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1.  Phosphodiesterase III inhibitor promotes drainage of cerebrovascular β-amyloid 
Brain amyloidosis is a key feature of Alzheimer's disease (AD). It also incorporates cerebrovascular amyloid β (Aβ) in the form of cerebral amyloid angiopathy (CAA) involving neurovascular dysfunction. We have recently shown by retrospective analysis that patients with mild cognitive impairment receiving a vasoactive drug cilostazol, a selective inhibitor of phosphodiesterase (PDE) III, exhibit significantly reduced cognitive decline. Here, we tested whether cilostazol protects against the disruption of the neurovascular unit and facilitates the arterial pulsation-driven perivascular drainage of Aβ in AD/CAA.
We explored the expression of PDE III in postmortem human brain tissue followed by a series of experiments examining the effects of cilostazol on Aβ metabolism in transgenic mice (Tg-SwDI mice) as a model of cerebrovascular β-amyloidosis, as well as cultured neurons.
We established that PDE III is abnormally upregulated in cerebral blood vessels of AD and CAA subjects and closely correlates with vascular amyloid burden. Furthermore, we demonstrated that cilostazol treatment maintained cerebral hyperemic and vasodilative responses to hypercapnia and acetylcholine, suppressed degeneration of pericytes and vascular smooth muscle cells, promoted perivascular drainage of soluble fluorescent Aβ1-40, and rescued cognitive deficits in Tg-SwDI mice. Although cilostazol decreased endogenous Aβ production in cultured neurons, C-terminal fragment of amyloid precursor protein expression was not altered in cilostazol-treated Tg-SwDI mice.
The predominant action of cilostazol on Aβ metabolism is likely to facilitate Aβ clearance due to the sustained cerebrovascular function in vivo. Our findings mechanistically demonstrate that cilostazol is a promising therapeutic approach for AD and CAA.
PMCID: PMC4184555  PMID: 25356424
2.  Regulation of matrix contraction in chronic venous disease 
The role of TGF-β1 in venous ulcer healing and the signaling cascades regulating dermal fibroblast function are poorly understood. To elucidate these processes, we hypothesized that TGF-β1 facilitates wound healing by increasing chronic venous insufficiency (CVI) induced matrix contraction via intracellular cross-talk between TGF-β1 and the ERK-1/2 MAP kinase signaling cascades.
Fibroblasts isolated from calf biopsies (LC) of patients with different severity of CVI (CEAP, Clinical Etiological Anatomical Pathological classes) were seeded into 200μl collagen gels under isometric conditions. Fibroblasts from neonatal foreskins (HS68), non-CVI patients (NC), and the ipsilateral normal thigh of each CVI patient (LT) served as controls. Thirteen patients with CVI (class 2, n=5; class 4, n=5; class 6, n=3) and 2 non-CVI controls (NC, n=2) were included in the study. All experimental conditions were determined by dose-response and time-course experiments. Gels were cultured with/without 0.1 ng/ml TGF-β1 and with/without 50 μM PD98059 (MEK and downstream MAPK inhibitor). Additional patient fibroblasts were transfected with constitutively active Ras (pCMV-Ras) or an empty vector (pCMV-β) with/without 0.1 ng/ml TGF-β1 and with/without 50 μm PD98059. The collagen gels were released after 4 days and the percent contraction was determined by area measurements using image analysis. Differences in α-smooth muscle actin (α-SMA) and ERK-1/2 MAPK (phosphorylated and total) protein levels were analyzed with western blotting.
Gels seeded with CVI fibroblasts contracted more than HS68, NC and LT fibroblasts. Inhibition of MAPK and/or stimulation with TGF-β1 increased the contraction of LC gels compared to un-stimulated controls. Agonist induced gel contraction correlated with CVI disease severity. α-SMA protein expression in LC fibroblasts increased with MAPK inhibition with/without TGF-β1 stimulation, and correlated with the degree of gel contraction. Transfection with pCMV-Ras (activator of ERK-1/2) inhibited gel contraction; this inhibition was not reversed by addition of TGF-β1. Transfection with the pCMV-β empty vector had no effect on gel contraction.
