estrogen in the Regulation of Blood Vessel Function]

Nihon Rinsho. Japanese Journal of Clinical Medicine. Mar, 2005  |  Pubmed ID: 15813131

Association of a Single Nucleotide Polymorphism in the Lipoxygenase ALOX15 5'-flanking Region (-5229G/A) with Bone Mineral Density

Journal of Bone and Mineral Metabolism. 2005  |  Pubmed ID: 15838625

The 12/15-lipoxygenase gene Alox15 has been identified as a susceptibility gene for bone mineral density (BMD) in mice through combined genetic and genomic analyses. Here we studied the association between bone mineral density and an ALOX15 gene single nucleotide polymorphism to assess the potential involvement of the human ALOX15 gene in postmenopausal osteoporosis. Specifically, we examined the association between a single nucleotide polymorphism at -5299G/A in the ALOX15 5'-flanking region with BMD in 319 postmenopausal Japanese women (66.7 +/- 8.9 years, mean +/- SD). We found that subjects bearing at least one variant A allele (GA + AA; n = 273) had significantly lower Z scores for lumbar spine and total body bone mineral density than did subjects with no A allele (GG; n = 46) (lumbar spine, -0.25 +/- 1.34 versus 0.48 +/- 1.70; P = 0.0014; total body, 0.25 +/- 1.01 vs 0.62 +/- 1.11; P = 0.048). These findings suggest that the ALOX15 gene is one of the genetic determinants of BMD in postmenopausal women. Accordingly, this polymorphism could be useful as a genetic marker for predicting the risk of osteoporosis.

Estrogen Receptor-binding Fragment-associated Antigen 9 is a Tumor-promoting and Prognostic Factor for Renal Cell Carcinoma

Cancer Research. May, 2005  |  Pubmed ID: 15867365

The estrogen receptor-binding fragment-associated antigen 9 (EBAG9) has been identified as a primary estrogen-responsive gene in human breast cancer MCF7 cells. A high expression of EBAG9 has been observed in invasive breast cancer and advanced prostate cancer, suggesting a tumor-promoting role of the protein in malignancies. Here we show that intratumoral (i.t.) administration of small interfering RNA against EBAG9 exerted overt regression of tumors following s.c. implantation of murine renal cell carcinoma (RCC) Renca cells. Overexpression of EBAG9 did not promote the proliferation of culture Renca cells; however, the inoculated Renca cells harboring EBAG9 (Renca-EBAG9) in BALB/c mice grew faster and developed larger tumors compared with Renca cells expressing vector alone (Renca-vector). After renal subcapsular implantation, Renca-EBAG9 tumors significantly enlarged compared with Renca-vector tumors in BALB/c mice, whereas both Renca-EBAG9 and Renca-vector tumors were developed with similar volumes in BALB/c nude mice. No apparent difference was observed in specific cytotoxic T-cell responses against Renca-EBAG9 and Renca-vector cells; nonetheless, the number of infiltrating CD8+ T lymphocytes was decreased in Renca-EBAG9 subcapsular tumors. Furthermore, immunohistochemical study of EBAG9 in 78 human RCC specimens showed that intense and diffuse cytoplasmic immunostaining was observed in 87% of the cases and positive EBAG9 immunoreactivity was closely correlated with poor prognosis of the patients. Multivariate analysis revealed that high EBAG9 expression was an independent prognostic predictor for disease-specific survival (P = 0.0485). Our results suggest that EBAG9 is a crucial regulator of tumor progression and a potential prognostic marker for RCC.

Tyrosine Phosphorylation of Paxillin Affects the Metastatic Potential of Human Osteosarcoma

Oncogene. Jul, 2005  |  Pubmed ID: 15870699

To acquire information on signal alteration corresponding to the changes in metastatic potential, we analysed protein tyrosine phosphorylation of low- and high-metastatic human osteosarcoma HuO9 sublines, which were recently established as the first metastatic model of human osteosarcoma. Tyrosine phosphorylation of proteins around 60, 70, and 120-130 kDa was enhanced in high-metastatic sublines. Among these proteins, the protein around 70 kDa, which was most remarkably phosphorylated, was identified as paxillin, a scaffold protein in integrin signaling. Activity of Src family kinase correlated well with metastatic potential, and a Src family kinase inhibitor, PP2, not only abolished tyrosine phosphorylation of paxillin but also impaired the motility of high-metastatic sublines. The expression of paxillin was also elevated in high-metastatic sublines, and knocking down of paxillin expression by RNAi method resulted in attenuated motility of high-metastatic cells. We also demonstrated that the phosphorylated form of paxillin is essential for the migration-promoting effect in human osteosarcoma. These findings suggest that enhanced activity of Src family kinases and overexpression of paxillin synergistically contribute to the high metastatic potential of human osteosarcoma through the hyperphosphorylation of paxillin.

Serum Lipid Survey and Its Recent Trend in the General Japanese Population in 2000

Journal of Atherosclerosis and Thrombosis. 2005  |  Pubmed ID: 15942120

To determine the recent serum lipid levels and other serum variables in the general Japanese population and trends in their changes over the past 40 years, a nationwide survey of serum lipid levels was conducted in 36 institutes from various districts around Japan in 2000. The total number of subjects was 12,839, aged 4 through 99 years. The mean total cholesterol level was 201 mg/dl; 202 mg/dl in men and 200 mg/dl in women. The mean HDL-cholesterol level was 59 mg/dl; 55 mg/dl in men and 65 mg/dl in women. The mean LDL-cholesterol level was 118 mg/dl; 121 mg/dl in men and 115 mg/dl in women. The mean triglyceride level was 118 mg/dl; 136 mg/dl in men and 92 mg/dl in women. The total cholesterol level slightly increased by 5 mg/dl in 10 years. Although the triglyceride level in women did not change, the triglyceride level in men increased over 10 years, especially in the 30s through 70s age bracket, indicating a possible increase in metabolic syndromes in the future. The present results will become the standard serum lipid level data for the Japanese people, and succeeding 10-year surveys will clarify the trends of lipid levels in this country.

[Epidemiology and Prevention of Elderly Hypertension]

Nihon Rinsho. Japanese Journal of Clinical Medicine. Jun, 2005  |  Pubmed ID: 15948373

Our understandings about hypertension has increased as results of epidemiological programs issuing about preventions of cardiovascular disease, which started mostly in the latter half of 20th century and now it is known as the one of the most influencing risk factors of cardiovascular and cerebrovascular disease in the developed countries. We were able to get plenty information about the pathophysiology of hypertension and several randomized controlled trials were committed according to these information. Here we will discuss about the epidemiology of elderly hypertension.

Impact of Blood Pressure Variability on Cardiovascular Events in Elderly Patients with Hypertension

Hypertension Research : Official Journal of the Japanese Society of Hypertension. Jan, 2005  |  Pubmed ID: 15969248

Blood pressure variability is one of the characteristic features of hypertension in the elderly. However, its clinical significance remains to be determined. We therefore examined the impact of blood pressure variability on the development of cardiovascular events in elderly hypertensive patients. A total of 106 consecutive hypertensive patients aged more than 60 years old (mean age, 73.9 +/- 8.1 years old; male, 54%), all of whom underwent 24-h ambulatory blood pressure monitoring, were followed up (median, 34 months; range, 3-60 months). During the follow-up period, 39 cardiovascular events were observed, including 14 cases of cerebral infarction and 7 cases of acute myocardial infarction. The coefficient of variation (CV) of 24-h systolic blood pressure (SBP) values was used as an index of blood pressure variability. The patients showed a mean CV value of 10.6%, and were divided into two groups according to this mean value as a cut-off point: a high CV group (n = 46) and a low CV group (n = 60). Although baseline clinical characteristics were similar in the two groups, Kaplan-Meier plots for event-free survival revealed that the rate of cardiovascular events was significantly higher in high CV group than in low CV group (p < 0.05). Cox's proportional hazards analysis showed that increased blood pressure variability (a high CV value of 24-h SBP) was an independent predictive variable for cardiovascular events. The CV value of daytime SBP and the SD value of both 24-h SBP and daytime SBP also had positive correlations with the onset of cardiovascular events. These results suggest that increased blood pressure variability may be an independent risk factor for cardiovascular events in elderly hypertensive patients.

VEGF-A and FGF-2 Synergistically Promote Neoangiogenesis Through Enhancement of Endogenous PDGF-B-PDGFRbeta Signaling

Journal of Cell Science. Aug, 2005  |  Pubmed ID: 16105884

Combined stimulation with VEGF-A, FGF-2, or PDGF-BB has emerged as a potent strategy for therapeutic angiogenesis, although the mechanisms underlying the synergism of these factors are not well understood. In the present study, we investigated the mechanism of synergism between VEGF-A and FGF-2 by using Matrigel plug assay in vivo and embryonic stem cell (ESC)-derived VEGF receptor 2 (VEGFR2)-positive cells in vitro. Experiments in vitro revealed that, in addition to having direct mitogenic effects, these molecules enhance intercellular PDGF-B signaling in a cell-type specific manner: VEGF-A enhances endothelial PDGF-B expression, whereas FGF-2 enhances mural PDGF receptor beta (PDGFRbeta) expression. Co-stimulation with VEGF-A and FGF-2 caused significant mural cell recruitment in vitro and formation of functional neovasculature in vivo, compared with single-agent stimulation. These effects were abrogated not only by anti-PDGFRbeta neutralizing antibody, but also by exogenous PDGF-BB, which could overwhelm the endogenous PDGF-BB distribution. These findings indicated the importance of preservation of the periendothelial PDGF-BB gradient. Thus, we demonstrated that the directional enhancement of endogenous PDGF-B-PDGFRbeta signaling is indispensable for the synergistic effect of VEGF-A and FGF-2 on neoangiogenesis in adults. The findings provide insights into the mechanisms underlying the effects of co-stimulation by growth factors, which could lead to rational design of therapeutic angiogenic strategies.

Hange-koboku-to, a Kampo Medicine, Modulates Cerebral Levels of 5-HT (5-hydroxytryptamine), NA (noradrenaline) and DA (dopamine) in Mice

Phytotherapy Research : PTR. Jun, 2005  |  Pubmed ID: 16114091

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.

[Malignant Lymphoma Manifested by Fever of Unexplained Origin and Pure Red Cell Aplasia in an Elderly Patient]

Nihon Ronen Igakkai Zasshi. Japanese Journal of Geriatrics. Jul, 2005  |  Pubmed ID: 16117486

A 76-year-old woman was admitted to the University of Tokyo Hospital in June 2002 because of fever of unexplained origin. She had suffered a high grade fever (above 39 degrees C) for 2 weeks. Initial evaluation revealed elevated CRP and pancytopenia. Bone marrow aspiration (BMA) was performed, and a diagnosis of pure red cell aplasia (PRCA) was made. One month later, she complained right hypochondrial pain, and aspiration from her enlarged gall bladder was performed. Her fever and PRCA ameliorated, and she was discharged in August, 2002. In April 2003, she was readmitted to our hospital because of the recurrence of high grade fever, elevation of CRP, and pancytopenia. BMA was performed and revealed diffuse large B cell lymphoma. In the case of extranodal lymphoma which only presents pyrexia, differentiation with other diseases is very difficult especially in the elderly. It is necessary to bear in mind the possibility that a hematological malignancy, especially malignant lymphoma, can be latent in elderly patient with fever of unknown origin.

Estrogen-responsive Finger Protein As a New Potential Biomarker for Breast Cancer

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Sep, 2005  |  Pubmed ID: 16144914

Estrogen-responsive finger protein (Efp) is a member of RING finger-B box-Coiled Coil family and is also a downstream target of estrogen receptor alpha. Previously, Efp was shown to mediate estrogen-induced cell growth, which suggests possible involvement in the development of human breast carcinomas. In this study, we examined expression of Efp in breast carcinoma tissues and correlated these findings with various clinicopathologic variables.

Polymorphisms in Four Genes Related to Triglyceride and HDL-cholesterol Levels in the General Japanese Population in 2000

Journal of Atherosclerosis and Thrombosis. 2005  |  Pubmed ID: 16205020

We studied the association of six common polymorphisms of four genes related to lipid metabolism with serum lipid levels. We selected single-nucleotide polymorphisms (SNPs) in the genes for cholesteryl ester transfer protein (CETP), lipoprotein lipase (LPL), hepatic lipase (LIPC), and apolipoprotein CIII (APOC3), and studied 2267 individuals randomly selected from the participants of Serum Lipid Survey 2000. There was a significant association of CETP polymorphism (D442G, Int14 +1 G --> A, and TaqIB), LPL polymorphism (S447X), and LIPC polymorphism (-514 --> CT) with HDL-cholesterol levels. We also found a significant association of LPL polymorphism (S447X) and APOC3 polymorphism (SstI) with triglyceride levels. This is the largest database showing the association of common genetic variants in lipid metabolism with serum lipid levels in the general Japanese population. Further study is necessary to elucidate the role of these gene polymorphisms in cardiovascular events.

Tako-tsubo Left Ventricular Dysfunction Caused by a Fall

Journal of the American Geriatrics Society. Dec, 2005  |  Pubmed ID: 16398918

[Sex Difference of Senescence and Diseases in the Elderly the Growing Importance of Gender-specific Geriatric Medicine]

Nihon Ronen Igakkai Zasshi. Japanese Journal of Geriatrics. Nov, 2005  |  Pubmed ID: 16408497

Diethylstilbestrol Increases the Density of Prolactin Cells in Male Mouse Pituitary by Inducing Proliferation of Prolactin Cells and Transdifferentiation of Gonadotropic Cells

Histochemistry and Cell Biology. Jul, 2006  |  Pubmed ID: 16468032

Diethylstilbestrol (DES) has been implicated in mammalian abnormalities. We examined the effects of DES on follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL) cells in the pituitaries of male mice treated with various doses of DES for 20 days. DES reduced the density of FSH and LH cells in a dose-dependent manner, but increased that of PRL cells. When the expression of estrogen receptor (ER) alpha and beta was assessed, an induction of ERbeta by DES was found predominantly in PRL cells. However, since these effects were abolished in ERalpha knockout mice, DES appears to act primarily through ERalpha. When the expression of Ki-67 and Pit-1 in PRL cells was examined at various time-points after DES treatment, some PRL cells became Ki-67 positive at 10-15 days, and Pit-1-positive cells were increased at 5-15 days. Furthermore, some FSH and LH cells became Pit-1 positive, and co-localized with PRL at 5-10 days. Our results indicate that DES increases PRL cells by inducing proliferation of PRL cells and transdifferentiation of FSH/LH cells to PRL cells.

