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1.  Evaluation of Postoperative Range of Motion and Functional Outcomes after Cruciate-Retaining and Posterior-Stabilized High-Flexion Total Knee Arthroplasty 
Yonsei Medical Journal  2012;53(4):794-800.
The purpose of this study was to compare postoperative range of motion and functional outcomes among patients who received high-flexion total knee arthroplasty using cruciate-retaining (CR-Flex) and posterior-stabilized (PS-Flex) type prostheses.
Materials and Methods
Among 127 patients (186 knees) who underwent high-flexion total knee arthroplasty between 2005 and 2007, 92 knees were placed in the CR-Flex group, and 94 knees were placed in the PS-Flex group. After two years of postoperative follow-up, clinical and radiographic data were reviewed. Postoperative non-weight-bearing range of knee motion, angle of flexion contracture and functional outcomes based on the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) functional sub-scale were assessed and compared between the two groups.
After the 2-year postoperative period, the mean range of motion was 131° in the CR-Flex group and 133° in the PS-Flex group. There were no significant differences in postoperative range of motion between the two groups. Only age at operation and preoperative range of motion were significantly associated with postoperative range of motion after high-flexion total knee arthroplasty. Postoperative functional outcomes based on the WOMAC functional sub-scale were slightly better in the CR-Flex group (9.2±9.1 points) than in the PS-Flex group (11.9±9.6 points); however, this difference was not statistically significant (p=non-significant).
The retention or substitution of the posterior cruciate ligament does not affect postoperative range of motion (ROM) or functional outcomes, according to 2 years of postoperative follow-up of high-flexion total knee arthroplasty.
PMCID: PMC3381472  PMID: 22665348
Total knee arthroplasty; range of motion; functional outcomes; cruciate-retaining; posterior-stabilized; high-flexion
2.  Long-Term Follow-Up Results of a Second-Generation Cementless Femoral Prosthesis with a Collar and Straight Distal Fixation Channels 
Yonsei Medical Journal  2011;53(1):186-192.
We evaluated the results of more than 10 years of follow-up of total hip arthroplasty using a second-generation cementless femoral prosthesis with a collar and straight distal fixation channels.
Materials and Methods
One hundred five patients (129 hips) who underwent surgery between 1991 and 1996 for primary total hip arthroplasty using cementless straight distal fluted femoral stems were followed for more than 10 years. Ninety-four hips in 80 patients were available for clinical and radiologic analysis. The mean age at the time of surgery was 47 years, and the mean duration of follow-up was 14.3 years.
The mean Harris hip scores had improved from 58 points to 88 points at the time of the 10-year follow-up. Activity-related thigh pain was reported in nine hips (10%). At the last follow-up, 93 stems (99%) were biologically stable and one stem (1%) was revised because of loosening. No hip had distal diaphyseal osteolysis. Proximal femoral stress-shielding was reported in 86 hips (91%). We found no significant relationship between collar-calcar contact and thigh pain, stem fixation status, or stress-shielding. The cumulative survival of the femoral stem was 99% (95% confidence interval, 98-100%) after 10 years.
The long-term results of total hip arthroplasty using a second-generation cementless femoral prosthesis with a collar and straight distal fixation channels were satisfactory; however, the high rate of proximal stress-shielding and the minimal effect of the collar indicate the need for some changes in the stem design.
PMCID: PMC3250326  PMID: 22187251
Total hip arthroplasty; second-generation; cementless; collar; straight distal fixation channel
3.  Label-free detection of kanamycin based on a G-quadruplex DNA aptamer-based fluorescent intercalator displacement assay 
Scientific Reports  2015;5:8125.
This work was the first to report that the kanamycin-binding DNA aptamer (5′-TGG GGG TTG AGG CTA AGC CGA-3′) can form stable parallel G-quadruplex DNA (G4-DNA) structures by themselves and that this phenomenon can be verified by nondenaturing polyacrylamide gel electrophoresis and circular dichroism spectroscopy. Based on these findings, we developed a novel label-free strategy for kanamycin detection based on the G4-DNA aptamer-based fluorescent intercalator displacement assay with thiazole orange (TO) as the fluorescence probe. In the proposed strategy, TO became strongly fluorescent upon binding to kanamycin-binding G4-DNA. However, the addition of kanamycin caused the displacement of TO from the G4-DNA–TO conjugate, thereby resulting in decreased fluorescent signal, which was inversely related to the kanamycin concentration. The detection limit of the proposed assay decreased to 59 nM with a linear working range of 0.1 μM to 20 μM for kanamycin. The cross-reactivity against six other antibiotics was negligible compared with the response to kanamycin. A satisfactory recovery of kanamycin in milk samples ranged from 80.1% to 98.0%, confirming the potential of this bioassay in the measurement of kanamycin in various applications. Our results also served as a good reference for developing similar fluorescent G4-DNA-based bioassays in the future.
PMCID: PMC4311242  PMID: 25634469
4.  Epigenetic regulation of miR-122 by PPARγ and hepatitis B virus X protein in hepatocellular carcinoma cells 
Hepatology (Baltimore, Md.)  2013;58(5):1681-1692.