TGF-β1-stimulation of CVI patient fibroblasts grown in 3D collagen gels results in conversion to a contractile phenotype through upregulation of α-SMA, and in enhanced gel contraction. Inhibition of MAPK further increases gel contraction, while Ras activation of ERK-1/2 inhibits TGF-β1-induced gel contraction. These responses correlate with increasing CEAP severity. CVI fibroblast mediated gel contraction is therefore regulated through cross-talk between the ERK-1/2 MAPK and TGF-β1 signaling cascades. These data identify potentially cliniclly relevant therapeutic molecular targets that could enhanc matrix contraction and thereby improve venous ulcer wound healing.
PMCID: PMC4004365  PMID: 19560950
TGF-β1; matrix contraction; chronic venous insufficiency
3.  Cilostazol Add-On Therapy in Patients with Mild Dementia Receiving Donepezil: A Retrospective Study 
PLoS ONE  2014;9(2):e89516.
Combinatorial therapy directed at both vascular and neurodegenerative aspects of dementia may offer a promising strategy for treatment of dementia, which often has a multifactorial basis in the elderly. We investigated whether the phosphodiesterase III inhibitor cilostazol, which is often used in the prevention of stroke and peripheral artery disease, may delay cognitive decline in the elderly receiving donepezil.
Medical records were retrospectively surveyed to identify patients who had received donepezil for more than one year and had undergone Mini-Mental State Examination (MMSE) at least at two time points. Those with an initial MMSE score of less than 27 points were subjected to analysis (n = 156), with a cut-point of 21/22 applied to assign them to mild (n = 70) and moderate/severe (n = 86) dementia. The change of total MMSE score per year was compared between patients who had received donepezil and those given both donepezil and cilostazol.
In patients with mild dementia who had received donepezil and cilostazol (n = 34; 77.2±6.8 years old), the annual change in MMSE score was −0.5±1.6 during an observational period of 28.6±11.7 months, with those receiving donepezil only (n = 36; 78.4±6.5 years old) scoring less (−2.2±4.1) during 30.4±12.8 months with a statistical intergroup difference (p = 0.022). Multivariate analysis showed that absence of cilostazol treatment was the only significant predictor of MMSE decline. A positive effect of cilostazol was found in three subscale scores of MMSE, orientation for time or place and delayed recall. By clear contrast, in patients with moderate/severe dementia, there were no intergroup differences in decrease of total or subscale MMSE scores between the two groups.
These results suggest potential for cilostazol treatment in the suppression of cognitive decline in patients receiving donepezil with mild dementia but not in those with moderate/severe dementia.
PMCID: PMC3935872  PMID: 24586841
4.  New Therapeutic Approaches for Alzheimer’s Disease and Cerebral Amyloid Angiopathy 
Accumulating evidence has shown a strong relationship between Alzheimer’s disease (AD), cerebral amyloid angiopathy (CAA), and cerebrovascular disease. Cognitive impairment in AD patients can result from cortical microinfarcts associated with CAA, as well as the synaptic and neuronal disturbances caused by cerebral accumulations of β-amyloid (Aβ) and tau proteins. The pathophysiology of AD may lead to a toxic chain of events consisting of Aβ overproduction, impaired Aβ clearance, and brain ischemia. Insufficient removal of Aβ leads to development of CAA and plays a crucial role in sporadic AD cases, implicating promotion of Aβ clearance as an important therapeutic strategy. Aβ is mainly eliminated by three mechanisms: (1) enzymatic/glial degradation, (2) transcytotic delivery, and (3) perivascular drainage (3-“d” mechanisms). Enzymatic degradation may be facilitated by activation of Aβ-degrading enzymes such as neprilysin, angiotensin-converting enzyme, and insulin-degrading enzyme. Transcytotic delivery can be promoted by inhibition of the receptor for advanced glycation end products (RAGE), which mediates transcytotic influx of circulating Aβ into brain. Successful use of the RAGE inhibitor TTP488 in Phase II testing has led to a Phase III clinical trial for AD patients. The perivascular drainage system seems to be driven by motive force generated by cerebral arterial pulsations, suggesting that vasoactive drugs can facilitate Aβ clearance. One of the drugs promoting this system is cilostazol, a selective inhibitor of type 3 phosphodiesterase. The clearance of fluorescent soluble Aβ tracers was significantly enhanced in cilostazol-treated CAA model mice. Given that the balance between Aβ synthesis and clearance determines brain Aβ accumulation, and that Aβ is cleared by several pathways stated above, multi-drugs combination therapy could provide a mainstream cure for sporadic AD.
