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2.  The Photoprotective Effect of S-Methylmethionine Sulfonium in Skin 
S-Methylmethionine sulfonium (SMMS) was reported to have wound-healing effects; we therefore have investigated the photoprotective effect of SMMS in the present study. SMMS increased the viability of keratinocyte progenitor cells (KPCs) and human dermal fibroblasts (hDFs) following ultraviolet B (UVB) irradiation, and reduced the UVB-induced apoptosis in these cells. SMMS increased the phosphorylation of extracellular signal-regulated kinases (ERK), and the inhibitor of the mitogen-activated protein kinase pathway significantly decreased the SMMS-induced viability of KPCs and hDFs. In addition, SMMS attenuated the UVB-induced reactive oxygen species (ROS) generation in KPCs and hDFs. SMMS induced the collagen synthesis and reduced the matrix metalloproteinase-1 expression in UVB-irradiated hDFs. In animal studies, application of 5% and 10% SMMS before and after UVB-irradiation significantly decreased the UVB-induced erythema index and depletion of Langerhans cells. In summary, SMMS protects KPCs and hDFs from UVB irradiation, and reduces UVB-induced skin erythema and immune suppression. Therefore, SMMS can be used as a cosmetic raw material, and protect skin from UVB.
PMCID: PMC4581185  PMID: 26225962
S-methylmethionine sulfonium; UVB protection; dermal fibroblasts; keratinocyte progenitor cells; erythema
3.  Fluoxetine Decreases the Proliferation and Adipogenic Differentiation of Human Adipose-Derived Stem Cells 
Fluoxetine was originally developed as an antidepressant, but it has also been used to treat obesity. Although the anti-appetite effect of fluoxetine is well-documented, its potential effects on human adipose-derived stem cells (ASCs) or mature adipocytes have not been investigated. Therefore, we investigated the mechanisms underlying the inhibitory effects of fluoxetine on the proliferation of ASCs. We also investigated its inhibitory effect on adipogenic differentiation. Fluoxetine significantly decreased ASC proliferation, and signal transduction PCR array analysis showed that it increased expression of autophagy-related genes. In addition, fluoxetine up-regulated SQSTM1 and LC3B protein expression as detected by western blotting and immunofluorescence. The autophagy inhibitor, 3-methyladenine (3-MA), significantly attenuated fluoxetine-mediated effects on ASC proliferation and SQSTM1/LC3B expression. In addition, 3-MA decreased the mRNA expression of two autophagy-related genes, beclin-1 and Atg7, in ASCs. Fluoxetine also significantly inhibited lipid accumulation and down-regulated the levels of PPAR-γ and C/EBP-α in ASCs. Collectively, these results indicate that fluoxetine decreases ASC proliferation and adipogenic differentiation. This is the first in vitro evidence that fluoxetine can reduce fat accumulation by inhibiting ASC proliferation and differentiation.
PMCID: PMC4519971  PMID: 26204837
adipose-derived stem cells; fluoxetine; autophagy; proliferation; adipogenic differentiation
4.  The Molecular Mechanism Underlying the Proliferating and Preconditioning Effect of Vitamin C on Adipose-Derived Stem Cells 
Stem Cells and Development  2014;23(12):1364-1376.
Although adipose-derived stem cells (ASCs) show promise for cell therapy, there is a tremendous need for developing ASC activators. In the present study, we investigated whether or not vitamin C increases the survival, proliferation, and hair-regenerative potential of ASCs. In addition, we tried to find the molecular mechanisms underlying the vitamin C-mediated stimulation of ASCs. Sodium-dependent vitamin C transporter 2 (SVCT2) is expressed in ASCs, and mediates uptake of vitamin C into ASCs. Vitamin C increased the survival and proliferation of ASCs in a dose-dependent manner. Vitamin C increased ERK1/2 phosphorylation, and inhibition of the mitogen-activated protein kinase (MAPK) pathway attenuated the proliferation of ASCs. Microarray and quantitative polymerase chain reaction showed that vitamin C primarily upregulated expression of proliferation-related genes, including Fos, E2F2, Ier2, Mybl1, Cdc45, JunB, FosB, and Cdca5, whereas Fos knock-down using siRNA significantly decreased vitamin C-mediated ASC proliferation. In addition, vitamin C-treated ASCs accelerated the telogen-to-anagen transition in C3H/HeN mice, and conditioned medium from vitamin C-treated ASCs increased the hair length and the Ki67-positive matrix keratinocytes in hair organ culture. Vitamin C increased the mRNA expression of HGF, IGFBP6, VEGF, bFGF, and KGF, which may mediate hair growth promotion. In summary, vitamin C is transported via SVCT2, and increased ASC proliferation is mediated by the MAPK pathway. In addition, vitamin C preconditioning enhanced the hair growth promoting effect of ASCs. Because vitamin C is safe and effective, it could be used to increase the yield and regenerative potential of ASCs.
