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1.  Cellular Anti-Melanogenic Effects of a Euryale ferox Seed Extract Ethyl Acetate Fraction via the Lysosomal Degradation Machinery 
The aim of this study was to investigate the effect of ethyl acetate fraction of Euryale ferox seed extracts (Efse-EA) on melanogenesis in immortalized mouse melanocyte cell line, melan-a. Efse-EA showed strong dose-dependent mushroom tyrosinase inhibitory activity. Treatment of melan-a cells with 30 μg/mL Efse-EA produced strong inhibition of cellular tyrosinase and melanin synthesis. Efse-EA significantly reduced the levels of melanogenesis-related proteins, such as tyrosinase, tyrosinase-related proteins 1 and 2, and microphthalmia-associated transcription factor. Because Efse-EA treatment reduced tyrosinase protein levels without changing its mRNA expression, we investigated whether this decrease was related to proteasomal or lysosomal degradation of tyrosinase. We found that chloroquine, a lysosomal proteolysis inhibitor, almost completely abolished both the down-regulation of tyrosinase and the inhibition of melanin synthesis induced by Efse-EA. These results suggested that Efse-EA may contribute to the inhibition of melanogenesis by altering lysosomal degradation of tyrosinase, and that this extract may provide a new cosmetic skin-whitening agent.
PMCID: PMC4463586  PMID: 25915032
Euryale ferox; seed; melanin; tyrosinase; lysosomal degradation
2.  Anti-inflammatory effects of Cordyceps mycelium (Paecilomyces hepiali, CBG-CS-2) in Raw264.7 murine macrophages 
Cordyceps (CS) is a traditional Chinese herb with various biological effects that include immune modulation. CBG-CS-2 is a strain, Paecilomyces hepiali, of the Cordyceps spp. The anti-inflammatory effects of CBG-CS-2 were investigated. The water-soluble fraction of CBG-CS-2 has high anti-inflammatory activity in LPS-induced Raw264.7 macrophages. We tested the role of CBG-CS-2 on the anti-inflammation cascade in LPS-stimulated Raw264.7 cells. CBG-CS-2 significantly decreased NO production, iNOS expression, and pro-inflammatory cytokine secretion in a dose-dependent manner. To investigate the mechanism by which CBG-CS-2 inhibits NO, iNOS, and pro-inflammatory cytokines, we examined the activities of NF-κB and AP-1 in LPS-activated macrophages. The results demonstrate that CBG-CS-2 suppresses the production and expression of NO, iNOS, and pro-inflammatory cytokines in LPS-activated macrophages via inhibition of NF-κB and AP-1, which may play an important role in inflammation. These findings suggest that CBG-CS-2 has modulatory effects on the inflammatory system in macrophages, and that it can serve as a useful anti-inflammatory dietary supplement or drug.
PMCID: PMC4371127  PMID: 25814919
Cordyceps; Paecilomyces hepiali; Anti-inflammation; CBG-CS-2
3.  Etanercept for steroid-refractory acute graft versus host disease following allogeneic hematopoietic stem cell transplantation 
The treatment for steroid-refractory acute graft versus host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT) needs to be standardized. We report our clinical experience with etanercept for steroid-refractory acute GVHD.
Eighteen patients who underwent allo-SCT and presented with steroid-refractory acute GVHD at Ajou University Hospital were studied retrospectively. They were given 25 mg of etanercept subcutaneously twice weekly for 4 weeks. The clinical responses were evaluated with regard to the severity of acute GVHD.
The median patient age was 43.5 years. Using nonparametric tests, etanercept had a down-grading effect on acute GVHD (p = 0.005), although no patient experienced complete remission. Partial responses were seen in 80%, 17%, and 57% of grade II to IV patients, respectively. Skin and gut GVHD were well controlled with etanercept, whereas hepatic GVHD was not. Four patients died of fatal infections. No factors affecting the clinical outcome of etanercept were identified.
Etanercept has a modest effect on steroid-refractory acute GVHD after allo-SCT, with tolerable side effects.
PMCID: PMC4164727  PMID: 25228839
Stem cell transplantation; Graft vs host disease; TNFR-Fc fusion protein
4.  Effects of Atomoxetine on Hyper-Locomotive Activity of the Prenatally Valproate-Exposed Rat Offspring 
Biomolecules & Therapeutics  2014;22(5):406-413.
A substantial proportion of patients with autism spectrum disorder (ASD) display hyperactivity as a comorbid symptom. Exposure to valproic acid (VPA) during pregnancy produces ASD-like core behavioral phenotypes as well as hyperactivity in offspring both in human and experimental animals, which makes it a plausible model to study ASD-related neurobiological processes. In this study, we examined the effects of two of currently available attention defecit hyperactivity disorder (ADHD) medications, methylphenidate (MPH) and atomoxetine (ATX) targeting dopamine and norepinephrine transporters (DAT and NET), respectively, on hyperactive behavior of prenatally VPA-exposed rat offspring. In the prefrontal cortex of VPA exposed rat offspring, both mRNA and protein expression of DAT was increased as compared with control. VPA function as a histone deacetylase inhibitor (HDACi) and chromatin immunoprecipitation experiments demonstrated that the acetylation of histone bound to DAT gene promoter was increased in VPA-exposed rat offspring suggesting epigenetic mechanism of DAT regulation. Similarly, the expression of NET was increased, possibly via increased histone acetylation in prefrontal cortex of VPA-exposed rat offspring. When we treated the VPA-exposed rat offspring with ATX, a NET selective inhibitor, hyperactivity was reversed to control level. In contrast, MPH that inhibits both DAT and NET, did not produce inhibitory effects against hyperactivity. The results suggest that NET abnormalities may underlie the hyperactive phenotype in VPA animal model of ASD. Profiling the pharmacological responsiveness as well as investigating underlying mechanism in multiple models of ASD and ADHD may provide more insights into the neurobiological correlates regulating the behavioral abnormalities.