PMCID: PMC4202741  PMID: 25368578
Alzheimer’s disease; cerebral amyloid angiopathy; treatment; perivascular drainage; cilostazol
5.  Miglitol improves postprandial endothelial dysfunction in patients with acute coronary syndrome and new-onset postprandial hyperglycemia 
Hyperglycemia, a risk factor for development of cardiovascular disease, causes endothelial dysfunction. Alpha-glucosidase inhibitors (α-GIs) improve postprandial hyperglycemia (PPHG) and may have favorable effects on associated cardiovascular disease. Effects of α-GIs in patients with acute coronary syndrome (ACS) and PPHG remain unclear; thus, we assessed the effect of α-GI miglitol on endothelial function in such patients by digital reactive hyperemia peripheral arterial tonometry (RH-PAT).
Fifty-four patients with ACS who underwent primary percutaneous coronary intervention were enrolled in the study: 36 with new-onset PPHG and 18 with normal glucose tolerance. Eighteen PPHG patients were given 50 mg of miglitol with each meal for 1 week. Endothelial function was assessed on the basis of the RH-PAT index (RHI) before and after the 1-week miglitol treatment. The other 18 PPHG patients and the 18 NGT patients were not given any anti-diabetic agent for 1 week, and endothelial function was assessed.
Postprandial RHI decreased significantly in patients with PPHG. Miglitol improved PPHG significantly; postprandial RHI also improved (p = 0.007). Significant inverse correlation was found between the postprandial change in RHI and postprandial fasting-to-60-minutes surge in glucose (r = -0.382, p = 0.009). Moreover, the improvement in endothelial function correlated with the reduced postprandial glucose surge achieved with miglitol (r = -0.462, p = 0.001).
Postprandial changes in glucose are related to endothelial dysfunction in ACS. Miglitol-based improvement in PPHG appears to improve endothelial function. The effect of miglitol on glucose-dependent endothelial function might improve outcomes of ACS.
PMCID: PMC3691582  PMID: 23777506
Postprandial hyperglycemia; Endothelial function; Reactive hyperemia peripheral arterial tonometry; Acute coronary syndrome; Alpha-glucosidase inhibitor; Miglitol
6.  Mitral valve repair in patient with absent right superior vena cava in visceroatrial situs solitus 
We report on a 74-year-old woman with an absence of right superior vena cava in visceroatrial situs solitus who underwent mitral valve plasty for severe mitral regurgitation. Preoperative three-dimensional computed tomography revealed an absent right and persistent left superior vena cava that drained into the right atrium by way of the coronary sinus. Perioperaively, placement of pulmonary artery catheter, site of venous cannulation, and management of associated rhythm abnormalities were great concern. Obtaining the information about this central venous malformation preoperatively, we performed mitral valve plasty without any difficulties related to this anomaly.
PMCID: PMC3560078  PMID: 23317475
Absent right superior vena cava; Persistent left superior vena cava; Visceroatrial situs solitus; Mitral valve plasty
7.  High HbA1c levels correlate with reduced plaque regression during statin treatment in patients with stable coronary artery disease: Results of the coronary atherosclerosis study measuring effects of rosuvastatin using intravascular ultrasound in Japanese subjects (COSMOS) 
The incidence of cardiac events is higher in patients with diabetes than in people without diabetes. The Coronary Atherosclerosis Study Measuring Effects of Rosuvastatin Using Intravascular Ultrasound in Japanese Subjects (COSMOS) demonstrated significant plaque regression in Japanese patients with chronic coronary disease after 76 weeks of rosuvastatin (2.5 mg once daily, up-titrated to a maximum of 20 mg/day to achieve LDL cholesterol <80 mg/dl).
In this subanalysis of COSMOS, we examined the association between HbA1c and plaque regression in 40 patients with HbA1c ≥6.5% (high group) and 86 patients with HbA1c <6.5% (low group).
In multivariate analyses, HbA1c and plaque volume at baseline were major determinants of plaque regression. LDL cholesterol decreased by 37% and 39% in the high and low groups, respectively, while HDL cholesterol increased by 16% and 22%, respectively. The reduction in plaque volume was significantly (p = 0.04) greater in the low group (from 71.0 ± 39.9 to 64.7 ± 34.7 mm3) than in the high group (from 74.3 ± 34.2 to 71.4 ± 32.3 mm3). Vessel volume increased in the high group but not in the low group (change from baseline: +4.2% vs −0.8%, p = 0.02). Change in plaque volume was significantly correlated with baseline HbA1c.
