Vinyl-Stilbene Inhibits Human Norovirus RNA Replication by Activating Heat-Shock Factor-1

Norovirus (NV) is the most common cause of viral gastroenteritis, with the potential to develop into a fatal disease in those who are immuno-compromised, and effective vaccines and treatments are still non-existent. In this study, we aimed to elucidate the molecular mechanism of the previously identified NV replication inhibitor utilizing a vinyl-stilbene backbone, AC-1858. First, we confirmed the inhibition of the NV RNA replication by a structural analog of AC-1858, AC-2288 with its exclusive cytoplasmic subcellular localization. We further validated the induction of one specific host factor, the phosphorylated form of heat shock factor (HSF)-1, and its increased nuclear localization by AC-1858 treatment. Finally, we verified the positive and negative impact of the siRNA-mediated downregulation and lentivirus-mediated overexpression of HSF-1 on NV RNA replication. In conclusion, these data suggest the restrictive role of the host factor HSF-1 in overall viral RNA genome replication during the NV life cycle.

Alteration in Cngb1 Expression upon Maternal Immune Activation in a Mouse Model and Its Possible Association with Schizophrenia Susceptibility

Objective@#The cyclic nucleotide-gated channel (Cng) regulates synaptic efficacy in brain neurons by modulating Ca2＋ levels in response to changes in cyclic nucleotide concentrations. This study investigated whether the expression of Cng channel, cyclic nucleotide-gated channel subunit beta 1 (Cngb1) exhibited any relationship with the pathophysiology of schizophrenia in an animal model and whether genetic polymorphisms of the human gene were associated with the progression of schizophrenia in a Korean population. @*Methods@#We investigated whether Cngb1 expression was related to psychiatric disorders in a mouse model of schizophrenia induced by maternal immune activation. A case-control study was conducted of 275 schizophrenia patients and 410 controls with single-nucleotide polymorphisms (SNPs) in the 5′-near region of CNGB1. @*Results@#Cngb1 expression was decreased in the prefrontal cortex in the mouse model. Furthermore, the genotype frequency of a SNP (rs3756314) of CNGB1 was associated with the risk of schizophrenia. @*Conclusion@#Our results suggest that CNGB1 might be associated with schizophrenia susceptibility and maternal immune activation. Consequently, it is hypothesized that CNGB1 may be involved in the pathophysiology of schizophrenia.

Cohort profile: the Ewha Birth and Growth Study / 한국역학회지

With the introduction of life-course epidemiology, researchers realized the importance of identifying risk factors in early life to prevent chronic diseases. This led to the establishment of the Ewha Birth and Growth Study in 2001; the study is a prospective birth cohort designed to provide evidence of early life risk factors for a child’s growth and health. Participants were recruited from those who visited Ewha Womans University Mokdong Hospital (a tertiary hospital in southwest Seoul, Korea) for prenatal care at 24-28 weeks of gestation. In total, 891 mothers enrolled in this study between 2001 and 2006 and their offspring (n=940) were followed-up. Regular check-up examinations of offspring were conducted at 3 years, 5 years, and 7 years of age and every year thereafter. To consider age-related health issues, extensive data were collected using questionnaires and measurements. In 2021, the study subjects will reach 19 years of age, and we are planning a check-up examination for early adulthood. About 20 years have passed since the cohort data were collected, and we have published results on childhood health outcomes associated with prenatal and birth characteristics, genetic and epigenetic characteristics related to childhood metabolism, the effects of exposure to endocrine disruptors, and dietary patterns in childhood. Recently, we started reporting on topics related to adolescent health. The findings will facilitate identification of early life risk factors for chronic diseases and the development of interventions for diseases later in life.

Cohort profile: the Ewha Birth and Growth Study / 한국역학회지

With the introduction of life-course epidemiology, researchers realized the importance of identifying risk factors in early life to prevent chronic diseases. This led to the establishment of the Ewha Birth and Growth Study in 2001; the study is a prospective birth cohort designed to provide evidence of early life risk factors for a child’s growth and health. Participants were recruited from those who visited Ewha Womans University Mokdong Hospital (a tertiary hospital in southwest Seoul, Korea) for prenatal care at 24-28 weeks of gestation. In total, 891 mothers enrolled in this study between 2001 and 2006 and their offspring (n=940) were followed-up. Regular check-up examinations of offspring were conducted at 3 years, 5 years, and 7 years of age and every year thereafter. To consider age-related health issues, extensive data were collected using questionnaires and measurements. In 2021, the study subjects will reach 19 years of age, and we are planning a check-up examination for early adulthood. About 20 years have passed since the cohort data were collected, and we have published results on childhood health outcomes associated with prenatal and birth characteristics, genetic and epigenetic characteristics related to childhood metabolism, the effects of exposure to endocrine disruptors, and dietary patterns in childhood. Recently, we started reporting on topics related to adolescent health. The findings will facilitate identification of early life risk factors for chronic diseases and the development of interventions for diseases later in life.