PMCID: PMC4201219  PMID: 25414770
Valproic acid; Autism; Hyperactivity; Norepinephrine transporter; Atomoxetine
5.  Subchronic Treatment of Donepezil Rescues Impaired Social, Hyperactive, and Stereotypic Behavior in Valproic Acid-Induced Animal Model of Autism 
PLoS ONE  2014;9(8):e104927.
Autism spectrum disorder (ASD) is a group of pervasive developmental disorders with core symptoms such as sociability deficit, language impairment, and repetitive/restricted behaviors. Although worldwide prevalence of ASD has been increased continuously, therapeutic agents to ameliorate the core symptoms especially social deficits, are very limited. In this study, we investigated therapeutic potential of donepezil for ASD using valproic acid-induced autistic animal model (VPA animal model). We found that prenatal exposure of valproic acid (VPA) induced dysregulation of cholinergic neuronal development, most notably the up-regulation of acetylcholinesterase (AChE) in the prefrontal cortex of affected rat and mouse offspring. Similarly, differentiating cortical neural progenitor cell in culture treated with VPA showed increased expression of AChE in vitro. Chromatin precipitation experiments revealed that acetylation of histone H3 bound to AChE promoter region was increased by VPA. In addition, other histone deacetyalse inhibitors (HDACIs) such as trichostatin A and sodium butyrate also increased the expression of AChE in differentiating neural progenitor cells suggesting the essential role of HDACIs in the regulation of AChE expression. For behavioral analysis, we injected PBS or donepezil (0.3 mg/kg) intraperitoneally to control and VPA mice once daily from postnatal day 14 all throughout the experiment. Subchronic treatment of donepezil improved sociability and prevented repetitive behavior and hyperactivity of VPA-treated mice offspring. Taken together, these results provide evidence that dysregulation of ACh system represented by the up-regulation of AChE may serve as an effective pharmacological therapeutic target against autistic behaviors in VPA animal model of ASD, which should be subjected for further investigation to verify the clinical relevance.
PMCID: PMC4136791  PMID: 25133713
6.  Postprandial glucose-lowering effects of fermented red ginseng in subjects with impaired fasting glucose or type 2 diabetes: a randomized, double-blind, placebo-controlled clinical trial 
Red ginseng is prepared by steaming raw ginseng, a process believed to increase the pharmacological efficacy. Further bioconversion of red ginseng through fermentation is known to increase its intestinal absorption and bioactivity, and bioconversion diminishes the toxicity of red ginseng’s metabolite. This study was conducted to investigate the effects of daily supplementation with fermented red ginseng (FRG) on glycemic status in subjects with impaired fasting glucose or type 2 diabetes.
This study was a four-week long, randomized, double-blind, placebo-controlled trial. Forty-two subjects with impaired fasting glucose or type 2 diabetes were randomly allocated to two groups assigned to consume either the placebo or fermented red ginseng (FRG) three times per day for four weeks. Fasting and postprandial glucose profiles during meal tolerance tests were assessed before and after the intervention.
FRG supplementation led to a significant reduction in postprandial glucose levels and led to an increase in postprandial insulin levels compared to the placebo group. There was a consistently significant improvement in the glucose area under the curve (AUC) in the FRG group. However, fasting glucose, insulin, and lipid profiles were not different from the placebo group.
Daily supplementation with FRG lowered postprandial glucose levels in subjects with impaired fasting glucose or type 2 diabetes.
Trial registration NCT01826409
PMCID: PMC4227112  PMID: 25015735
Fermented red ginseng; Type 2 diabetes; Impaired fasting glucose; Postprandial glucose
7.  An 8-wk, randomized, double-blind, placebo-controlled clinical trial for the antidiabetic effects of hydrolyzed ginseng extract 
Journal of Ginseng Research  2014;38(4):239-243.
To investigate the antidiabetic effects of hydrolyzed ginseng extract (HGE) for Korean participants in an 8-wk, randomized, double-blinded, placebo-controlled clinical trial.
Impaired fasting glucose participants [fasting plasma glucose (FPG) ≥ 5.6mM or < 6.9mM] who had not been diagnosed with any disease and met the inclusion criteria were recruited for this study. The 23 participants were randomly divided into either the HGE (n = 12, 960 mg/d) or placebo (n = 11) group. Outcomes included measurements of efficacy (FPG, postprandial glucose, fasting plasma insulin, postprandial insulin, homeostatic model assessment-insulin resistance, and homeostatic model assessment-β) and safety (adverse events, laboratory tests, electrocardiogram, and vital signs).
