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1.
Opt Lett ; 48(11): 2837-2840, 2023 Jun 01.
Article in English | MEDLINE | ID: mdl-37262223

ABSTRACT

To allow a high quality factor (Q-factor) to a sub-wavelength dielectric resonator, quasi-bound states in the continuum (Q-BICs) have gained much interest. However, the Q-BIC resonance condition is too sensitive to the geometry of the resonator, and its practical broadband generation on a single-wafer platform has been limited. Here we present that, employing the base angle as a structural degree of freedom, the truncated nano-cone resonator supports the Q-BIC resonance with a high Q-factor of >150 over a wide wavelength range of >100 nm. We expect our approach will boost the utilization of the Q-BIC resonance for various applications requiring broadband spectral tuning.

2.
Digit Health ; 8: 20552076221143249, 2022.
Article in English | MEDLINE | ID: mdl-36532114

ABSTRACT

Background: Artificial intelligence-enabled electrocardiogram has become a substitute tool for echocardiography in left ventricular ejection fraction estimation. However, the direct use of artificial intelligence-enabled electrocardiogram may be not trustable due to the uncertainty of the prediction. Objective: The study aimed to establish an artificial intelligence-enabled electrocardiogram with a degree of confidence to identify left ventricular dysfunction. Methods: The study collected 76,081 and 11,771 electrocardiograms from an academic medical center and a community hospital to establish and validate the deep learning model, respectively. The proposed deep learning model provided the point estimation of the actual ejection fraction and its standard deviation derived from the maximum probability density function of a normal distribution. The primary analysis focused on the accuracy of identifying patients with left ventricular dysfunction (ejection fraction ≤ 40%). Since the standard deviation was an uncertainty indicator in a normal distribution, we used it as a degree of confidence in the artificial intelligence-enabled electrocardiogram. We further explored the clinical application of estimated standard deviation and followed up on the new-onset left ventricular dysfunction in patients with initially normal ejection fraction. Results: The area under receiver operating characteristic curves (AUC) of detecting left ventricular dysfunction were 0.9549 and 0.9365 in internal and external validation sets. After excluding the cases with a lower degree of confidence, the artificial intelligence-enabled electrocardiogram performed better in the remaining cases in internal (AUC = 0.9759) and external (AUC = 0.9653) validation sets. For the application of future left ventricular dysfunction risk stratification in patients with initially normal ejection fraction, a 4.57-fold risk of future left ventricular dysfunction when the artificial intelligence-enabled electrocardiogram is positive in the internal validation set. The hazard ratio was increased to 8.67 after excluding the cases with a lower degree of confidence. This trend was also validated in the external validation set. Conclusion: The deep learning model with a degree of confidence can provide advanced improvements in identifying left ventricular dysfunction and serve as a decision support and management-guided screening tool for prognosis.

3.
PeerJ ; 9: e11152, 2021.
Article in English | MEDLINE | ID: mdl-33986982

ABSTRACT

Nursing assistants (NAs) working in nursing homes (NHs) are at higher risk for work-related musculoskeletal symptoms (WRMSs) than their counterparts working in other health care settings. Worldwide, NAs have ranked shoulders in the top three body parts at risk of WRMSs. However, factors associated with their shoulder WRMSs are currently unknown. The aim of this study was to identify these associated risk factors among NAs working in NHs. 440 NAs from 47 nursing homes (with 60-90% response rate from each nursing home), recruited by convenience sampling, participated in this cross-sectional study in 2014-2015. A validated and reliable questionnaire was used for data collection. Information on demographic, job content questionnaire (JCQ), perceived physical exertion (PE), workstyle, ergonomic and manual handling knowledge and other work-related factors was collected using a self-administered questionnaire. 53% of the participants reported experiencing with WRMSs in their shoulders. Nine associated factors of shoulder WRMSs were identified using bivariate analysis. With the adjustment of age and gender using multivariable logistic regression, body mass index (OR = .931, 95% CI [.874-.991]), job title of health workers (OR = 2.72, 95% CI [1.18-6.25]) and workstyle-working through pain (OR = 1.06, 95% CI [1.01-1.11]) remained as predictors. Effort should be directed at integrating "workstyle intervention" into lifestyle physical activity training for NAs.