Statins Protect Human Aortic Smooth Muscle Cells from Inorganic Phosphate-induced Calcification by Restoring Gas6-Axl Survival Pathway

Circulation Research. Apr, 2006  |  Pubmed ID: 16556867

Vascular calcification is clinically important in the development of cardiovascular disease. It is reported that hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) inhibited vascular calcification in several clinical trials. However, the mechanism is poorly understood. Recently, it has been suggested that apoptosis is one of the important processes regulating vascular smooth muscle cell (VSMC) calcification. In this study, we investigated the effect of statins on VSMC calcification by testing their effect on apoptosis, focusing in particular on regulation of the survival pathway mediated by growth arrest-specific gene 6 (Gas6), a member of the vitamin K-dependent protein family, and its receptor, Axl. In human aortic smooth muscle cells (HASMC), statins significantly inhibited inorganic phosphate (Pi)-induced calcification in a concentration-dependent manner (reduced by 49% at 0.1 micromol/L atorvastatin). The inhibitory effect of statins was mediated by preventing apoptosis, which was increased by Pi in a concentration-dependent manner, and not by inhibiting sodium-dependent phosphate cotransporter (NPC) activity, another mechanism regulating HASMC calcification. Furthermore, the antiapoptotic effect of statins was dependent on restoration of Gas6, whose expression was downregulated by Pi. Restoration of Gas6 mRNA by statins was mediated by mRNA stabilization, and not by an increase in transcriptional activity. Suppression of Gas6 using small interfering RNA and the Axl-extracellular domain abolished the preventive effect of statins on Pi-induced apoptosis and calcification. These data demonstrate that statins protected HASMC from Pi-induced calcification by inhibiting apoptosis via restoration of the Gas6-Axl pathway.

[Atherosclerosis]

Nihon Rinsho. Japanese Journal of Clinical Medicine. Apr, 2006  |  Pubmed ID: 16689338

Pleiotropic Actions of Vitamin K: Protector of Bone Health and Beyond?

Nutrition (Burbank, Los Angeles County, Calif.). Jul-Aug, 2006  |  Pubmed ID: 16815498

Vitamin K is a nutrient that was originally identified as an essential factor for blood coagulation. Recently, vitamin K has emerged as a potential protector against osteoporosis, atherosclerosis, and hepatocarcinoma. Accumulated evidence indicates that subclinical non-hemostatic vitamin K deficiency in extrahepatic tissues, particularly in bone and possibly in vasculature, exists widely in the otherwise healthy adult population. Vitamins K1 and K2 have been shown to exert protective effects against osteoporosis, although it is important that the beneficial effects will be further confirmed by large-scale, randomized, clinical trials. Increasing evidence implicates a role for vitamin K in calcification of arteries and atherogenesis. Moreover, the therapeutic potential of vitamin K2 as an antihepatoma drug has recently been highlighted. Most of the new biological functions of vitamin K in bone, vasculature, and hepatoma cells are considered attributable to promotion of gamma-carboxylation of glutamic acid residues in vitamin K-dependent proteins, which is shared by vitamins K1 and K2. In contrast, vitamin K2-specific, gamma-carboxylation-unrelated functions have also been demonstrated. Thus, biological differences between vitamins K1 and K2 and potential involvement of gamma-carboxylation-independent actions in the new roles of vitamin K remain open issues. Molecular bases of coagulation-unrelated pleiotropic actions of vitamin K and its implications in human health deserve further investigations.

Prevalence of Metabolic Syndrome in the General Japanese Population in 2000

Journal of Atherosclerosis and Thrombosis. Aug, 2006  |  Pubmed ID: 16908953

To determine the prevalence of metabolic syndrome in the Japanese general population, we analyzed data from a nationwide survey conducted in 2000. According to the Japanese new diagnostic criteria for metabolic syndrome in 2005, we analyzed 3,264 people aged from 20 to 79 (men, 1,917; women, 1,347) from the total participants. The incidence of metabolic syndrome was 7.8%. Men had a higher incidence (12.1%) than women (1.7%). Most of the women satisfying the criteria were 50 years old or over, while the incidence in men started to rise from their 30s. When we applied the criteria of Adult Treatment Panel III, the incidence was about 3-fold higher. In this population visceral obesity was associated with metabolic abnormalities, such as higher LDL-cholesterol, triglyceride, glucose, and blood pressure and lower HDL-cholesterol. Thus we determined the incidence of metabolic syndrome and each metabolic abnormality in the Japanese general population in 2000 and found an association of visceral obesity with metabolic abnormalities. Intervention to reduce the incidence of metabolic syndrome in Japan is necessary to reduce the risk of cardiovascular disease.

Reference Values for 6-min Walk Distance in Asian Adults May Not Be Different from That of Caucasian Adults

Respirology (Carlton, Vic.). Sep, 2006  |  Pubmed ID: 16916347

Identification of Novel Steroid Target Genes Through the Combination of Bioinformatics and Functional Analysis of Hormone Response Elements

Biochemical and Biophysical Research Communications. Jan, 2006  |  Pubmed ID: 16289377

Steroid hormone receptors including androgen receptor (AR), glucocorticoid receptor (GR), progesterone receptor (PR), and mineralocorticoid receptor (MR) recognize and bind to identical consensus hormone response elements (HREs), which consist of two hexameric half-sites (5'-AGAACA-3') arranged as inverted repeats with a 3-bp spacer. Although only a few near-consensus HRE sequences have been identified in the transcriptional regulatory regions of known steroid target genes, it has been unclear whether the exact consensus sequences function as bona fide HREs in vivo. A genome-wide in silico screening of palindromic HREs identified 565 exact consensus sequences in human genome (NCBI 35 assembly). In this study, of 565 exact consensus elements, functional in vivo receptor binding was evaluated regarding 26 sequences located within 10 kb upstream to the 5' end of annotated genes through chromatin immunoprecipitation (ChIP) assay using cells endogenously expressing steroid hormone receptors. Hormone responsiveness of proximal gene expression was examined through quantitative RT-PCR. As far as performing ChIP assay for AR, GR, and PR, 14 of 26 elements significantly recruited at least one of the receptors by hormone treatment (>2-fold enrichment versus vehicle). In terms of gene expression in the vicinity of the above 14 functional perfect HREs, four genes were upregulated by >2-fold with hormone treatment. The present data suggest that the combination of bioinformatics analysis and quantitative experimental evaluation is useful to identify novel functional HREs that may contribute to the transcriptional regulation of steroid target genes.

[An Elderly Case with Nontuberculous Mycobacteria Acompanied by Unilateral Massive Pleural Effusion Following the Video-assisted Thoracic Surgery (VATS) for Lung Cancer]

Nihon Ronen Igakkai Zasshi. Japanese Journal of Geriatrics. Sep, 2006  |  Pubmed ID: 17073297

We report an elderly case with nontuberculous mycobacteria (NTM). Four years after left lung upper lobectomy due to lung cancer by the video-assisted thoracic surgery (VATS), an 81 year-old patient complained of general fatigue and appetite loss. Although he did not exhibit fever or respiratory tract symptoms, a Chest X ray film revealed unilateral massive pleural effusion in the left lung. NTM (Runyon classification type II) was grown in the sputum culture. Neither mycobacterium tuberculosis DNA nor M. avium-intracellulare complex DNA was detected by polymerase chain reaction. The pleural effusion adenosine deaminase (ADA) activity was 127.6U/l. NTM was considered as the most probable diagnosis. After admission his condition and appetite improved. Chest computed tomography (CT) scan showed reduction of left pleural effusion, but another pulmonary nodule lesions were sustained. Although the abnormal findings on chest CT did not totally resolve, we did not prescribe antituberculosis drugs, based on the comprehensive assessment of his NTM disease state. The pathogenesis and diagnosis of HTM in elderly cases was discussed.

Signaling Pathway of Nitric Oxide Production Induced by Ginsenoside Rb1 in Human Aortic Endothelial Cells: a Possible Involvement of Androgen Receptor

Biochemical and Biophysical Research Communications. Feb, 2007  |  Pubmed ID: 17196933

Ginsenosides have been shown to stimulate nitric oxide (NO) production in aortic endothelial cells. However, the signaling pathways involved have not been well studied in human aortic endothelial cells. The present study was designed to examine whether purified ginsenoside Rb1, a major active component of ginseng could actually induce NO production and to clarify the signaling pathway in human aortic endothelial cells. NO production was rapidly increased by Rb1. The rapid increase in NO production was abrogated by treatment with nitric oxide synthetase inhibitor, L-NAME. Rb1 stimulated rapid phosphorylation of Akt (Ser473), ERK1/2 (Thr202/Thr204) and eNOS (Ser1177). Rapid phosphorylation of eNOS (Ser1177) was prevented by SH-5, an Akt inhibitor or wortmannin, PI3-kinase inhibitor and partially attenuated by PD98059, an upstream inhibitor for ERK1/2. Interestingly, NO production and eNOS phosphorylation at Ser1177 by Rb1 were abolished by androgen receptor antagonist, nilutamide. The results suggest that PI3kinase/Akt and MEK/ERK pathways and androgen receptor are involved in the regulation of acute eNOS activation by Rb1 in human aortic endothelial cells.

Gas6/Axl-PI3K/Akt Pathway Plays a Central Role in the Effect of Statins on Inorganic Phosphate-induced Calcification of Vascular Smooth Muscle Cells

European Journal of Pharmacology. Feb, 2007  |  Pubmed ID: 17196959

Apoptosis is essential for the initiation and progression of vascular calcification. Recently, we showed that 3-hydroxy-3-methylglutaryl (HMG) CoA reductase inhibitors (statins) have a protective effect against vascular smooth muscle cell calcification by inhibiting apoptosis, where growth arrest-specific gene 6 (Gas6) plays a pivotal role. In the present study, we clarified the downstream targets of Gas6-mediated survival signaling in inorganic phosphate (Pi)-induced apoptosis and examined the effect of statins. We found that fluvastatin and pravastatin significantly inhibited Pi-induced apoptosis and calcification in a concentration-dependent manner in human aortic smooth muscle cells (HASMC), as was found with atorvastatin previously. Gas6 and its receptor, Axl, expression were downregulated in the presence of Pi, and recombinant human Gas6 (rhGas6) significantly inhibited apoptosis and calcification in a concentration-dependent manner. During apoptosis, Pi suppressed Akt phosphorylation, which was reversed by rhGas6. Wortmannin, a specific phosphatidylinositol 3-OH kinase (PI3K) inhibitor, abolished the increase in Akt phosphorylation by rhGas6 and eliminated the inhibitory effect of rhGas6 on both Pi-induced apoptosis and calcification, suggesting that PI3K-Akt is a downstream signal of the Gas6-mediated survival pathway. Pi reduced phosphorylation of Bcl2 and Bad, and activated caspase 3, all of which were reversed by rhGas6. The inhibitory effect of statins on Pi-induced apoptosis was accompanied by restoration of the Gas6-mediated survival signal pathway: upregulation of Gas6 and Axl expression, increased phosphorylation of Akt and Bcl2, and inhibition of Bad and caspase 3 activation. These findings indicate that the Gas6-mediated survival pathway is the target of statins' effect to prevent vascular calcification.

Q89R Polymorphism in the LDL Receptor-related Protein 5 Gene is Associated with Spinal Osteoarthritis in Postmenopausal Japanese Women

Spine. Jan, 2007  |  Pubmed ID: 17202888

An association study investigating the genetic etiology for spinal osteoarthritis.

Beta-defensin Overexpression Induces Progressive Muscle Degeneration in Mice

American Journal of Physiology. Cell Physiology. Jun, 2007  |  Pubmed ID: 17215327

Defensins comprise a family of cationic antimicrobial peptides characterized by conserved cysteine residues. They are produced in various organs including skeletal muscle and are identified as key elements in the host defense system as potent effectors. At the same time, defensins have potential roles in the regulation of inflammation and, furthermore, can exert cytotoxic effects on several mammalian cells. Here, we developed transgenic mice overexpressing mouse beta-defensin-6 to explore the pathophysiological roles of the defensin family as a novel mediator of inflammatory tissue injury. Unexpectedly, the transgenic mice showed short lifespan, poor growth, and progressive myofiber degeneration with functional muscle impairment, predominant centronucleated myofibers, and elevated serum creatine kinase activity, as seen in human muscular dystrophy. Furthermore, some of the transgenic myofibers showed IkappaBalpha accumulation, which would be related to the myofiber apoptosis of limb-girdle muscular dystrophy type 2A. The present findings may unravel a concealed linkage between the innate immune system and the pathophysiology of degenerative diseases.

Increased Expression of Estrogen-related Receptor Alpha (ERRalpha) is a Negative Prognostic Predictor in Human Prostate Cancer

International Journal of Cancer. Journal International Du Cancer. Jun, 2007  |  Pubmed ID: 17294452

The nuclear receptor ERRalpha (estrogen-related receptor alpha) is known to modulate the estrogen-signaling pathway, but the biological significance of ERRalpha in the prostate remains unclear. We investigated the expression of ERRalpha in human prostate tissues and cancer cell lines to evaluate the potential roles of the receptor in prostate cancer (PC). Western blot analysis of ERRalpha was performed in three cell lines of human PC (LNCaP, DU145 and PC-3). The expressions of ERRalpha in cancerous lesions (n = 106) and benign foci (n = 99) of 106 surgically obtained prostate specimens were evaluated by immunohistochemistry. The relationships between the ERRalpha expression and clinicopathological features were evaluated. Western blot analysis using the polyclonal anti-ERRalpha antibody detected a 52 kD band in all three PC cell lines. Positive immunostaining of ERRalpha in the nuclei was found in 73 (69%) cancerous and 47 (47.5%) benign epithelium, whereas the stromal tissues were negative for ERRalpha. The mean immunoreactivity score (IR score) of the cancerous lesions (3.5 +/- 2.6) was significantly higher than that of the benign foci (1.8 +/- 2.1) (p < 0.0001). The IR score of the cancerous lesions significantly correlated with the Gleason score (p = 0.0135). Univariate and multivariate hazard analyses revealed significant correlations between elevated ERRalpha expression and poor cancer-specific survival (p = 0.0141 and 0.0367, respectively). The enhanced expression of ERRalpha might play a role in the development of human PC and serve as a significant prognostic factor for the disease.

Improvement of Cancer-targeting Therapy, Using Nanocarriers for Intractable Solid Tumors by Inhibition of TGF-beta Signaling

Proceedings of the National Academy of Sciences of the United States of America. Feb, 2007  |  Pubmed ID: 17307870

Transforming growth factor (TGF)-beta plays a pivotal role in regulation of progression of cancer through effects on tumor microenvironment as well as on cancer cells. TGF-beta inhibitors have recently been shown to prevent the growth and metastasis of certain cancers. However, there may be adverse effects caused by TGF-beta signaling inhibition, including the induction of cancers by the repression of TGF-beta-mediated growth inhibition. Here, we present an application of a short-acting, small-molecule TGF-beta type I receptor (TbetaR-I) inhibitor at a low dose in treating several experimental intractable solid tumors, including pancreatic adenocarcinoma and diffuse-type gastric cancer, characterized by hypovascularity and thick fibrosis in tumor microenvironments. Low-dose TbetaR-I inhibitor altered neither TGF-beta signaling in cancer cells nor the amount of fibrotic components. However, it decreased pericyte coverage of the endothelium without reducing endothelial area specifically in tumor neovasculature and promoted accumulation of macromolecules, including anticancer nanocarriers, in the tumors. Compared with the absence of TbetaR-I inhibitor, anticancer nanocarriers exhibited potent growth-inhibitory effects on these cancers in the presence of TbetaR-I inhibitor. The use of TbetaR-I inhibitor combined with nanocarriers may thus be of significant clinical and practical importance in treating intractable solid cancers.