After 8 wk of HGE supplementation, FPG and postprandial glucose were significantly decreased in the HGE group compared to the placebo group. No clinically significant changes in any safety parameter were observed. Our study revealed that HGE is a potent antidiabetic agent that does not produce noticeable adverse effects.
HGE supplementation may be effective for treating impaired fasting glucose individuals.
PMCID: PMC4213818  PMID: 25379002
clinical trial; hydrolyzed ginseng extract; impaired fasting glucose; oral glucose tolerance test; Panax ginseng
8.  The influence of the Korean traditional Chungkookjang on variables of metabolic syndrome in overweight/obese subjects: study protocol 
Metabolic syndrome is a set of disorders that increases the risk of developing cardiovascular disease. The primary target of treatment of patients with metabolic syndrome is therapeutic lifestyle change. Numerous preclinical study have reported positive effects of chungkookjang in in vivo models of diabetes and obesity, but there is a paucity of controlled clinical trials on variables of metabolic syndrome in obese subjects. Thus, the objective of this trial is to examine the effect of chungkookjang compared to placebo on variables of metabolic syndrome in overweight/obese subjects.
This double-blind randomized controlled crossover trial will be conducted on 120 overweight/obese subjects; aged 19–29 years. Subjects will be recruited from the Chonbuk National University, Jeonju, South Korea. Enrolled subjects will be randomly assigned to two groups of equal number; one group received 35 g of chungkookjang (n = 60) and the other group received placebo (n = 60) on a regular daily basis for 12 weeks. After a 12-week washout period, the groups will be crossed over. In addition to anthropometric measures and blood pressure, glucose parameter, lipid profile, adipocytokine, and carnitine assay will be determined at baseline and 12 week. Also, safety will be assessing by measuring total bilirubin, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, total protein, albumin, blood urea nitrogen, creatinine, and creatine kinase at baseline and 12 weeks. 24-hour dietary recalls were collected at the baseline and at the end of the trial.
This trial will evaluate the effects of chungkookjang on variables of metabolic syndrome in overweight/obese subjects. The results of this study may contribute to the reduction of risk factor for metabolic syndrome caused by obesity.
Trial registration
Clinical trials NCT01811511.
PMCID: PMC3827839  PMID: 24171779
Chungkookjang; Metabolic syndrome; Overweight; Obesity; Diabetes
9.  Gastrointestinal Tract Abnormalities Induced by Prenatal Valproic Acid Exposure in Rat Offspring 
Toxicological Research  2013;29(3):173-179.
In-utero exposure to valproic acid (VPA) has been known as a potent inducer of autism spectrum disorder (ASD), not only in humans, but also in animals. In addition to the defects in communication and social interaction as well as repetitive behaviors, ASD patients usually suffer from gastrointestinal (GI) problems. However, the exact mechanism underlying these disorders is not known. In this study, we examined the gross GI tract structure and GI motility in a VPA animal model of ASD. On embryonic day 12 (E12), 4 pregnant Sprague-Dawley (SD) rats were subcutaneously injected with VPA (400 mg/kg) in the treatment group, and with phosphate buffered saline (PBS) in the control group; the resulting male offspring were analyzed at 4 weeks of age. VPA exposure decreased the thickness of tunica mucosa and tunica muscularis in the stomach and ileum. Other regions such as duodenum, jejunum, and colon did not show a significant difference. In high-resolution microscopic observation, atrophy of the parietal and chief cells in the stomach and absorptive cells in the ileum was observed. In addition, decreased staining of the epithelial cells was observed in the hematoxylin and eosin (H&E)-stained ileum section. Furthermore, decreased motility in GI tract was also observed in rat offspring prenatally exposed to VPA. However, the mechanism underlying GI tract defects in VPA animal model as well as the association between abnormal GI structure and function with ASD is yet to be clearly understood. Nevertheless, the results from the present study suggest that this VPA ASD model undergoes abnormal changes in the GI structure and function, which in turn could provide beneficial clues pertaining to the pathophysiological relevance of GI complications and ASD phenotypes.
PMCID: PMC3877996  PMID: 24386517
Valproic acid; ASD; GI motility; GI thickness; Epithelial cells
10.  The effectiveness of fermented turmeric powder in subjects with elevated alanine transaminase levels: a randomised controlled study 
Previous animal studies have shown that Curcuma longa (turmeric) improves liver function. Turmeric may thus be a promising ingredient in functional foods aimed at improving liver function. The purpose of the study is to investigate the hepatoprotective effect of fermented turmeric powder (FTP) on liver function in subjects with elevated alanine transaminase (ALT) levels.
A randomised, double-blind, placebo-controlled trial was conducted between November 2010 and April 2012 at the clinical trial center for functional foods of the Chonbuk National University Hospital. The trial included 60 subjects, 20 years old and above, who were diagnosed mild to moderate elevated ALT levels between 40 IU/L and 200 IU/L. Sixty subjects were randomised to receive FTP 3.0 g per day or placebo 3.0 g per day for 12 weeks. The treatment group received two capsules of FTP three times a day after meals, for 12 weeks. The primary efficacy endpoint was change in the ALT levels in the two groups. The secondary efficacy endpoints included its effect on aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), total bilirubin (TB), and lipid profiles. Safety was assessed throughout the study using ongoing laboratory tests. Adverse events (AEs) were also recorded.