MiR-122, a pivotal liver specific miRNA, has been implicated in several liver diseases including hepatocellular carcinoma (HCC) and hepatitis C and B viral infection. This study aimed to explore epigenetic regulation of miR-122 in human hepatocellular carcinoma (HCC) cells and to examine the effect of hepatitis C virus (HCV) and hepatitis B virus (HBV). We performed microRNA microarray analysis and identified miR-122 as the most up-regulated miRNA (6-fold) in human hepatocellular cancer cells treated with 5′aza-2′deoxycytidine (5-Aza-CdR, DNA methylation inhibitor) and 4-phenylbutyric acid (PBA, histone deacetylation inhibitor). Real-time PCR analysis verified significant upregulation of miR-122 by 5′aza and PBA in HCC cells, and to a lesser extent in primary hepatocytes. Peroxisome proliferator activated receptor-gamma (PPARγ) and retinoid X receptor alpha (RXRα) complex was found to be associated with the DR1 and DR2 consensus site in the miR-122 gene promoter which enhanced miR-122 gene transcription. 5-Aza-CdR and PBA treatment increased the association of PPARγ/RXRα, but decreased the association of its co-repressors (N-CoR and SMRT), with the miR-122 DR1 and DR2 motifs. The aforementioned DNA-protein complex also contains SUV39H1, a H3K9 histone methyl transferase, which downregulates miR-122 expression. Our findings establish a novel role of the PPARγ binding complex for epigenetic regulation of miR-122 in human HCC cells. Moreover, we show that hepatitis B virus X protein (HBX) binds PPARγ and inhibits the transcription of miR-122, whereas hepatitis C viral particles exhibited no significant effect; these findings provide mechanistic insight into reduction of miR-122 in patients with HBV but not with HCV infection.
PMCID: PMC3773012  PMID: 23703729
miR-122; PPARγ; HCC; epigenetic regulation; Hepatitis B virus X protein; HCV; liver; hepatocytes
5.  Suppression of lung inflammation in an LPS-induced acute lung injury model by the fruit hull of Gleditsia sinensis 
The fruit hull of Gleditsia sinensis (FGS) used in traditional Asian medicine was reported to have a preventive effect on lung inflammation in an acute lung injury (ALI) mouse model. Here, we explored FGS as a possible therapeutics against inflammatory lung diseases including ALI, and examined an underlying mechanism for the effect of FGS.
The decoction of FGS in water was prepared and fingerprinted. Mice received an intra-tracheal (i.t.) FGS 2 h after an intra-peritoneal (i.p.) injection of lipopolysaccharide (LPS). The effect of FGS on lung inflammation was determined by chest imaging of NF-κB reporter mice, counting inflammatory cells in bronchoalveolar lavage fluid, analyzing lung histology, and performing semi-quantitative RT-PCR analysis of lung tissue. Impact of Nrf2 on FGS effect was assessed by comparing Nrf2 knockout (KO) and wild type (WT) mice that were treated similarly.
Bioluminescence from the chest of the reporter mice was progressively increased to a peak at 16 h after an i.p. LPS treatment. FGS treatment 2 h after LPS reduced the bioluminescence and the expression of pro-inflammatory cytokine genes in the lung. While suppressing the infiltration of inflammatory cells to the lungs of WT mice, FGS post-treatment failed to reduce lung inflammation in Nrf2 KO mice. FGS activated Nrf2 and induced Nrf2-dependent gene expression in mouse lung.
FGS post-treatment suppressed lung inflammation in an LPS-induced ALI mouse model, which was mediated at least in part by Nrf2. Our results suggest a therapeutic potential of FGS on inflammatory lung diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/1472-6882-14-402) contains supplementary material, which is available to authorized users.
PMCID: PMC4203922  PMID: 25318387
Gleditsia sinensis; Traditional Asian medicine; Therapeutics; Acute lung inflammation; Nrf2
6.  NADPH Oxidase and the Cardiovascular Toxicity Associated with Smoking 
Toxicological Research  2014;30(3):149-157.
Smoking is one of the most serious but preventable causes of cardiovascular disease (CVD). Key aspects of pathological process associated with smoking include endothelial dysfunction, a prothrombotic state, inflammation, altered lipid metabolism, and hypoxia. Multiple molecular events are involved in smokinginduced CVD. However, the dysregulations of reactive oxygen species (ROS) generation and metabolism mainly contribute to the development of diverse CVDs, and NADPH oxidase (NOX) has been established as a source of ROS responsible for the pathogenesis of CVD. NOX activation and resultant ROS production by cigarette smoke (CS) treatment have been widely observed in isolated blood vessels and cultured vascular cells, including endothelial and smooth muscle cells. NOX-mediated oxidative stress has also been demonstrated in animal studies. Of the various NOX isoforms, NOX2 has been reported to mediate ROS generation by CS, but other isoforms were not tested thoroughly. Of the many CS constituents, nicotine, methyl vinyl ketone, and α,β-unsaturated aldehydes, such as, acrolein and crotonaldehyde, appear to be primarily responsible for NOX-mediated cytotoxicity, but additional validation will be needed. Human epidemiological studies have reported relationships between polymorphisms in the CYBA gene encoding p22phox, a catalytic subunit of NOX and susceptibility to smoking-related CVDs. In particular, G allele carriers of A640G and -930A/G polymorphisms were found to be vulnerable to smoking-induced cardiovascular toxicity, but results for C242T studies are conflicting. On the whole, evidence implicates the etiological role of NOX in smoking-induced CVD, but the clinical relevance of NOX activation by smoking and its contribution to CVD require further validation in human studies. A detailed understanding of the role of NOX would be helpful to assess the risk of smoking to human health, to define high-risk subgroups, and to develop strategies to prevent or treat smoking-induced CVD.
