Seon-Young Lee

EGCG attenuates autoimmune arthritis by inhibition of STAT3 and HIF-1α with Th17/Treg control.

Epigallocatechin-3-gallate (EGCG) is a green tea polyphenol exerting potent anti-oxidant and anti-inflammatory effects by inhibiting signaling and gene expression. The objective of the study was to evaluate the effect of EGCG on interleukin (IL)-1 receptor antagonist knockout (IL-1RaKO) autoimmune arthritis models. IL-1RaKO arthritis models were injected intraperitoneally with EGCG three times per week after the first immunization. EGCG decreased the arthritis index and showed protective effects against joint destruction in the IL-1RaKO arthritis models. The expression of pro-inflammatory cytokines, oxidative stress proteins, and p-STAT3 (Y705) and p-STAT3 (S727), mTOR and HIF-1α were significantly lower in mice treated with EGCG. EGCG reduced osteoclast markers in vivo and in vitro along with anti-osteoclastic activity was observed in EGCG-treated IL-1RaKO mice. The proportion of Foxp3+ Treg cells increased in the spleens of mice treated with EGCG, whereas the proportion of Th17 cells reduced. In vitro, p-STAT3 (Y705) and p-STAT3 (S727), HIF1α and glycolytic pathway molecules were decreased by EGCG. EGCG suppressed the activation of mTOR and subsequently HIF-1α, which is considered as a metabolic check point of Th17/Treg differentiation supporting the therapeutic potential of EGCG in autoimmune arthritis.

Human rotavirus genotypes in hospitalized children, South Korea, April 2005 to March 2007.

Availability of new rotavirus vaccines highlights the need to maintain and enhance rotavirus strain surveillance. We collected stool samples from children with gastroenteritis admitted to eight hospitals in South Korea from April 2005 to March 2007. Of the 6057 samples collected, 1337 (22%) were positive for rotavirus by one of several antigen detection assays. G and P genotypes were identified for 1299 (97%) of rotavirus-positive specimens. G1P[8] (36%) was the most prevalent strain, followed by G3P[8] (16%), G4P[6] (8.9%) and G1P[6] (8.2%). G1P[8] was also the most prevalent strain in each hospital. Seasonal peaks of rotavirus infection were noted from November 2005 to April 2006 and January to March 2007. This large-scale surveillance study provides important insights into rotavirus genotype distribution and pattern changes in South Korea.

IL-17-mediated mitochondrial dysfunction impairs apoptosis in rheumatoid arthritis synovial fibroblasts through activation of autophagy.

Fibroblast-like synoviocytes (FLSs) are a major cell population of the pannus that invades cartilage and bone in rheumatoid arthritis (RA). FLS resistance to apoptosis is a major characteristic of RA. The aims of this study were to investigate the effects of interleukin-17 (IL-17) and IL-17-producing T helper (Th17) cells on resistance to apoptosis in FLSs from RA patients (RA FLSs) and their roles in mitochondrial dysfunction and autophagy. Mitochondrial function was assessed in RA FLSs and FLSs from osteoarthritis patients (OA FLSs). FLSs were treated with IL-17 and their morphological features, respiratory level and mitochondrial gene expression were measured. The effects of IL-17 and Th17 cells on the relationship between autophagy and apoptosis were evaluated by measuring the expression of apoptosis-related genes using sodium nitroprusside or 3-methyladenine. The mitochondria of FLSs isolated from RA and osteoarthritis patients displayed different morphological and physiological features. RA FLSs exhibited greater autophagosome formation and greater dysfunction of mitochondrial respiration compared with OA FLSs. IL-17 induced mitochondrial dysfunction and autophagosome formation in RA FLSs, suggesting that they were resistant to apoptosis. Autophagy-related antiapoptosis induced by IL-17 was restored by inhibition of autophagy, suggesting a relationship between mitochondrial dysfunction and cell survival in RA FLSs. Th17 cells and IL-17 increased autophagy of RA FLSs by causing mitochondrial dysfunction. Our findings suggest that, in RA, interactions between RA FLSs and Th17 cells may be involved in the tumorous growth of FLSs and the formation of pannus in joints.

Association of current and past smoking with metabolic syndrome in men

OBJECTIVES The objective of this study was to determine the relationship between past smoking and the risk factors for metabolic syndrome. METHODS From January 2007 to December 2007, a total of 3,916 over thirty years old male health screen examinees were divided into the nonsmoking, smoking, ex-smoking groups. The diagnosis of metabolic syndrome was based on the criteria of the NCEP ATP (Executive Summary of The Third Report of The National Cholesterol Education Program). Metabolic syndrome was defined as the presence of three or more of the following: a blood pressure > or =130/85 mmHg, a fasting glucose level > or = 110 mg/dL, a HDL-C (High Density Lipoprotein Cholesterol) level < 40 mg/dL, a triglyceride level > or = 150 mg/dL and, a waist circumference men > or = 102 cm, but a waist to hip ratio > 0.90 was used as a surrogate for the waist circumference. RESULTS After adjustment for age, alcohol consumption and, exercise in the smokers, for the ex-smokers compared with the nonsmokers, the odds ratio (OR) of a lower HDL cholesterol level (< 40 mg/dL) was 1.29 (95% CI=1.03-1.61) in the smokers, the ORs of a higher triglyceride level were 1.35 (95% CI=1.09-1.66) in the ex-smokers and, 2.12 (95% CI=1.75-2.57) in the smokers, and the OR of a waist to hip ratio was 1.25 (95% CI=1.03-1.52) in the ex-smokers. When there were over three components of metabolic syndrome in the ex-smokers and smokers as compared with the nonsmokers, the odds ratio against the risk of metabolic syndrome were 2.39 (95% CI=1.00-6.63) and 2.37 (95% CI=1.02-6.46), respectively. CONCLUSIONS The present study suggested that there is an association of smoking with metabolic syndrome in men.