Influence of clozapine on neurodevelopmental protein expression and behavioral patterns in animal model of psychiatric disorder induced by low-level of lead

Exposure to lead during pregnancy is a risk factor for the development of psychiatric disorders in the offspring. In this study, we investigated whether exposure to low levels of lead acetate (0.2%) in drinking water during pregnancy and lactation causes behavioral impairment and affects the expression of proteins associated with neurodevelopment. Lead exposure altered several parameters in rat offspring compared with those unexposed in open-field, social interaction, and pre-pulse inhibition tests. These parameters were restored to normal levels after clozapine treatment. Western blot and immunohistochemical analyses of the hippocampus revealed that several neurodevelopmental proteins were downregulated in lead-exposed rats. The expression was normalized after clozapine treatment (5 mg/kg/day, postnatal day 35–56). These findings demonstrate that downregulation of several proteins in lead-exposed rats affected subsequent behavioral changes. Our results suggest that lead exposure in early life may induce psychiatric disorders and treatment with antipsychotics such as clozapine may reduce their incidence.

Effects of Tianeptine on Adult Rats Following Prenatal Stress

OBJECTIVE: Exposing a pregnant female to stress during the critical period of embryonic fetal brain development increases the risk of psychiatric disorders in the offspring. The objective of this study was to investigate the effect of antidepressant tianeptine on prenatally stressed (PNS) rats. METHODS: In this study, a repeated variable stress paradigm was applied to pregnant rats during the last week of gestation. To investigate the effects of antidepressant tianeptine on PNS rats, behavioral and protein expression analyses were performed. Forced swim test, open field test, and social interaction test were performed to determine changes in PNS rats compared to non-stressed offspring. Haloperidol was used as a positive control as an antipsychotic drug based on previous studies. RESULTS: Behavioral changes were restored after treatment with tianeptine or haloperidol. Western blot and immunohistochemical analyses of the prefrontal cortex revealed downregulation of several neurodevelopmental proteins in PNS rats. After treatment with tianeptine or haloperidol, their expression levels were increased. CONCLUSION: Downregulation of several proteins in PNS rats might have caused subsequent behavioral changes in PNS rats. After tianeptine or haloperidol treatment, behavioral changes in PNS rats were restored. Therefore, tianeptine might decrease incidence of prenatal stress related-psychiatric disorders such as depression and schizophrenia.

Effects of tianeptine on symptoms of fibromyalgia via BDNF signaling in a fibromyalgia animal model

Previous reports have suggested that physical and psychological stresses may trigger fibromyalgia (FM). Stress is an important risk factor in the development of depression and memory impairments. Antidepressants have been used to prevent stress-induced abnormal pain sensation. Among various antidepressants, tianeptine has been reported to be able to prevent neurodegeneration due to chronic stress and reverse decreases in hippocampal volume. To assess the possible effect of tianeptine on FM symptoms, we constructed a FM animal model induced by restraint stress with intermittent cold stress. All mice underwent nociceptive assays using electronic von Frey anesthesiometer and Hargreaves equipment. To assess the relationship between tianeptine and expression levels of brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), and phosphorylated cAMP response element-binding protein (p-CREB), western blotting and immunohistochemistry analyses were performed. In behavioral analysis, nociception tests showed that pain threshold was significantly decreased in the FM group compared to that in the control group. Western blot and immunohistochemical analyses of medial prefrontal cortex (mPFC) and hippocampus showed downregulation of BDNF and p-CREB proteins in the FM group compared to the control group. However, tianeptine recovered these changes in behavioral tests and protein level. Therefore, this FM animal model might be useful for investigating mechanisms linking BDNF-CREB pathway and pain. Our results suggest that tianeptine might potentially have therapeutic efficacy for FM.