Sixty subjects were randomised in the study (30 into the FTP group, 30 into the placebo group), and among them, twelve subjects were excluded from the analysis for protocol violation, adverse events or consent withdrawal. The two groups did not differ in baseline characteristics. After 12 weeks of treatment, 48 subjects were evaluated. Of the 48 subjects, 26 randomly received FTP capsules and 22 received placebo. The FTP group showed a significant reduction in ALT levels after 12 weeks of treatment compared with the placebo group (p = 0.019). There was also observed that the serum AST levels were significantly reduce in the FTP group than placebo group (p = 0.02). The GGT levels showed a tendency to decrease, while the serum alkaline phosphatase (ALP), TB, and lipids levels were not modified. There were no reported severe AEs during this study, or abnormalities observed on blood glucose, total protein, albumin, blood urea nitrogen (BUN), and creatinine levels.
The data of this trial indicate that FTP is effective and safe, generally well-tolerated without severe AEs, in the treatment of subjects with elevated ALT levels over a 12 weeks period.
Trial registration http://NCT01634256
PMCID: PMC3600681  PMID: 23497020
11.  Transcriptional Upregulation of Plasminogen Activator Inhibitor-1 in Rat Primary Astrocytes by a Proteasomal Inhibitor MG132 
Biomolecules & Therapeutics  2013;21(2):107-113.
Plasminogen activator inhibitor-1 (PAI-1) is a member of serine protease inhibitor family, which regulates the activity of tissue plasminogen activator (tPA). In CNS, tPA/PAI-1 activity is involved in the regulation of a variety of cellular processes such as neuronal development, synaptic plasticity and cell survival. To gain a more insights into the regulatory mechanism modulating tPA/PAI-1 activity in brain, we investigated the effects of proteasome inhibitors on tPA/PAI-1 expression and activity in rat primary astrocytes, the major cell type expressing both tPA and PAI-1. We found that submicromolar concentration of MG132, a cell permeable peptide-aldehyde inhibitor of ubiquitin proteasome pathway selectively upregulates PAI-1 expression. Upregulation of PAI-1 mRNA as well as increased PAI-1 promoter reporter activity suggested that MG132 transcriptionally increased PAI-1 expression. The induction of PAI-1 downregulated tPA activity in rat primary astrocytes. Another proteasome inhibitor lactacystin similarly increased the expression of PAI-1 in rat primary astrocytes. MG132 activated MAPK pathways as well as PI3K/Akt pathways. Inhibitors of these signaling pathways reduced MG132-mediated upregulation of PAI-1 in varying degrees and most prominent effects were observed with SB203580, a p38 MAPK pathway inhibitor. The regulation of tPA/PAI-1 activity by proteasome inhibitor in rat primary astrocytes may underlie the observed CNS effects of MG132 such as neuroprotection.
PMCID: PMC3762318  PMID: 24009867
MG132; Lactacystin; p38; Plasminogen activator inhibitor-1; Tissue plasminogen activator
12.  Preventive Effect of Korean Red Ginseng for Acute Respiratory Illness: A Randomized and Double-Blind Clinical Trial 
Journal of Korean Medical Science  2012;27(12):1472-1478.
Korean Red Ginseng (KRG) is a functional food and has been well known for keeping good health due to its anti-fatigue and immunomodulating activities. However, there is no data on Korean red ginseng for its preventive activity against acute respiratory illness (ARI). The study was conducted in a randomized, double-blinded, placebo-controlled trial in healthy volunteers (Clinical Trial Number: NCT01478009). Our primary efficacy end point was the number of ARI reported and secondary efficacy end point was severity of symptoms, number of symptoms, and duration of ARI. A total of 100 volunteers were enrolled in the study. Fewer subjects in the KRG group reported contracting at least 1 ARI than in the placebo group (12 [24.5%] vs 22 [44.9%], P = 0.034), the difference was statistically significant between the two groups. The symptom duration of the subjects who experienced the ARI, was similar between the two groups (KRG vs placebo; 5.2 ± 2.3 vs 6.3 ± 5.0, P = 0.475). The symptom scores were low tendency in KRG group (KRG vs placebo; 9.5 ± 4.5 vs 17.6 ± 23.1, P = 0.241). The study suggests that KRG may be effective in protecting subjects from contracting ARI, and may have the tendency to decrease the duration and scores of ARI symptoms.
PMCID: PMC3524425  PMID: 23255845
Ginseng; Influenza; Prevention and Control; Symptom Duration; Safety
13.  Dendroaspis natriuretic peptide regulates the cardiac L-type Ca2+ channel activity by the phosphorylation of α1c proteins 
Experimental & Molecular Medicine  2012;44(6):363-368.
