Search

In the study here, the potential applicability of KMRC011 - an agonist of toll-like receptor-5 – as a countermeasure for radiation toxicities was evaluated. Following a single 5.5 Gy total body irradiation (TBI, surface absorbed dose = 7 Gy) of Co60 γ-rays, mortality rates and degrees of pathological lesions that developed over 80 days were compared in monkeys that received TBI only and a group that was injected once with KMRC011 (10 μg/kg) after TBI. Compared to the TBI-only hosts (80%), the death rate was significantly improved by the use of KMRC011 (40%), all deaths in both groups occurred in the period from Days 19-24 post-TBI. Further analysis of monkeys that survived until the end of the experiment showed that AST and ALT levels were elevated only in the TBI group, and that radiation-induced tissue damage was alleviated by the KMRC011 injection. Additionally, expression of cell death-related proteins was lower in tissues from the KMRC011-treated hosts than in those in the TBI-only group. Other measured parameters, including body weight, food uptake, and hematological values did not significantly differ between the two groups over the entire period. The results of this study, thus demonstrate that KMRC011 could potentially be used as a medical countermeasure for the treatment of acute radiation exposure.

High-dose radiation-induced tissue damage is a major limiting factor in the medical application of nuclear technology. Herein, we tested 28-day repeated-dose toxicity of KMRC011, an agonist of toll-like receptor (TLR) 5, which is being developed as a medical countermeasure for radiation, using cynomolgus monkeys. KMRC011 (0.01, 0.02 or 0.04 mg/kg/day) was intramuscularly injected once daily for 4 weeks, and each two monkeys in both control and 0.04 mg/kg/day group were observed for an additional 2-week recovery period. There were no dose-related toxicological changes in mortality, clinical observations, body weight, food consumption, ophthalmological findings, electrocardiographs, coagulation, serum chemistry, organ weights, or urinalysis and urine chemistry. Although treatment-related changes, such as increased white blood cells, increased absolute and relative neutrophils, decreased relative lymphocytes and inflammatory lesions, were noted in the maximum dose group, these findings were not observed after the 2-week recovery period. Further, we considered that the kidneys and heart may be target organs of TLR5 agonists, as well as the spleen, and that autophagic signals can be triggered in tissue damage and the repair process. Importantly, accumulation of p62 protein, an indicator of autophagy, and a decrease of caveolin-1 protein, a regulator of TLR5 protein half-life, were found in both tissues from the highest dose group. Therefore, we conclude that the no-observed-adverse-effect level for KMRC011 may be greater than 0.04 mg/kg/day in male and female monkeys. Additionally, we propose that further studies are needed to identify the molecular signals, which are related to KMRC011-induced adverse effects.

The physical properties of DNA have been suggested to play a central role in spatio-temporal organization of eukaryotic chromosomes. Experimental correlations have been established between the local nucleotide content of DNA and the frequency of inter- and intra-chromosomal contacts but the underlying physical mechanism remains unknown. Here, we combine fluorescence resonance energy transfer (FRET) measurements, precipitation assays, and molecular dynamics simulations to characterize the effect of DNA nucleotide content, sequence, and methylation on inter-DNA association and its correlation with DNA looping. First, we show that the strength of DNA condensation mediated by poly-lysine peptides as a reduced model of histone tails depends on the DNA’s global nucleotide content but also on the local nucleotide sequence, which turns out to be qualitatively same as the condensation by spermine. Next, we show that the presence and spatial arrangement of C5 methyl groups determines the strength of inter-DNA attraction, partially explaining why RNA resists condensation. Interestingly, multi-color single molecule FRET measurements reveal strong anti-correlation between DNA looping and DNA–DNA association, suggesting that a common biophysical mechanism underlies them. We propose that the differential affinity between DNA regions of varying sequence pattern may drive the phase separation of chromatin into chromosomal subdomains.