4.
Opt Lett ; 45(9): 2502-2505, 2020 May 01.
Article in English | MEDLINE | ID: mdl-32356801

ABSTRACT

Hyperbolic metasurfaces have attracted much interest due to novel optical properties including self-focusing, diffraction-less propagation, and negative refraction. However, conventional hyperbolic metasurfaces employing transverse-magnetic-like (TM-like) guided modes operate limited to short wavelengths. Here, we propose a broadband hyperbolic metasurface utilizing the transverse-electric-like (TE-like) guided modes of silver nanowires. The symmetric TE-like mode of the nanowire metasurface supports strong near-field coupling through the metallic element for hyperbolicity from visible to near-infrared wavelengths. Using numerical simulations, we examine the modal and dispersion properties depending on the wavelength and geometry. Particularly, negative refraction at the interface between a hyperbolic metasurface and the normal-dispersion planar waveguide is also demonstrated.

6.
ACS Appl Mater Interfaces ; 6(19): 16956-65, 2014 Oct 08.
Article in English | MEDLINE | ID: mdl-25226068

ABSTRACT

In this paper, we report and discuss our successful synthesis of monodispersed, polystyrene-coated gold core-shell nanoparticles (Au@PS NPs) for use in highly efficient, air-stable, organic light-emitting diodes (OLEDs) and organic photovoltaics (OPVs). These core-shell NPs retain the dual functions of (1) the plasmonic effect of the Au core and (2) the stability and solvent resistance of the cross-linked PS shell. The monodispersed Au@PS NPs were incorporated into a poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) film that was located between the ITO substrate and the emitting layer (or active layer) in the devices. The incorporation of the Au@PS NPs provided remarkable improvements in the performances of both OLEDs and OPVs, which benefitted from the plasmonic effect of the Au@PS NPs. The OLED device with the Au@PS NPs achieved an enhancement of the current efficiency that was 42% greater than that of the control device. In addition, the power conversion efficiency was increased from 7.6% to 8.4% in PTB7:PC71BM-based OPVs when the Au@PS NPs were embedded. Direct evidence of the plasmonic effect on optical enhancement of the device was provided by near-field scanning optical microscopy measurements. More importantly, the Au@PS NPs induced a remarkable and simultaneous improvement in the stabilities of the OLED and OPV devices by reducing the acidic and hygroscopic properties of the PEDOT:PSS layer.

7.
J Am Chem Soc ; 136(28): 9982-9, 2014 Jul 16.
Article in English | MEDLINE | ID: mdl-24927484

ABSTRACT

The tuning of interfacial properties at selective and desired locations on the particles is of great importance to create the novel structured particles by breaking the symmetry of their surface property. Herein, a dramatic transition of both the external shape and internal morphology of the particles of polystyrene-b-poly(4-vinylpyridine) (PS-b-P4VP) was induced by precise positioning of size-controlled Au nanoparticle surfactants (Au NPs). The size-dependent assembly of the Au NPs was localized preferentially at the interface between the P4VP domain at the particle surface and the surrounding water, which generated a balanced interfacial interaction between two different PS/P4VP domains of the BCP particles and water, producing unique convex lens-shaped BCP particles. In addition, the neutralized interfacial interaction, in combination with the directionality of the solvent-induced ordering of the BCP domains from the interface of the particle/water, generated defect-free, vertically ordered porous channels within the particles. The mechanism for the formation of these novel nanostructures was investigated systemically by varying the size and the volume fraction of the Au NPs. Furthermore, these convex lens-shaped particles with highly ordered channels can be used as a microlens, in which the light can be concentrated toward the focal point with enhanced near-field signals. And, these particles can possess additional optical properties such as unique distribution of light scattering as a result of the well-ordered Au cylinders that filled into the channels, which hold great promise for use in optical, biological-sensing, and imaging applications.