Dendroaspis natriuretic peptide (DNP), a new member of the natriuretic peptide family, is structurally similar to atrial, brain, and C-type natriuretic peptides. However, the effects of DNP on the cardiac function are poorly defined. In the present study, we examined the effect of DNP on the cardiac L-type Ca2+ channels in rabbit ventricular myocytes. DNP inhibited the L-type Ca2+ current (ICa,L) in a concentration dependent manner with a IC50 of 25.5 nM, which was blocked by an inhibitor of protein kinase G (PKG), KT5823 (1 µM). DNP did not affect the voltage dependence of activation and inactivation of ICa,L. The α1c subunit of cardiac L-type Ca2+ channel proteins was phosphorylated by the treatment of DNP (1 µM), which was completely blocked by KT5823 (1 µM). Finally, DNP also caused the shortening of action potential duration in rabbit ventricular tissue by 22.3 ± 4.2% of the control (n = 6), which was completely blocked by KT5823 (1 µM). These results clearly indicate that DNP inhibits the L-type Ca2+ channel activity by phosphorylating the Ca2+ channel protein via PKG activation.
PMCID: PMC3389074  PMID: 22366884
calcium channels, L-type; cyclic GMP-dependent protein kinases; dendroaspis natriuretic peptide; myocytes, cardiac; rabbits
14.  Posterior Lumbar Interbody Fusion Using Compressive Bone Graft with Allograft and Autograft in the Pyogenic Discitis 
Asian Spine Journal  2012;6(1):15-21.
Study Design
This is a retrospective study.
To evaluate the advantages and effects of posterior lumbar interbody fusion (PLIF) using allograft and posterior instrumentation in the lumbar pyogenic discitis, which are resistant to antibiotics.
Overview of Literature
To present preliminary results of PLIF using a compressive bone graft with allograft and pedicle screw fixation in the lumbar pyogenic discitis.
Fifteen patients who had lumbar pyogenic discitis were treated by posterior approach from May 2004 to July 2008. The mean follow-up duration was 27.2 ± 18.68 months. The standing radiographs of the lumbar spine and clinical results were compared and analyzed in order to assess the bony union, the changes in the distance between the two vertebral bodies and the changes in the lordotic angle formed between the fused bodies immediately after surgery and at the final follow-up.
Fifteen solid unions at an average of 15.2 ± 3.5 weeks after operation. The mean preoperative lordotic angle of the affected segments was 14.3 ± 15.1°, compared to 20.3 ± 12.3° after surgery and 19.8 ± 15.2° at last follow-up. For the functional result according to the Kirkaldy-Willis criteria, the outcome was excellent in 9, good in 5, fair in 1, and there were no poor cases. The average visual analogue scale score was decreased from 7.4 before surgery to 3.4 at 2 weeks postoperative.
The main advantage in the procedure of PLIF using compressive bone graft with allograft and post instrumentation is early ambulation. We believe that this is another good procedure for patients with poor general condition because a further autograft bone harvest is not required.
PMCID: PMC3302910  PMID: 22439083
Lumbar spine; Discitis; Posterior lumbar interbody fusion; Homologous transplantation
15.  Cyclin B1 expression regulated by cytoplasmic polyadenylation element binding protein in astrocytes 
Astrocytes are the most abundant cell in the brain, playing vital roles in neuronal survival, growth and function. Understanding the mechanism(s) regulating astrocyte proliferation will have important implications in brain development, response to injury, and tumorigenesis. Cyclin B1 is well known to be a critical regulator of mitotic entry via its interaction with cyclin dependent kinase 1. In rat astrocytes, we now show that the mRNA binding protein cytoplasmic polyadenylation element binding protein 1 (CPEB1) is associated with cyclin B1 mRNA and this interaction is enriched at the centrosome. In addition, if growth arrested astrocytes are stimulated to divide, CPEB1 is phosphorylated and cyclin B1 mRNA is polyadenylated, both hallmarks of CPEB1 activation, resulting in an increase in cylcin B1 protein. CPEB1 binding to mRNA initially inhibits translation; therefore, removing CPEB1 from mRNA should result in an increase in translation due to de-repression. Indeed, when we either knocked-down CPEB1 protein with siRNA or sequestered it from endogenous mRNA by expressing RNA containing multiple CPEB1 binding sites, cyclin B1 protein was increased and cell proliferation was stimulated. Our data suggest a mechanism where CPEB1 is bound and repressing cyclin B1 mRNA translation until a signal to proliferate phosphorylates CPEB1 resulting in an increase in cylcin B1 protein and progression into mitosis. Our results demonstrate for the first time a role for CPEB1 in regulating cell proliferation in the brain.
PMCID: PMC3169319  PMID: 21865454
16.  A placebo-controlled trial of Korean red ginseng extract for preventing Influenza-like illness in healthy adults 
Standardized Korean red ginseng extract has become the best-selling influenza-like illness (ILI) remedy in Korea, yet much controversy regarding the efficacy of the Korean red ginseng (KRG) in reducing ILI incidence remains. The aim of the study is to assess the efficacy of the KRG extract on the ILI incidence in healthy adults.