To assess the relevance of previous epidemiologic studies on bisphosphonate-related osteonecrosis of the jaw (BRONJ), we first conducted a systematic review of large population-based observational studies and evaluated the validity of claims-based algorithms for the identification of BRONJ. Studies containing primary observational epidemiologic data regarding bisphosphonate (BP) exposure and outcomes of osteonecrosis of the jaw were systematically reviewed. Using surrogates for identifying potential BRONJ cases from a population-based hospital registry, validation was performed through medical chart review. Positive predictive value (PPV) was estimated for each diagnostic code and for the overall algorithm utilized. Various strategies to increase PPV were also performed. Seventeen studies were systematically reviewed and presented with variations in study quality as well as inconsistent findings. Moreover, there was a high level of methodological heterogeneity. A total of 1920 patients were identified through the ICD-10 algorithm with potential BRONJ, although only 109 cases were confirmed, corresponding to an overall PPV of 5.68% (95% confidence interval [CI] 4.68-6.81). Only K10.2 (inflammatory conditions of the jaw) exhibited a relatively high PPV of 26.18%, which increased to 74.47% after confinement to BP users. Other strategies to increase PPV value were not effective. Our findings showed that the overall PPV for BRONJ identification was very low, indicating low validity of the current algorithm and possible overestimation of ONJ occurrence. There is an urgent need to develop more reliable and specific operational definitions for the identification of BRONJ cases in large population databases. © 2016 American Society for Bone and Mineral Research.

Despite the previous studies showing the relationship between microalbuminuria and insulin resistance, longitudinal effect of insulin resistance on development of microalbuminuria is not clearly identified in non-diabetic population.One thousand six hundred three non-diabetic Korean men without microalbuminuria in 2005 had been followed up for the development of microalbuminuria until 2010. Microalbuminuria was evaluated by urine-albumin creatinine ration, and insulin resistance was evaluated by homeostasis model assessment of insulin resistance (HOMA-IR). Cox proportional hazards model was used to estimate the risk for microalbuminuria according to the tertile of HOMA-IR.During 5465.8 person-y of average follow-up, microalbuminuria developed in 76 (4.7%) participants. Incidence of microalbuminuria increased in proportion to the level of HOMA-IR (tertile 1: 3.0%, tertile 2: 4.1%, tertile 3: 7.1%, P0.001). When the 1st tertile of HOMA-IR was set as reference, hazard ratios and 95% confidence interval were 1.15 (0.56-2.35) and 2.07 (1.05-4.09) for those in the 2nd and 3rd tertiles of HOMA-IR, even after adjusting multiple covariates, respectively (P for linear trend=0.054).Increased insulin resistance was a predictor of microalbuminuria in Korean men.

Considering that cigarette smoke condensate (CSC) is primarily absorbed through the alveoli in the lungs, herein, we used a mouse alveolar macrophage cell line (MH-S cells). After 24 h exposure, CSC decreased dose-dependently cell viability accompanying an increase in intracellular ROS and NO level. CSC structurally or functionally damaged organelles including mitochondria, ER and lysosome and enhanced the expression of proteins related to apoptosis, ER stress and DNA damage accompanying an elevated proportion of annexin V-bound cells. Meanwhile, the expression of certain proteins related to mitochondrial dynamics (OPA1 and DRP1) and autophagy (ATG5) did not overall show significant dose-dependent change in cells exposed to CSC. More importantly, conversion of LC3-I to LC3B-II, a representative marker for autophagy, was also unclear. Considering that intracellular organelles work together in harmony to perform defense mechanism against foreign bodies, we investigated changes in immune response following CSC exposure. The level of IFN-γ and MIP-1α was elevated in CSC-exposed cells, whereas the MCP-1α level decreased. The expression of chemokine receptors (CD195 and CXCR2) and an adhesion molecule (CD54) increased by CSC treatment, the expression of certain antigen presentation-related proteins (MHC class II, CD40, and CD80) were also enhanced. Meanwhile, the expression of CD86, a co-stimulatory molecule for antigen presentation, dose-dependently decreased. In conclusion, we suggest that CSC may induce apoptotic cell death and disturbance in host defense mechanisms by impairing function of cellular components.