PMCID: PMC4046194  PMID: 24524758
5.  Antiangiogenic Therapy Impedes Infiltration by CD4+ and CD8+ Cells Into an Early Colon Tumor 
Journal of Cancer Prevention  2015;20(2):129-135.
While the majority of angiogenesis studies have focused on the late stages of cancer, the emergence of neovascularization in colon tumorigenesis has been observed an earlier stage than expected. Recent reports implied that early angiogenesis might be a defense mechanism to stimulate the natural clearance of microadenomas during colon tumorigenesis. However, little is known about how early angiogenesis affects the natural clearance of tumors.
Spontaneous colon tumors were developed in adenomatous polyposis coli conditional knockout mice with Cre recombinase adenovirus administration. Vascular endothelial growth factor (VEGF) antagonist, DC101, was administrated to determine the effect of early angiogenesis and then infiltration of immune cells into tumor and concentration of cytokines were evaluated.
The continuous administration of the VEGF receptor 2 antagonist DC101 in the mouse models impeded the infiltration by CD4+ and CD8+ cells into the tumor region. Furthermore, the administration of the VEGF antagonist decreased the amounts of anti-tumoral cytokines such as interleukin (IL)-6 and IL-10.
We revealed that newly formed vessels during tumorigenesis can be channels for particular anti-tumoral immune cells. Our results may confer insight for the clinical development of an efficient antiangiogenic therapeutic manual and a timely chemoprevention to suppress tumor growth.
PMCID: PMC4492357  PMID: 26151046
Colon tumorigenesis; Angiogenesis; Antiangiogenic therapy
7.  Treatment of Patients with Refractory Atopic Dermatitis Sensitized to House Dust Mites by Using Sublingual Allergen Immunotherapy 
Annals of Dermatology  2015;27(1):82-86.
Even though atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, its treatment remains a challenge in clinical practice, with most approaches limited to symptomatic, unspecific anti-inflammatory, or immunosuppressive treatments. Many studies have shown AD to have multiple causes that activate complex immunological and inflammatory pathways. However, aeroallergens, and especially the house dust mite (HDM), play a relevant role in the elicitation or exacerbation of eczematous lesions in many AD patients. Accordingly, allergen-specific immunotherapy has been used in AD patients with the aim of redirecting inappropriate immune responses. Here, we report three cases of refractory AD sensitized to HDM who were treated with sublingual immunotherapy.
PMCID: PMC4323609  PMID: 25673938
Atopic dermatitis; Pyroglyphidae; Sublingual immunotherapy
8.  Clinical Availability of Component-Resolved Diagnosis Using Microarray Technology in Atopic Dermatitis 
Annals of Dermatology  2014;26(4):437-446.
Various allergens play a role in the elicitation or exacerbation of eczematous skin lesions in atopic dermatitis (AD), and much research effort has been focused on improving diagnostic tests to identify causative allergens.
The purpose of this study was to evaluate the diagnostic effectiveness of a newly introduced microarray-based specific immunoglobulin E detection assay, ImmunoCAP ISAC, for use in AD patients.
The serum samples of 25 AD patients were tested by using ISAC and a multiple allergen simultaneous test-enzyme immunoassay (MAST-EIA). In addition, 10 of the 25 patients underwent skin prick testing (SPT). The positive reaction rates to allergens in each test and the agreements, sensitivities, and specificities of ISAC and MAST-EIA were evaluated versus the SPT results.
For ISAC versus SPT, the overall results were as follows: sensitivity, 90.0%; specificity, 98.2%; positive predictive value (PPV), 90.0%; and negative predictive value (NPV), 98.2%. The total agreement and κ value for ISAC versus SPT were 96.9% and 0.882, respectively. For MAST-EIA versus SPT, the sensitivity was 80.0%, specificity 92.7%, PPV 66.7%, and NPV 96.2%. The total agreement and κ value for MAST-EIA versus SPT were 90.8% and 0.672, respectively. The overall agreement between the ISAC and MAST-EIA results was 88%.
The ISAC results in AD correlated well with the SPT results, and compared favorably to the MAST-EIA results. This study demonstrates the potential of ISAC as a convenient allergic diagnostic method in AD patients.