PMCID: PMC4206741  PMID: 25343008
Smoking; Cigarette; NADPH oxidase; Reactive oxygen species; Oxidative stress; Cardiovascular disease
7.  The Sensitivity of Cancer Cells to Pheophorbide a-Based Photodynamic Therapy Is Enhanced by NRF2 Silencing 
PLoS ONE  2014;9(9):e107158.
Photodynamic therapy (PDT) has emerged as an effective treatment for various solid tumors. The transcription factor NRF2 is known to protect against oxidative and electrophilic stress; however, its constitutive activity in cancer confers resistance to anti-cancer drugs. In the present study, we investigated NRF2 signaling as a potential molecular determinant of pheophorbide a (Pba)-based PDT by using NRF2-knockdown breast carcinoma MDA-MB-231 cells. Cells with stable NRF2 knockdown showed enhanced cytotoxicity and apoptotic/necrotic cell death following PDT along with increased levels of singlet oxygen and reactive oxygen species (ROS). A confocal microscopic visualization of fluorogenic Pba demonstrated that NRF2-knockdown cells accumulate more Pba than control cells. A subsequent analysis of the expression of membrane drug transporters showed that the basal expression of BCRP is NRF2-dependent. Among measured drug transporters, the basal expression of breast cancer resistance protein (BCRP; ABCG2) was only diminished by NRF2-knockdown. Furthermore, after incubation with the BCRP specific inhibitor, differential cellular Pba accumulation and ROS in two cell lines were abolished. In addition, NRF2-knockdown cells express low level of peroxiredoxin 3 compared to the control, which implies that diminished mitochondrial ROS defense system can be contributing to PDT sensitization. The role of the NRF2-BCRP pathway in Pba-PDT response was further confirmed in colon carcinoma HT29 cells. Specifically, NRF2 knockdown resulted in enhanced cell death and increased singlet oxygen and ROS levels following PDT through the diminished expression of BCRP. Similarly, PDT-induced ROS generation was substantially increased by treatment with NRF2 shRNA in breast carcinoma MCF-7 cells, colon carcinoma HCT116 cells, renal carcinoma A498 cells, and glioblastoma A172 cells. Taken together, these results indicate that the manipulation of NRF2 can enhance Pba-PDT sensitivity in multiple cancer cells.
PMCID: PMC4165896  PMID: 25226504
8.  Hedgehog Signaling Pathway Regulates Autophagy in Human Hepatocellular Carcinoma Cells 
Hepatology (Baltimore, Md.)  2013;58(3):995-1010.
Hedgehog (Hh) signaling plays an important role in embryonic development and in the regulation of a variety of cellular functions. Aberrant activation of Hh signaling has been implicated in several human cancers including hepatocellular carcinoma (HCC). In this study we examined the pathobiological functions and molecular mechanisms of Hh signaling pathway in HCC cells. Treatment of cultured human HCC cells (Huh7, Hep3B and HepG2) with the Hh signaling ligand (recombinant Shh) or agonist, SAG and purmorphamine, prevented the induction of autophagy. In contrast, GANT61 (a small molecule inhibitor of Gli1 and Gli2) induced autophagy, as determined by immunobloting for microtubule-associated protein light chain 3 (LC3) and p62, GFP-LC3 puncta, monodansylcadaverine (MDC) staining and transmission electron microscopy. Hh inhibition-induced autophagy was associated with upregulation of Bnip3, as determined by immunoblotting and real-time PCR assay. Knockdown of Bnip3 by RNAi impaired GANT61-induced autophagy. Additionally, Hh inhibition-induced autophagy was associated with Bnip3-mediated displacement of Bcl-2 from Beclin-1, as determined by immunoblotting and immunoprecipitation assays. Furthermore, inhibition of Hh signaling increased HCC cell apoptosis and decreased cell viability, as determined by caspase and WST-1 assays. Pharmacological or genetic inhibition of autophagy by 3-methyladenine (3-MA) or Beclin-1 siRNA partially suppressed GANT61-induced cell apoptosis and cytotoxicity. In a tumor xenograft model using SCID mice inoculated with Huh7 cells, administration of GANT61 inhibited tumor formation and decreased tumor volume; this effect was partially blocked by the autophagy inhibitor, 3-MA. These findings provide novel evidence that hedgehog inhibition induces autophagy through upregulation of Bnip3 and that this mechanism contributes to apoptosis. Therefore, the status of autophagy is a key factor that determines the therapeutic response to Hh-targeted therapies.
PMCID: PMC3706478  PMID: 23504944
Hedgehog signaling; GANT61; autophagy; hepatocellular carcinoma; apoptosis
9.  Minimum 5-year Follow-up Results of Minimally Invasive Total Knee Arthroplasty Using Mini-Keel Modular Tibial Implant 
Knee Surgery & Related Research  2014;26(3):149-154.
To evaluate the minimum 5-year mid-term clinical and radiological results of minimally invasive surgery total knee arthroplasty (MIS-TKA) using a mini-keel modular tibia component.
Materials and Methods
We retrospectively evaluated 254 patients (361 cases) who underwent MIS-TKA between 2005 and 2006. The latest clinical and radiological assessments were done in 168 cases that had been followed on an outpatient basis for more than 5 postoperative years. Clinical results were assessed using the Hospital for Special Surgery (HSS) score and Knee Society score. Radiological evaluation included measurements of knee alignment.