Graduate School of Education, Seoul National University,Seoul, KoreaOBJECTIVES: This study investigated the associationbetween bone mineral density (BMD) and periodontitisin a representative sample of Korean adults.MATERIAL AND METHODS: Of 36 188 individuals whoparticipated in the Korea National Health and NutritionExamination Survey in 2008, 2009, and 2010, 9977participants aged ≥40 years were included in this cross-sectional study. The associations of BMD of lumbarspine, total femur, and femoral neck with periodontitiswere investigated using logistic regression analysis.Additionally, dose–response relationships with BMDdivided into quintiles and the association between oste-oporosis and periodontitis were investigated.RESULTS: With the set of Community PeriodontalIndex (CPI) ≥ 3 as a dependent variable, logistic regres-sion analysis revealed that a decrease of BMD was sig-nificantly associated with higher odds of periodontitis[range of adjusted odds ratios (AORs); 1.15–1.20,P < 0.001 for all BMD sites]. Similarly, these associa-tions were also found in the CPI 4 model. With regardto dose–response relations, the lower the BMD quintile,the higher the AORs appeared with statistical signifi-cance in the CPI ≥ 3 model. (P for trend < 0.001) Partic-ipants with osteoporosis had 2.26 and 1.91 times higherodds for CPI ≥ 3 and CPI 4, respectively, than thosewith normal BMD, indicating a significant associationbetween the two diseases.CONCLUSIONS: Our results suggest that BMD issignificantly associated with periodontitis.Oral Diseases (2014) 20, 609–615Keywords: osteoporosis; periodontitis; bone mineral density;osteopenia; National Health and Nutrition Examination Survey;Community Periodontal Index

Background Studies on factors which may predict the risk of diabetes are scarce. This prospective cohort study was conducted to determine the association between adiponectin and type 2 diabetes among Korean men and women. Methods A total of 42,845 participants who visited one of seven health examination centers located in Seoul and Gyeonggi province, Republic of Korea between 2004 and 2008 were included in this study. The incidence rates of diabetes were determined through December 2011. To evaluate the effects of adiponectin on type 2 diabetes, the Cox proportional hazard model was used. Results Of the 40,005 participants, 959 developed type 2 diabetes during a 6-year follow-up. After the adjustment for age, body mass index (BMI), and waist circumference, the risks for type 2 diabetes in participants with normoglycemia had a 1.70-fold (95% confidence interval [CI], 1.21 to 2.38) increase in men and a 1.83-fold (95% CI, 1.17 to 2.86) increase in women with the lowest tertile of adiponectin when compared to the highest tertile of adiponectin. For participants with impaired fasting glucose (IFG), the risk for type 2 diabetes had a 1.46-fold (95% CI, 1.17 to 1.83) increase in men and a 2.52-fold (95% CI, 1.57 to 4.06) increase in women with the lowest tertile of adiponectin. Except for female participants with normoglycemia, all the risks remained significant after the adjustment for fasting glucose and other confounding variables. Surprisingly, BMI and waist circumference were not predictors of type 2 diabetes in men or women with IFG after adjustment for fasting glucose and other confounders. Conclusion A strong association between adiponectin and diabetes was observed. The use of adiponectin as a predictor of type 2 diabetes is considered to be useful.

The aims of this study were to determine (1) whether the urinary mid pregnancy and placental delivery oxidative stress levels are related to the intrauterine condition and (2) whether long-lasting adverse oxidative stress is related to the birth size. We investigated pregnant women when they were at 24-28 weeks of pregnancy from October 2001 to May 2003 and at their delivery. Samples were obtained at each investigation time. Other information of mothers and their birth records were tracked from medical charts at Ewha Womans University Hospital in Seoul, South Korea. We quantified mid pregnancy oxidative stress by measuring urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) in 272 subjects. Intrauterine oxidative stress at delivery was measured by placental levels of 8-OHdG and MDA in 54 and 38 subjects, respectively. To identify the correlated intrauterine oxidative stress conditions, we evaluated kappa statistics and Pearson's correlations between maternal and placental oxidative stress. The relationships between intrauterine oxidative stress and birth sizes were examined by a general linear model. The levels of oxidative stress were divided to two groups based on their 75th percentile values. There was no correlation between urinary mid pregnancy and placental delivery oxidative stress levels for both MDA (kappa index=0.32, r=0.21) and 8-OHdG (kappa index=-0.13, r=-0.11). Both the urinary mid pregnancy and delivery 8-OHdG levels were significantly related to birth size. The birth size was largest in the 8-OHdG group. In addition, birth size was worse in the group with both high urinary mid pregnancy and placental oxidative stress than in any other combinations of low and high groups of urinary mid pregnancy and placental delivery oxidative stress. This evidence for a weak correlation between urinary mid pregnancy and placental delivery oxidative stress levels and its interactive effects on birth size suggest that the period from the middle to the end of pregnancy is critical window to intrauterine growth and also represents a modifiable period of the intrauterine condition. Therefore, applying interventions to pregnant women with high oxidative stress levels at midterm could contribute to increasing birth sizes.