PMCID: PMC4135097  PMID: 25143671
Atopic dermatitis; Microarray-based specific IgE detection assay
9.  Metabolic Syndrome and Chronic Kidney Disease in an Adult Korean Population: Results from the Korean National Health Screening 
PLoS ONE  2014;9(5):e93795.
This study was aimed to examine the prevalence of metabolic syndrome (MS) and chronic kidney disease (CKD), and the association between MS and its components with CKD in Korea.
We excluded diabetes to appreciate the real impact of MS and performed a cross-sectional study using the general health screening data of 10,253,085 (48.86±13.83 years, men 56.18%) participants (age, ≥20 years) from the Korean National Health Screening 2011. CKD was defined as dipstick proteinuria ≥1 or an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2.
The prevalence of CKD was 6.15% (men, 5.37%; women, 7.15%). Further, 22.25% study population had MS (abdominal obesity, 27.98%; hypertriglyceridemia, 30.09%; low high-density cholesterol levels, 19.74%; high blood pressure, 43.45%; and high fasting glucose levels, 30.44%). Multivariate-adjusted analysis indicated that proteinuria risk increased in participants with MS (odds ratio [OR] 1.884, 95% confidence interval [CI] 1.867–1.902, P<0.001). The presence of MS was associated with eGFR<60 mL/min/1.73 m2 (OR 1.364, 95% CI 1.355–1.373, P<0.001). MS individual components were also associated with an increased CKD risk. The strength of association between MS and the development of CKD increase as the number of components increased from 1 to 5. In sub-analysis by men and women, MS and its each components were a significant determinant for CKD.
MS and its individual components can predict the risk of prevalent CKD for men and women.
PMCID: PMC4013132  PMID: 24807226
10.  Farnesoid X Receptor Ligand Prevents Cisplatin-Induced Kidney Injury by Enhancing Small Heterodimer Partner 
PLoS ONE  2014;9(1):e86553.
The farnesoid X receptor (FXR) is mainly expressed in liver, intestine and kidney. We investigated whether 6-ethyl chenodeoxycholic acid (6ECDCA), a semisynthetic derivative of chenodeoxycholic aicd (CDCA, an FXR ligand), protects against kidney injury and modulates small heterodimer partner (SHP) in cisplatin-induced kidney injury. Cisplatin inhibited SHP protein expression in the kidney of cisplatin-treated mice and human proximal tubular (HK2) cells; this effect was counteracted by FXR ligand. Hematoxylin and eosin staining revealed the presence of tubular casts, obstructions and dilatations in cisplatin-induced kidney injury, which was attenuated by FXR ligand. FXR ligand also attenuated protein expression of transforming growth factor-β1 (TGF-β1), Smad signaling, and the epithelial-to-mesenchymal transition process, inflammatory markers and cytokines, and apoptotic markers in cisplatin-treated mice. Cisplatin induced NF-κB activation in HK2 cell; this effect was attenuated by pretreatment with FXR ligand. In SHP knockdown by small interfering RNA, cisplatin-induced activation of TGF-β1, p-JNK and Bax/Bcl-2 ratio was not attenuated, while SHP overexpression and FXR ligand inhibited expression of these proteins in cisplatin-pretreated HK2 cells. In conclusion, FXR ligand, 6ECDCA prevents cisplatin-induced kidney injury, the underlying mechanism of which may be associated with anti-fibrotic, anti-inflammatory, and anti-apoptotic effects through SHP induction.
PMCID: PMC3903546  PMID: 24475141
11.  Concomitant Impact of High-Sensitivity C-Reactive Protein and Renal Dysfunction in Patients with Acute Myocardial Infarction 
Yonsei Medical Journal  2013;55(1):132-140.
The present study aimed to investigate the impact of high-sensitivity C-reactive protein (hs-CRP) and renal dysfunction on clinical outcomes in acute myocardial infarction (AMI) patients.
Materials and Methods
The study involved a retrospective cohort of 8332 patients admitted with AMI. The participants were divided into 4 groups according to the levels of estimated glomerular filtration rate (eGFR) and hs-CRP: group I, no renal dysfunction (eGFR ≥60 mL·min-1·1.73 m-2) with low hs-CRP (≤2.0 mg/dL); group II, no renal dysfunction with high hs-CRP; group III, renal dysfunction with low hs-CRP; and group IV, renal dysfunction with high hs-CRP. We compared major adverse cardiac events (MACE) over a 1-year follow-up period.