We will conduct a randomized, double-blind, placebo-controlled study at the onset of the influenza seasons. A total of 100 subjects 30-70 years of age will be recruited from the general populations. The subjects will be instructed to take 9 capsules per day of either the KRG extract or a placebo for a period of 3 months. The primary outcome measure is to assess the frequency of ILI onset in participated subjects. Secondary variable measures will be included severity and duration of ILI symptoms. The ILI symptoms will be scored by subjects using a 4-point scale.
This study is a randomized placebo controlled trial to evaluate the efficacy of the KRG extract compared to placebo and will be provided valuable new information about the clinical and physiological effects of the KRG extract on reduction of ILI incidence including flu and upper respiratory tract infections. The study has been pragmatically designed to ensure that the study findings can be implemented into clinical practice if KRG extract can be shown to be an effective reduction strategy in ILI incidence.
Trial Registration
PMCID: PMC3297520  PMID: 22314101
17.  Influence of the Chungkookjang on histamine-induced wheal and flare skin response: a randomized, double-blind, placebo controlled trial 
Allergic disease is a consequence of exposure to normally innocuous substances that elicit the activation of mast cells. Mast-cell-mediated allergic response is involved in many diseases such as anaphylaxis, urticaria, allergic rhinitis, asthma and allergic dermatitis. The development of food products for the prevention of allergic disease is an important subject in human health. The chungkookjang (CKJ) has been reported to exhibit antiallergic inflammatory activity. Therefore, the aim of the study is to examine the effects of the CKJ to reduce histamine-induced wheal and flare skin responses.
A randomized, double-blind, placebo-controlled study in 60 healthy subjects will be carried out. Sixty volunteers (aged 20-80) who gave a written consent before entering the study will be randomized in two groups of thirty subjects each. The skin prick test with histamine solution of 10 mg/ml will be performed on the ventral forearm, 10 cm from the elbow. The subjects will be instructed to take 35 g per day of either the CKJ pills or a placebo pills for a period of 3 months. Diameters of wheal and flare will be assessing 15 minutes after performing the above-mentioned skin prick test. The primary outcome is change in wheal and flare responses. Secondary outcomes will be include change in serum histamine, immunoglobulin E, cytokines (interferon-gamma, interleukin-4, -10, and tumor necrosis factor-alpha), and eosinophil cationic protein.
This study will show the potential anti-inflammatory properties of the CKJ in their skin activity when histamine is the challenging agent as occurs in the clinical situation. And the present protocol will confirm the efficacy and safety of the CKJ for allergy symptoms, suggesting more basic knowledge to conduct further randomized controlled trials (RCT). If this study will be successfully performed, the CKJ will be an alternative dietary supplemental remedy for allergy patients.
Trial Registration
PMCID: PMC3295693  PMID: 22136279
18.  Cytotoxicities and Quantitative Structure Activity Relationships of B13 Sulfonamides in HT-29 and A549 Cells 
B13 analogues are being considered as therapeutic agents for cancer cells, since B13 is a ceramide analogue and inhibits ceramidase to promote apoptosis in cancer cells. B13 sulfonamides are assumed to have biological activity similar to B13, since they are made by bioisosterically substituting the carboxyl moiety of B13 with sulfone group. Twenty B13 sulfonamides were evaluated for their in vitro cytotoxicities against human colon cancer HT-29 and lung cancer A549 cell lines using MTT assays. Replacement of the amide group with a sulfonamide group increased cytotoxicity in both cancer cell lines. The sulfonamides with long alkyl chains exhibited activities two to three times more potent than that of B13 and compound (15) had the most potent activity with IC50 values of 27 and 28.7µM for HT-29 and A549, respectively. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to carry out QSAR molecular modeling of these compounds. The predictive CoMSIA models for HT-29 and A549 gave cross-validated q2 values of 0.703 and 0.830, respectively. From graphical analysis of these models, we suppose that the stereochemistry of 1,3-propandiol is not important for activity and that introduction of a sulfonamide group and long alkyl chains into B13 can increase cytotoxicity.
PMCID: PMC3282231  PMID: 22359481
B13; Ceramide; Cytotoxicity; QSAR; Sulfonamides
19.  The Protective Effect of Epigallocatechin-3 Gallate on Ischemia/Reperfusion Injury in Isolated Rat Hearts: An ex vivo Approach 
The aim of this study was to evaluate the preventive role of epigallocatechin-3 gallate (EGCG, a derivative of green tea) in ischemia/reperfusion (I/R) injury of isolated rat hearts. It has been suggested that EGCG has beneficial health effects, including prevention of cancer and heart disease, and it is also a potent antioxidant. Rat hearts were subjected to 20 min of normoxia, 20 min of zero-flow ischemia and then 50 min of reperfusion. EGCG was perfused 10 min before ischemia and during the whole reperfusion period. EGCG significantly increased left ventricular developed pressure (LVDP) and increased maximum positive and negative dP/dt (+/-dP/dtmax). EGCG also significantly increased the coronary flow (CF) at baseline before ischemia and at the onset of the reperfusion period. Moreover, EGCG decreased left ventricular end diastolic pressure (LVEDP). This study showed that lipid peroxydation was inhibited and Mn-SOD and catalase expressions were increased in the presence of EGCG. In addition, EGCG increased levels of Bcl-2, Mn-superoxide dismutase (SOD), and catalase expression and decreased levels of Bax and increased the ratio of Bcl-2/Bax in isolated rat hearts. Cleaved caspase-3 was decreased after EGCG treatment. EGCG markedly decreased the infarct size while attenuating the increase in lactate dehydrogenase (LDH) levels in the effluent. In summary, we suggest that EGCG has a protective effect on I/R-associated hemodynamic alteration and injury by acting as an antioxidant and anti-apoptotic agent in one.