Adrenomedullin Insufficiency Increases Allergen-induced Airway Hyperresponsiveness in Mice

Journal of Applied Physiology (Bethesda, Md. : 1985). Jun, 2007  |  Pubmed ID: 17332272

Adrenomedullin (ADM), a newly identified vasodilating peptide, is reported to be expressed in lungs and have a bronchodilating effect. We hypothesized whether ADM could be involved in the pathogenesis of bronchial asthma. We examined the role of ADM in airway responsiveness using heterozygous ADM-deficient mice (AM+/-) and their littermate control (AM+/+). Here, we show that airway responsiveness is enhanced in ADM mutant mice after sensitization and challenge with ovalbumin (OVA). The immunoreactive ADM level in the lung tissue after methacholine challenge was significantly greater in the wild-type mice than that in the mutant. However, the impairment of ADM gene function did not affect immunoglobulins (OVA-specific IgE and IgG1), T helper 1 and 2 cytokines, and leukotrenes. Thus the conventional mechanism of allergen-induced airway responsiveness is not relevant to this model. Furthermore, morphometric analysis revealed that eosinophilia and airway hypersecretion were similarly found in both the OVA-treated ADM mutant mice and the OVA-treated wild-type mice. On the other hand, the area of the airway smooth muscle layer of the OVA-treated mutant mice was significantly greater than that of the OVA-treated wild-type mice. These results suggest that ADM gene disruption may be associated with airway smooth muscle hyperplasia as well as enhanced airway hyperresponsiveness. ADM mutant mice might provide novel insights to study the pathophysiological role of ADM in vivo.

Tako-tsubo-like Left Ventricular Dysfunction in a Patient with Chronic Total Occlusion of the Left Anterior Descending Artery

International Journal of Cardiology. Jun, 2007  |  Pubmed ID: 17434632

This report describes a case of tako-tsubo-like left ventricular dysfunction in a patient with chronically occluded left anterior descending artery. A 74-year-od female, experiencing severe pain due to osteoarthritis, presented with chest pain lasting for 6 h. Electrocardiography revealed ST-segment elevation in the anterior and lateral walls. Left ventriculography in the acute phase displayed an akinetic apex and hyperkinetic basal region. Emergent coronary angiography revealed total occlusion of the left anterior descending artery. Although direct coronary angioplasty to the totally occluded left anterior descending artery was unsuccessful, the left ventricular function returned to normal within three weeks after admission. Thallium scintigraphy showed no significant abnormality, and cardiac enzyme elevation showed only a slight increase. In this case, tako-tsubo-like left ventricular dysfunction was considered to occur in the presence of chronically occluded left anterior descending artery.

Cytochrome P450 2B6 is a Growth-inhibitory and Prognostic Factor for Prostate Cancer

The Prostate. Jul, 2007  |  Pubmed ID: 17455229

Cytochrome P450s (CYPs) influence the biological effects of carcinogens, drugs and hormones including testosterones. Among them, Cytochrome P450 2B6 (CYP2B6) plays a critical role in the deactivation of testosterone. In the present study, we examined CYP2B6 expression in human prostate tissues and prostate cancer.

Long-term Oxygen Administration Reduces Plasma Adrenomedullin Levels in Patients with Obstructive Sleep Apnea Syndrome

Sleep Medicine. Dec, 2007  |  Pubmed ID: 17512795

Obstructive sleep apnea syndrome (OSAS) is recognized as one of the risk factors of hypertension and cardiovascular disorders. In the current study, we hypothesized that the hypoxic stress caused by obstructive sleep apnea would increase circulating adrenomedullin (ADM) levels in untreated OSAS patients compared to an age-matched control group. We further hypothesized that oxygen administration treatment may decrease OSAS-induced hypoxic stress and ADM levels.

[Reproducible Efficacy of Tricyclic Antidepressant on Chronic Pain in an Elderly Patient with Osteoporosis]

Nihon Ronen Igakkai Zasshi. Japanese Journal of Geriatrics. Mar, 2007  |  Pubmed ID: 17527030

An 81-year-old woman was admitted due to exacerbation of chronic back pain from a vertebral osteoporosis fracture. The lumbar MRI examination revealed compression fracture of Th12 and L1 bones. Initial treatment with roxoprofen, calcitonin, bupurenorfin, and morphine did not achieve pain reduction in the patient. Because her geriatric depression scale score was low, we next tried to treat the pain using an antidepressant. Although the pain was improved by amitriptyline, the side effects of dry mouth and urinary incontinence were occurred. Milnacipran, a serotonin and norepinephrine reuptake inhibitor (SNRI), was then tried for the treatment of the chronic pain instead of amitriptyline, but the pain was increased. Then, she was given amitriptyline again for treatment of the chronic back pain instead of SNRI. The second-time amitriptyline treatment was effective to reduce the pain, with minimal side-effects. Because chronic pain due to osteoporosis is often difficult to treat in elderly patients, the classic antidepressant, amitriptyline, may help pain control by narcotics and anti-inflammatory agents in some elderly patients.

Association of a Single Nucleotide Polymorphism in the WISP1 Gene with Spinal Osteoarthritis in Postmenopausal Japanese Women

Journal of Bone and Mineral Metabolism. 2007  |  Pubmed ID: 17593496

The Wnt-beta-catenin signaling pathway that regulates bone density is also involved in cartilage development and homeostasis in vivo. Here, we assumed that genetic variation in Wnt-beta-catenin signaling genes can affect the pathogenesis of cartilage related diseases, such as osteoarthritis. Wnt-1-induced secreted protein 1 (WISP1) is a target of the Wnt pathway and directly regulated by beta-catenin. In the present study, we analyzed the association of a single nucleotide polymorphism (SNP) in the WISP1 3'-UTR region with the development of radiographically observable osteoarthritis of the spine. For this purpose, we evaluated the presence of osteophytes, endplate sclerosis, and narrowing of disc spaces in 304 postmenopausal Japanese women. We compared those who carried the G allele (GG or GA, n = 184) with those who did not (AA, n = 120). We found that the subjects without the G allele (AA) were significantly over-represented in the subjects having higher endplate sclerosis score (P = 0.0069; odds ratio, 2.91; 95% confidence interval, 1.34-6.30 by logistic regression analysis). On the other hand, the occurrence of disc narrowing and osteophyte formation did not significantly differ between those with and without at least one G allele. Thus, we suggest that a genetic variation in the WISP1 gene locus is associated with spinal osteoarthritis, in line with the involvement of the Wnt-beta-catenin-regulated gene in bone and cartilage metabolism.

[Risk Factors Associated with the Duration of Hospitalization in Emergency Admitted Patients with Aspiration Pneumonia]

Nihon Kokyūki Gakkai Zasshi = the Journal of the Japanese Respiratory Society. Jul, 2007  |  Pubmed ID: 17682462

We retrospectively analyzed risk factors which affect the duration of hospitalization of patients who were given diagnoses of aspiration pneumonia and admitted on an emergency basis for 24 hours because of acute events in emergency. The research was conducted on 67 hospitalized patients aged 25-99. who were admitted because of aspiration pneumonia from March 2002 to May 2004. We analyzed the relationships between the duration of hospitalization and factors such as age, sex, severity of pneumonia, number of lobes with inflammation and the duration of tracheal intubation. The mean duration of hospitalization was 24.8 days which was approximately 1.6 times as long as that of all diseases in our hospital. Simple regression analysis suggested that the mean duration of hospitalization correlates significantly with age and the duration of hospitalization, while multiple regression analysis indicates that age is the only significant factor related to duration of hospitalization. However, there was no significant correlation between the duration of hospitalization and the severity of pneumonia. These data indicate that the duration of hospitalization is considerably affected by age, but not the treatment of pneumonia itself. Therefore we should pursue not only the appropriate treatment for aspiration pneumonia but also make an effort for early intervention in the support plan for discharge based on the social background of each elderly patient.

Polymorphisms of Apolipoprotein E and Methylenetetrahydrofolate Reductase in the Japanese Population

Journal of Atherosclerosis and Thrombosis. Aug, 2007  |  Pubmed ID: 17704619

The aim of this study is to analyze the effect of apolipoprotein E (apo E) and methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms on serum lipid and homocysteine levels in the general Japanese population.

Primary Role of Functional Ischemia, Quantitative Evidence for the Two-hit Mechanism, and Phosphodiesterase-5 Inhibitor Therapy in Mouse Muscular Dystrophy

PloS One. 2007  |  Pubmed ID: 17726536

Duchenne Muscular Dystrophy (DMD) is characterized by increased muscle damage and an abnormal blood flow after muscle contraction: the state of functional ischemia. Until now, however, the cause-effect relationship between the pathogenesis of DMD and functional ischemia was unclear. We examined (i) whether functional ischemia is necessary to cause contraction-induced myofiber damage and (ii) whether functional ischemia alone is sufficient to induce the damage.

[Evaluation of Megatrials with Antihyperlipidemic Agents in Japan]

Nihon Rinsho. Japanese Journal of Clinical Medicine. Jul, 2007  |  Pubmed ID: 17821901

Sirt1 Modulates Premature Senescence-like Phenotype in Human Endothelial Cells

Journal of Molecular and Cellular Cardiology. Nov, 2007  |  Pubmed ID: 17916362

Yeast Sir2 plays critical roles in gene silencing, stress resistance and longevity. Mammalian Sirt1 NAD(+)-dependent protein deacetylase, the closest homolog of Sir2, regulates cell cycle, cellular senescence, apoptosis and metabolism, by functional interactions with a number of biological molecules such as p53. To investigate a role of Sirt1 in endothelial dysfunction and premature senescence, we examined the effects of Sirt1 inhibition in human umbilical vein endothelial cells (HUVEC). Sirt1 inhibition by sirtinol, which is a 2-hydroxy-1-napthaldehyde derivative, or siRNA for Sirt1-induced premature senescence-like phenotype, as judged by increased senescence-associated beta-galactosidase (SA-beta-gal) activity, sustained growth arrest and enlarged and flattened cell morphology at 10 days after the treatment. Sixty-four percent of sirtinol (60 mumol/L)-treated HUVEC was SA-beta-gal-positive, whereas only 17% of vehicle-treated cells were positive. Sirt1 inhibition by sirtinol or Sirt1 siRNA increased PAI-1 expression and decreased both protein expression and activity of eNOS. Treatment with sirtinol or Sirt1 siRNA increased acetylation of p53, while p53 expression was unaltered. Impaired epidermal growth factor-induced activation of mitogen-activated protein kinases was associated with Sirt1 inhibition-induced senescence-like growth arrest. Conversely, overexpression of Sirt1 prevented hydrogen peroxide-induced SA-beta-gal activity, morphological changes and deranged expression of PAI-1 and eNOS. These results showed that Sirt1 inhibition increased p53 acetylation and induced premature senescence-like phenotype in parallel with increased PAI-1 and decreased eNOS expression. Our data suggest that Sirt1 may exert protective effects against endothelial dysfunction by preventing stress-induced premature senescence and deranged expression of PAI-1 and eNOS.

Effects of Age and Sex on Plasma Adrenomedullin Levels in Patients with Obstructive Sleep Apnea Syndrome

Journal of the American Geriatrics Society. Nov, 2007  |  Pubmed ID: 17979911

Calcitonin Gene-related Peptide Mediates Acid-induced Lung Injury in Mice

Respirology (Carlton, Vic.). Nov, 2007  |  Pubmed ID: 17986107

Acid-induced lung injury from aspiration is one of the most important causes of ARDS. Calcitonin gene-related peptide (CGRP) is a neuropeptide that has various biological actions. The current study investigated whether CGRP might have pathophysiological roles in acid-induced lung injury.

[A 94-year-old Woman with Nontuberculous Mycobacterium Who Developed Small Intestinal Intussusception Associated with a Percutaneous Endoscopic Jejunostomy Tube]

Nihon Ronen Igakkai Zasshi. Japanese Journal of Geriatrics. Sep, 2007  |  Pubmed ID: 18049013

We report a 94-year-old woman, who underwent percutaneous endoscopic Jejunostomy (PEJ) tube feeding for enteral nutrition, developed the intussusception of the small intestine. She suffered from nontuberculous mycobacterium (NTM), and her lung inflammation deteriorated due to aspiration pneumonia and malnutrition. Because of old age, dysphagia, esophageal hiatus hernia, gastro-esophageal reflux and her bedridden condition due to severe osteoporosis, oral nutritional supplementation is nearly impossible. To reduce the aspiration risk, we chose PEJ instead of percutaneous endoscopic gastrostomy (PEG) as the route of tube feeding. Six months after the placement of a PEJ tube, aspiration pneumonia was diagnosed and she was readmitted to our hospital. During hospitalization, she had sudden diarrhea, vomiting, and lower abdominal pain. Abdominal CT scan and radiographs using contrast medium showed small intestinal intussusception related to the PEJ tube. We observed the clinical course without performing surgery, pulling it back towards the stomach and placing an ileus tube, because the small intestine was not completely obstructed. Two months later, although she suffered from aspiration pneumonia once more, she remained in a stable condition without further intervention so that she could move to aother hospital. Recently PEJ has been expected to prevent aspiration pneumonia, but we believe that it can be a risk factor for intussusception. Although the PEJ can be a good parenteral nutrition route for frail elderly with dysphagia, we need to consider possible complications including intussusception.

Small Intestinal Intussusceptions Caused by Percutaneous Endoscopic Jejunostomy Tube Placement

Journal of the American Geriatrics Society. Dec, 2007  |  Pubmed ID: 18081681

A Functional Single Nucleotide Polymorphism in the Vitamin-K-dependent Gamma-glutamyl Carboxylase Gene (Arg325Gln) is Associated with Bone Mineral Density in Elderly Japanese Women

Bone. Feb, 2007  |  Pubmed ID: 17029979

The vitamin-K-dependent gamma-glutamyl carboxylase (GGCX) carboxylates vitamin-K-dependent proteins including bone Gla protein (osteocalcin) and matrix Gla protein, which play important roles in bone metabolism. Therefore, GGCX polymorphism might explain in part individual susceptibility to osteoporosis. In the present study, polymorphisms in the exons of this gene were screened in Japanese elderly women and a non-synonymous single nucleotide polymorphisms (SNP) were found; c.8762 G>A; (Arg325Gln). When the kinetic parameters of GGCX325-Gln and GGCX325-Arg were compared in vitro, Vmax/Km was significantly higher for GGCX325-Gln (944.4+/-9.21 pmol/30 min/mg/mM FLEEL) than for GGCX325-Arg (671.9+10.79 pmol/30 min/mg/mM FLEEL) (p=0.018). Then, association study of this polymorphism with forearm bone mineral density (BMD) of Japanese postmenopausal women (n=500, age 73.6+/-5.74) was conducted. As a result, the body mass index (BMI)-adjusted Z score in the subpopulation older than 75 years (n=207) was higher in those with 325-Gln (0.650+/-0.883, mean+/-SD) than those with 325-Arg/Gln or 325-Arg (0.133+/-0.650) (p=0.0383). This is the first report to demonstrate the different activities of GGCX between the common genotypes and their association with BMD.