The 4 groups demonstrated a graded association with increased MACE rates (group I, 8.8%; group II, 13.8%; group III, 18.6%; group IV, 30.1%; p<0.001). In a Cox proportional hazards model, mortality at 12 months increased in groups II, III, and IV compared with group I [hazard ratio (HR) 2.038, 95% confidence interval (CI) 1.450-2.863, p<0.001; HR 3.003, 95% CI 2.269-3.974, p<0.001; HR 5.087, 95% CI 3.755-6.891, p<0.001].
High hs-CRP, especially in association with renal dysfunction, is related to the occurrence of composite MACE, and indicates poor prognosis in AMI patients.
PMCID: PMC3874927  PMID: 24339298
C-reactive protein; glomerular filtration rate; myocardial infarction
12.  Incidence, Predictive Factors, and Clinical Outcomes of Acute Kidney Injury after Gastric Surgery for Gastric Cancer 
PLoS ONE  2013;8(12):e82289.
Postoperative acute kidney injury (AKI), a serious surgical complication, is common after cardiac surgery; however, reports on AKI after noncardiac surgery are limited. We sought to determine the incidence and predictive factors of AKI after gastric surgery for gastric cancer and its effects on the clinical outcomes.
We conducted a retrospective study of 4718 patients with normal renal function who underwent partial or total gastrectomy for gastric cancer between June 2002 and December 2011. Postoperative AKI was defined by serum creatinine change, as per the Kidney Disease Improving Global Outcomes guideline.
Of the 4718 patients, 679 (14.4%) developed AKI. Length of hospital stay, intensive care unit admission rates, and in-hospital mortality rate (3.5% versus 0.2%) were significantly higher in patients with AKI than in those without. AKI was also associated with requirement of renal replacement therapy. Multivariate analysis revealed that male gender; hypertension; chronic obstructive pulmonary disease; hypoalbuminemia (<4 g/dl); use of diuretics, vasopressors, and contrast agents; and packed red blood cell transfusion were independent predictors for AKI after gastric surgery. Postoperative AKI and vasopressor use entailed a high risk of 3-month mortality after multiple adjustments.
AKI was common after gastric surgery for gastric cancer and associated with adverse outcomes. We identified several factors associated with postoperative AKI; recognition of these predictive factors may help reduce the incidence of AKI after gastric surgery. Furthermore, postoperative AKI in patients with gastric cancer is an important risk factor for short-term mortality.
PMCID: PMC3857284  PMID: 24349249
13.  Increased Phosphorylation of PI3K/Akt/mTOR in the Obstructed Kidney of Rats with Unilateral Ureteral Obstruction 
Chonnam Medical Journal  2013;49(3):108-112.
The present study aimed to investigate changes in the mammalian target of rapamycin (mTOR) signaling pathway in the obstructed kidney of rats with unilateral ureteral obstruction (UUO). Male Sprague-Dawley rats were unilaterally obstructed by ligation of the left proximal ureter for 7 days. Control rats were treated in the same way except that no ligature was made. The expression levels of phosphorylated phosphatidylinositol 3-kinase (PI3K), Akt, and mTOR were determined in the kidney by semiquantitative immunoblotting. The protein expression levels of transforming growth factor (TGF)-β1, Bax, and Bcl-2 were also determined in the kidney. The phosphorylation of PI3K, Akt, and mTOR was increased in the kidney of ureteral obstruction rats compared with the control. In the obstructed kidney, the protein expression of TGF-β1 and Bax was also increased, whereas Bcl-2 expression was decreased. In conclusion, the phosphorylation of PI3K/Akt/mTOR was increased in the obstructed kidney of rats with UUO.
PMCID: PMC3881205  PMID: 24400212
mTOR protein, rat; Ureteral Obstruction; Fibrosis; Apoptosis
14.  Antiapoptotic Effect of Paricalcitol in Gentamicin-induced Kidney Injury 
While the anti-apoptotic effect of paricalcitol has been demonstrated in various animal models, it is not yet clear whether paricalcitol attenuates the apoptosis in gentamicin (GM)-induced kidney injury. We investigated the effect of paricalcitol on apoptotic pathways in rat kidneys damaged by GM. Rats were randomly divided into three groups: 1) Control group (n=8), where only vehicle was delivered, 2) GM group (n=10), where rats were treated with GM (150 mg/kg/day) for 7 days, 3) PARI group (n=10), where rats were co-treated with paricalcitol (0.2 µg/kg/day) and GM for 7 days. Paricalcitol attenuated renal dysfunction by GM administration in biochemical profiles. In terminal deoxynucleotidyl transferase dUTP nick end labeling staining, increased apoptosis was observed in GM group, which was reversed by paricalcitol co-treatment. Immunoblotting using protein samples from rat cortex/outer stripe of outer medulla showed increased Bax/Bcl-2 ratio and cleaved form of caspase-3 in GM group, both of which were reversed by paricalcitol. The phosphorylated Jun-N-terminal kinase (JNK) expression was increase in GM, which was counteracted by paricalcitol. The protein expression of p-Akt and nitro-tyrosine was also enhanced in GM-treated rats compared with control rats, which was reversed by paricalcitol co-treatment. Paricalcitol protects GM-induced renal injury by antiapoptotic mechanisms, including inhibition of intrinsic apoptosis pathway and JNK.