The average postoperative knee range of motion and HSS score were 134.3°±12.4° and 92.7°±7.0°, respectively. The average postoperative femorotibial angle and tibial component alignment angle were 5.2°±1.7° valgus and 90.2°±1.6°, respectively. The average tibial component posterior inclination was 4.8°±2.1°. The percentage of cases with tibial component alignment angle of 90°±3° was 96.1%, and that with the femorotibial angle of 6°±3° valgus was 94.0%. Radiolucent lines were observed in 20 cases (12.0%): around the femur, tibia, and patella in 14 cases, 10 cases, and 1 case, respectively. However, they were less than 2 mm and non-progressive in all cases. The survival rate was 99.4% and there was no implant-related revision.
MIS-TKA using a mini-keel modular tibial plate showed satisfactory results, a high survival rate, and excellent clinical and radiological results in the mid-term follow-up.
PMCID: PMC4163572  PMID: 25229044
Knee; Arthroplasty; Minimally invasive; Mini-keel tibial component
10.  Fermentation with Aquilariae Lignum Enhances the Anti-Diabetic Activity of Green Tea in Type II Diabetic db/db Mouse 
Nutrients  2014;6(9):3536-3571.
The major components of tea may be significantly influenced according to the type of fermentation, and consequently the effects of different teas will differ. We examined whether green tea fermented with Aquilariae Lignum (fGT) shows a stronger anti-diabetic effect than unfermented green tea (GT) on mice with type 2 diabetes. To evaluate the anti-obesity effect of fGT, we assessed body weight, fecal excretion, serum leptin levels, exocrine pancreatic zymogen granule contents, and periovarian fat weight and adiponectin contents. Blood glucose levels, pancreatic weight, and numbers of pancreatic islet insulin- and glucagon-producing cells were determined to evaluate anti-hypoglycemic effects, while total cholesterol, triglyceride, and low- and high-density lipoprotein levels were determined to evaluate anti-hyperlipidemic effects. The antioxidant effect of fGT was detected by measuring malondialdehyde and glutathione contents and the activities of catalase and superoxide dismutase. fGT showed anti-obesity, anti-hypoglycemic, anti-hyperlipidemia, and antioxidant effects. Additionally, fGT exerted stronger anti-diabetic effects compared with GT. Collectively, these results suggested that fGT fermented with the appropriate amounts of Aquilariae Lignum (49:1) has a stronger effect compared with GT. Thus, fGT is a promising and potent new therapeutic agent for type 2 diabetes.
PMCID: PMC4179175  PMID: 25207824
BKS.Cg-+Leprdb/+Leprdb/OlaHsd (db/db) mice; obese; diabetes; fermented green tea with Aquilariae Lignum; synergistic
11.  15-PGDH inhibits hepatocellular carcinoma growth through 15-keto-PGE2/PPARγ-mediated activation of p21WAF1/Cip1 
Oncogene  2013;33(9):1101-1112.
15-hydroxyprostaglandin dehydrogenase (15-PGDH) is a key enzyme in prostaglandin metabolism. This study provides important evidence for inhibition of hepatocellular carcinoma (HCC) growth by 15-PGDH through the 15-keto-PGE2/PPARγ/p21WAF1/Cip1 signaling pathway. Forced overexpression of 15-PGDH inhibited HCC cell growth in vitro, whereas knockdown of 15-PGDH enhanced tumor growth parameters. In a tumor xenograft model in SCID mice, inoculation of human HCC cells (Huh7) with overexpression of 15-PGDH led to significant inhibition of tumor growth, while knockdown of 15-PGDH enhanced tumor growth. In a separate tumor xenograft model in which mouse HCC cells (Hepa1-6) were inoculated into syngeneic C57BL/6 mice, intratumoral injection of adenovirus vector expressing 15-PGDH (pAd-15-PGDH) significantly inhibited xenograft tumor growth. The anti-tumor effect of 15-PGDH is mediated through its enzymatic product, 15-keto-PGE2, which serves as an endogenous PPARγ ligand. Activation of PPARγ by 15-PGDH-derived 15-keto-PGE2 enhanced the association of PPARγ with the p21WAF1/Cip1 promoter and increased p21 expression and association with CDK2, CDK4 and PCNA. Depletion of p21 by shRNA reversed 15-PGDH-induced inhibition of HCC cell growth; overexpression of p21 prevented 15-PGDH knockdown-induced tumor cell growth. These results demonstrate a key 15-PGDH/15-keto-PGE2-mediated activation of PPARγ and p21WAF1/Cip1 signaling cascade that regulates hepatocarcinogenesis and tumor progression.
PMCID: PMC3912217  PMID: 23542179
Hepatocellular carcinoma (HCC); 15-hydroxyprostaglandin dehydrogenase (15-PGDH); 15-keto-PGE2; p21; PPARγ; liver
12.  Endosomolytic reducible polymeric electrolytes for cytosolic protein delivery 
Biomacromolecules  2013;14(8):2570-2581.