[An Elderly Case with Group B Streptococcal Bacteremia, Subcutaneous Abscess and Reactive Polyarthritis]

Nihon Ronen Igakkai Zasshi. Japanese Journal of Geriatrics. Nov, 2007  |  Pubmed ID: 18198461

We report a 77-year-old woman with Group B streptococcal bacteremia, subcutaneous abscess and reactive polyarthritis. Two years previously she suffered from atrial fibrillation and osteoarthritis of the knee. After she was admitted for treatment of the knee joint with hyaluronate sodium, she complained of pain in the left shoulder and both knees. Pyogenic arthritis was suspected and administration of cefazolin was started immediately after blood culture. One set of blood cultures showed Group B streptococcus. Therefore the antibiotic was changed to ampicillin. To investigate the cause of polyarthritis, enhanced CT of the left shoulder and both knees was performed and demonstrated fluid collection with marginal enhancement, suggesting a bacterial abscess. However, findings of arthrocentesis and synovial fluid culture were incompatible with bacterial arthritis. A subcutaneous abscess, which appeared at 5 days after admission to the hospital, was not connected to the synovial fluid, suggesting reactive arthritis was the main cause of her polyarthritis. We performed drainage surgery and one week later, the clinical symptoms and inflammatory findings mostly disappeared. Several microbes are able to cause reactive arthritis, however, cases with Group B streptococcus are very rare. Group B streptococcus infection should be taken into consideration not only in patients with diabetes and cerebrovascular disease but also in elderly patients.

Low Testosterone Level is an Independent Determinant of Endothelial Dysfunction in Men

Hypertension Research : Official Journal of the Japanese Society of Hypertension. Nov, 2007  |  Pubmed ID: 18250551

We investigated whether a low plasma testosterone level is related to endothelial dysfunction in men with coronary risk factors. One hundred and eighty-seven consecutive male outpatients (mean age+/-SD: 47+/-15 years) who underwent measurement of flow-mediated vasodilation (FMD) of the brachial artery using ultrasonography were enrolled. The relationship between plasma hormones and FMD was analyzed. Total and free testosterone and dehydroepiandrosterone-sulfate (DHEA-S) were significantly correlated with %FMD (r=0.261, 0.354 and 0.295, respectively; p<0.001), while estradiol and cortisol were not. %FMD in the highest quartile of free testosterone was 1.7-fold higher than that in the lowest quartile. Multiple regression analysis revealed that total and free testosterone were related to %FMD independent of age, body mass index, hypertension, hyperlipidemia, diabetes mellitus and smoking (beta=0.198 and 0.247, respectively; p<0.01), and were independent of age, body mass index, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, fasting plasma glucose, smoking and nitroglycerin-induced dilation (beta=0.196 and 0.227, respectively; p<0.01). DHEA-S was not significantly related to %FMD in multivariate analysis. In conclusion, a low plasma testosterone level was associated with endothelial dysfunction in men independent of other risk factors, suggesting a protective effect of endogenous testosterone on the endothelium.

Effect of Nasal Continuous Positive Airway Pressure Treatment on Plasma Adrenomedullin Levels in Patients with Obstructive Sleep Apnea Syndrome: Roles of Nocturnal Hypoxia and Oxidant Stress

Hypertension Research : Official Journal of the Japanese Society of Hypertension. Nov, 2007  |  Pubmed ID: 18250556

Obstructive sleep apnea syndrome (OSAS) is recognized as one of the risk factors of hypertension and cardiovascular disorders. In the current study, we hypothesized that the hypoxic stress and oxidative stress caused by obstructive sleep apnea would increase circulating adrenomedullin (ADM) levels in untreated OSAS patients as compared to an age and body mass index (BMI)-matched control group and an age-matched, but normal-BMI control group. We further hypothesized that nasal continuous positive airway pressure (nCPAP) treatment may decrease OSAS-induced hypoxic stress, oxidative stress and ADM levels. To examine these hypotheses, we measured circulating ADM and reactive oxygen species (ROS) from leukocytes before and after nCPAP therapy in OSAS patients. The circulating levels of ADM and amount of ROS in untreated OSAS patients were significantly greater than those in the controls. No differences in ADM levels were found between the increased-BMI controls and normal-BMI controls. We observed that nCPAP treatment decreased sleep apneas, nocturnal oxyhemoglobin desaturation, the circulating ADM, and ROS production by leukocytes in OSAS patients. The ADM levels were associated with the magnitude of oxyhemoglobin desaturation rather than the number of sleep apneas. These observations suggest that nCPAP therapy could reduce OSAS-induced nocturnal hypoxemia, generation of ROS, and ADM in patients with OSAS.

Increase in Oxidative Stress Levels in Elderly Patients with Obstructive Sleep Apnea Syndrome: Effects of Age and Sex

Journal of the American Geriatrics Society. Mar, 2008  |  Pubmed ID: 18315673

[Paroxetine-induced Hyponatremia in an Elderly Man Due to the Syndrome of Inappropriate Secretion of Antidiuretic Hormone]

Nihon Ronen Igakkai Zasshi. Japanese Journal of Geriatrics. Jan, 2008  |  Pubmed ID: 18332578

We report an 82-year old man prescribed paroxetine who had hyponatremia and in whom the syndrome of inappropriate secretion of antidiuretic hormone was diagnosed. He had taken sulpiride for depressed mental status. However, he showed parkinsonism, which was an adverse effect from the treatment of sulpiride. Therefore sulpiride was changed to selective serotonin reuptake inhibitor, paroxetine 10mg daily. His depressed mental status deteriorated after paroxetine treatment started. His depression had not lessened after 12 days, and the dosage was increased to 20mg daily. On the 15th day after starting paroxetine, routine laboratory tests showed that his serum sodium level was 126 mEq/l. We recognized that his confusion and loss of appetite were symptoms of hyponatremia, rather than of worsening depression. Laboratory data revealed hyponatremia, low serum osmolarity (242 mOsm/kg) with a relatively high level of serum antidiuretic hormone, and concentrated urine (439 mOsm/kg). We diagnosed the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), associated with paroxetine. The dosage of paroxetine was reduced gradually and the serum sodium level returned to normal on day 2 after medication ceased completely. Paroxetine produces fewer adverse effects than other types of antidepressants. However, its use can be associated with inappropriate secretion of antidiuretic hormone in the body and may lead to SIADH, which is characterized by hyponatremia, a potentially fatal condition that is typically asymptomatic until it becomes severe. SIADH is more likely in some populations, including the elderly. Serum sodium levels should be monitored closely, especially in elderly patients.

Association of Plasma Dehydroepiandrosterone-sulfate Levels with Endothelial Function in Postmenopausal Women with Coronary Risk Factors

Hypertension Research : Official Journal of the Japanese Society of Hypertension. Jan, 2008  |  Pubmed ID: 18360020

Age-related decline of plasma dehydroepiandrosterone-sulfate (DHEA-S) levels may be associated with the risk of cardiovascular disease in women. We investigated whether plasma DHEA-S levels are related to endothelial function in postmenopausal women with coronary risk factors. One hundred and fifteen postmenopausal women (mean age+/-SD: 57+/-5 years; range: 48-65 years) who underwent measurement of flow-mediated vasodilation (FMD) of the brachial artery using ultrasonography were enrolled. Plasma hormone levels were determined in the morning after a 14-h fast, and the relationship between hormone levels and FMD was analyzed. DHEA-S was significantly correlated with %FMD (r=0.392, p<0.001), while estradiol, total testosterone and cortisol were not. %FMD in the highest quartile of DHEA-S was 1.8-fold higher than that in the lowest quartile (5.3+/-1.3 vs. 2.9+/-2.0 [means+/-SD], p<0.01). Multiple regression analysis revealed that DHEA-S was related to %FMD independent of age, body mass index, hypertension, hyperlipidemia, diabetes mellitus and smoking (beta=0.344, p<0.01), and was itself independent of age, body mass index, systolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, fasting plasma glucose and smoking (beta=0.291, p<0.05). In conclusion, plasma DHEA-S levels were weakly but significantly related to endothelial function in postmenopausal women independent of other coronary risk factors, suggesting a protective effect of DHEA on the endothelium.

Mechanism of Pi-induced Vascular Calcification

Journal of Atherosclerosis and Thrombosis. Apr, 2008  |  Pubmed ID: 18385534

Vascular calcification is clinically important in the development of cardiovascular disease. It has been suggested that apoptosis is one of the processes regulating calcification in vascular smooth muscle cells (VSMC). In this review, we discuss the role of apoptosis in inorganic phosphate (Pi)- induced calcification, focusing on regulation of the survival pathway mediated by growth arrest- specific gene 6 (Gas6). Further, we mention the beneficial effect of statins mediated by inhibition of apoptosis which is accompanied by restoration of the Gas6-mediated survival pathway. These findings indicate that Gas6 is a novel target of statins' effects to prevent vascular calcification.

Association of a Single Nucleotide Polymorphism in the Insulin-like Growth Factor-1 Receptor Gene with Spinal Disc Degeneration in Postmenopausal Japanese Women

Spine. May, 2008  |  Pubmed ID: 18469701

An association study investigating the genetic etiology for spinal disc degeneration.

Raloxifene Analogue LY117018 Suppresses Oxidative Stress-induced Endothelial Cell Apoptosis Through Activation of ERK1/2 Signaling Pathway

European Journal of Pharmacology. Jul, 2008  |  Pubmed ID: 18541231

A selective estrogen receptor modulator, raloxifene, has been shown to reduce cardiovascular events in relatively high-risk postmenopausal women with osteoporosis. However, the mechanisms by which raloxifene exerts a pharmacological effect on cardiovascular organs have not been fully elucidated. The present study was designed to examine whether the raloxifene analogue, 6-hydroxy-2-(p-hydroxyphenyl)-benzo(b) thien-3-yl-p-(2-(pyrrolidinyl)ethoxy phenyl ketone (LY117018), could inhibit apoptosis and to clarify the signaling pathway in vascular endothelial cells. LY117018 significantly inhibited hydrogen peroxide-induced apoptosis in bovine carotid artery endothelial cells. The anti-apoptotic effect of LY117018 was abolished by an estrogen receptor antagonist, 7alpha,7beta-(9[(4,4,5,5,5-Pentafluoropentyl)sulfinyl]nonyl) estra-1,3,5(10)-triene-3,17-diol (ICI 182,780). Mitogen-activated protein kinases (MAPK), including p38, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase1/2 (ERK1/2), and Akt, have been shown to act as apoptotic or anti-apoptotic signals. Phosphorylation of p38, JNK, ERK1/2 and Akt was examined. LY117018 increased ERK1/2 phosphorylation but did not enhance the phosphorylation of p38, JNK, or Akt. The anti-apoptotic effect of LY117018 was prevented by treatment with 2-[2'-amino-3'-methoxyphenyl]-oxanaphthalen-4-one (PD98059), an upstream inhibitor of ERK1/2. LY117018 stimulated an increase in ERK1/2 phosphorylation, which was diminished by ICI 182,780. The activation of ERK/1/2 by LY117018 was not inhibited by the transcription inhibitor, actinomycin D. These results suggest that estrogen receptors and the ERK1/2 signaling pathway are involved in the anti-apoptotic action of LY117018 in vascular endothelial cells.

Antiplatelet Cilostazol, an Inhibitor of Type III Phosphodiesterase, Improves Swallowing Function in Patients with a History of Stroke

Journal of the American Geriatrics Society. Jun, 2008  |  Pubmed ID: 18554369

Cilostazol Inhibits Oxidative Stress-induced Premature Senescence Via Upregulation of Sirt1 in Human Endothelial Cells

Arteriosclerosis, Thrombosis, and Vascular Biology. Sep, 2008  |  Pubmed ID: 18556572

Cilostazol, a selective inhibitor of PDE3, has a protective effect on endothelium after ischemic vascular damage, through production of nitric oxide (NO). The purpose of the present study was to clarify the molecular mechanisms underlying the preventive effect of treatment with cilostazol on oxidative stress-induced premature senescence in human endothelial cells.

FOXP1 is an Androgen-responsive Transcription Factor That Negatively Regulates Androgen Receptor Signaling in Prostate Cancer Cells

Biochemical and Biophysical Research Communications. Sep, 2008  |  Pubmed ID: 18640093

Androgen and androgen receptor (AR) play important roles in the formation and the progression of prostate cancer. AR activates its target genes by recruiting various coregulators and transcriptional factors. Here we show that the FOXP1 forkhead transcription factor is a novel androgen-regulated gene. By sequencing DNA fragments obtained from chromatin immunoprecipitation (ChIP), a bona-fide AR binding site (ARBS) is identified in an intron region of FOXP1 gene. FOXP1 can be induced by androgen in hormone-sensitive prostate cancer LNCaP cells at both mRNA and protein levels. In particular, a smaller FOXP1 variant, FOXP1D, is upregulated in response to androgen. Notably, we demonstrate that FOXP1 directly interacts with AR and negatively regulates AR signaling ligand-dependently, as exemplified by the transcriptional repression of PSA gene regulated by androgen-dependent FOXP1 recruitment on its enhancer region. We show that several other forkhead transcription factors are also androgen-responsive in LNCaP cells. Our study provides a new insight to the function of forkhead transcription factors that modulates AR signaling as an androgen-regulated transcriptional factor, which would contribute to the tumorigenesis of prostate cancer.

[Treatment and Intervention for Sustaining Functional Activities in Community-dwelling Elderly People]

Clinical Calcium. Nov, 2008  |  Pubmed ID: 18974452

In order to sustain functional activities in the elderly, promotion of nursing care and preventive intervention is important in terms of successful aging and healthy longevity. In particular, reduction of falls and fall-related injuries as well as treatments of osteoporosis is necessary for keeping activities of daily living. Fall-prevention programs and interventions including exercise and nutrition are recently prevailing among community-dwelling elderly Japanese people, some of which are revealed to have beneficial effects.

Nocturia in Elderly People with Hypertension--no Influence of Low-dose Thiazide Added to Losartan

Journal of the American Geriatrics Society. Nov, 2008  |  Pubmed ID: 19016956

Airspace Enlargement with Airway Cell Apoptosis in Klotho Mice: a Model of Aging Lung

The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. Dec, 2008  |  Pubmed ID: 19126841

Homozygous mutant klotho (KL(-/-)) mice exhibit various characteristics resembling those of human aging, including emphysema. However, age-related changes of lungs have not been fully elucidated. Here, we investigated the structural, functional, biochemical, and cell kinetic alterations of lungs in KL(-/-) mice at 2-12 weeks of age. Homogeneous airspace enlargement and decreased lung elastic recoil were observed in KL(-/-) mice with aging. The apoptotic cells in airway walls in KL(-/-) mice were approximately 6 times greater than those in wild-type (KL(+/+)) mice at 2 weeks of age. However, lipid peroxidation and elastase activity of lungs were not increased in KL(-/-) mice. Western blotting suggested that protein levels of epidermal growth factor (EGF) and phosphorylated extracellular signal-regulated kinase were decreased in KL(-/-) mice. These data suggest that significantly increased apoptosis of airway cells via inhibition of the EGF-dependent pathway may be involved in the development of the aging lungs in KL(-/-) mice.