PMCID: PMC3222794  PMID: 22128257
Epigallocatechin-3 gallate; Ischemia/reperfusion injury; Apoptosis; Antioxidant
20.  Valproic acid inhibits neural progenitor cell death by activation of NF-κB signaling pathway and up-regulation of Bcl-XL 
At the beginning of neurogenesis, massive brain cell death occurs and more than 50% of cells are eliminated by apoptosis along with neuronal differentiation. However, few studies were conducted so far regarding the regulation of neural progenitor cells (NPCs) death during development. Because of the physiological role of cell death during development, aberration of normal apoptotic cell death is detrimental to normal organogenesis.
Apoptosis occurs in not only neuron but also in NPCs and neuroblast. When growth and survival signals such as EGF or LIF are removed, apoptosis is activated as well as the induction of differentiation. To investigate the regulation of cell death during developmental stage, it is essential to investigate the regulation of apoptosis of NPCs.
Neural progenitor cells were cultured from E14 embryonic brains of Sprague-Dawley rats. For in vivo VPA animal model, pregnant rats were treated with VPA (400 mg/kg S.C.) diluted with normal saline at E12. To analyze the cell death, we performed PI staining and PARP and caspase-3 cleavage assay. Expression level of proteins was investigated by Western blot and immunocytochemical assays. The level of mRNA expression was investigated by RT-PCR. Interaction of Bcl-XL gene promoter and NF-κB p65 was investigated by ChIP assay.
In this study, FACS analysis, PI staining and PARP and caspase-3 cleavage assay showed that VPA protects cultured NPCs from cell death after growth factor withdrawal both in basal and staurosporine- or hydrogen peroxide-stimulated conditions. The protective effect of prenatally injected VPA was also observed in E16 embryonic brain. Treatment of VPA decreased the level of IκBα and increased the nuclear translocation of NF-κB, which subsequently enhanced expression of anti-apoptotic protein Bcl-XL.
To the best of our knowledge, this is the first report to indicate the reduced death of NPCs by VPA at developmentally critical periods through the degradation of IκBα and the activation of NF-κB signaling. The reduced NPCs death might underlie the neurodevelopmental defects collectively called fetal valproate syndrome, which shows symptoms such as mental retardation and autism-like behavior.
PMCID: PMC3158748  PMID: 21722408
21.  Prenatal exposure of ethanol induces increased glutamatergic neuronal differentiation of neural progenitor cells 
Prenatal ethanol exposure during pregnancy induces a spectrum of mental and physical disorders called fetal alcohol spectrum disorder (FASD). The central nervous system is the main organ influenced by FASD, and neurological symptoms include mental retardation, learning abnormalities, hyperactivity and seizure susceptibility in childhood along with the microcephaly. In this study, we examined whether ethanol exposure adversely affects the proliferation of NPC and de-regulates the normal ratio between glutamatergic and GABAergic neuronal differentiation using primary neural progenitor culture (NPC) and in vivo FASD models.
Neural progenitor cells were cultured from E14 embryo brain of Sprague-Dawley rat. Pregnant mice and rats were treated with ethanol (2 or 4 g/kg/day) diluted with normal saline from E7 to E16 for in vivo FASD animal models. Expression level of proteins was investigated by western blot analysis and immunocytochemical assays. MTT was used for cell viability. Proliferative activity of NPCs was identified by BrdU incorporation, immunocytochemistry and FACS analysis.
Reduced proliferation of NPCs by ethanol was demonstrated using BrdU incorporation, immunocytochemistry and FACS analysis. In addition, ethanol induced the imbalance between glutamatergic and GABAergic neuronal differentiation via transient increase in the expression of Pax6, Ngn2 and NeuroD with concomitant decrease in the expression of Mash1. Similar pattern of expression of those transcription factors was observed using an in vivo model of FASD as well as the increased expression of PSD-95 and decreased expression of GAD67.
These results suggest that ethanol induces hyper-differentiation of glutamatergic neuron through Pax6 pathway, which may underlie the hyper-excitability phenotype such as hyperactivity or seizure susceptibility in FASD patients.
PMCID: PMC2996361  PMID: 21073715
22.  The Clinical and Radiological Availability of Percutaneous Balloon Kyphoplasty as a Treatment for Osteoporotic Burst Fractures 
Asian Spine Journal  2008;2(1):9-14.
Study Design
We retrospectively assessed the results of percutaneous balloon kyphoplasty (KP) by clinical and radiological methods.
To evaluate the outcome of KP as a treatment for osteoporotic burst fractures.
Overview of Literature
Many surgeons are concerned about the possibility of neurological complications after percutaneous kyphoplasty for osteoporotic burst fractures, secondary to intra-canal cement leakage.