Effects of Adrenal Androgen Levels on Bone Age Advancement in Prepubertal Children: Using the Ewha Birth and Growth Cohort Study

Bone age (BA) advancement in prepubertal children may be associated with earlier onset of puberty and obesity. This study aimed to define the effects of adrenal androgen levels on the advancement of BA in prepubertal children, independent of obesity. During July and August 2011, we examined BA in 200 prepubertal children aged 7–9 years who were part of the Ewha Birth & Growth Cohort Study. BA was assessed by the Greulich-Pyle method. An index of BA advancement was calculated as the ratio of BA to chronological age (CA) (BA/CA), and this ratio was classified into 3 tertiles. We analyzed the relationship between BA advancement and anthropometric characteristics and adrenal hormone levels. The number of overweight children increased from the first group to the third group (P(Trend) = 0.03). The levels of adrenal androgens showed a significant positive correlation with the tertile groups after adjusting for age and sex (testosterone: r = 0.26, P < 0.001; dehydroepiandrosterone: r = 0.21, P < 0.001; androstenedione: r = 0.20, P < 0.001). Further, after controlling for body mass index (BMI), sex, and age, the BA/CA was found to be positively correlated with androstenedione (β = 0.04, R² = 3.7%) and testosterone levels (β = 0.05, R² = 4.7%). Based on our results, it is suggested that adrenal androgen levels are associated with BA advancement independent of BMI.

Toxicokinetics of paraquat in Korean patients with acute poisoning

To conduct a kinetic study of paraquat (PQ), we investigated 9 patients with acute PQ intoxication. All of them ingested more than 20 ml of undiluted PQ herbicide to commit suicide and arrived at our hospital early, not later than 7 h after PQ ingestion. The urine dithionite test for PQ in all of the nine patients was strongly positive at emergency room. Blood samples were obtained every 30 min for the first 2~3 h and then every 1 or 2 h, as long as the clinical progression was stable among the patients for 30 h after PQ ingestion. The area under the plasma concentration-time curve (AUCinf), which was extrapolated to infinity, was calculated using the trapezoidal rule. Toxicokinetic parameters, such as the terminal elimination half-life, apparent oral clearance, and apparent volume of distribution (Vd/F) were calculated. The maximum PQ concentration (Cmax) and the time to reach maximum PQ concentration (Tmax) were also obtained. Plasma PQ concentrations in nine patients were well described by a bi-exponential curve with a mean terminal elimination half-life of 13.1+/-6.8 h. Cmax and AUCinf were 20.8+/-25.7 mg/l and 172.5+/-160.3 h.mg/l, respectively. Apparent volume of distribution and apparent oral clearance were 50.9+/-61.3 l/kg and 173.4+/-111.2 l/h, respectively. There were a significant correlation (r =0.84; p<0.05) between the PQ amount ingested and Cmax. AUCinf also showed a significant correlation (r =0.83; p<0.05) with the PQ amount ingested. These correlations provide evidence that PQ has dose-linear toxicokinetic characteristics.

The Effect of Environmental Tobacco Smoke Exposure and Glutathione S-Transferase Polymorphism on Childhood Behavioral Development during Mid-Pregnancy and Early Childhood / 신경정신의학

OBJECTIVES: The author investigated the relationship between the environmental tobacco smoke exposure during mid-pregnancy and early childhood and neurobehavioral outcomes of preschool children and if there is any effect of the genetic polymorphism of glutathione S-transferase (GST) M1 and T1 on this relationship. METHODS: The participants were the pregnant women (week 24-28) who visited the obstetrics and gynecology department (between 2001 and 2004). They had been evaluated for their sociodemographic data including direct and environmental tobacco smoke exposure history and the urine specimen had been sampled for the measurement of cotinine. The offsprings' urine specimen and blood sampling had been done and the socioeconomic data including the environmental tobacco smoke exposure history was evaluated at age 3. The cotinine level of urine specimen was measured and GST polymorphism was analyzed. The offsprings completed Korean-Childhood Behavioral Check List (K-CBCL) at age 4-5. RESULTS: The environmental tobacco smoke exposure during mid-pregnancy based on urine cotinine level has a significant association with increased total score and externalizing problem score of K-CBCL (p<0.05). The environmental tobacco smoke exposure based on urine cotinine level at age 3 is associated increased total score, externalizing problem score and internalizing problem score of K-CBCL with no statistical significance. The environmental tobacco smoke exposure after controlling for tobacco smoke exposure during pregnancy, however, is significantly associated with the increased externalizing problem scores (p=0.04). The environmental tobacco smoke exposure is associated with increased total score, externalizing problem score and internalizing problem score of K-CBCL with GSTM1 null type or GSTT1 null type at age 3 although there was no statistical significance. CONCLUSION: The environmental tobacco smoking exposure during pregnancy and at early childhood is associated with childhood behavioral problems. The clinical implication of this study is that it is important to avoid the environmental tobacco smoke exposure during pregnancy and early childhood and to monitor the possible emergence of behavioral problems of children.