8.
ACS Nano ; 8(4): 3302-12, 2014 Apr 22.
Article in English | MEDLINE | ID: mdl-24593128

ABSTRACT

In this report, we propose a metal-metal core-shell nanocube (NC) as an advanced plasmonic material for highly efficient organic solar cells (OSCs). We covered an Au core with a thin Ag shell as a scattering enhancer to build Au@Ag NCs, which showed stronger scattering efficiency than Au nanoparticles (AuNPs) throughout the visible range. Highly efficient plasmonic organic solar cells were fabricated by embedding Au@Ag NCs into an anodic buffer layer, poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS), and the power conversion efficiency was enhanced to 6.3% from 5.3% in poly[N-9-hepta-decanyl-2,7-carbazole-alt-5,5-(4,7-di-2-thienyl-2,1,3-benzothiadiazole)] (PCDTBT):[6,6]-phenyl C71-butyric acid methyl ester (PC70BM) based OSCs and 9.2% from 7.9% in polythieno[3,4-b]thiophene/benzodithiophene (PTB7):PC70BM based OSCs. The Au@Ag NC plasmonic PCDTBT:PC70BM-based organic solar cells showed 2.2-fold higher external quantum efficiency enhancement compared to AuNPs devices at a wavelength of 450-700 nm due to the amplified plasmonic scattering effect. Finally, we proved the strongly enhanced plasmonic scattering efficiency of Au@Ag NCs embedded in organic solar cells via theoretical calculations and detailed optical measurements.

9.
J Clin Densitom ; 16(3): 283-286, 2013.
Article in English | MEDLINE | ID: mdl-23562363

ABSTRACT

The purpose of this study was to determine whether antecedent administration of ¹8F-fluorodeoxyglucose (FDG) used in positron emission tomography (PET) scanning results in corruption of bone mineral density (BMD) and body composition measured by dual-energy X-ray absorptiometry (DXA) system. DXA measurements of BMD and body composition had been performed twice, before and after ¹8F-FDG PET scan in 30 patients. The comparison of pre-values and post-values of all BMD values showed a decrease after the injection. However, only the decrease of whole-body BMD (WB-BMD) was statistically significant (p < 0.05). Whole-body fat mass had increased and whole-body lean body mass had decreased after the injection of ¹8F-FDG, and these were statistically significant (p < 0.05). There is statistically significant correlation between the injected ¹8F-FDG dose and a decrease of WB-BMD (r = -0.405; p < 0.05). The findings of this study suggest that when both ¹8F-FDG PET and DXA measurements for whole-body composition are performed in close-time proximity, ¹8F-FDG PET scans should follow the DXA measurement. Otherwise, BMD measurements of total femur or lumbar spine could be followed by ¹8F-FDG PET in close-time proximity.


Subject(s)
Absorptiometry, Photon/methods , Body Composition , Bone Density/physiology , Femur/diagnostic imaging , Fluorodeoxyglucose F18/administration & dosage , Lumbar Vertebrae/diagnostic imaging , Chromatography, High Pressure Liquid , Chromatography, Thin Layer , Dose-Response Relationship, Drug , Female , Femur/metabolism , Fluorodeoxyglucose F18/pharmacokinetics , Follow-Up Studies , Humans , Injections, Intravenous , Lumbar Vertebrae/metabolism , Male , Middle Aged , Prospective Studies , Radiopharmaceuticals/administration & dosage , Radiopharmaceuticals/pharmacokinetics , Reproducibility of Results
10.
Bioorg Med Chem Lett ; 23(2): 537-42, 2013 Jan 15.
Article in English | MEDLINE | ID: mdl-23218712

ABSTRACT

Novel benzamide derivatives were synthesized and tested at in vitro assay by measuring fold increase of glucokinase activity at 5.0 mM glucose concentration. Among the prepared compounds, YH-GKA was found to be an active glucokinase activator with EC(50) of 70 nM. YH-GKA showed similar glucose AUC reduction of 29.6% (50 mg/kg) in an OGTT study with C57BL/J6 mice compared to 29.9% for metformin (300 mg/kg). Acute treatment of the compound in C57BL/J6 and ob/ob mice elicited basal glucose lowering activity. In subchronic study with ob/ob mice, YH-GKA showed significant decrease in blood glucose levels and no adverse effects on serum lipids or body weight. In addition, YH-GKA exhibited high bioavailability and moderate elimination in preclinical species.