We performed KP as a treatment for osteoporotic burst fractures. We studied 12 patients/13 vertebrae. The two control groups consisted of patients who only underwent conservative treatment and those who underwent posterior instrumentation and fusion. We measured each preoperative/postoperative vertebral kyphotic deformity angle (KDA) using simple lateral spine images and checked for leakage of cement, as well. The preoperative/postoperative visual analog scale (VAS) scores for back pain, degree of daily activity, and postoperative complications were evaluated.
The mean improvement in KDA after KP was 9.7±2.2°. The mean preoperative and postoperative VAS scores for back pain were 8.3±0.4 and 3.1±0.17, respectively. Regarding the control group, the mean postoperative VAS score for the conservative group and the posterior surgery group decreased by 4.5±0.17 and 3.2±0.19, respectively. There was no statistically significant difference between the KP and posterior surgery groups (p=0.125). However, there was a statistically significant difference between the KP and conservative treatment groups (p=0.012).
KP is safe and useful for treating osteoporotic burst fractures.
PMCID: PMC2857483  PMID: 20411136
Thoracolumbar spine; Osteoporotic burst fracture; Percutaneous balloon kyphoplasty; Cement leakage
23.  Outcome of postoperative intratumoral bleomycin injection for cystic craniopharyngioma. 
Journal of Korean Medical Science  2002;17(2):254-259.
Total excision is a treatment of choice in preventing the relapse of craniopharyngioma, but for tumors involving an extensive area, it is often associated with an increased risk of complications. We have performed a partial or subtotal tumor removal followed by repeated injection of bleomycin into the remaining tumor through a subcutaneous reservoir as postoperative adjuvant therapy. A retrospective review of clinical, radiological, and surgical data was performed for 10 patients (5 males and 5 females; age, 3-65 yr; follow-up duration, 12-79 months) with cystic craniopharyngiomas. The measurements of lactate dehydrogenase (LDH) level at each aspiration were performed. The shrinkage and/or stabilization of tumor was initially noted in all cases. The recurrence of tumor was seen in 4 cases (40%). The decreased or increased level of LDH was interpreted as tumor shrinkage or recurrence, respectively. The transient toxic reactions were observed in 3 patients (30%). Our study demonstrates that postoperative bleo-mycin injection for cystic craniopharyngioma, although does not appear to eradicate the tumor, decreases and stabilizes the tumor size, when used as an adjuvant therapy in young patients.
PMCID: PMC3054855  PMID: 11961313
24.  A case of polymyositis with dilated cardiomyopathy associated with interferon alpha treatment for hepatitis B. 
Journal of Korean Medical Science  2002;17(1):141-143.
Polymyositis is a rare complication of interferon alpha treatment as a result of immune-modulating role of the drug itself. In this case, interferon alpha induced polymyositis and cardiomyopathy is diagnosed in a 33-yr-old male patient with history of chronic hepatitis B. To treat hepatitis B, interferon alpha was administered until the proximal muscle weakness developed. Thereafter, sixteen cycles of immunoglobulin treatment (400 mg/kg) along with corticosteroids were instituted and led to an improvement in subjective symptoms with decreases in level of CPK and LDH. However, dilated cardiomyopathy has not improved in spite of the cessation of interferon treatment. Unlike the persistently elevated serum HBV DNA level, the serum ALT and AST levels have gradually decreased. Our case shows that clinical symptoms of polymyositis improved with steroid and immunoglobulin treatment without deterioration of the hepatitis B. To our knowledge, this is the first case of polymyositis associated with dilated cardiomyopathy after the administration of interferon in a patient with hepatitis B.
PMCID: PMC3054837  PMID: 11850606
25.  Autologous stem cell transplantation in the treatment of refractory rheumatoid arthritis. 
Journal of Korean Medical Science  2002;17(1):129-132.
The concept of using high-dose immunosuppressive treatment (HDIT) with autologous stem cell transplantation (ASCT) to treat patients with refractory rheumatoid arthritis has been provided by animal studies and anecdotal case reports. Over the past five years, an increasing number of patients with refractory rheumatoid arthritis have received HDIT with ASCT as an adjunct to intense immunosuppression. Here, we present a case of refractory rheumatoid arthritis in a 54-yr-old woman using HDIT with ASCT. Peripheral blood stem cells were mobilized with cyclophosphamide (4 g/m(2)) followed by G-CSF (5 microg/kg/day). Leukapheresis continued daily until the number of harvested progenitor cells reached 2 x 10(6) CD34+ cells/kg after CliniMax CD34+ positive selection. For HDIT, high-dose cyclophosphamide (total dose 200 mg/kg) and antithymocyte globulin (total dose 90 mg/kg) were administered and CD34+ cells were infused 24 hr after HDIT. The patient tolerated the treatment well but experienced an episode of neutropenic fever. She achieved an early dramatic improvement of joint symptoms during therapy. Fifty percent of improvement of rheumatoid arthritis by the American College of Rheumatology (ACR 50) preliminary definition was fulfilled during the 6 months following ASCT. Although further long-term follow-up is required, the patient's activity of arthritis has been stable since receiving HDIT with ASCT.
PMCID: PMC3054838  PMID: 11850603

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