A Case of Severe Bevacizumab-induced Ischemic Pancolitis, Treated with Conservative Management / 대한소화기학회지

Bevacizumab (Avastin(R)) is a monoclonal antibody against the vascular endothelial growth factor (VEGF) receptor that increases the overall survival rate when added to standard chemotherapy regimens in patients with metastatic colorectal cancer. The known toxicities of bevacizumab are hypertension, proteinuria, wound healing complications, arterial thrombosis, bleeding, and gastrointestinal complications. Especially ischemic colitis can rapidly develop into bowel perforation, so an emergency operation often is needed. Recently, a 65-year-old male patient developed ischemic pancolitis after FOLFOX (85 mg/m2 Oxaliplatin, d1;200 mg/m2 Leucovorin, d1;400 mg/m2 5-FU iv bolus, d1-2;and 600 mg/m2 5-FU, d1-2, every two wk) and Bevacizumab combination chemotherapy was administered. However, he recovered after early conservative care without surgery. We report this case with a review of literature.

The Effects of Intrauterine Oxidative Stress and Antioxidant Vitamins on Childhood Behavioral Development at Age 4 Years / 신경정신의학

OBJECTIVES : We aimed to define the effects of antioxidant vitamins and oxidative stress in the intrauterine period on childhood neurobehavioral development. METHODS : The behavioral status of 100 children (aged four) at Ewha Womans University Mokdong Hospital in Korea was examined using the K-CBCL. Their maternal vitamin and oxidative stress status were analyzed at midterm as intrauterine circumstance indices. The relationship between intrauterine condition and childhood behavioral development was analyzed using a general linear model. RESULTS : K-CBCL scores were lower in the group which took high levels of maternal vitamins B6 and B12 than scores in the group which too low levels of these vitamin. In contrast, the group with high maternal oxidative stress exhibited higher scores in behavioral problem scales. After adjusting for inborn and childhood environmental covariates, K-CBCL differences were statistically significant in the B2 group comparison (high group vs. low group;total problem : 47.0+/-1.0 vs. 53.0+/-1.8, internalizing problem 46.5+/-1.0 vs. 51.2+/-1.8). In addition, significant highest means of K-CBCL were in low vitamin and high oxidative stress group than other combined groups. CONCLUSION : We have established a relationship between maternal vitamins and oxidative stress during pregnancy, and a 4 year-old child's behavioral development. This suggests that preventive efforts during pregnancy are influential on early childhood behavioral problems.

The influence of some intrauterine growth variables on neonatal blood pressure / 소아과

PURPOSE: 'Programming' describes the process that stimulus at a critical period of development has lifelong effects. The fact that low birth weight links to the risk of elevated blood pressures in adult life is well known. This study aims to examine whether this link is evident in the newborn by investigating the relationship of the intrauterine growth indices and neonatal blood pressure(BP). METHODS: We studied 127 neonates who were born at Ewha Womans' Hospital and their mothers enrolled our cohort study during pregnancy. Data on the mothers and details of the birth records were tracked and collected from medical charts. Neonatal BP was measured within 24 hours after birth. RESULTS: Neonatal SBP was positively correlated to intrauterine growth indices; birth weight(BW)(r= 0.4), head circumference(HC)(r=0.4), and birth height(r=0.3). However, an inverse relationship existed, between HC/BW ratio and neonatal SBP(r=-0.4). After adjusting for the baby's sex, maternal BP, and gestational age, neonatal SBP still associated with intrauterine growth indices. SBP was 7 mmHg higher in the highest BW group(> or =90 percentiles) compared to the lowest group( or =90 percentiles) compared in the lowest group(<10 percentiles). CONCLUSION: This study could not find the evidence that intrauterine growth retardation affect on elevated neonatal BP. It suggests that the initiating events of BP programming may occur during postnatal growth period. To identify the critical starting period that intrauterine growth retardation leads to elevated BP, a study tracking BP changes from birth to childhood is required.