Subject(s)
Benzamides/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Drug Discovery , Glucokinase/metabolism , Hypoglycemic Agents/therapeutic use , Pyridines/therapeutic use , Animals , Benzamides/chemical synthesis , Benzamides/chemistry , Benzamides/pharmacology , Cells, Cultured , Diabetes Mellitus, Type 2/enzymology , Enzyme Activation/drug effects , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Mice , Mice, Inbred C57BL , Mice, Obese , Molecular Structure , Phenethylamines/chemical synthesis , Phenethylamines/chemistry , Phenethylamines/pharmacology , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/pharmacology
11.
J Androl ; 33(6): 1254-62, 2012.
Article in English | MEDLINE | ID: mdl-22604628

ABSTRACT

Erectile dysfunction (ED) reflects a risk for systemic cardiovascular diseases by virtue of a common etiology of vascular endothelial dysfunction, which is increasingly reported to affect young adults. On the basis of physiological phenomenon of reactive hyperemia (RH), systemic and penile endothelial functions in healthy young adults were compared with the use of digital data on arterial waveforms before and after RH induction. Between July 2009 and March 2011, 32 young adult volunteers with normal erectile functions were recruited. Questionnaires on medical histories and sexual functions and blood samples for testosterone and biochemical analyses were obtained. Dilatation index (DI) and penile arterial waveform amplitude (PAWA) ratios for assessing systemic and penile endothelial function were acquired with an air pressure sensing system on the arm and a penile arterial waveform analyzing system on the penis, respectively. A total cholesterol/high-density lipoprotein (TC/HDL) ratio greater than 4.1 was used to define high risk for ED. Remarkable positive correlation was noted between DI and PAWA ratio (r = .640, P < .001). DI showed significant positive associations with serum testosterone (P = .012) and serum HDL level, whereas it showed negative correlations with total triglyceride and glycosylated hemoglobulin levels, body weight, waist circumference, body mass index, and diastolic blood pressure. Similarly, the PAWA ratio showed significant positive correlations with serum testosterone (P < .001) and HDL levels, but negative associations with body weight, waist circumference, and body mass index. Both DI and PAWA ratio successfully identified participants at high risk for ED (eg, TC/HDL ratio > 4.1; P < .05). Our results demonstrated that penile endothelial function can be assessed by evaluating systemic endothelial function in young healthy adults for early identification of risk for ED.


Subject(s)
Endothelium, Vascular/physiopathology , Erectile Dysfunction/physiopathology , Penis/blood supply , Adult , Arteries/physiology , Cardiovascular Diseases/etiology , Cholesterol, HDL/blood , Humans , Hyperemia/complications , Male , Penile Erection , Risk , Testosterone/blood , Triglycerides/blood , Young Adult
12.
J Sex Med ; 9(4): 1094-105, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22239850

ABSTRACT

INTRODUCTION: High prevalence of erectile dysfunction in young adults has raised much concern regarding early identification of risk factors for timely intervention. AIM: This study aimed at identifying young males at risk through a novel penile arterial waveform analyzing system. METHODS: Between July 2009 and December 2010, 30 young adult volunteers of age 18 to 29 without known history of vascular diseases or erectile dysfunction were recruited. MAIN OUTCOME MEASURES: Basic demographic and anthropometric characteristics (i.e., age, body weight, body height, body mass index, waist circumference) were recorded. Blood samples were obtained for determining levels of testosterone, glycosylated hemoglobin, triglyceride, fasting sugar, low- and high-density lipoproteins (HDL). Data obtained from visual sexual stimulation (VSS) RigiScan and the penile arterial waveform amplitude (PAWA) ratios were compared in terms of their correlations with anthropometric and serum biochemical parameters using Pearson's correlation analysis. RESULTS: PAWA ratios were found to correlate with Rigidity (tip and base) (r = 0.425, P = 0.019 and r = 0.664, P < 0.001, respectively). Significant associations of PAWA ratios were noted not only with serum testosterone level but also with risk factors for metabolic and cardiovascular diseases including total triglyceride, HDL, age, waist circumference, body mass index, and diastolic blood pressure. However, VSS RigiScan failed in identifying significant correlations with HDL, age, and diastolic blood pressure. CONCLUSIONS: Not only could the penile waveform analyzing system assess penile endothelial function in young adults, but the results also showed significant associations with their serum testosterone levels and metabolic parameters. The findings suggest that PAWA ratio may serve as an indicator for early identification and treatment of young adults at risk of erectile dysfunction.