PMCID: PMC3823957  PMID: 24227945
Apoptosis; Gentamicin; Kidney; Paricalcitol
15.  Clinical Impact of Hospital-Acquired Anemia in Association with Acute Kidney Injury and Chronic Kidney Disease in Patients with Acute Myocardial Infarction 
PLoS ONE  2013;8(9):e75583.
Hospital-acquired anemia (HAA) is common in patients with acute myocardial infarction (AMI) and is an independent indicator of long-term mortality in these patients. However, limited information exists regarding the development and prognostic impact of HAA associated with acute kidney injury (AKI) and chronic kidney disease (CKD) in AMI patients.
Methods and Results
We retrospectively analyzed 2,289 patients with AMI, and excluded those with anemia at admission. The study population included 1,368 patients, of whom 800 (58.5%) developed HAA. Age, Hgb level at admission, Length of hospital stay, documented in-hospital bleeding and use of glycoprotein IIb/IIIa inhibitor, presence of CKD and occurrence of AKI were significantly associated with the development of HAA. HAA was significantly associated with higher 3-year mortality (4.8% and 11.4% for non-HAA and HAA patients, respectively; P < 0.001). After adjustment for multivariable confounders, the risk for long-term mortality was increased in HAA patients with AKI and/or CKD but not in HAA patients without AKI and/or CKD, compared to non-HAA patients (HAA patients without AKI and CKD, hazard ratio [HR]: 1.34, 95% confidence interval [CI]: 0.70–2.56; HAA patients with either AKI or CKD, HR: 2.80, 95% CI: 1.37–5.73; HAA patients with AKI and CKD, HR: 3.25, 95% CI: 1.28–8.24; compared with the non-HAA group).
AKI and CKD were strongly associated with the development of HAA in AMI patients. HAA, when accompanied by AKI or CKD, is an independent risk predictor for long-term mortality in AMI patients.
PMCID: PMC3782440  PMID: 24086579
16.  Proteinuria as a Risk Factor for Mortality in Patients with Colorectal Cancer 
Yonsei Medical Journal  2013;54(5):1194-1201.
We investigated the effects of proteinuria and renal insufficiency on all-cause mortality in patients with colorectal cancer, with special emphasis on cancer staging and cancer-related deaths.
Materials and Methods
We retrospectively studied a cohort of patients with colorectal cancer. In protocol 1, patients were classified into four groups based on the operability of cancer and proteinuria: group 1, early-stage cancer patients (colorectal cancer stage ≤3) without proteinuria; group 2, early-stage cancer patients with proteinuria; group 3, advanced-stage cancer patients without proteinuria (colorectal cancer stage=4); and group 4, advanced-stage cancer patients with proteinuria. In protocol 2, patients were classified into four similar groups based on cancer staging and renal insufficiency (eGFR <60 mL/min/1.73 m2). Between January 1, 1998 and December 31, 2009, 3379 patients were enrolled in this cohort and followed until May 1, 2012 or until death.
The number of patients with proteinuria was 495 (14.6%). The prevalence of proteinuria was higher in advanced-stage cancer (n=151, 22.3%) than in early-stage cancer patients (n=344, 12.7%). After adjusting for age, gender and other clinical variables, the proteinuric, early-stage cancer group was shown to be associated with an adjusted hazard ratio of 1.67 and a 95% confidence interval of 1.38-2.01, compared with non-proteinuric early-stage cancer patients. However, renal insufficiency was not associated with colorectal cancer mortality.
Proteinuria is an important risk factor for cancer mortality, especially in relatively early colorectal cancer.
PMCID: PMC3743186  PMID: 23918569
Cancer; death; proteinuria; GFR; stage
17.  Acute Kidney Injury in Patients with Sepsis and Septic Shock: Risk Factors and Clinical Outcomes 
Yonsei Medical Journal  2013;54(4):965-972.
The aim of this study was to investigate clinical characteristics and risk factors of acute kidney injury (AKI) in patients with sepsis and septic shock. Additionally, we explored whether the severity of AKI affects on the clinical outcomes.