We aimed to assess how metabolic profiles, surrogate markers of insulin resistance, and subclinical atherosclerosis are interrelated in subjects with impaired fasting glucose (IFG) and investigate whether the diagnosis of metabolic syndrome (MetS) further increases the risk of cardiovascular disease among subjects already at risk. We analyzed 1739 Korean subjects with IFG. The parameters of MetS, plasma adiponectin level, and pulse wave velocity (PWV) were assessed. Subjects with MetS had unfavorable metabolic parameters, lower adiponectin level, and higher peripheral PWV compared to those without MetS. Adiponectin correlated with fasting glucose, waist circumference, triglyceride, HDL-cholesterol, BMI, HOMA-IR, and the number of MetS components. In addition to blood pressure, peripheral PWV was associated with triglyceride, waist circumference, and the number of MetS components while aortic PWV correlated positively with fasting plasma glucose. Multiple linear regression analysis revealed that adiponectin correlated with HDL-cholesterol, HOMA-IR, fasting glucose, waist circumference, and triglyceride, peripheral PWV with blood pressure, body mass index, waist circumference, and the number of MetS components, and aortic PWV with fasting plasma glucose. In subjects with IFG, concurrent MetS increases PWV and has an unfavorable effect on cardiovascular risks, and these risks were further increased by additional MetS components.

As indicators of obesity, waist circumference (WC), body mass index (BMI), and adiponectin are well-known risk factors for diabetes mellitus. The objectives of this study were to measure the independent association between these obesity indicators and diabetes and to examine the combined effect of these indicators on diabetes in a Korean population. The WC, BMI, and serum adiponectin were measured in 4459 healthy Koreans and were classified into tertile groups for men and women. The independent and combined associations of the obesity indicators with diabetes were measured using logistic regression analyses. Diabetes was defined as fasting serum glucose greater than 126 mg/dL or taking medication. Levels of adiponectin were inversely associated with BMI and WC and directly associated with age and high-density lipoprotein (HDL) cholesterol (P < .001). After adjusting for age, BMI, WC, and other lifestyle factors, low levels of adiponectin were associated with an increased prevalence of diabetes. Further adjustment for HDL cholesterol and triglyceride attenuated this association in women but not men. The combined effects of WC and adiponectin on diabetes progressively increased; however, the interaction of these 2 variables was not statistically significant. The combined effect of BMI and adiponectin on diabetes showed similar results. These results suggest that adiponectin was associated with diabetes. The association was independent of BMI and WC and was partly modified by HDL and triglyceride. There were no effect modifications of adiponectin with WC and BMI on diabetes.

Pregnancy is associated with increased susceptibility to oxidative stress. Deficiencies in antioxidants during pregnancy and placental oxidant-antioxidant imbalance may impair the development of the fetoplacental unit or the eventual offspring. In order to elucidate the association of prenatal status of vitamin C with the oxidative stress and apoptotic activity in normal full-term placentas, we evaluated the content of placental lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and the trophoblast apoptotic index in normal-term human pregnancies. Tissue samples of placentas obtained from 80 normal-term pregnancies were categorized into 40 cases with a lower level of prenatal vitamin C (8.997 microg/ml) and 40 cases with a higher level of prenatal vitamin C (or =11.734 microg/ml). We evaluated the placental LOX-1 content and the trophoblast apoptotic index with Western blot analysis and immunohistochemistry, and then determined their correlation with the prenatal status of vitamin C. We confirmed that the trophoblast expression for the endothelial scavenger receptor LOX-1 and the apoptotic activity were significantly lower in the group with a higher prenatal level of vitamin C, indicating that placental oxidative stress and the apoptotic index were associated with the maternal status of vitamin C. We therefore postulate that the maternal status of antioxidant vitamins during pregnancy can affect fetal development.

A B-cell activating factor of the tumor necrosis factor (TNF) family (BAFF) is an essential B-cell survival factor. Myasthenia gravis (MG) is one of the most typical antibody-mediated autoimmune disorders. To test whether serum BAFF levels are increased in MG patients, we compared the serum BAFF levels of 40 MG patients with those of 30 healthy controls. Serum BAFF levels of MG group were significantly higher than those of healthy group. These results suggested that the BAFF might play a role in the immunopathogenesis of MG and further study on B-cell and T-cell activation may be needed.