Despite the numerous vital functions of proteins in the cytosolic compartment, less attention has been paid to the delivery of protein drugs to the cytosol than to the plasma membrane. To address this issue and effectively deliver charged proteins into the cytoplasm, we used endosomolytic, thiol-triggered degradable polyelectrolytes as carriers. The cationic, reducible polyelectrolyte RPC-bPEI0.8kDa2 was synthesized by the oxidative polymerization of thiolated branched polyethyleneimine (bPEI). The polymer was converted to the anionic, reducible polyelectrolyte RPA-bPEI0.8kDa2 by introducing carboxylic acids. The two reducible polyelectrolytes (RPC-bPEI0.8kDa2 and RPA-bPEI0.8kDa2) were complexed with counter-charged model proteins (bovine serum albumin (BSA) and lysozyme (LYZ)), forming polyelectrolyte/protein complexes of less than 200 nm in size at weight ratios (WR) of ≥ 1. The resultant complexes maintained a proton buffering capacity nearly equivalent to that of the polyelectrolytes in the absence of protein complexation and were cytocompatible with MCF7 human breast carcinoma cells. Under cytosol-mimicking thiol-rich conditions, RPC-bPEI0.8kDa2/BSA and RPA-bPEI0.8kDa2/LYZ complexes increased significantly in size and released the loaded protein, unlike the protein complexes with non-reducible polyelectrolytes (bPEI25kDa and bPEI25kDaCOOH). The polyelectrolyte/protein complexes showed similar cellular uptake to the corresponding proteins alone, but the former allowed more protein to escape into the cytosol from endolysosomes than the latter as a result of the endosomolytic function of the polyelectrolytes. In addition, the proteins in the polyelectrolyte/protein complexes kept their intrinsic secondary structures. In conclusion, the results show the potential of the designed endosomolytic, reducible polyelectrolytes for the delivery of proteins to the cytosol.
PMCID: PMC3759265  PMID: 23841591
Cytosolic delivery; Endosomolytic polymer; Polyelectrolyte; Polyethyleneimine; Protein delivery; Reducible polymer
13.  Isoniazid Could Be Used for Antibiotic-loaded Bone Cement for Musculoskeletal Tuberculosis: An In Vitro Study 
Antibiotic-loaded bone cement (ALBC) has been used in serious cases of musculoskeletal tuberculosis, but the type and amount of antibiotic that should be used in ALBC have not been determined.
We therefore determined the (1) elution characteristics and (2) antimycobacterial activity of isoniazid- and rifampicin-loaded bone cement.
A total of 240 elution samples of each of three discs from 40 g bone cement mixed with one of eight dosages: 1 g, 2 g, and 4 g isoniazid, 1 g, 2 g, and 4 g rifampicin, and a combination of 1 + 1 g or 2 + 2 g of isoniazid and rifampicin. The polymerization of rifampicin-loaded bone cement was delayed to mean 122.5 ± 31.1 minutes. We measured the quantity of isoniazid and rifampicin and the antimycobacterial activity on Days 1, 3, 7, 14, and 30.
Isoniazid eluted in almost all the samples while rifampicin was detected only on Day 1 with 2 g (0.7 ± 0.4 ug/mL/day), and until Day 14 with 4 g (0.1 ± 0.0u g/mL/day). Most of the samples containing isoniazid showed antimycobacterial activity while the samples containing rifampicin showed antimycobacterial activity only on Day 1 with 1 g (0.52 ± 0.18 ug/mL), until Day 14 with 2 g (0.03 ± 0.00 ug/mL), and until Day 30 with 4 g (1.84 ± 1.90 ug/mL).
Rifampicin was unsuitable for ALBC because of its delayed polymerization. Isoniazid eluted and showed antimycobacterial activity for 30 days.
Clinical Relevance
The data suggest isoniazid could be considered for use in ALBC for musculoskeletal tuberculosis if used with systemic treatment. For preventing resistance and systemic toxicity, a combination with a second-line drug and an in vivo study would be needed.
PMCID: PMC3676586  PMID: 23504536
14.  Effects of resveratrol on the insulin signaling pathway of obese mice 
Journal of Veterinary Science  2014;15(2):179-185.
The present study was conducted to investigate the effects of resveratrol on the insulin signaling pathway in the liver of obese mice. To accomplish this, we administered resveratrol to high fat diet-induced obese mice and examined the levels of protein phosphorylation in the liver using an antibody array. The phosphorylation levels of 10 proteins were decreased in the high fat diet and resveratrol (HFR) fed group relative to the levels in the high fat diet (HF) fed group. In contrast, the phosphorylation levels of more than 20 proteins were increased in the HFR group when compared with the levels of proteins in the HF group. Specifically, the phosphorylation levels of Akt (The308, Tyr326, Ser473) were restored to normal by resveratrol when compared with the levels in the HF group. In addition, the phosphorylation levels of IRS-1 (Ser636/Ser639), PI-3K p85-subunit α/γ(Tyr467/Tyr199), PDK1 (Ser241), GSK-3α (S21) and GSK-3 (Ser9), which are involved in the insulin signaling pathway, were decreased in the HF group, whereas the levels were restored to normal in the HFR group. Overall, the results show that resveratrol restores the phosphorylation levels of proteins involved in the insulin signaling pathway, which were decreased by a high fat diet.
PMCID: PMC4087218  PMID: 24675832
Akt phosphorylation; antibody array; insulin signaling pathway; obese mice; resveratrol
15.  Avatar DNA Nanohybrid System in Chip-on-a-Phone 
Scientific Reports  2014;4:4879.