Adiponectin Antagonizes Stimulatory Effect of Tumor Necrosis Factor-alpha on Vascular Smooth Muscle Cell Calcification: Regulation of Growth Arrest-specific Gene 6-mediated Survival Pathway by Adenosine 5'-monophosphate-activated Protein Kinase

Endocrinology. Apr, 2008  |  Pubmed ID: 18174285

Adiponectin exhibits diverse protective effects against atherogenesis and antagonizes many effects of TNFalpha. Here, we investigated the effect of adiponectin and TNFalpha on vascular calcification, a critical event in the development and progression of vascular disease. In human aortic smooth muscle cells (HASMC), TNFalpha augmented inorganic phosphate (Pi)-induced calcification, whereas adiponectin significantly suppressed it and abolished the stimulatory effect of TNFalpha in a concentration-dependent manner. Similarly, adiponectin ameliorated the accelerating effect of TNFalpha on Pi-induced apoptosis, the essential process of HASMC calcification. Furthermore, these effects of TNFalpha and adiponectin were associated with AMP-activated protein kinase (AMPK)-dependent growth arrest-specific gene 6 (Gas6) expression and Akt signaling. The AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), induced phosphorylation of AMPK and significantly inhibited Pi-induced calcification in HASMC. Conversely, pharmacological inhibition of AMPK by compound C blocked both AMPK activation and the inhibitory effect of adiponectin on calcification, providing evidence that AMPK plays a regulatory role in vascular calcification. Reporter assay revealed that adiponectin restored Gas6 promoter activity decreased by TNFalpha, and the effect of adiponectin was abrogated by compound C. These results demonstrate that adiponectin antagonizes the stimulatory effect of TNFalpha on vascular calcification by restoration of the AMPK-dependent Gas6-mediated survival pathway.

Estrogen Receptor-binding Fragment-associated Gene 9 Expression and Its Clinical Significance in Human Testicular Cancer

International Journal of Urology : Official Journal of the Japanese Urological Association. Mar, 2009  |  Pubmed ID: 19207611

We previously demonstrated that estrogen receptor-binding fragment-associated gene 9 (EBAG9) is a tumor promoting factor in renal cell carcinoma (Ogushi T, Cancer Res. 2005; 65: 3700). Here, we evaluated EBAG9 expression and its clinical significance in normal and malignant human testicular tissues.

A Selective Estrogen Receptor Modulator Inhibits TNF-alpha-induced Apoptosis by Activating ERK1/2 Signaling Pathway in Vascular Endothelial Cells

Vascular Pharmacology. Jul, 2009  |  Pubmed ID: 19275968

Tumor necrosis factor (TNF-alpha) is a pleiotropic cytokine exerting both inflammatory and cell death activity and is thought to play a role in the pathogenesis of atherosclerosis. The present study was designed to examine whether the raloxifene analogue, LY117018 could inhibit TNF-alpha-induced apoptosis in vascular endothelial cells and to clarify the involved mechanisms. Apoptosis of endothelial cells was determined by DNA fragmentation assay and the activation of caspase-3. LY117018 significantly inhibited TNF-alpha-induced caspase-3 activation and cell DNA fragmentation levels in bovine carotid artery endothelial cells. The inhibitory effect of LY117018 was abolished by an estrogen receptor antagonist ICI 182,780. p38 MAPK, JNK, ERK1/2 and Akt have been shown to act as apoptotic or anti-apoptotic signals. TNF-alpha stimulated the phosphorylation levels of p38 MAPK, JNK, ERK1/2 and Akt in vascular endothelial cells. TNF-alpha-induced apoptosis was significantly decreased by SB203580, a p38 MAPK inhibitor or SP600125, a JNK inhibitor, but was enhanced by an ERK1/2 pathway inhibitor, PD98059 or a PI3-kinase/Akt pathway inhibitor, wortmannin. The anti-apoptotic effect of LY117018 was abrogated only by PD98059 but was not affected by the inhibitors for p38 MAPK, JNK, or Akt. LY117018 stimulated the further increase in phosphorylation of ERK1/2 in TNF-alpha treated endothelial cells but it did not affect phosphorylation levels of p38 MAPK, JNK or Akt. These results suggest that LY 110718 prevents caspase-3 dependent apoptosis induced by TNF-alpha in vascular endothelial cells through activation of the estrogen receptors and the ERK1/2 signaling pathway.

Bone Mass Effects of a Smad6 Gene Polymorphism in Japanese Postmenopausal Women

Journal of Bone and Mineral Metabolism. 2009  |  Pubmed ID: 19277452

Smad6 plays pivotal roles in the negative regulation of transforming growth factor beta (TGFbeta) family signaling as one of the feedback molecules. Here, we analyzed whether the human Smad6 gene is involved in the regulation of bone mass, using association analysis between bone mineral density (BMD) and single-nucleotide polymorphism (SNP) in the Smad6 gene. Association of an SNP at IVS3+26115A>C (intron 3, rs755451) in the Smad6 gene with BMD was examined in 721 Japanese postmenopausal Japanese women (age 65.2 +/- 9.6 years; mean +/- SD). The subjects bearing at least one variant C allele (CC +/- AC; n = 387) had significantly lower Z-scores for total body and lumbar BMD than the subjects with no C allele (AA; n = 334) (total body, 0.23 +/- 0.98 versus 0.50 +/- 1.07; P = 0.0004; lumbar spine, -0.20 +/- 1.38 versus 0.10 +/- 1.48; P = 0.0050). These findings suggest that the Smad6 gene is a candidate for the genetic determinants of BMD in postmenopausal women, and this SNP could be useful as a genetic marker for predicting the risk of osteoporosis.

Association of Estrogen Receptor Alpha and Histone Deacetylase 6 Causes Rapid Deacetylation of Tubulin in Breast Cancer Cells

Cancer Research. Apr, 2009  |  Pubmed ID: 19318565

Estrogen receptor alpha (ERalpha) is a nuclear receptor that functions as a ligand-activated transcription factor. Besides its genomic action in nuclei, ERalpha could exert nongenomic actions at the plasma membrane. To investigate the mechanism underlying the nongenomic action of ERalpha in breast cancer cells, we generated a construct of membrane-targeted ERalpha (memER), an expression vector of ERalpha 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 ERalpha genomic action in MCF-7 cells, the agent showed an agonistic function in the memER-HDAC6 association and tubulin deacetylation. These findings suggest that ERalpha 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 ERalpha-positive breast cancer cells.

TRIM44 Interacts with and Stabilizes Terf, a TRIM Ubiquitin E3 Ligase

Biochemical and Biophysical Research Communications. May, 2009  |  Pubmed ID: 19358823

Terf/TRIM17 is a member of the TRIM family of proteins, which is characterized by the RING finger, B-box, and coiled-coil domains. In the present study, we found that terf interacts with TRIM44. Terf underwent ubiquitination in vitro in the presence of the E2 enzyme UbcH6; this suggests that terf exhibits E3 ubiquitin ligase activity. It was also found that terf was conjugated with polyubiquitin chains and stabilized by the proteasome inhibitor in mammalian cells; this suggested that terf rendered itself susceptible to proteasomal degradation through polyubiquitination. We also found that TRIM44 inhibited ubiquitination of terf, and thus stabilized the protein. The N-terminal region of TRIM44 contains a zinc-finger domain found in ubiquitin hydrolases (ZF UBP) and ubiquitin specific proteases (USPs). Thus, we proposed that TRIM44 may function as a new class of the "USP-like-TRIM" which regulates the activity of associated TRIM proteins.

Expression of Cytochrome P450 3A4 and Its Clinical Significance in Human Prostate Cancer

Urology. Aug, 2009  |  Pubmed ID: 19501880

To evaluate CYP3A4 expression in human prostrate cancer (PCa) tissues. Enzymes of the cytochrome P450 (CYP) family are key inactivators of testosterone in the liver and prostate. We previously reported that CYP2B6 is a growth-inhibitory and prognostic factor in human PCa; however, the status of CYP3A4 in PCa remains unclear.

Sirolimus and Everolimus Induce Endothelial Cellular Senescence Via Sirtuin 1 Down-regulation: Therapeutic Implication of Cilostazol After Drug-eluting Stent Implantation

Journal of the American College of Cardiology. Jun, 2009  |  Pubmed ID: 19520256

The aim of this study was to compare the effects of paclitaxel, sirolimus, and everolimus on the senescent phenotype in human endothelial cells, and to further investigate possible involvement of mammalian sirtuin 1 (Sirt1) down-regulation as a mechanism.

Vitamin K2 Suppresses Proliferation and Motility of Hepatocellular Carcinoma Cells by Activating Steroid and Xenobiotic Receptor

Endocrine Journal. 2009  |  Pubmed ID: 19550077

Vitamin K2, known as a cofactor for gamma-carboxylase, also serves as a ligand of a nuclear receptor, Steroid and Xenobiotic Receptor (SXR). Several clinical trials revealed that vitamin K2 reduced de novo formation and recurrence of hepatocellular carcinoma (HCC). To examine the role of SXR in HCC as a receptor activated by vitamin K2, the cells stably overexpressing SXR were established using a HCC cell line, HuH7. Overexpression of SXR resulted in reduced proliferation and motility of the cells. Further suppression of proliferation and motility was observed when SXR overexpressing clones were treated with vitamin K2. These results suggest that the activation of SXR could contribute to tumor suppressive effects of vitamin K2 on HCC cells.

Validity and Usefulness of Aortic Arch Calcification in Chest X-ray

Journal of Atherosclerosis and Thrombosis. Jun, 2009  |  Pubmed ID: 19556724

Arterial calcification is associated with cardiovascular (CV) disease, to be leading to vessel wall stiffness and causing the management of hemodynamics in the elderly more difficult. Here, we compared the extent of calcification in the aortic arch by reviewing chest X-rays to that in the abdominal aorta as assessed by more detailed examinations. In addition, the validity of the grading and the relationship of this useful grading to clinical risk factors were evaluated.

A1330V Variant of the Low-density Lipoprotein Receptor-related Protein 5 (LRP5) Gene Decreases Wnt Signaling and Affects the Total Body Bone Mineral Density in Japanese Women

Endocrine Journal. 2009  |  Pubmed ID: 19571442

Wnt signaling is an important regulator of bone homeostasis. The Wnt co-receptor, namely, low-density lipoprotein receptor-related protein 5 (LRP5), initiates Wnt signal transduction. Recently, we and several other groups have shown that there is a single nucleotide polymorphism (SNP) located in the exon 18 of the LRP5 gene that leads to an amino acid change (3989C > T, A1330V), and is associated with lumbar spine, femoral neck, and radial bone mineral density (BMD), and incidence of fracture. These data suggest that the A1330V variation in the LRP5 gene may affect the pathogenesis of osteoporosis. However, the functional basis of the A1330V variation remains unclear. In the present study, we analyzed the effect of the A1330V variation on Wnt activity. We also investigated the association between this LRP5 SNP and total body BMD using 739 postmenopausal women. LRP5 with the A1330V SNP were transiently coexpressed with Wnt3a in 293T cells and their activity was evaluated by the TCF-Lef reporter assay. In vitro, the TCF-Lef activity in presence of Wnt3a in cells expressing LRP5 and carrying the T allele (Valine at 1330 (V1330)) of exon 18 was significantly reduced as compared to the wild-type allele. The association between the A1330V SNP and total body BMD were replicated in 739 postmenopausal Japanese women (AA vs. VV; P = 0.0026). These data suggest that the V1330 variant in the LRP5 gene decreases Wnt activity, which in turn decreases the BMD.

Association of a Single Nucleotide Polymorphism in the Constitutive Androstane Receptor Gene with Bone Mineral Density

Geriatrics & Gerontology International. Sep, 2009  |  Pubmed ID: 19702932

Nuclear receptors play an important role in bone metabolism. In bone cells, the vitamin D receptor (VDR) and the steroid and xenobiotic receptor (SXR) are activated by vitamin D and vitamin K2, respectively. VDR and SXR are the NR1I subfamily members of nuclear receptors. We speculated that the constitutive androstane receptor (CAR), the third member of the NR1I subfamily, also could be implicated in the regulation of bone metabolism. Therefore, we analyzed expression of CAR mRNA in osteoblasts and then examined association of a single nucleotide polymorphism (SNP) in the human CAR gene at intron 2 (IVS2-99C>T, rs2502815) with bone mineral density (BMD).

Association of Plasma Sex Hormone Levels with Functional Decline in Elderly Men and Women

Geriatrics & Gerontology International. Sep, 2009  |  Pubmed ID: 19702939

We aimed to determine whether plasma sex hormone levels are associated with activities of daily living (ADL), cognition, depression and vitality in elderly individuals with functional decline.

[A Case of a Primary Effusion Lymphoma in the Elderly]

Nihon Ronen Igakkai Zasshi. Japanese Journal of Geriatrics. 2009  |  Pubmed ID: 20139653

We report a 90-year-old man who was given a diagnosis of pleural effusion lymphoma (PEL) based on the detailed immunochemical and DNA analyses of the pleural effusion. He was bed-ridden and on enteral nutrition due to severe Alzheimer's disease, and also had diabetes mellitus. He was transferred to our hospital with fever and massive pleural effusion. A cytological examination of the pleural effusion revealed class 5 atypical lymphocytes with a high nucleus/cytoplasm ratio. The origin of the atypical cells could not be determined by flow cytometry of the pleural effusion, which only suggested the existence of inflammatory changes. Considering his general physical status, further investigations were not performed. The respiratory failure progressed, and he died on the 45(th) hospital day. At autopsy, no atypical cells were identified in his organs other than in the right thoracic space. We conducted immunochemical staining after making a cell block from the effusion sample. Most of the atypical cells were CD30 positive, with human herpes virus-8 (HHV-8)-associated protein. A PCR analysis of the immunoglobulin heavy chain gene detected monoclonal rearrangement, thus indicating the atypical cells to be involved in the B-cell lineage. These findings led to a final diagnosis of PEL. PEL is a rare type of lymphoma confined to the body cavities without any prominent tumor mass, and its pathogenesis is related to HHV-8 infection. PEL develops mostly in immunocompromised patients, such as those with AIDS. However, it may also occur in elderly patients as well. We should therefore also consider the possibility of PEL in elderly patients presenting with pleural effusion of unknown origin.