Metformin Prevents Fatty Liver and Improves Balance of White/Brown Adipose in an Obesity Mouse Model by Inducing FGF21

Obesity and its associated metabolic disorders are related to the onset of fatty liver and the balance of white adipose tissue (WAT) and brown adipose tissue (BAT). We hypothesized that metformin, an effective pharmacological treatment for type 2 diabetes, would inhibit white adipogenesis, fatty liver, and metabolic dysfunction. Metformin was treated daily for 14 weeks in a high-fat dieting C57BL/6J mice. Serum biomarkers were analyzed and protein level was assessed using confocal staining or flow cytometry. The development of lipid drops in the liver cells and white adipocyte was measured using hematoxylin and eosin or Oil Red O stains. Gene expressions were analyzed with quantitative real-time PCR. Metformin treatment decreased the body weight and improved the metabolic profile of obese mice. In obese mice, metformin also induced the expression of BAT-related markers and increased fibroblast growth factor (FGF) 21 expression in the liver and in white adipocyte. Metformin suppressed white adipocyte differentiation via induction of FGF21. Metformin improves Treg/Th17 balance in CD4+ T cells in mice with high-fat diet-induced obesity. Metformin also improves glucose metabolism and metabolic disorder. Interleukin-17 deficiency also decreases inflammation in mice. Therefore, metformin may be therapeutically useful for the treatment of obesity and metabolic dysfunction.

The association of cardiovascular risk factors with nonalcoholic fatty liver disease in health checkup examinees

OBJECTIVES The purpose of this study was to evaluate the relationship of nonalcoholic fatty liver and cardiovascular risk factors. METHODS This study was conducted to investigate the association of nonalcoholic fatty liver and cardiovascular risk factors for adult men (n=2976) and women (n=2442) who were over 19 years old, after excluding the HBsAg(+) or anti-HCV(+) patients and the men and women with increased alcohol intake (men: 40 g/week, women: 20 g/week). RESULTS Compared with the normal liver subjects, the nonalcoholic fatty liver subjects showed a significantly increased frequency of abnormal systolic blood pressure (> or =120 mmHg), fasting blood sugar (> or =100 mg/dL), total cholesterol (> or =200 mg/dL), triglyceride (> or =150 mg/dL), high density lipoprotein cholesterol (<40 mg/dL), low density lipoprotein cholesterol (> or =130 g m/dL) and abdominal obesity in men, and all these measures were significantly increased in the women except for abnormal HDL cholesterol. After adjusting for the body mass index, age, smoking, exercise and a nonalcoholic liver, the odds ratios of an abnormal waist hip ratio were 1.35(95% Confidence Interval=1.05-4.72) in the mild fatty liver, 1.61(1.19-2.18) in the moderate fatty liver, 2.77(1.57-4.92) in the severe fatty liver compared with a normal liver. The adjusted odds ratios for abnormal fasting blood sugar were 1.26(1.03-1.53) in the mild fatty liver, 1.62(1.27-2.06) in the moderate fatty liver and 1.77(1.12-2.78) in the severe fatty liver. The adjusted odds ratios for abnormal triglyceride were 1.38(1.11-1.72) in the mild fatty liver, 1.73(0.33-2.24) in the moderate fatty liver and 1.91(1.17-3.10) in the severe fatty liver of men. Adjusted odds ratios for abnormal triglyceride were 1.50(1.04-2.15) in mild, 1.71(1.07-2.68) in moderate, 1.81(0.69-4.38) in severe fatty liver of women. CONCLUSIONS The nonalcoholic fatty liver subjects had more cardiovascular risk factors compared with the normal liver subjects. Thus, prevention and treatment of the nonalcoholic fatty liver is necessary by lifestyle modifications such as restriction of alcohol intake, no smoking, exercise and adequate eating habits.