Materials and Methods
Data were collected retrospectively in a single center. Among 5680 patients who visited emergency department from January to December 2010, 992 patients with sepsis and septic shock were enrolled. Patients were divided into two groups, patients who developed AKI or not, to compare the baseline characteristics, and laboratory and physiologic data. Patients with AKI were subdivided according to its stages for survival analysis.
AKI was developed in 57.7% of patients. Multivariable logistic regression analysis revealed that development of septic AKI was associated with older age, pre-existing chronic kidney disease, use of angiotensin converting enzyme inhibitor or angiotensin receptor blocker, presence of shock, positive blood culture results, and low white blood cell and platelet counts. Hospital mortality was higher in AKI group. Crude Kaplan-Meier survival curves demonstrated reduced 30-day survival rate was significantly associated with the severity of acute kidney injury.
The development of septic AKI was associated with poor clinical outcomes. Furthermore, the severity of AKI was associated with increased mortality.
PMCID: PMC3663224  PMID: 23709433
Acute kidney injury; mortality; risk factors; sepsis; septic shock
18.  Percutaneous Coronary Intervention for Acute Myocardial Infarction in Elderly Patients with Renal Dysfunction: Results from the Korea Acute Myocardial Infarction Registry 
Journal of Korean Medical Science  2013;28(7):1027-1033.
This study aimed to evaluate the effects of percutaneous coronary intervention (PCI) on short- and long-term major adverse cardiac events (MACE) in elderly (>75 yr old) acute myocardial infarction (AMI) patients with renal dysfunction. As part of Korea AMI Registry (KAMIR), elderly patients with AMI and renal dysfunction (GFR<60 mL/min) received either medical (n=439) or PCI (n=1,019) therapy. Primary end point was in-hospital death. Secondary end point was MACE during a 1 month and 1 yr follow-up. PCI group showed a significantly lower incidence of in-hospital death (20.0% vs 14.3%, P=0.006). Short-term and long-term MACE rates were higher in medical therapy group (31.9% vs 19.0%; 57.7% vs 31.3%, P<0.001), and this difference was mainly attributed to cardiac death (29.3% vs 17.6%; 51.9% vs 25.0%, P<0.001). MACE-free survival time after adjustment was also higher in PCI group on short-term (hazard ratio, 0.67; confidence interval, 0.45-0.98; P=0.037) and long-term follow-up (hazard ratio, 0.61, confidence interval, 0.45-0.83; P=0.002). In elderly AMI patients with renal dysfunction, PCI therapy yields favorable in-hospital and short-term and long-term MACE-free survival.
PMCID: PMC3708073  PMID: 23853485
Acute Myocardial Infarction; Renal Dysfunction; Elderly; Percutaneous Coronary Intervention; Major Adverse Cardiac Event
19.  Paricalcitol Attenuates 4-Hydroxy-2-Hexenal-Induced Inflammation and Epithelial-Mesenchymal Transition in Human Renal Proximal Tubular Epithelial Cells 
PLoS ONE  2013;8(5):e63186.
4-Hydroxy-2-hexenal (HHE), the aldehyde product of lipid peroxidation, may be responsible for the pathogenesis of progressive renal disease. Recently, paricalcitol (19-nor-1,25-dihydroxyvitamin D2) was shown to be renoprotective through its anti-inflammatory and antifibrotic effects in various experimental nephropathy models. In this study, we investigated the effects of paricalcitol on inflammation and epithelial-mesenchymal transition (EMT) after HHE-induced renal tubular epithelial cell injury. To investigate the molecular mechanisms underlying HHE-induced renal tubular cell injury, the human proximal tubular epithelial (HK-2) cells cultured with 10 µM HHE in the presence or absence of paricalcitol. In HK-2 cells, paricalcitol attenuated the HHE-induced expression of extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase, and prevented nuclear factor-κB (NF-κB) activation. The expression of the inflammatory proteins inducible nitric oxide synthase and cyclooxygenase-2 was attenuated by paricalcitol pretreatment. In addition, HHE increased the expression of the transforming growth factor (TGF)-β/Smad signaling proteins and fibrotic proteins, such as α-smooth muscle actin and connective tissue growth factor; this inducible expression was suppressed by pretreatment with paricalcitol. Treatment with HHE resulted in the activation of the β-catenin signaling pathway, and paricalcitol pretreatment reduced the expression of β-catenin in HHE-treated HK-2 cells. Coimmunoprecipitation shows that paricalcitol induced vitamin D receptor (VDR)/β-catenin complex formation in HK-2 cells. Also immunofluorescence staining revealed that co-localization of VDR and β-catenin in the nuclei. ICG-001, an inhibitor of β-catenin, decreased the expression of TGF-β1 and attenuated HHE-induced tubular EMT. These results show that paricalcitol attenuated HHE-induced renal tubular cell injury by suppressing inflammation and EMT process through inhibition of the NF-κB, TGF-β/Smad, and β-catenin signaling pathways.