EBAG9 is a Tumor-promoting and Prognostic Factor for Bladder Cancer

International Journal of Cancer. Journal International Du Cancer. Feb, 2009  |  Pubmed ID: 19030177

Upregulation of EBAG9 expression has been observed in several malignant tumors such as advanced breast and prostate cancers, indicating that EBAG9 may contribute to tumor proliferation. In the present study, we assess the role of EBAG9 in bladder cancer. We generated human bladder cancer EJ cells stably expressing FLAG-tagged EBAG9 (EJ-EBAG9) or empty vector (EJ-vector), and investigated whether EBAG9 overexpression modulates cell growth and migration in vitro as well as the in vivo tumor formation of EJ transfectants in xenograft models of BALB/c nude mice. EBAG9 overexpression promoted EJ cell migration, while the effect of EBAG9 to cultured cell growth was rather minimal. Tumorigenic experiments in nude mice showed that the size of EJ-EBAG9-derived tumors was significantly larger than EJ-vector-derived tumors. Loss-of-function study for EBAG9 using small interfering RNA (siRNA) in xenografts with parental EJ cells showed that the intra-tumoral injection of EBAG9 siRNA markedly reduced the EJ tumor formation compared with control siRNA. Furthermore, immunohistochemical study for EBAG9 expression was performed in 60 pathological bladder cancer specimens. Intense and diffuse cytoplasmic immunostaining was observed in 45% of the bladder cancer cases. Positive EBAG9 immunoreactivity was closely correlated with poor prognosis of the patients (p = 0.0001) and it was an independent prognostic predictor for disease-specific survival in multivariate analysis (p = 0.003). Our results indicate that EBAG9 would be a crucial regulator of tumor progression and a potential prognostic marker for bladder cancer.

Comparison of the Effects of the Kinase Inhibitors Imatinib, Sorafenib, and Transforming Growth Factor-beta Receptor Inhibitor on Extravasation of Nanoparticles from Neovasculature

Cancer Science. Jan, 2009  |  Pubmed ID: 19037999

There are a number of kinase inhibitors that regulate components of the neovasculature. We previously reported the use of transforming growth factor (TGF)-beta inhibitor on neovasculature in stroma-rich tumor models to increase the intratumoral distribution of nanoparticles. Here, we compared the effects of two other kinase inhibitors, imatinib and sorafenib, with TGF-beta inhibitor (LY364947) on extravasation of a modeled nanoparticle, 2 MDa dextran. We first used a mouse model of neoangiogenesis, the Matrigel plug assay, to compare neovasculature formed inside of and around Matrigel plugs (intraplug and periplug regions, respectively). Intraplug vasculature was more strongly pericyte covered, whereas periplug vasculature was less covered. In this model, TGF-beta inhibitor exhibited the most potent effect on intraplug vasculature in increasing the extravasation of dextran, whereas sorafenib had the strongest effect on periplug vasculature. Although imatinib and TGF-beta inhibitor each reduced pericyte coverage, imatinib also reduced the density of endothelium, resulting in a decrease in overall delivery of nanoparticles. These findings were confirmed in two tumor models, the CT26 colon cancer model and the BxPC3 pancreatic cancer model. The vasculature phenotype in the CT26 model resembled that in the periplug region, whereas the latter resembled that in the intraplug region. Consistent with this, sorafenib most potently enhanced the accumulation of nanoparticles in the CT26 model, whereas TGF-beta inhibitor did in the BxPC3 model. In conclusion, the appropriate strategy for optimization of tumor vasculature for nanoparticles may differ depending on tumor type, and in particular on the degree of pericyte coverage around the vasculature.

Amyloid Precursor Protein is a Primary Androgen Target Gene That Promotes Prostate Cancer Growth

Cancer Research. Jan, 2009  |  Pubmed ID: 19117996

Androgen receptor (AR) is a critical transcription factor that regulates various target genes and contributes to the pathophysiology of prostate cancer hormone dependently. Here, we identify amyloid precursor protein (APP) as a primary androgen target through chromatin immunoprecipitation (ChIP) combined with genome tiling array analysis (ChIP-chip). ChIP-treated DNA were obtained from prostate cancer LNCaP cells with R1881 or vehicle treatment using AR or acetylated histone H3 antibodies. Ligand-dependent AR binding was further enriched by PCR subtraction. Using chromosome 21/22 arrays, we identified APP as one of the androgen-regulated genes with adjacent functional AR binding sites. APP expression is androgen-inducible in LNCaP cells and APP immunoreactivity was correlated with poor prognosis in patients with prostate cancer. Gain-of-function and loss-of-function studies revealed that APP promotes the tumor growth of prostate cancer. The present study reveals a novel APP-mediated pathway responsible for the androgen-dependent growth of prostate cancer. Our findings will indicate that APP could be a potential molecular target for the diagnosis and treatment of prostate cancer.

[Past, Present and Future of Geriatric Education in Japan]

Nihon Ronen Igakkai Zasshi. Japanese Journal of Geriatrics. 2010  |  Pubmed ID: 21301155

Effects of Testosterone in Older Men with Mild-to-moderate Cognitive Impairment

Journal of the American Geriatrics Society. Jul, 2010  |  Pubmed ID: 20672465

Visceral Fat Accumulation and Metabolic Risk Factor Clustering in Older Adults

Journal of the American Geriatrics Society. Sep, 2010  |  Pubmed ID: 20863325

To examine the relationship between visceral fat area (VFA) evaluated using computed tomography (CT) scans and the number of metabolic risk factors in older adults.

Glucocorticoid-induced Gene Tripartite Motif-containing 63 (TRIM63) Promotes Differentiation of Osteoblastic Cells

Endocrine Journal. 2010  |  Pubmed ID: 20173306

Glucocorticoids exert their function by regulating glucocorticoid-responsive genes through interaction with glucocorticoid receptor alpha (GRalpha), a nuclear receptor. Glucocorticoids also affect bone metabolism; this is evidenced by the fact that GRalpha is expressed in several kinds of cells in bone tissue, including osteoblasts, osteocytes, osteoclasts, mononuclear cells in bone marrow, and hypertrophic chondrocytes. Glucocorticoids are known to induce osteoblastic differentiation and bone formation. However, this effect of glucocorticoids on bone tissue is still controversial since long-term use of glucocorticoids results in osteoporosis in vivo. To identify glucocorticoid-regulated genes in human osteoblastic cells, SaOS2 cells were treated with dexamethasone (10(-8) M) for 6 hours, and were then subjected to microarray analysis. Genes such as C/EBPdelta, DUSP1, Per1 and TRIM63 were found to be induced by dexamethasone. The induction of mRNAs of these genes by dexamethasone (10(-8) M, 10(-7) M, and 10(-6) M) was confirmed by quantitative real-time polymerase chain reaction (PCR). TRIM63, also called muscle-specific ring finger protein 1 (MuRF1), was reported to be an E3 ubiquitin ligase expressed mainly in muscular tissue. SaOS2 cells overexpressing exogenous TRIM63 showed increased expression of an osteoblastic differentiation marker gene, alkaline phosphatase, with reduced proliferation. These results suggest that TRIM63 is a candidate for genes mediating the glucocorticoid-induced promotion of osteoblastic differentiation.

Androgen Receptor-dependent Activation of Endothelial Nitric Oxide Synthase in Vascular Endothelial Cells: Role of Phosphatidylinositol 3-kinase/akt Pathway

Endocrinology. Apr, 2010  |  Pubmed ID: 20194727

The mechanisms of testosterone-induced vasodilatation are not fully understood. This study investigated the effect of testosterone on nitric oxide (NO) synthesis and its molecular mechanism using human aortic endothelial cells (HAEC). Testosterone at physiological concentrations (1-100 nm) induced a rapid (15-30 min) increase in NO production, which was associated with phosphorylation and activation of endothelial NO synthase (eNOS). Then, the involvement of the androgen receptor (AR), which is abundantly expressed in HAEC, was examined. The effect of testosterone on eNOS activation and NO production were abolished by pretreatment with an AR antagonist nilutamide and by transfection with AR small interference RNA. In contrast, testosterone-induced eNOS phosphorylation was unchanged by pretreatment with an aromatase inhibitor or by transfection with ERalpha small interference RNA. 5alpha-Dihydrotestosterone, a nonaromatizable androgen, also stimulated eNOS phosphorylation. Next, the signaling cascade that leads to eNOS phosphorylation was explored. Testosterone stimulated rapid phosphorylation of Akt in a time- and dose-dependent manner, with maximal response at 15-60 min. The rapid phosphorylation of eNOS or NO production induced by testosterone was inhibited by Akt inhibitor SH-5 or by phosphatidylinositol (PI) 3-kinase inhibitor wortmannin. Co-immunoprecipitation assays revealed a testosterone-dependent interaction between AR and the p85alpha subunit of PI3-kinase. In conclusion, testosterone rapidly induces NO production via AR-dependent activation of eNOS in HAEC. Activation of PI3-kinase/Akt signaling and the direct interaction of AR with p85alpha are involved, at least in part, in eNOS phosphorylation.

SIRT1/eNOS Axis As a Potential Target Against Vascular Senescence, Dysfunction and Atherosclerosis

Journal of Atherosclerosis and Thrombosis. May, 2010  |  Pubmed ID: 20215708

Sir2 (silent information regulator-2), an NAD(+)-dependent histone deacetylase, is highly conserved in organisms ranging from archaea to humans. Yeast Sir2 is responsible for silencing at repeated DNA sequences in mating-type loci, telomeres and rDNA, and plays critical roles in DNA repair, stress resistance and longevity.The phenomenon of human aging is known to be a critical cardiovascular risk factor. Senescence of endothelial cells has been proposed to be involved in vascular dysfunction and atherogenesis. Recent studies have demonstrated that mammalian Sirt1 NAD(+)-dependent protein deacetylase, the closest homologue of Sir2, regulates vascular angiogenesis, homeostasis and senescence. This review focuses on SIRT1 as a potential therapeutic target against atherosclerosis.

[A Case of Limbic Encephalitis with Small Cell Lung Carcinoma in Which the Cognitive Function Improved and Redeteriorated During Tumor Therapy]

Nihon Ronen Igakkai Zasshi. Japanese Journal of Geriatrics. 2010  |  Pubmed ID: 20339211

We report the findings regarding a 70-year-old man with paraneoplastic limbic encephalitis. He presented with a chief complaint of inability to recall any events. He had been well until one month before admission, and then he abruptly began to show progressive amnesia. At admission, the patient's score on the Revised Hasegawa Dementia Scale (HDS-R) showed a decline to 13/30, thus indicating the existence of severe disorientation and an impaired memory. The brain CT and EEG showed no specific abnormalities and an analysis of cerebrospinal fluid showed only a mild increase in the total protein level. A chest X-ray film revealed a mass in the right hilum, while a histological analysis of the biopsied specimen finally established a diagnosis of small cell lung carcinoma. The FDG-PET and the enhanced brain MRI showed a single small metastatic lesion in the cerebellum. After the 1st course of chemotherapy and whole brain radiation, cognitive function, especially the short-term memory, remarkably improved and the HDS-R score increased to 21/30. However, the tumor again increased in size during the 3(rd) and 4(th) courses of chemotherapy. Interestingly, cognitive function also worsened again and the score of HDS-R declined to 15/30, 20 weeks after the start of chemotherapy. Limbic encephalitis can be associated with malignant tumors, such as small cell lung carcinoma, and some reported cases have shown a cognitive improvement after tumor therapy. In our case, we also observed a reworsening of the cognitive function in association with the acquired chemoresistence.

Association of Low Testosterone with Metabolic Syndrome and Its Components in Middle-aged Japanese Men

Hypertension Research : Official Journal of the Japanese Society of Hypertension. Jun, 2010  |  Pubmed ID: 20339372

Epidemiological studies have shown that low testosterone is associated with metabolic syndrome (MetS) in Caucasian men. We investigated whether testosterone level is related to the prevalence of MetS in middle-aged Japanese men. A cross-sectional survey was conducted in 194 men aged 30-64 years (49+/-9). Blood sampling was performed in the morning after a 12-h fast, and the relationship between plasma hormone and MetS was analyzed. Low total testosterone was associated with MetS according to the Japanese criteria (HRs of 2.02 by quartile of testosterone; 95% CI=1.43-2.87) and the International Diabetes Federation criteria (HRs of 1.68 by quartile of testosterone; 95% CI=1.25-2.25). Age-adjusted regression analyses revealed that testosterone was significantly related to the MetS parameters of obesity (beta=-0.365 and -0.343 for waist circumference and body mass index, respectively), hypertension (beta=-0.278 and -0.157 for systolic and diastolic blood pressure, respectively), dyslipidemia (beta=-0.242 and 0.228 for triglycerides and high-density lipoprotein cholesterol, respectively), insulin resistance (beta=-0.253 and -0.333 for fasting plasma glucose and homeostasis model assessment of insulin resistance, respectively) and adiponectin (beta=0.216). Inclusion of waist circumference into the model largely weakened the association of testosterone with other metabolic risk factors. In contrast, high estradiol was associated with MetS and its parameters, mostly attributing to the positive correlation between estradiol and obesity. Dehydroepiandrosterone sulfate was not associated with MetS or its parameters. These results suggest that low testosterone is associated with MetS and its parameters in middle-aged Japanese men. The association between estradiol and MetS needs further investigation.

Involvement of Androgen Receptor in Nitric Oxide Production Induced by Icariin in Human Umbilical Vein Endothelial Cells

FEBS Letters. Jun, 2010  |  Pubmed ID: 20416296

Icariin, a flavonoid isolated from Epimedii herba, stimulated phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177, Akt (Ser473) and ERK1/2 (Thr202/Tyr204). The icariin-induced eNOS phosphorylation was abolished by an androgen receptor (AR) antagonist, nilutamide in human umbilical vein endothelial cells (HUVECs). Furthermore, it was also reduced in the cells transfected with small interfering RNA in which the expression of AR was broken down. The icariin-induced eNOS phosphorylation was inhibited by wortmannin, a phosphatidylinositol 3-kinase (PI3K) inhibitor and partially attenuated by PD98059, an upstream inhibitor for ERK1/2. These data suggest that icariin stimulates release of NO by AR-dependent activation of eNOS in HUVECs. PI3K/Akt and MAPK-ERK kinase (MEK)/ERK1/2 pathways were involved in the phosphorylation of eNOS by icariin.

Effects of Dehydroepiandrosterone Supplementation on Cognitive Function and Activities of Daily Living in Older Women with Mild to Moderate Cognitive Impairment

Geriatrics & Gerontology International. Oct, 2010  |  Pubmed ID: 20497239

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.