Subject(s)
Impotence, Vasculogenic/diagnosis , Penis/blood supply , Adolescent , Adult , Anthropometry , Blood Pressure/physiology , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Cross-Sectional Studies , Early Diagnosis , Endothelium, Vascular/physiopathology , Glycated Hemoglobin/metabolism , Humans , Impotence, Vasculogenic/epidemiology , Male , Mass Screening , Risk Factors , Testosterone/blood , Triglycerides/blood , Young Adult
13.
Ann Biomed Eng ; 39(11): 2857-68, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21769542

ABSTRACT

Not only does erectile dysfunction (ED) reflect penile vascular disorder in the majority of patients, but it also implicates their high systemic cardiovascular risk. Based on the principle of reactive hyperemia after a brief period of penile ischemia, in this study, we tested the validity of a new Penile Arterial Waveform Analyzer (PAWA) in assessing the relative increase in post-ischemic penile perfusion. Twenty young adult males (mean age 24.24 ± 2.45) without known history of cardiovascular diseases were recruited, whose anthropometric characteristics were recorded and their serum testosterone levels as well as biochemical profiles were determined. A penile cuff was applied to each subject, with cuff pressure being increased from 80 to 250 mmHg, each for 4 min, followed by reperfusion for 7 min. By dividing the area under waveform contour of hyperemic and baseline signals after Ensemble Empirical Mode Decomposition (EEMD), a Penile Perfusion Index (PPI) was calculated. Penile Brachial Index (PBI) was also obtained for comparison. The results not only showed a significant agreement between PPI and serum testosterone levels, but also a superiority of PPI to PBI in distinguishing the high- and low-risk groups for potential ED (PPI: p = 0.039 vs. PBI: p = 0.147). PPI was also demonstrated to show significant correlations with waist circumference (p < 0.001), body mass index (p = 0.005), body weight, total triglyceride, high-density lipoprotein, and systolic and diastolic pressures (all p < 0.05). In conclusion, we proposed a portable and easy-to-operate system in assessing the relative increase in penile perfusion after brief ischemia. The PPI thus obtained correlated significantly with serum testosterone levels as well as key anthropometric and serum biochemical parameters even in apparently healthy young adults, suggesting its potential as a sensitive tool in monitoring penile vascular function and risk for ED.


Subject(s)
Erectile Dysfunction/physiopathology , Penis , Plethysmography/instrumentation , Adult , Anthropometry , Arteries/physiopathology , Blood Pressure , Body Mass Index , Body Weight , Cardiovascular Diseases/physiopathology , Equipment Design/instrumentation , Equipment Design/methods , Humans , Lipoproteins, HDL , Male , Penis/blood supply , Penis/physiopathology , Plethysmography/methods , Reproducibility of Results , Risk Factors , Signal Processing, Computer-Assisted/instrumentation , Testosterone/blood
14.
IEEE Trans Biomed Eng ; 58(2): 243-52, 2011 Feb.
Article in English | MEDLINE | ID: mdl-20923726

ABSTRACT

Although current technique of photoplethysmography (PPG) is a popular noninvasive method of waveform contour analysis in assessing arterial stiffness, data obtained are frequently affected by various environmental and physiological factors. We proposed an easily operable air pressure sensing system (APSS) for radial arterial signal capturing. Totally, 108 subjects (young, the aged with or without diabetes) were recruited from July 2009 to May 2010. Arterial waveform signals from the wrist were obtained and analyzed using Hilbert-Huang transformation (HHT). Through ensemble empirical mode decomposition (EEMD), the signals were decomposed into eight intrinsic mode functions (IMF1-8) of which IMF5 was found to be the desired signal with a discernible diastolic peak. The results showed significant differences in reflection index (RI) and stiffness index (SI) from the young subjects and those from the aged participants with or without diabetes. Significant differences in RI and SI were also noted between subjects with well-controlled diabetes and those without. Good reproducibility and correlation were demonstrated. In conclusion, the present study proposed the application of radial arterial signal capturing subsystem and HHT in acquiring more reliable data on RI and SI compared with the conventional PPG method.