Despite similar improvements in lipid levels, plaque regression was less pronounced in patients with high HbA1c levels compared with those with low levels. Tight glucose control during statin therapy may enhance plaque regression in patients with stable coronary disease.
Trial registration, Identifier NCT00329160
PMCID: PMC3444370  PMID: 22831708
Atherosclerosis; Coronary artery disease; Intravascular ultrasound; HbA1c; Rosuvastatin
8.  Hepatitis C virus enhances incidence of idiopathic pulmonary fibrosis 
AIM: To investigate the cumulative development incidence and predictive factors for idiopathic pulmonary fibrosis in hepatitis C virus (HCV) positive patients.
METHODS: We studied 6150 HCV infected patients who were between 40-70 years old (HCV-group). Another 2050 patients with hepatitis B virus (HBV) were selected as control (HBV-group). The mean observation period was 8.0 ± 5.9 years in HCV-group and 6.3 ± 5.5 years in HBV-group. The primary goal is the development of idiopathic pulmonary fibrosis (IPF) in both groups. The cumulative appearance rate of IPF and independent factors associated with the incidence rate of IPF were calculated using the Kaplan-Meier method and the Cox proportional hazard model. All of the studies were performed retrospectively by collecting and analyzing data from the patient records in our hospital.
RESULTS: Fifteen patients in HCV-group developed IPF. On the other hand, none of the patients developed IPF in HBV-group. In HCV-group, the cumulative rates of IPF development were 0.3% at 10th year and 0.9% at 20th year. The IPF development rate in HCV-group was higher than that in HBV-group (P = 0.021). The IPF development rate in patients with HCV or HBV was high with statistical significance in the following cases: (1) patients ≥ 55 years (P < 0.001); (2) patients who had smoking index (package per day × year) of ≥ 20 (P = 0.002); (3) patients with liver cirrhosis (P = 0.042).
CONCLUSION: Our results indicate that age, smoking and liver cirrhosis enhance the development of IPF in HCV positive patients.
PMCID: PMC2751899  PMID: 18855988
Hepatitis B virus; Hepatitis C virus; Idiopathic pulmonary fibrosis; A retrospective cohort study
9.  Psychological and weight-related characteristics of patients with anorexia nervosa-restricting type who later develop bulimia nervosa 
Patients with anorexia nervosa-restricting type (AN-R) sometimes develop accompanying bulimic symptoms or the full syndrome of bulimia nervosa (BN). If clinicians could predict who might change into the bulimic sub-type or BN, preventative steps could be taken. Therefore, we investigated anthropometric and psychological factors possibly associated with such changes.
All participants were from a study by the Japanese Genetic Research Group for Eating Disorders. Of 80 patients initially diagnosed with AN-R, 22 changed to the AN-Binge Eating/Purging Type (AN-BP) and 14 to BN for some period of time. The remaining 44 patients remained AN-R only from the onset to the investigation period. Variables compared by ANOVA included anthropometric measures, personality traits such as Multiple Perfectionism Scale scores and Temperament and Character Inventory scores, and Beck Depression Inventory-II scores.
In comparison with AN-R only patients, those who developed BN had significantly higher current BMI (p < 0.05) and maximum BMI in the past (p < 0.05). They also scored significantly higher for the psychological characteristic of parental criticism (p < 0.05) and lower in self-directedness (p < 0.05), which confirms previous reports, but these differences disappeared when the depression score was used as a co-variant. No significant differences were obtained for personality traits or depression among the AN-R only patients irrespective of their duration of illness.
The present findings suggest a tendency toward obesity among patients who cross over from AN-R to BN. Low self-directedness and high parental criticism may be associated with the development of BN by patients with AN-R, although the differences may also be associated with depression.