Effects of Hyperhomocysteinemia on the Immunohistochemical Reactivity for Vimentin in the Retinal Glial Cell

It has been suggested that the elevated plasma homocysteine may lead to retinal dysfunction. We investigated the effects of plasma levels of homocysteine and folate on the retinal glial cells' injuries. Male Sprague-Dawley rats were raised either on a control diet or on an experimental diet containing 3.0 g/kg homocystine without folic acid for 10 weeks. Plasma homocysteine concentrations were measured by a HPLC-fluorescence detection method. Plasma folate and vitamin B12 levels were analyzed by a radioimmunoassay. The response of Muller cells which are the principal glial cells of the retina was immunohistochemically examined using an antibody for vimentin, a cytoskeletal protein belonging to the family of intermediate filament. At 2 weeks, the homocystine diet induced a twofold increase in plasma homocysteine, and a concomitant increase in the expression of vimentin in the Muller cells' processes spanning from the inner to outer membranes of the retina indicating arterial degeneration. At 10 weeks, the homocystine diet induced a fourfold increase in plasma homocystine, but vimentin immunoreactivity in the retinas was similar in both groups. In conclusion, increased plasma homocysteine levels have influence on morphological and functional changes of Muller cells in the retina.

Increased Apoptotic Activity of Human Trophoblasts in Pregnancy-Induced Hypertension: Assessment by the Caspase-related M30 CytoDeath Antibody / 대한해부학회지

Pregnancy-induced hypertension (PIH) is a multi-system disorder unique to human pregnancy. Although the etiology of PIH is still unknown, there is a large evidence suggesting that abnormal trophoblast invasion is occurring in early pregnancy and that this may contribute to relative placental hypoxia and oxidative stress that may further exacerbate placental pathology. This study was undertaken to determine placental Cu/Zn superoxide dismutase (SOD) and Mn SOD activities and evaluate the use of M30 CytoDeath antibody to assess trophoblasts apoptotic activity in normal and PIH pregnancies. We also compared apoptotic rates as detected by M30 and TdT-mediated dUTP nickend labelling (TUNEL). Placental expression of Cu/Zn SOD and Mn SOD were reduced in PIH as compared to normal pregnancies. M30 immunoreactivity occurred predominantly in the syncytiotrophoblasts, and a significantly higher number of M30 positive cells in the preeclamptic placentas were found when compared with normal placentas. The number of M30 positive cells correlated with another apoptotic index previously detected by TUNEL method.

Effects of Folate Supplementation on Cerebral Nuclear Factor-kappa B (NF-kappaB) and Endothelial Nitric Oxide Synthase Activities in Experimental Hyperhomocysteinemia / 대한해부학회지

Homocysteine is a significant but modifiable risk factor for vascular diseases, including stroke. While several pathological processes may be involved, homocysteine can cause significant endothelial impairment and compromise vascular nitric oxide (NO) bioactivity. Endothelial dysfunction can be characterized not only by impaired vasoreactivity with decreased availability of NO but also abnormal inflammatory cell-endothelial interactions and increased expression of cell adhesion molecules. Nuclear factor-kappa B (NF-kappaB) is a transcriptional factor which plays a coordinating role in inflammation and cellular proliferation and may be involved in early atherosclerosis. Experimentally, we investigated the effects of folate supplementation on endothelial nitric oxide synthase (eNOS) activity in the hyperhomocysteinemic rat brain and related the changes of eNOS activity to the expression of NF-kappaB. Animals were raised on an experimental diet containing 0.3% homocystine for 4 weeks or on a 0.3% homocystine diet for 2 weeks with or without folate supplementation (8 mg/kg diet). The cerebrovascular endothelial nitric oxide synthase (eNOS) activity was investigated by the immunohistochemical method. Cerebral contents of eNOS and NF-kappaB were also evaluated with the western blot analysis. At 4 wks, diet- induced hyperhomocysteinemia up to 4-fold (control: 6.5+/-0.4 micromol/L, homocystine: 26.2+/-2.5 micromol/L), and a reduction in the expression of cerebral eNOS with a concomitant increase in NF-kappaB. Dietary folate supplementation caused a significant decrease in plasma homocysteine levels with a concomitant increase in hyperhomocysyeinemia-induced reduction of the cerebral eNOS and decrease in hyperhomocysyeinemia-induced NF-kappaB expression.