Long admired for informational role and recognition function in multidisciplinary science, DNA nanohybrids have been emerging as ideal materials for molecular nanotechnology and genetic information code. Here, we designed an optical machine-readable DNA icon on microarray, Avatar DNA, for automatic identification and data capture such as Quick Response and ColorZip codes. Avatar icon is made of telepathic DNA-DNA hybrids inscribed on chips, which can be identified by camera of smartphone with application software. Information encoded in base-sequences can be accessed by connecting an off-line icon to an on-line web-server network to provide message, index, or URL from database library. Avatar DNA is then converged with nano-bio-info-cogno science: each building block stands for inorganic nanosheets, nucleotides, digits, and pixels. This convergence could address item-level identification that strengthens supply-chain security for drug counterfeits. It can, therefore, provide molecular-level vision through mobile network to coordinate and integrate data management channels for visual detection and recording.
PMCID: PMC4019957  PMID: 24824876
16.  Hemodynamic responses in rat brain during transcranial direct current stimulation: a functional near-infrared spectroscopy study 
Biomedical Optics Express  2014;5(6):1812-1821.
In the present study, we monitored hemodynamic responses in rat brains during transcranial direct current stimulation (tDCS) using functional near-infrared spectroscopy (fNIRS). Seven rats received transcranial anodal stimulation with 200 μA direct current (DC) on their right barrel cortex for 10 min. The concentration changes of oxygenated hemoglobin (oxy-Hb) were continuously monitored during stimulation (10 min) and after stimulation (20 min). The trend of hemodynamic response changes was modeled using linear regression, and the relationship between incremental and decremental rates of oxy-Hb was investigated by correlation analysis. Our results showed that the oxy-Hb concentration was almost linearly increased and decreased during and after stimulation, respectively. In addition, a significant negative correlation (p < 0.05) was found between the rate of increase of oxy-Hb during stimulation and the rate of decrease of oxy-Hb after stimulation, indicating that the recovery time after tDCS may not depend on the total amount of hemodynamic changes in the stimulated brain area. Our results also demonstrated considerable individual variability in the rate of change of hemodynamic responses even with the same direct current dose to identical brain regions. This suggests that individual differences in tDCS after-effects may originate from intrinsic differences in the speed of DC stimulation “uptake” rather than differences in the total capacity of DC uptake, and thus the stimulation parameters may need to be customized for each individual in order to maximize tDCS after-effects.
PMCID: PMC4052913  PMID: 24940542
(170.0170) Medical optics and biotechnology; (170.2655) Functional monitoring and imaging; (170.6510) Spectroscopy, tissue diagnostics
17.  Apolipoprotein A-I and HDL Have Anti-Inflammatory Effects on Adipocytes via Cholesterol Transporters: ATP-Binding Cassette (ABC) A-1, ABCG-1 and Scavenger Receptor B-1(SRB-1) 
Circulation research  2013;112(10):1345-1354.
Macrophage accumulation in adipose tissue associates with insulin resistance and increased cardiovascular disease risk. We previously have shown that generation of reactive oxygen species (ROS) and monocyte chemotactic factors after exposure of adipocytes to saturated fatty acids (SFAs) such as palmitate occurs via translocation of NADPH oxidase 4 (NOX4) into lipid rafts (LRs). The anti-inflammatory effects of apolipoprotein A-I (apoA-I) and HDL on macrophages and endothelial cells appears to occur via cholesterol depletion of LRs. However, little is known concerning anti-inflammatory effects of HDL and apoA-I on adipocytes.
To determine whether apoA-I and HDL inhibit inflammation in adipocytes and adipose tissue, and whether this is dependent on LRs.
Methods and Results
In 3T3L-1 adipocytes, apoA-I, HDL and methyl-β-cyclodextrin inhibited chemotactic factor expression. ApoA-I and HDL also disrupted LRs, reduced plasma membrane cholesterol content, inhibited NOX4 translocation into LRs, and reduced palmitate-induced ROS generation and monocyte chemotactic factor expression. Silencing ABCA-1 abrogated the effect of apoA-I, but not HDL, while silencing ABCG-1 or SRB-1 abrogated the effect of HDL but not apoA-I. In vivo, apoA-I transgenic mice fed a high fat, high sucrose, cholesterol-containing diet showed reduced chemotactic factor and pro-inflammatory cytokine expression and reduced macrophage accumulation in adipose tissue.
ApoA-I and HDL have anti-inflammatory effects in adipocytes and adipose tissue similar to their effects in other cell types. These effects are consistent with disruption and removal of cholesterol from LRs, which are regulated by cholesterol transporters such as ABCA-1, ABCG-1 and SRB-1.
PMCID: PMC3767575  PMID: 23501697
Adipocytes; ABC transporters; cholesterol; HDL; Apolipoprotein A-I
18.  Antimicrobial Susceptibility Pattern and Epidemiology of Female Urinary Tract Infections in South Korea, 2010-2011 
Antimicrobial Agents and Chemotherapy  2013;57(11):5384-5393.