Identification of Non-synonymous Polymorphisms in the WDSOF1 Gene As Novel Susceptibility Markers for Low Bone Mineral Density in Japanese Postmenopausal Women

Bone. Sep, 2010  |  Pubmed ID: 20601284

Genetic factors are important for the development of osteoporosis. During the search for novel markers of single-nucleotide polymorphisms (SNPs) associated with bone mineral density (BMD) by performing a large-scale SNP screen with 251 Japanese postmenopausal women utilizing 50K SNP array, we here focused on the rs1370005 in the WD repeats and SOF1 domain-containing (WDSOF1) gene because we could found common non-synonymous variants in this WDSOF1 gene. The analysis of linkage disequilibrium (LD) in the WDSOF1 gene revealed that rs1370005 and 3 other non-synonymous SNPs (Arg47Ser, Pro108Leu and Ile194Val) lie in a 30-kb region of high LD. Quantitative real-time PCR (qRT-PCR) analysis showed that WDSOF1 mRNA was expressed in mouse primary osteoblasts and osteoclasts, suggesting that WDSOF1 plays some roles in the bone metabolism. We examined the 3 non-synonymous SNPs in WDSOF1 gene in 750 Japanese postmenopausal women. A trend test showed that Arg47Ser, Pro108Leu, and Ile194Val genotypes were significant associated with total body BMD (Arg47Ser; P=0.021, Pro108Leu; P=0.022 and Ile194Val; P=0.009). We also compared Z scores for total body BMD between the subjects bearing at least one minor allele and those lacking the minor allele using unpaired t test. Subjects with the one or two minor alleles had significantly lower Z scores for total body BMD (Arg47Ser; P=0.010, Pro108Leu; P=0.019 and Ile194Val; P=0.003). The present study suggests that these non-synonymous WDSOF1 polymorphisms play a role in the genetic susceptibility to osteoporosis.

Induction of Endothelial Nitric Oxide Synthase, SIRT1, and Catalase by Statins Inhibits Endothelial Senescence Through the Akt Pathway

Arteriosclerosis, Thrombosis, and Vascular Biology. Nov, 2010  |  Pubmed ID: 20705918

Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) have pleiotropic vascular protective effects besides cholesterol lowering. Recently, experimental and clinical studies have indicated that senescence of endothelial cells is involved in endothelial dysfunction and atherogenesis. Therefore, the present study was performed to determine whether statins would reduce endothelial senescence and to clarify the molecular mechanisms underlying the antisenescent property of statins.

Pregnane X Receptor Knockout Mice Display Osteopenia with Reduced Bone Formation and Enhanced Bone Resorption

The Journal of Endocrinology. Dec, 2010  |  Pubmed ID: 20876238

The steroid and xenobiotic receptor (SXR) and its murine ortholog pregnane X receptor (PXR) are nuclear receptors that are expressed mainly in the liver and intestine where they function as xenobiotic sensors. In addition to its role as a xenobiotic sensor, previous studies in our laboratories and elsewhere have identified a role for SXR/PXR as a mediator of bone homeostasis. Here, we report that systemic deletion of PXR results in marked osteopenia with mechanical fragility in female mice as young as 4 months old. Bone mineral density (BMD) of PXR knockout (PXRKO) mice was significantly decreased compared with the BMD of wild-type (WT) mice. Micro-computed tomography analysis of femoral trabecular bones revealed that the three-dimensional bone volume fraction of PXRKO mice was markedly reduced compared with that of WT mice. Histomorphometrical analysis of the trabecular bones in the proximal tibia showed a remarkable reduction in bone mass in PXRKO mice. As for bone turnover of the trabecular bones, bone formation is reduced, whereas bone resorption is enhanced in PXRKO mice. Histomorphometrical analysis of femoral cortical bones revealed a larger cortical area in WT mice than that in PXRKO mice. WT mice had a thicker cortical width than PXRKO mice. Three-point bending test revealed that these morphological phenotypes actually caused mechanical fragility. Lastly, serum levels of phosphate, calcium, and alkaline phosphatase were unchanged in PXRKO mice compared with WT. Consistent with our previous results, we conclude that SXR/PXR promotes bone formation and suppresses bone resorption thus cementing a role for SXR/PXR as a key regulator of bone homeostasis.

[Molecular Mechanism of Vascular Aging: Impact of Vascular Smooth Muscle Cell Calcification Via Cellular Senescence]

Clinical Calcium. Nov, 2010  |  Pubmed ID: 21037384

Atherosclerotic vascular damage associated with aging manifest several features, namely atherosis, sclerosis and calcified change, finally leading to cardiovascular (CV) events. Accumulating recent reports show the importance of cellular senescence in atherosclerogenesis; however, few reports have addressed whether cellular senescence is associated with smooth muscle cells (SMC) calcification. Recent report has demonstrated the association of senescent phenotypic change with osteoblastic trans-differentiation in VSMC. In addition, our new findings show that the possibility of dynamic action of sirtuin, which is well known as a longevity gene, as a negative regulator in the cellular senescence-related vascular calcification. Strategies how to manage senescent phenotypic change in VSMC may provide novel therapeutic opportunities for the prevention of vascular calcification.

[Can Statins Slow the Process of Vascular Calcification? Possibilities of Lipid-lowering Therapy and Pleiotropic Effect by Statin Treatment]

Clinical Calcium. Nov, 2010  |  Pubmed ID: 21037393

Widespread vascular calcification is a ubiquitous feature of aging and is prevalent in association with several atherosclerotic diseases. HMG-CoA reductase inhibitors (statins) have been shown to exert protective potentials against cardiovascular diseases via the lipid-lowering and/or their independent pleiotropic effects. Recently, statins have been extensively investigated as potential therapeutic agents capable of slowing the progression of vascular and valvular calcification. However, accumulating recent evidences show that there are conflicting data regarding beneficial effects of statins on progression of cardiovascular calcification. In particular, regarding coronary artery calcification, which is shown to can predict coronary events, it still remains unclear and controversial. To address the positioning of statins as therapeutic strategy for cardiovascular calcification more clearly, clinical studies by intensive therapy using statins throughout long-term period is indispensable in near future. In addition, future investigation about the detailed molecular mechanisms how statins affect calcification process in vascular cells is necessary.

Association of HTRA1 Promoter Polymorphism with Spinal Disc Degeneration in Japanese Women

Journal of Bone and Mineral Metabolism. Mar, 2010  |  Pubmed ID: 19798546

HTRA1 (high-temperature requirement A1) has been implicated in the modulation of various disease pathologies. HTRA1 expression is upregulated in osteoarthritic joints, suggesting that it may contribute to the development of this debilitating disease. Moreover, recent reports have shown that the rs11200638, a single nucleotide polymorphism (SNP) in the promoter region of the HTRA1 gene, is strongly associated with an increased prevalence of age-related macular degeneration (AMD). In the present study, we examined the expression of the HTRA1 in human primary chondrocytes and an association between the rs11200638 SNP and radiographic features of spinal disc degeneration in 513 postmenopausal Japanese women. HTRA1 mRNA was detected and increased by TGF-beta treatment in human primary chondrocytes. As an association study of rs11200638 SNP in the HTRA1 gene, the subjects without the G allele (AA; n = 89) had a significantly higher spinal disc space narrowing score than the subjects bearing at least one G allele (GG + GA; n = 424) (P = 0.0292). We found that subjects without the G allele (AA) were significantly overrepresented in the subjects having a higher (> or =4) disc space narrowing score (P = 0.013; odds ratio 1.97; 95% confidence interval 1.15-3.37 by logistic regression analysis). A genetic variation at the HTRA1 gene promoter locus is associated with spinal disc degeneration, suggesting an involvement of the HTRA1 gene in osteoarthritis.

Low Testosterone Level As a Predictor of Cardiovascular Events in Japanese Men with Coronary Risk Factors

Atherosclerosis. May, 2010  |  Pubmed ID: 19963216

Recent epidemiological studies have found that testosterone deficiency is associated with higher mortality largely due to cardiovascular (CV) disease in community-dwelling older men. We investigated whether a low plasma testosterone level could predict cardiovascular events in middle-aged Japanese men with coronary risk factors.

Aortic Arch Calcification Detectable on Chest X-ray is a Strong Independent Predictor of Cardiovascular Events Beyond Traditional Risk Factors

Atherosclerosis. May, 2010  |  Pubmed ID: 20006335

Arterial calcification makes the management of hemodynamics more difficult. Some reports have previously shown that simple assessment of aortic calcification using plain radiography is associated with cardiovascular (CV) events; however, these studies simply assessed whether aortic calcification was present or absent only, without considering its extent. Here, we evaluated validity of grading aortic arch calcification (AAC) to predict new CV events.

Androgen Receptor-dependent Transactivation of Growth Arrest-specific Gene 6 Mediates Inhibitory Effects of Testosterone on Vascular Calcification

The Journal of Biological Chemistry. Mar, 2010  |  Pubmed ID: 20048160

Recent epidemiological studies have found that androgen deficiency is associated with a higher incidence of cardiovascular disease in men. However, little is known about the mechanism underlying the cardioprotective effects of androgens. Here we show the inhibitory effects of testosterone on vascular calcification and a critical role of androgen receptor (AR)-dependent transactivation of growth arrest-specific gene 6 (Gas6), a key regulator of inorganic phosphate (P(i))-induced calcification of vascular smooth muscle cells (VSMC). Testosterone and nonaromatizable androgen dihydrotestosterone inhibited P(i)-induced calcification of human aortic VSMC in a concentration-dependent manner. Androgen inhibited P(i)-induced VSMC apoptosis, an essential process for VSMC calcification. The effects on VSMC calcification were mediated by restoration of P(i)-induced down-regulation of Gas6 expression and a subsequent reduction of Akt phosphorylation. These effects of androgen were blocked by an AR antagonist, flutamide, but not by an estrogen receptor antagonist, ICI 182,780. We then explored the mechanistic role of the AR in Gas6 expression and found an abundant expression of AR predominantly in the nucleus of VSMC and two consensus ARE sequences in the Gas6 promoter region. Dihydrotestosterone stimulated Gas6 promoter activity, and this effect was abrogated by flutamide and by AR siRNA. Site-specific mutation revealed that the proximal ARE was essential for androgen-dependent transactivation of Gas6. Furthermore, chromatin immunoprecipitation assays demonstrated ligand-dependent binding of the AR to the proximal ARE of Gas6. These results indicate that AR signaling directly regulates Gas6 transcription, which leads to inhibition of vascular calcification, and provides a mechanistic insight into the cardioprotective action of androgens.

Age-related Changes in Plasma Androgen Levels and Their Association with Cardiovascular Risk Factors in Male Japanese Office Workers

Geriatrics & Gerontology International. Jan, 2010  |  Pubmed ID: 20102380

To assess the age-related change in plasma androgen levels in healthy middle-aged men and whether any clinical parameters are associated with the hormonal change.

Differential Expression of Estrogen-related Receptors Beta and Gamma (ERRbeta and ERRgamma) and Their Clinical Significance in Human Prostate Cancer

Cancer Science. Mar, 2010  |  Pubmed ID: 20128821

Estrogen-related receptor (ERR) is a nuclear receptor that modulates the estrogen-signaling pathway. Here, we investigated the expression of both ERRbeta and ERRgamma in human prostate tissues. Using original rabbit polyclonal anti-ERRbeta and anti-ERRgamma antibodies, the expression of ERRbeta and ERRgamma was evaluated by immunohistochemical analysis of cancerous lesions (n = 107) and benign foci (n = 92), obtained by radical prostatectomy. Stained slides were evaluated for the proportion of immunoreactive cells and their staining intensity. Total immunoreactivity scores (IR scores; range, 0-8) were calculated as the sum of the proportion and intensity scores. The relationship between the clinicopathological characteristics of the patients and the expression of the three ERRs (ERRalpha, ERR beta, and ERR gamma) was evaluated. IR scores for ERRbeta and ERRgamma were significantly lower in cancerous lesions than that in benign foci (P < 0.0001, for both). Clinicopathological analyses revealed that the patients with low ERRgamma IR scores (

Polypharmacy As a Risk for Fall Occurrence in Geriatric Outpatients

Geriatrics & Gerontology International. Dec, 2011  |  Pubmed ID: 22212467

Objective:  To investigate the predictors of falls, such as comorbidity and medication, in geriatric outpatients in a longitudinal observational study. Methods:  A total of 172 outpatients (45 men and 126 women, mean age 76.9 ± 7.0 years) were evaluated. Physical examination, clinical history and medication profile were obtained from each patient at baseline. These patients were followed for up to 2 years and falls were self-reported to their physicians. The factors associated with falls were analyzed statistically. Results:  A total of 32 patients experienced falls within 2 years. On univariate analysis, older age, osteoporosis, number of comorbid conditions and number of drugs were significantly associated with falls within 2 years. On multiple logistic regression analysis, the number of drugs was associated with falls, independent of age, sex, number of comorbid conditions and other factors that were significantly associated in univariate analysis. A receiver-operator curve evaluating the optimal cut-off value for the number of drugs showed that taking five or more drugs was a significant risk. Conclusion:  In geriatric outpatients, polypharmacy is associated with falls. Intervention studies are needed to clarify the causal relationship between polypharmacy, comorbidity and falls. Geriatr Gerontol Int 2011; ••: ••-••.

Risk Stratification Based on Metabolic Syndrome As Well As Non- Metabolic Risk Factors in the Assessment of Carotid Atherosclerosis

Journal of Atherosclerosis and Thrombosis. 2011  |  Pubmed ID: 21427506

We aimed to develop a new approach to risk stratification using metabolic syndrome as well as traditional non-metabolic risk factors, and to examine its validity in carotid atherosclerosis.

[Inflammatory Control on Lifestyle-related Diseases and Bone Metabolism]

Clinical Calcium. May, 2011  |  Pubmed ID: 21532119

Recent findings suggest that chronic inflammation is involved in lifestyle related diseases and osteoporosis. Members of nuclear receptor superfamily have regulatory effects on inflammatory processes and cytokine responses which contribute to prevention and treatment of above diseases. Here, recent studies are described that these nuclear receptors have regulatory roles called transrepression in chronic inflammatory diseases through their interactions with transcription factors and cell-signaling systems.

Single-nucleotide Polymorphism in the Hyaluronan and Proteoglycan Link Protein 1 (HAPLN1) Gene is Associated with Spinal Osteophyte Formation and Disc Degeneration in Japanese Women

European Spine Journal : Official Publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society. Apr, 2011  |  Pubmed ID: 20953637

Spinal osteoarthritis including disc degeneration is a very common condition in the axial skeletons of aged people. Recently, spinal osteoarthritis has been shown to be influenced by specific genetic risk factors. Vertebral osteophytes, endplate sclerosis, and intervertebral disc narrowing are recognized as radiographic features of spinal disc degeneration. HAPLN1 is a key component of the cartilage extracellular matrix; thus, variations in this gene may affect the pathogenesis of cartilage-related diseases such as spinal degeneration. Here, we examine the association between an HAPLN1 gene polymorphism and the radiographic features of spinal degeneration. We evaluated the degree of endplate sclerosis, osteophyte formation, and disc space narrowing in 622 Japanese postmenopausal women. Four SNPs in the HAPLN1 gene-in the 5' flanking region, intron 1, intron 2, and intron 4-were analyzed using the TaqMan polymerase chain reaction method. We found that compared to subjects with the CC or CT genotype, those with the TT genotype for an SNP at intron 2 (rs179851) were significantly overrepresented among the subjects with higher scores for osteophyte formation (P = 0.0001; odds ratio 2.12; 95% confidence interval 1.45-3.11, as determined by logistic regression analysis) and disc space narrowing (P = 0.0057; odds ratio 1.83; 95% confidence interval 1.19-2.83). Consistent with the involvement of the HAPLN1 gene in cartilage metabolism, a variation in a specific HAPLN1 gene locus may be associated with spinal degeneration.