Subject(s)
Algorithms , Blood Pressure Determination/methods , Blood Pressure/physiology , Radial Artery/physiology , Wavelet Analysis , Adult , Age Factors , Aged , Female , Humans , Male , Middle Aged , Reproducibility of Results
15.
Article in English | MEDLINE | ID: mdl-19964280

ABSTRACT

This study proposes a method of measuring vasodilatation via air pressure sensing to assess the function of endothelium cells. The vasodilatation index is calculated according to the change of area of waveform caused by stimulation to the blood vessels, and uses this index to reflect the function of endothelium cells; therefore, early self-monitoring of cardiovascular dysfunction and arterial stiffness can be easily and effectively achieved. Only a few minutes are needed for conducting a self endothelial function assessment. Furthermore, this study improves the high cost pressure sensors used in Reactive Hyperemia Peripheral Arterial Tonometry (RH-PAT) and its inconveniences. 30 test subjects with no previous cardiovascular disease record were included for testing the reproducibility of the instrument. It has been proven that the air pressure sensing method proposed in this study has higher reproducibility and practicality than the Photoplethysmography (PPG) system for assessing the function of endothelium cells.


Subject(s)
Endothelium, Vascular/physiopathology , Pulse , Animals , Arteries/pathology , Endothelial Cells/pathology , Endothelium, Vascular/pathology , Equipment Design , Hyperemia/pathology , Male , Manometry/methods , Photoplethysmography/methods , Rats , Rats, Inbred WKY , Signal Processing, Computer-Assisted , Software , Vasodilation
16.
Arch Pharm Res ; 32(5): 721-7, 2009 May.
Article in English | MEDLINE | ID: mdl-19471887

ABSTRACT

Peroxisome proliferator-activated receptor (PPAR) gamma is known to be a key regulator of insulin resistance. PAR-1622 is a novel small molecule compound synthesized in Dong-A research center. In this study, we characterized the pharmacological profiles of PAR-1622, a selective partial activator of PPARgamma. In transient transactivation assays, PAR-1622 [(S)-2-ethoxy-3(4-(5-(4-(5-(methoxymethyl)isoxazol-3-yl)phenyl)-3-methylthiophen-2-yl)methoxy)phenyl)propanoic acid] showed a partial activator against human PPARgamma with an EC(50) of 41 nM and a maximal response of 37% relative to the full agonist rosiglitazone without activating human PPARdelta. PAR-1622 was 56 folds more selective for human PPARgamma than for human PPARalpha (EC(50), 2304 nM), which means that it is a selective partial activator of PPARgamma. PAR-1622 also showed a partial activator against mouse PPARgamma with an EC(50) of 427 nM and a maximal response was 57% of that of rosiglitazone. INT-131, a selective PPARgamma partial agonist in clinical stage, also was a partial activator against human PPARgamma with an EC(50) of 83 nM and a maximal response achieved by INT-131 was 49% of that observed with full agonist rosiglitazone. In functional assays using human mesenchymal stem cells, PAR-1622 induced adipocyte differentiation, which was 3-fold more potent with a comparable maximum response compared to INT-131. Furthermore, PAR-1622 significantly improved hyperglycemia in db/db when orally administered at a dose of 1 mg/kg/day for 5 days. In hemodilution assays with Evans Blue, rosiglitazone significantly increased the plasma volume in ICR mice that were orally administered 30 mg/kg/day for 9 days; however, PAR-1622 showed no significant effects on plasma volume, similar to INT-131. These results suggest that PAR-1622 is a selective partial activator of PPARgamma and has excellent antihyperglycemic activities and a broad safety profile for fluid retention.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/pharmacology , Isoxazoles/pharmacology , PPAR gamma/agonists , Propionates/pharmacology , Thiophenes/pharmacology , Water-Electrolyte Balance/drug effects , Adipogenesis/drug effects , Administration, Oral , Animals , Blood Glucose/drug effects , Blood Volume/drug effects , Cells, Cultured , Diabetes Mellitus, Type 2/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Partial Agonism , Genes, Reporter , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/toxicity , Isoxazoles/administration & dosage , Isoxazoles/toxicity , Male , Mesenchymal Stem Cells/drug effects , Mesenchymal Stem Cells/metabolism , Mice , Mice, Inbred ICR , PPAR gamma/genetics , PPAR gamma/metabolism , Propionates/administration & dosage , Propionates/toxicity , Rosiglitazone , Thiazolidinediones/pharmacology , Thiophenes/administration & dosage , Thiophenes/toxicity , Transfection
17.
Bioorg Med Chem Lett ; 18(18): 4993-6, 2008 Sep 15.
Article in English | MEDLINE | ID: mdl-18771917