This study aimed to (i) investigate the antimicrobial susceptibilities of bacteria that cause urinary tract infections (UTIs) in outpatient and inpatient settings and (ii) evaluate the risk factors for emerging antimicrobial drug resistance in UTIs in South Korea. In total, 3,023 samples without duplication were collected from females between 25 and 65 years of age who had been diagnosed with a urinary tract infection. Multicenter patient data were collected using a Web-based electronic system and then evaluated. The isolation rates of Escherichia coli, Klebsiella pneumoniae, and Enterococcus faecium in the outpatient setting were 78.1, 4.7, and 1.3%, respectively; in the inpatient setting, the isolation rates of these microorganisms were 37.8, 9.9, and 14.8%, respectively. The susceptibilities of E. coli to amikacin, amoxicillin-clavulanic acid, cefotaxime, cefoxitin, ciprofloxacin, piperacillin-tazobactam, and imipenem in the outpatient setting were 99.4, 79.8, 89.4, 92.8, 69.8, 96.9, and 100.0%, respectively; in the inpatient setting, the susceptibilities to these antibiotics were 97.8, 73.9, 73.7, 82.1, 53.6, 93.2, and 100.0%, respectively. The most unique and common risk factor for emerging antimicrobial-resistant E. coli, K. pneumoniae, and E. faecium was previous exposure to antimicrobials. On the basis of these data, the use of fluoroquinolones should be reserved until culture data are available for the treatment of UTIs in South Korea. The present study will serve as a useful reference for Far Eastern Asia.
PMCID: PMC3811252  PMID: 23959315
19.  Enhancement of Platelet Aggregation by Ursolic Acid and Oleanolic Acid 
Biomolecules & Therapeutics  2014;22(3):254-259.
The pentacyclic triterpenoid ursolic acid (UA) and its isomer oleanolic acid (OA) are ubiquitous in food and plant medicine, and thus are easily exposed to the population through natural contact or intentional use. Although they have diverse health benefits, reported cardiovascular protective activity is contentious. In this study, the effect of UA and OA on platelet aggregation was examined on the basis that alteration of platelet activity is a potential process contributing to cardiovascular events. Treatment of UA enhanced platelet aggregation induced by thrombin or ADP, which was concentration-dependent in a range of 5–50 μM. Quite comparable results were obtained with OA, in which OA-treated platelets also exhibited an exaggerated response to either thrombin or ADP. UA treatment potentiated aggregation of whole blood, while OA failed to increase aggregation by thrombin. UA and OA did not affect plasma coagulation assessed by measuring prothrombin time and activated partial thromboplastin time. These results indicate that both UA and OA are capable of making platelets susceptible to aggregatory stimuli, and platelets rather than clotting factors are the primary target of them in proaggregatory activity. These compounds need to be used with caution, especially in the population with a predisposition to cardiovascular events.
PMCID: PMC4060080  PMID: 25009707
Ursolic acid; Oleanolic acid; Platelet aggregation
20.  Gradient Microfluidics Enables Rapid Bacterial Growth Inhibition Testing 
Analytical Chemistry  2014;86(6):3131-3137.
Bacterial growth inhibition tests have become a standard measure of the adverse effects of inhibitors for a wide range of applications, such as toxicity testing in the medical and environmental sciences. However, conventional well-plate formats for these tests are laborious and provide limited information (often being restricted to an end-point assay). In this study, we have developed a microfluidic system that enables fast quantification of the effect of an inhibitor on bacteria growth and survival, within a single experiment. This format offers a unique combination of advantages, including long-term continuous flow culture, generation of concentration gradients, and single cell morphology tracking. Using Escherichia coli and the inhibitor amoxicillin as one model system, we show excellent agreement between an on-chip single cell-based assay and conventional methods to obtain quantitative measures of antibiotic inhibition (for example, minimum inhibition concentration). Furthermore, we show that our methods can provide additional information, over and above that of the standard well-plate assay, including kinetic information on growth inhibition and measurements of bacterial morphological dynamics over a wide range of inhibitor concentrations. Finally, using a second model system, we show that this chip-based systems does not require the bacteria to be labeled and is well suited for the study of naturally occurring species. We illustrate this using Nitrosomonas europaea, an environmentally important bacteria, and show that the chip system can lead to a significant reduction in the period required for growth and inhibition measurements (<4 days, compared to weeks in a culture flask).
PMCID: PMC3988682  PMID: 24548044
21.  A reusable evanescent wave immunosensor for highly sensitive detection of bisphenol A in water samples 
Scientific Reports  2014;4:4572.
This paper proposed a compact and portable planar waveguide evanescent wave immunosensor (EWI) for highly sensitive detection of BPA. The incident light is coupled into the planar waveguide chip via a beveled angle through undergoing total internal reflection, where the evanescent wave field forms and excites the binding fluorophore-tagged antibodies on the chip surface. Typical calibration curves obtained for BPA has detection limits of 0.03 μg/L. Linear response for BPA ranged from 0.124 μg/L–9.60 μg/L with 50% inhibition concentration for BPA of 1.09 ± 0.25 μg/L. The regeneration of the planar optical waveguide chip allows the performance of more than 300 assay cycles within an analysis time of about 20 min for each assay cycle. By application of effective pretreatment procedure, the recoveries of BPA in real water samples gave values from 88.3% ± 8.5% to 103.7% ± 3.5%, confirming its application potential in the measurement of BPA in reality.
PMCID: PMC3975238  PMID: 24699239
22.  Family Economic Empowerment and Mental Health Among AIDS-Affected Children Living in AIDS-Impacted Communities: Evidence from a Randomized Evaluation in Southwestern Uganda 
We examine whether an innovative family economic empowerment intervention addresses mental health functioning of AIDS-affected children in communities heavily impacted by HIV/AIDS in Uganda.
A cluster randomized controlled trial (RCT) consisting of two study arms: a treatment condition (n=179) and a control condition (n=118) was used to examine the impact of the family economic empowerment intervention on children’s levels of hopelessness and depression. The intervention comprised of matched children savings accounts, financial management workshops, and mentorship. Data were collected at baseline and 12 months post-intervention.