Plasma Sex Hormone Levels and Mortality in Disabled Older Men and Women

Geriatrics & Gerontology International. Apr, 2011  |  Pubmed ID: 21143567

To investigate the relationship between circulating sex hormone levels and subsequent mortality in disabled elderly.

Coronary Artery Calcification and Cerebral Small Vessel Disease. Association of Systemic Atherosclerosis

Circulation Journal : Official Journal of the Japanese Circulation Society. 2011  |  Pubmed ID: 21178293

Association of Polypharmacy with Fall Risk Among Geriatric Outpatients

Geriatrics & Gerontology International. Oct, 2011  |  Pubmed ID: 21545384

To investigate the association of fall risk with comorbidities and medications in geriatric outpatients in a cross-sectional design.

ARFGAP3, an Androgen Target Gene, Promotes Prostate Cancer Cell Proliferation and Migration

International Journal of Cancer. Journal International Du Cancer. Jun, 2011  |  Pubmed ID: 21647875

ADP ribosylation factor GTPase-activating protein 3 (ARFGAP3) is a GTPase-activating protein that associates with the Golgi apparatus and regulates the vesicular trafficking pathway. In the present study, we examined the contribution of ARFGAP3 to prostate cancer cell biology. We showed that ARFGAP3 expression was induced by 100 nM of dihydrotestosterone (DHT) at both the mRNA and protein levels in androgen-sensitive LNCaP cells. We generated stable transfectants of LNCaP cells with FLAG-tagged ARFGAP3 or a control empty vector and showed that ARFGAP3 overexpression promoted cell proliferation and migration compared with control cells. We found that ARFGAP3 interacted with paxillin, a focal adhesion adaptor protein that is important for cell mobility and migration. Small interfering RNA (siRNA)-mediated knockdown of ARFGAP3 showed that ARFGAP3 siRNA markedly reduced LNCaP cell growth. Androgen receptor (AR)-dependent transactivation activity on prostate-specific antigen (PSA) enhancer was synergistically promoted by exogenous ARFGAP3 and paxillin expression, as shown by luciferase assay in LNCaP cells. Thus, our results suggest that ARFGAP3 is a novel androgen-regulated gene that can promote prostate cancer cell proliferation and migration in collaboration with paxillin.

Sirtuin 1 Retards Hyperphosphatemia-induced Calcification of Vascular Smooth Muscle Cells

Arteriosclerosis, Thrombosis, and Vascular Biology. Sep, 2011  |  Pubmed ID: 21719763

Arterial calcification is associated with cardiovascular disease as a complication of advanced atherosclerosis. Aged vascular cells manifest some morphological features of a senescent phenotype. Recent studies have demonstrated that mammalian sirtuin 1 (SIRT1), a histone deacetylase, is an exciting target for cardiovascular disease management. Here, we investigated the role of SIRT1 in a calcification model of vascular smooth muscle cells (SMCs).

Pulmonary Features Associated with Being Underweight in Older Men

Journal of the American Geriatrics Society. Aug, 2011  |  Pubmed ID: 21848827

Obstructive Sleep Apnea Exacerbates Endothelial Dysfunction in People with Metabolic Syndrome

Journal of the American Geriatrics Society. Aug, 2011  |  Pubmed ID: 21848831

Actions of the Japan Geriatric Society in Response to the 2011 off the Pacific Coast of Tohoku Earthquake: First Report

Geriatrics & Gerontology International. Oct, 2011  |  Pubmed ID: 21951776

PROX1 Suppresses Vitamin K-induced Transcriptional Activity of Steroid and Xenobiotic Receptor

Genes to Cells : Devoted to Molecular & Cellular Mechanisms. Nov, 2011  |  Pubmed ID: 22023334

Steroid and Xenobiotic Receptor (SXR) belongs to nuclear receptor superfamily. It was shown that secondary bile acids such as lithocholic acid and several chemical compounds such as rifampicin could be ligands for this receptor. Recently, we have demonstrated that vitamin K2 also serves as a ligand for SXR and activation of SXR by vitamin K2 suppressed proliferation and motility of hepatocellular carcinoma (HCC) cells. To analyze function of SXR in HCC cells, we overexpressed exogenous SXR double-tagged with FLAG and HA in a HCC cell line, HepG2 cells, and purified SXR-binding molecules by immunoprecipitation from the nuclear extracts of these cells. Several binding molecules were identified by TOF-MS analyses. One of the SXR-binding molecules was a transcription factor PROX1. We confirmed the interaction of PROX1 and SXR in HEK293 cells. Then, we have shown that AF2 domain of SXR is necessary for binding with PROX1. We further demonstrated that PROX1 negatively regulated the transcriptional activity of SXR by promoter analyses of SXR target gene. These results suggest that PROX1 could negatively regulate SXR signals in some tumor cells, such as HCC cells, where both SXR and PROX1 are expressed.

Clinical Significance of Steroid and Xenobiotic Receptor and Its Targeted Gene CYP3A4 in Human Prostate Cancer

Cancer Science. Feb, 2012  |  Pubmed ID: 22050110

The steroid and xenobiotic receptor (SXR) regulates cytochrome P450 (CYP) enzymes, which are key inactivators of testosterone in the liver and prostate. In the present study, we investigated SXR expression in human prostate tissues. We determined SXR immunoreactivity using an anti-SXR antibody in benign (n = 78) and cancerous (n = 106) tissues obtained by radical prostatectomy. Stained slides were evaluated for the proportion and staining intensity of immunoreactive cells. Total immunoreactivity (IR) scores (range: 0-8) were calculated as the sum of the proportion and intensity scores. Associations between the clinicopathological features of the patients, SXR status, and CYP3A4 immunoreactivity were analyzed. Western blot analyses validated the specificity of the anti-SXR antibody in 293T cells transfected with pcDNA-FLAG-SXR. Positive (IR score: ≥ 2) nuclear SXR staining was observed in 91% (71/78) of benign foci and 47% (50/106) of cancerous lesions. Immunoreactivity scores were significantly lower in the cancerous lesions than in the benign foci (P < 0.0001). Clinicopathological analyses showed that cancer-specific survival in patients with high SXR IR scores (≥4) was significantly increased (P = 0.046). Combined data of present and previous studies showed that high IR scores for both the SXR and CYP3A4 correlated with significantly better cancer-specific survival rates in multivariate regression analyses (hazard ratio: 2.15, 95% confidence interval: 1.25-3.55, P = 0.007). We showed differential SXR expression in human prostate tissues. The high expression of the SXR and CYP3A4 is a strong prognostic indicator of favorable outcomes in prostate cancer, and could be a therapeutic target. (Cancer Sci 2012; 103: 176-180).

Toward the Realization of a Better Aged Society: Messages from Gerontology and Geriatrics

Geriatrics & Gerontology International. Jan, 2012  |  Pubmed ID: 22188494

1. BACKGROUND: Recent medical advancements, and improvements in hygiene and food supply have led to Japan having the longest life expectancy in the world. Over the past 50 years, the percentage of the elderly population has increased fourfold from 5.7% in 1960 to 23.1% in 2010. This change has occurred at the fastest rate in the world. Compared with France, where the percentage of the elderly population has increased just twofold in the past 100 years, Japanese society is aging at an unprecedented rate. In addition, the percentage of the very elderly (aged 75 years and over), comprising more frail people, exceeded 10% of the nation's population in 2008. In such a situation, many elderly Japanese wish to spend their later years healthy, and wish to achieve great accomplishments in their lives. To achieve that, rather than considering an aging population as a negative social phenomenon, we should create a society where elderly people can enjoy a healthy, prosperous life through social participation and contribution. Factors that hamper the elderly from leading a healthy life include various psychological and social problems occurring in older age, as well as a high incidence of diseases. Therefore, gerontology, which focuses on health promotion of the elderly by encompassing the study of social welfare, psychology, environment and social systems; and geriatrics, which focuses on health care of elderly people and carried out research, education and practices to promote health in the elderly, are becoming more important. Furthermore, along with a need for multidisciplinary care to support geriatric medicine, the development of a comprehensive education system for aged-care professionals is awaited. Thus, we should now recognize the importance of gerontology and geriatrics, and a reform of medical-care services should be made in order to cope with the coming aged society. Population aging is a global phenomenon. The actions being taken by Japan, the world's most aged society, have been closely watched by the rest of the world. Japan's aged society has been posing not only medical, nursing and welfare problems, but also complex problems closely associated with economy, industry and culture. Therefore, to solve these problems, a macroscopic integration and cooperation among industries, education institutions, administration and community through an interdisciplinary approach including medical science, nursing science, nursing care, study of social welfare, social science, engineering, psychology, economics, religion and ethics should be made. Regarding the promotion of gerontology, the "Committee for Establishing a Scientific Community for Sustainable Aged Society" of the Science Council of Japan also prepared a proposal and this was announced on 20 April 2011. 2. CURRENT SITUATION AND PROBLEMS: (1) Promotion of social participation and contribution of elderly people In Japan, the overall labor force rate is expected to decrease in the near future as a result of the low birth rate and high life expectancy. In contrast, many elderly people, particularly the young-old, have sufficient physical strength to fulfil their job duties and make a social contribution. For these people, a social structure where elderly people can work should be developed through re-educating the elderly and providing various job types. Promotion of social participation and contribution of the elderly is expected to cause a substantial increase in the labor force. Furthermore, it is also expected to contribute to not only the upturn of national economic activity through an increase in total consumption, but also a decrease in the number of elderly people who are likely to be in need of care. Therefore, in order for elderly people to be engaged in various social activities, strategies for developing a social structure for re-education, various employment statuses and employment opportunities should be prepared. However, as the total number of jobs is fixed, consideration should also be given to young workers. (2) Fostering medical specialists for aging Older people often suffer from many diseases, together with geriatric syndromes with multiple etiologies. Signs and symptoms vary according to each individual, and are often atypical; therefore, the patients visit different hospitals and receive many screening tests and prescriptions at the same time. To solve this problem, an effective screening system carried out by a primary-care doctor, and privacy-preserving medical data sharing among hospitals and clinics are needed. In a geriatric clinical setting, health-care professionals should be aware of the physical traits of older people who often develop not only dementia, but also geriatric syndromes, such as depression, falls and urinary incontinence, so that a holistic approach with consideration of nursing care is required. However, the existing Japanese medical education system is not prepared for medical professionals enabled to respond to the aforementioned requirements. Thus, the fostering of medical professionals who can provide comprehensive care - especially for the oldest-old - such as geriatric specialists and medical professionals who understand the principles of elderly care, is urgently needed. (3) Diagnosis of elderly-specific diseases and reform of medical-care services In Japan, the diagnostic system for elderly-specific diseases, including dementia, and reform of medical care services are markedly delayed. The current status concerning diagnosis, care and nursing should be investigated to collect academic data. In order to accumulate evidence for providing safe elderly care and nursing, the promotion of clinical research and a marked expansion of geriatric medical centers with high-level medical services are eagerly awaited. (4) Promotion of home-based care and multidisciplinary care To reduce the length of stay in acute hospitals, to reduce the physical burden of health-care professionals working at acute hospitals and to meet the demand of older people who prefer to remain in their own homes, further promotion of home-based care is needed. In addition, "multidisciplinary care" is increasingly needed to meet various demands in the medical care and welfare of the elderly. It is considered important to share countermeasures against the problems of disease prevention, medicine, care and welfare among health-care professionals in medicine, care and welfare, and cooperate by making the best use of health-care professionals' specialties. 3. CONTENTS OF THE PROPOSAL: The subcommittee for aging, thus, provided the following proposal: 1 Development and promotion of systems that enable elderly people to participate socially and make a contribution using an interdisciplinary approach among the various areas, including nursing science, nursing care, study of social welfare, social science, psychology, economics, religion and ethics, as well as medical sciences; 2 Promotion of gerontology, reform and enhancement of geriatrics in undergraduate, postgraduate and lifelong education; 3 Building geriatric medical centers in each area, and accumulating large-scale evidence of geriatric diseases and geriatrics; and 4 Structural development and promotion of home-based care and multidisciplinary care. Through implementation of the above measures, Japan is expected to function as a successful example for the rest of the world.

Testosterone Deficiency Accelerates Neuronal and Vascular Aging of SAMP8 Mice: Protective Role of ENOS and SIRT1

PloS One. 2012  |  Pubmed ID: 22238626

Oxidative stress and atherosclerosis-related vascular disorders are risk factors for cognitive decline with aging. In a small clinical study in men, testosterone improved cognitive function; however, it is unknown how testosterone ameliorates the pathogenesis of cognitive decline with aging. Here, we investigated whether the cognitive decline in senescence-accelerated mouse prone 8 (SAMP8), which exhibits cognitive impairment and hypogonadism, could be reversed by testosterone, and the mechanism by which testosterone inhibits cognitive decline. We found that treatment with testosterone ameliorated cognitive function and inhibited senescence of hippocampal vascular endothelial cells of SAMP8. Notably, SAMP8 showed enhancement of oxidative stress in the hippocampus. We observed that an NAD(+)-dependent deacetylase, SIRT1, played an important role in the protective effect of testosterone against oxidative stress-induced endothelial senescence. Testosterone increased eNOS activity and subsequently induced SIRT1 expression. SIRT1 inhibited endothelial senescence via up-regulation of eNOS. Finally, we showed, using co-culture system, that senescent endothelial cells promoted neuronal senescence through humoral factors. Our results suggest a critical role of testosterone and SIRT1 in the prevention of vascular and neuronal aging.

Oct1 Regulates Cell Growth of LNCaP Cells and is a Prognostic Factor for Prostate Cancer

International Journal of Cancer. Journal International Du Cancer. Mar, 2012  |  Pubmed ID: 21387309

The androgen receptor (AR) plays a critical role in the development and the progression of prostate cancer. Alterations in the expression of AR coregulators lead to AR hypersensitivity, which is one of the mechanisms underlying the progression of prostate cancer into a castrate-resistant state. Octamer transcription factor 1 (Oct1) is a ubiquitous member of the POU-homeodomain family that functions as a coregulator of AR. In our study, the contribution of Oct1 to prostate cancer development was examined. Immunocytochemistry analysis showed that Oct1 is expressed in the nuclei of LNCaP cells. siRNA-mediated silencing of Oct1 expression inhibited LNCaP cell proliferation. Immunohistochemical analysis of Oct1 expression in tumor specimens obtained from 102 patients with prostate cancer showed a positive correlation of Oct1 immunoreactivity with a high Gleason score and AR immunoreactivity (p = 0.0042 and p < 0.0001, respectively). Moreover, patients with high immunoreactivity of Oct1 showed a low cancer-specific survival rate, and those patients with high immunoreactivities of both Oct1 and AR exhibited poorer cancer-specific prognosis. Multivariate hazard analysis revealed a significant correlation between high Oct1 immunoreactivity and poor cancer-specific survival (p = 0.012). These results demonstrate that Oct1 can be a prognostic factor in prostate cancer as a coregulator of AR and may lead to the development of a new therapeutic intervention for prostate cancer.