PMCID: PMC3656901  PMID: 23690997
20.  Gross Hematuria Associated with Genitourinary Tuberculosis 
Chonnam Medical Journal  2013;49(1):48-49.
A 27-year-old man presented to the emergency department with sudden onset of massive gross hematuria and urinary retention. Contrast-enhanced computed tomography imaging showed uneven, dilated calices and a narrowing of the renal pelvis in the left kidney; in addition, a large hematoma was noted in the urinary bladder. An emergency cystoscopy was performed following detection of the hematoma and blood clots were removed. A lesional biopsy, a tuberculosis (TB) culture, and urine cytology showed positive results for Mycobacterium tuberculosis. The clinical manifestations of genitourinary tuberculosis are nonspecific and are usually detected at a chronic stage. In conclusion, we report an unusual cause of acute kidney injury associated with a subacute stage of genitourinary tuberculosis that caused mucosal erosion and bleeding in the bladder.
PMCID: PMC3651987  PMID: 23678478
Tuberculosis; Acute kidney injury; Hematuria
21.  Serratia marcescens Peritonitis in a Diabetic Patient Receiving Continuous Ambulatory Peritoneal Dialysis 
Infection & Chemotherapy  2013;45(1):105-107.
We report a case of Serratia marcescens peritonitis in a 45-year-old man with insulin-dependent diabetes mellitus undergoing continuous ambulatory peritoneal dialysis (CAPD). The patient presented with abdominal pain and cloudy dialysate. Empiric antibiotic therapy was initiated intraperitoneally with cefazolin and ceftazidime for 5 days. Cultures of the dialysate revealed S. marcescens, and the treatment was subsequently changed to gentamicin and ceftazidime. Oral ciprofloxacin was also added. The patient's abdominal pain and the dialysate white blood cell (WBC) count, however, did not improve. The indwelling CAPD catheter was therefore removed. This is an unusual case report in the Korean literature of S. marcescens peritonitis in a patient receiving CAPD.
PMCID: PMC3780930  PMID: 24265957
Serratia marcescens; Continuous ambulatory peritoneal dialysis; Peritonitis
22.  Activation of the Renal PI3K/Akt/mTOR Signaling Pathway in a DOCA-Salt Model of Hypertension 
Chonnam Medical Journal  2012;48(3):150-154.
The present study investigated the changes that occurred in the mammalian target of rapamycin (mTOR) signaling pathway in the kidney as a result of deoxycorticosterone acetate (DOCA)-salt hypertension. Rats were implanted with DOCA strips (200 mg/kg) 1 week after unilateral nephrectomy and were then supplied with 0.9% saline to drink. Four weeks after DOCA implantation, systolic blood pressure (SBP) was measured by use of the tail-cuff method. The expression levels of phosphorylated phosphatidylinositol-3-kinase (PI3K), Akt, and mTOR, as well as the protein expression levels of ED-1 and cyclooxygenase-2 (COX-2), transforming growth factor-β1 (TGF-β1), α-smooth muscle actin (SMA), caspase-3, Bax, and Bcl-2, were then examined in the kidney by semiquantitative immunoblotting. DOCA-salt hypertensive rats were found to have significantly increased SBP as well as an increased kidney weight-to-body weight ratio. Moreover, the phosphorylation of PI3K, Akt, and mTOR was increased in the kidney of DOCA-salt hypertensive rats compared with the control, as was the protein expression of ED-1, COX-2, TGF-β1, and α-SMA. The expression levels of caspase-3 and Bax were increased significantly, whereas Bcl-2 expression was decreased. In conclusion, the phosphorylation of PI3K/Akt/mTOR was increased in the kidney of DOCA-salt hypertensive rats.
PMCID: PMC3539094  PMID: 23323219
Deoxycorticosterone; Hypertension; Kidney
23.  EBV-positive diffuse large B-cell lymphoma in a patient with primary Sjögren’s syndrome and membranous glomerulonephritis 
BMC Nephrology  2012;13:149.
Sjögren’s syndrome is a systemic autoimmune disease in which lymphatic cells destroy the salivary and lacrimal glands. Glomerulonephritis is thought to be a rare occurrence in primary Sjögren’s syndrome. Furthermore, concurrent glomerular involvement and lymphoma in patients with Sjögren’s syndrome has seldom been reported.