Monosodium urate crystal-induced triggering receptor expressed on myeloid cells 1 is associated with acute gouty inflammation

OBJECTIVE Triggering receptor expressed on myeloid cells 1 (TREM-1), which amplifies the inflammation elicited by the Toll-like receptor pathway, was originally implicated in sepsis and bacterial infection. However, it has been suggested that TREM-1 may also play an important role in non-infectious inflammation. The present study was conducted to investigate whether TREM-1 is involved in human acute gouty inflammation. METHODS A total of 37 gout patients were recruited between March 2011 and January 2014 from Seoul St Marys Hospital. The expression of TREM-1 on mononuclear cells was assessed using FACS analysis, immunostaining and real-time RT-PCR. To block the TREM-1 signal, soluble TREM-1 (sTREM-1) or the synthetic blocking peptide LP17 was used. The concentration of sTREM-1 was assessed by ELISA. RESULTS FACS analysis and real-time RT-PCR demonstrated that TREM-1 expression was higher in the SF mononuclear cells of acute gouty arthritis patients than in peripheral blood mononuclear cells (PBMCs). Immunohistochemical staining of tophi tissues revealed TREM-1 expression, with confocal microscopy demonstrating TREM-1 expression on tophi tissue macrophages. We also demonstrated that MSU treatment induced TREM-1 expression on the PBMCs of acute gout patients in vitro. Although blockade of TREM-1 did not directly suppress MSU-induced IL-1β production of PBMCs in vitro, the concentration of soluble TREM-1 was higher in the SF of gout vs OA patients and was positively correlated with serum CRP. CONCLUSION TREM-1 is induced by MSU and is associated with the inflammation of human acute gouty arthritis.

Metformin ameliorates experimental-obesity-associated autoimmune arthritis by inducing FGF21 expression and brown adipocyte differentiation

Rheumatoid arthritis (RA) is a systemic autoimmune disease involving excessive inflammation. Recently, RA associated with a metabolic disorder was revealed to be non-responsive to RA medications. Metformin has been reported to have a therapeutic effect on RA and obesity. The aim of this investigation was to study the therapeutic effect and the underlying mechanism of metformins action in an experimental model of collagen-induced arthritis (CIA) associated with obesity. Metformin was administered daily for 13 weeks to mice with CIA that had been fed a high-fat diet. Metformin ameliorated the development of CIA in obese mice by reducing autoantibody expression and joint inflammation. Furthermore, metformin decreased the expression levels of pSTAT3 and pmTOR and had a small normalizing effect on the metabolic profile of obese CIA mice. In addition, metformin increased the production of pAMPK and FGF21. Metformin also induced the differentiation of brown adipose tissue (BAT), which led to a reciprocal balance between T helper (Th) 17 and regulatory T (Treg) cells in vitro and in vivo. These results suggest that metformin can dampen the development of CIA in obese mice and reduce metabolic dysfunction by inducing BAT differentiation. Thus, metformin could be a therapeutic candidate for non-responsive RA.

Grim19 Attenuates DSS Induced Colitis in an Animal Model

DSS induced colitis is a chronic inflammatory disease characterized by inflammation in the gastrointestinal tract, which destabilizes the gut and induces an uncontrolled immune response. Although DSS induced colitis is generally thought to develop as a result of an abnormally active intestinal immune system, its pathogenesis remains unclear. Gene associated with retinoid interferon induced mortality (Grim) 19 is an endogenous specific inhibitor of STAT3, which regulates the expression of proinflammatory cytokines. In this study, we investigated the influence of GRIM19 in a DSS induced colitis mouse model. We hypothesized that Grim19 would ameliorate DSS induced colitis by altering STAT3 activity and intestinal inflammation. Grim19 ameliorated DSS induced colitis severity and protected intestinal tissue. The expression of STAT3 and proinflammatory cytokines such as IL-1β and TNF-α in colon and lymph nodes was decreased significantly by Grim19. Moreover, DSS induced colitis progression in a Grim19 transgenic mouse line was inhibited in association with a reduction in STAT3 and IL-17 expression. These results suggest that Grim19 attenuates DSS induced colitis by suppressing the excessive inflammatory response mediated by STAT3 activation.

Factors associated with metabolic syndrome and related medical costs by the scale of enterprise in Korea.

ObjectivesThe purpose of this study was to identify the risk factors of metabolic syndrome (MS) and to analyze the relationship between the risk factors of MS and medical cost of major diseases related to MS in Korean workers, according to the scale of the enterprise.MethodsData was obtained from annual physical examinations, health insurance qualification and premiums, and health insurance benefits of 4,094,217 male and female workers who underwent medical examinations provided by the National Health Insurance Corporation in 2009. Logistic regression analyses were used to the identify risk factors of MS and multiple regression was used to find factors associated with medical expenditures due to major diseases related to MS.ResultThe study found that low-income workers were more likely to work in small-scale enterprises. The prevalence rate of MS in males and females, respectively, was 17.2% and 9.4% in small-scale enterprises, 15.9% and 8.9% in medium-scale enterprises, and 15.9% and 5.5% in large-scale enterprises. The risks of MS increased with age, lower income status, and smoking in small-scale enterprise workers. The medical costs increased in workers with old age and past smoking history. There was also a gender difference in the pattern of medical expenditures related to MS.ConclusionsHealth promotion programs to manage metabolic syndrome should be developed to focus on workers who smoke, drink, and do little exercise in small scale enterprises.