PMCID: PMC2275291  PMID: 18267038
10.  Hyperglycemia alters PI3k and Akt signaling and leads to endothelial cell proliferative dysfunction 
Diabetes mellitus is a major risk factor for the development of vascular complications. We hypothesized that hyperglycemia decreases endothelial cell (EC) proliferation and survival via phosphatidylinositol 3-kinase (PI3k) and Akt signaling pathways. We cultured human umbilical vein ECs (HUVEC) in 5, 20, or 40 mM d-glucose. Cells grown in 5, 20, and 40 mM mannitol served as a control for osmotic effects. We measured EC proliferation for up to 15 days. We assessed apoptosis by annexin V and propidium iodide staining and flow cytometry, analyzed cell lysates obtained on culture day 8 for total and phosphorylated PI3k and Akt by Western blot analysis, and measured Akt kinase activity using a GSK fusion protein. HUVEC proliferation was also tested in the presence of pharmacological inhibitors of PI3k-Akt (wortmannin and LY294002) and after transfection with a constitutively active Akt mutant. ECs in media containing 5 mM d-glucose (control) exhibited log-phase growth on days 7–10. d-Glucose at 20 and 40 mM significantly decreased proliferation versus control (P < 0.05 for both), whereas mannitol did not impair EC proliferation. Apoptosis increased significantly in HUVEC exposed to 40 mM d-glucose. dGlucose at 40 mM significantly decreased tyrosine-phosphorylated PI3k, threonine 308-phosphorylated-Akt, and Akt activity relative to control 5 mM d-glucose. Pharmacological inhibition of PI3k-Akt resulted in a dose-dependent decrease in EC proliferation. Transfection with a constitutively active Akt mutant protected ECs by enhancing proliferation when grown in 20 and 40 mM d-glucose. We conclude that d-glucose regulates Akt signaling through threonine phosphorylation of Akt and that hyperglycemia-impaired PI3k-Akt signaling may promote EC proliferative dysfunction in diabetes.
PMCID: PMC1618822  PMID: 15964918
endothelial cell proliferation; diabetes mellitus; phosphatidylinositol 3-kinase; protein kinase B; Akt; endothelial cell apoptosis
11.  Mid-Ventricular Obstructive Hypertrophic Cardiomyopathy Associated with an Apical Aneurysm: Evaluation of Possible Causes of Aneurysm Formation 
Yonsei Medical Journal  2007;48(5):879-882.
Mid-ventricular obstructive hypertrophic cardiomyopathy (MVOHCM) is a rare type of cardiomyopathy, associated with apical aneurysm formation in some cases. We report a patient presenting with ventricular fibrillation, an ECG with an above normal ST segment, and elevated levels of cardiac enzymes but normal coronary arteries. Left ventriculography revealed a left ventricular obstruction without apical aneurysm. There was a significant pressure gradient between the apical and basal sites of the left ventricle. Cine magnetic resonance imaging (MRI), performed on the 10th hospital day, showed asymmetric septal hypertrophy, mid-ventricular obstruction, and an apical aneurysm with a thrombus. The first evaluation by contrast-enhanced imaging showed a subendocardial perfusion defect and delayed enhancement. It was speculated that the intraventricular pressure gradient, due to mid-ventricular obstruction, triggered myocardial infarction, which subsequently resulted in apical aneurysm formation.
PMCID: PMC2628158  PMID: 17963350
Mid-ventricular obstructive hypertrophic cardiomyopathy; magnetic resonance imaging
12.  Mid-Ventricular Hypertrophic Obstructive Cardiomyopathy Presenting with Acute Myocardial Infarction 
Texas Heart Institute Journal  2007;34(4):475-478.
Mid-ventricular hypertrophic obstructive cardiomyopathy is a rare type of cardiomyopathy that can be accompanied by apical aneurysm. We report the case of a patient who presented with ventricular fibrillation, ST-segment elevation on electrocardiography, and cardiac-enzyme elevation, in the presence of normal coronary arteries. Echocardiography and magnetic resonance imaging showed an hourglass appearance of the left ventricle with an aneurysm in the apex. Left-heart catheterization and continuous-wave Doppler echocardiography revealed a pressure gradient between the apical and basal chambers of the left ventricle. Impaired coronary artery circulation might play a role in the development of mid-ventricular obstruction in patients with mid-ventricular hypertrophic obstructive cardiomyopathy.
PMCID: PMC2170479  PMID: 18172535
Cardiomyopathy, hypertrophic/complications/physiopathology; heart aneurysm/etiology; magnetic resonance imaging; myocardial infarction; thallium radioisotopes/diagnostic use; tomography, emission computed, single-photon; ventricular outflow obstruction/diagnosis

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