Case presentation
A 52-year-old woman with primary Sjögren’s syndrome developed membranous glomerulonephritis and Epstein-Barr virus-positive diffuse large B-cell lymphoma (DLBCL). She was diagnosed with Sjögren’s syndrome based on the dry eyes, dry mouth, positive anti-nuclear antibody test, anti-Ro (SS-A) antibody, salivary gland biopsy, and salivary scintigraphy. Moreover, renal biopsy confirmed the diagnosis of membranous glomerulonephritis. Three months later, her small bowel was perforated with pneumoperitoneum, and the biopsy revealed Epstein-Barr virus-positive DLBCL.
We observed the first case of primary Sjögren’s syndrome associated with Epstein-Barr Virus-positive DLBCL and membranous glomerulonephritis. Because of the possibility of malignancy-associated membranous glomerulonephritis in patients with primary Sjögren’s syndrome, we should be careful and examine such patients for hidden malignancy.
PMCID: PMC3519503  PMID: 23151312
Primary Sjögren’s syndrome; Membranous glomerulonephritis; EBV-positive diffuse large B-cell lymphoma
24.  The Pivotal Role of Reactive Oxygen Species Generation in the Hypoxia-Induced Stimulation of Adipose-Derived Stem Cells 
Stem Cells and Development  2011;20(10):1753-1761.
Adipose-derived stem cells (ASCs) offer a potential alternative for tissue repair and regeneration. We have recently shown that hypoxia stimulates ASCs and enhances the regenerative potential of ASCs, which is beneficial for ASC therapy. In the present study, we further investigated a key mediator and a signal pathway involved in the stimulation of ASC during hypoxia. Culturing ASC in a hypoxic incubator (2% oxygen tension) increased the proliferation and migration, and this was mediated by Akt and ERK pathways. To determine the generation of reactive oxygen species (ROS), 2′,7′-dichlorofluorescin diacetate intensity was detected by fluorescence-activated cell sorting. Hypoxia significantly increased the dichlorofluorescin diacetate intensity, which was greatly reduced by N-acetyl-cysteine and diphenyleneiodonium treatment. Likewise, the hypoxia-induced proliferation and migration of ASCs were reversed by N-acetyl-cysteine and diphenyleneiodonium treatment, suggesting the involvement of ROS generation in ASC stimulation. Further, we examined the activation of receptor tyrosine kinases and observed that hypoxia stimulated the phosphorylation of platelet-derived growth factor receptor-β. In summary, the ROS produced by ASCs in response to hypoxia was mostly likely due to NADPH oxidase activity. The increased cellular ROS was accompanied by the phosphorylation of platelet-derived growth factor receptor-β as well as by the activation of ERK and Akt signal pathways. Our results suggest a pivotal role for ROS generation in the stimulation of ASCs by hypoxia.
PMCID: PMC3182032  PMID: 21265612
25.  Suboptimal medical care of patients with ST-Elevation Myocardial Infarction and Renal Insufficiency: results from the Korea acute Myocardial Infarction Registry 
BMC Nephrology  2012;13:110.
The clinical outcomes of ST-segment elevation myocardial infarction (STEMI) are poor in patients with renal insufficiency. This study investigated changes in the likelihood that patients received optimal medical care throughout the entire process of myocardial infarction management, on the basis of their glomerular filtration rate (GFR).
This study analyzed 7,679 patients (age, 63 ± 13 years; men 73.6%) who had STEMI and were enrolled in the Korea Acute Myocardial Infarction Registry (KAMIR) from November 2005 to August 2008. The study subjects were divided into 5 groups corresponding to strata used to define chronic kidney disease stages.
Patients with lower GFR were less likely to present with typical chest pain. The average symptom-to-door time, door-to-balloon time, and symptom-to-balloon time were longer with lower GFR than higher GFR. Primary reperfusion therapy was performed less frequently and the results of reperfusion therapy were poorer in patients with renal insufficiency; these patients were less likely to receive adjunctive medical treatment, such as treatment with aspirin, clopidogrel, β-blocker, angiotensin-converting enzyme (ACE) inhibitor/angiotensin-receptor blocker (ARB), or statin, during hospitalization and at discharge. Patients who received less intense medical therapy had worse clinical outcomes than those who received more intense medical therapy.
Patients with STEMI and renal insufficiency had less chance of receiving optimal medical care throughout the entire process of MI management, which may contribute to worse outcomes in these patients.
PMCID: PMC3467157  PMID: 22966970
Myocardial infarction; Optimal medical care; Renal function

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