Using multivariate analysis with several socio-economic controls, we find that children in the treatment condition (receiving the intervention) report significant improvement in their mental health functioning. Specifically, the intervention reduces hopelessness and depression levels. On the other hand, children in the control condition (not receiving the intervention) report no changes on both measures.
The findings indicate that children with poor mental health functioning living in communities affected by HIV/AIDS may benefit from innovative family economic empowerment interventions. As measures of mental health functioning, both hopelessness and depression have long-term negative psychosocial and developmental impacts on children. These findings have implications for public health programs intended for long-term care and support of children living in resource poor, AIDS-impacted communities.
PMCID: PMC3578660  PMID: 23410851
23.  Periarticular Injection with Corticosteroid Has an Additional Pain Management Effect in Total Knee Arthroplasty 
Yonsei Medical Journal  2014;55(2):493-498.
Although the analgesic effects of corticosteroids have been well documented, little information is available on periarticular injection (PI) containing corticosteroids for early postoperative pain management after total knee arthroplasty (TKA). We performed a prospective double-blind randomized trial to evaluate the efficacy and safety of an intraoperative corticosteroid PI in patients undergoing TKA.
Materials and Methods
Seventy-six consecutive female patients undergoing bilateral staged TKA were randomized to receive steroid or non-steroid PI, with 3 months separating the procedures. The steroid group received PI with a mixture containing triamcinolone acetonide (40 mg). The non-steroid group received the same injection mixture without corticosteroid. During the postoperative period, nighttime pain, functional recovery [straight leg raising (SLR) ability and maximal flexion], patient satisfaction, and complications were recorded. Short-term postoperative clinical scores and patient satisfaction were evaluated at 6 months.
The pain level was significantly lower in the PI steroid than the non-steroid group on the night of the operation (VAS, 1.2 vs. 2.3; p=0.021). Rebound pain was observed in both groups at POD1 (VAS, 3.2 vs. 3.8; p=0.248), but pain remained at a low level thereafter. No significant differences were seen in maximal flexion, frequency of acute rescuer, clinical scores, and patient satisfaction. The steroid group was able to perform SLR earlier than the non-steroid group (p=0.013). The incidence of complications was similar between the groups.
PI containing a corticosteroid provided an additional pain-relieving effect on the night of the operation. In addition, corticosteroid PI did not increase the perioperative complications of TKA.
PMCID: PMC3936618  PMID: 24532523
Corticosteroid; periarticular injection; pain; total knee arthroplasty
24.  Seoritae Extract Reduces Prostate Weight and Suppresses Prostate Cell Proliferation in a Rat Model of Benign Prostate Hyperplasia 
Seoritae is a type of black soybean that is known to have health-promoting effects due to its high isoflavone and anthocyanin contents. We evaluated whether Seoritae extract (SE) had beneficial effects on the reduction of prostate weight in a rat model of benign prostatic hyperplasia (BPH). BPH was induced by intramuscular injections of testosterone enanthate once a week for 5 weeks in Sprague-Dawley rats, and rats were treated with or without daily oral doses of SE during BPH induction. After 5 weeks, the oxidative stress (superoxide dismutase and 8-hydroxy-2-deoxyguanosine), apoptosis (caspase-3), and activity of 5-alpha reductase were evaluated in the serum and prostate. The SE treatment group showed a significant decrease in prostate weight, oxidative stress, apoptosis, and 5-alpha reductase activity compared to the nontreated BPH group. These results show that SE is effective in decreasing the weight and proliferation of the prostate, and suggest that SE may be an effective treatment for BPH.
PMCID: PMC3950473  PMID: 24701239
25.  Large-scale synthesis of highly emissive and photostable CuInS2/ZnS nanocrystals through hybrid flow reactor 
We report a high-yield, low-cost synthesis route to colloidal CuInS2/ZnS (CIS/ZnS) nanocrystals (NCs) with Cu vacancies in the crystal lattice. Yellow-emitting CIS/ZnS core/shell NCs of high luminescence were facilely synthesized via a stepwise, consecutive hybrid flow reactor approach. It is based on serial combination of a batch-type mixer and a flow-type furnace. In this reactor, the flow rate of the solutions was typically 1 mL/min, 100 times larger than that of conventional microfluidic reactors. This method can produce gram quantities of material with a chemical yield in excess of 90% with minimal solvent waste. This is a noninjection-based approach in 1-dodecanethiol (DDT) with excellent synthetic reproducibility and large-scale capability. The optical features and structure of the obtained CIS/ZnS NCs have been characterized by UV–vis and fluorescence spectroscopies, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), energy-dispersive X-ray spectroscopy (EDX) and high-resolution transmission electron microscopy (HRTEM). The resulting CIS/ZnS NCs in chloroform exhibit quantum yield (QY) of 61.4% with photoemission peaking at 561 nm and full width at half maximum (FWHM) of 92 nm. The as-synthesized CIS/ZnS NCs were proven to have excellent photostability. The synthesized CIS/ZnS NCs can be a promising fluorescent probe for biological imaging and color converting material for light-emitting diode due to Cd-free constituents.
PMCID: PMC3996094  PMID: 24533662
CuInS2/ZnS nanocrystals; Hybrid flow reactor; Large-scale synthesis; Photostability

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