ABSTRACT

Aryl-tetrahydropyridine derivatives were prepared and their PPARalpha/gamma dual agonistic activities were evaluated. Among them, compound (S)-5b was identified as a potent PPARalpha/gamma dual agonist with an EC(50) of 1.73 and 0.64 microM in hPPARalpha and gamma, respectively. In diabetic (db/db) mice, compound (S)-5b showed good glucose lowering efficacy and favorable pharmacokinetic properties.


Subject(s)
PPAR alpha/agonists , PPAR gamma/agonists , Pyridines/chemical synthesis , Pyridines/pharmacology , Animals , Combinatorial Chemistry Techniques , Diabetes Mellitus, Type 2/drug therapy , Disease Models, Animal , Drug Design , Mice , Molecular Structure , Pyridines/chemistry , Rats , Rats, Sprague-Dawley
18.
Eur J Pharmacol ; 595(1-3): 119-25, 2008 Oct 24.
Article in English | MEDLINE | ID: mdl-18727927

ABSTRACT

Peroxisome proliferator-activated receptor (PPAR) alpha and gamma are key regulators of lipid homeostasis and insulin resistance. In this study, we characterize the pharmacological profiles of PAR-5359, a dual agonist of PPARalpha and gamma with well-balanced activities. In transient transactivation assay, PAR-5359 (3-(4-(2[4-(4chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethoxy)-phenyl)-(2S)-ethoxy-propionic acid) significantly activated human and mouse PPARalpha and gamma without activating PPARdelta. In functional assays using human mesenchymal stem cells and human hepatoma HepG2 cells, PAR-5359 significantly induced adipocyte differentiation and human ApoA1 secretion, which coincided with its transactivation potencies against the corresponding human receptor subtypes. Interestingly, PAR-5359 showed equivalent potencies against the mouse receptor subtypes (alpha and gamma; 2.84 microM and 3.02 microM, respectively), which suggests the possibility that PAR-5359 could simultaneously activates each subtype of receptors subtype in under physiological conditions. In an insulin-resistant ob/ob mouse model, PAR-5359 significantly reduced plasma insulin levels, improved insulin sensitivity (HOMA-IR), and completely normalized plasma glucose levels. In a severe diabetic db/db mouse model, PAR-5359 dose-dependently reduced the plasma levels of glucose (ED(30) = 0.07 mg/kg). Furthermore, it lowered plasma levels of non HDL- (ED(30) = 0.13 mg/kg) and total cholesterol (ED(30) = 0.03 mg/kg) in high cholesterol diet-fed rats for 4 days treatment. These results suggest that PAR-5359 has the balanced activities for PPARalpha and PPARgamma in vivo as well as in vitro. And its balanced activities may render PAR-5359 as a pharmacological tool in elucidating the complex roles of PPARalpha/gamma dual agonists.


Subject(s)
Diabetes Mellitus/drug therapy , Hyperlipidemias/drug therapy , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/pharmacology , Obesity/drug therapy , PPAR alpha/agonists , PPAR gamma/agonists , Propionates/pharmacology , Pyridines/pharmacology , Adipocytes/drug effects , Adipocytes/metabolism , Adipogenesis/drug effects , Animals , Apolipoprotein A-I/metabolism , Blood Glucose/metabolism , Cell Line, Tumor , Cells, Cultured , Diabetes Mellitus/metabolism , Diabetes Mellitus/physiopathology , Disease Models, Animal , Dose-Response Relationship, Drug , Humans , Hyperlipidemias/metabolism , Hyperlipidemias/physiopathology , Insulin/blood , Insulin Resistance , Male , Mesenchymal Stem Cells/drug effects , Mesenchymal Stem Cells/metabolism , Mice , Mice, Obese , Obesity/metabolism , Obesity/physiopathology , PPAR alpha/genetics , PPAR alpha/metabolism , PPAR gamma/genetics , PPAR gamma/metabolism , Rats , Rats, Sprague-Dawley , Recombinant Fusion Proteins/agonists , Time Factors
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