Apurinic/apyrimidinic endonuclease 1 (APE1) is an enzyme responsible for the initial step in the base excision repair pathway and is known to be a potential drug target for treating cancers, because its expression is associated with resistance to DNA-damaging anticancer agents. Although several inhibitors already have been identified, the identification of novel kinds of potential inhibitors of APE1 could provide a seed for the development of improved anticancer drugs. For this purpose, we first classified known inhibitors of APE1. According to the classification, we constructed two distinct pharmacophore models. We screened more than 3 million lead-like compounds using the pharmacophores. Hits that fulfilled the features of the pharmacophore models were identified. In addition to the pharmacophore screen, we carried out molecular docking to prioritize hits. Based on these processes, we ultimately identified 1,338 potential inhibitors of APE1 with predicted binding affinities to the enzyme.
Antineoplastic Agents ; Classification ; DNA Repair ; Molecular Docking Simulation

Stress induces degeneration of brain structures and functions. Particularly, hippocampus is sensitive to stressful stimulations. In the present study, the change of synaptic related molecules in the mouse dentate gyrus was examined with immunohistochemistry after restraint stress. We subjected mice to restraint stress for 6 h per day for 4 days. As a result, the number of Ki-67, a marker for proliferation, and doublecortin (DCX), a marker for neurogenesis, immunoreactive cells was decreased in the stress group. On the other hand, the intensity of calbindinD-28k, a marker of pre-existing granule cells, immunoreactivity was increased in the granule cell layer after 4 days restraint stress. As well as, the immunoreactivity of synaptic related molecules, postsynaptic density-95 (PSD-95), growth association protein-43 (GAP-43) and beta-NADPH-d reactivity were increased in the inner molecular layer of dentate gyrus after 4 days restraint stress. In conclusion, this study shows that repeated restraint stress suppresses neurogenesis in dentate gyrus and strengthens synaptic plasticity of existing granule cells.
Animals ; Brain ; Dentate Gyrus* ; Hand ; Hippocampus ; Immunohistochemistry ; Mice* ; Neurogenesis ; Plastics*

Voluntary running is known to dramatically increase the cell proliferation and neurogenesis in the dentate gyrus of the adult mouse hippocampus. However, it is crucial to realize that adding excitatory neurons could result in serious maladaptive outcomes for hippocampal circuit function. To investigate the response of mature granule cells on the increase of cell proliferation during voluntary running, we investigated the temporal change of calbindin-D28k (a marker for mature granule cells) using immunohistochemistry during voluntary running with upregulated neurogenesis. By using immunohistochemsitry for Ki-67 and doublecortin (DCX), we observed that the cell proliferation and differentiation of granule cells increased at 1 week of voluntary running. We found that, at 6 weeks of voluntary running, the cell proliferation and differentiation of granule cells returned to sedentary control levels. On the other hand, calbindin-D28k immunoreactivity decreased in the granular cell layer of the dentate gyrus and CA3 region of hippocampus after 1 week of voluntary running. At 6 weeks of voluntary running, the density of the calbindin-D28k in the granular cell layer and CA3 region was returned to the sedentary control level. These results demonstrate that the cell proliferation and differentiation are increased at early point of voluntary running, and the granule cell activity in the dentate gyrus is temporally changed for response to the increase of cell proliferation and differentiation during voluntary running.
Adult ; Animals ; Calbindin 1* ; Cell Proliferation ; Dentate Gyrus* ; Hand ; Hippocampus ; Humans ; Immunohistochemistry ; Mice* ; Neurogenesis ; Neurons ; Running*

BACKGROUND: Recent guidelines recommend that all cirrhotics undergo screening upper endoscopy to identifly risk patients for bleeding from varices. The aim of this study was to determine whether clinical and laboratory variables were predictive of the occurrence and progression of esophageal varices. METHODS: This is a retrospective analysis of cirrhotics who had a screening upper endoscopy during 10 years after liver biopsy. Fifty-eight patients were recruited. Univariate/multivariate analysis was used to evaluate associations between the development and progression of esophageal varices and patients characteristics including platelet count, liver chemistry value, prothrombin time, shunt index(heart to liver uptake ratio) through transrectal TI-201 liver scan, probability(P)-value (Y=3.3431-0.8160 x ALT/AST ratio-0.0343 x prothrombin time+2.6963 x shunt index, P=e(y)/(e(y)+1)), ascites, splenomegaly, hepatic encephalopathy. RESULTS: There were 36 patients without esophageal varices or with stable varices during 10 years and 22 patients with new developed esophageal varices or progressive varices during 10 years as determined by upper endoscopy. On multivariate analysis, patients with a probability(P)-value of > or = 0.647 and a platelet count of < or = 100,500/mm3 had a risk of the development and progression of esophageal varices. CONCLUSIONS: Non-endoscopic predictors (probability(P)-value and platelet count) could be used to stratify patients with cirrhosis for the risk of the development and progression of esophageal varices and such stratification could be used to improve the effectiveness of screening upper endoscopy for esophageal varices.
Ascites ; Biopsy ; Blood Platelets ; Chemistry ; Endoscopy ; Esophageal and Gastric Varices* ; Fibrosis ; Hemorrhage ; Hepatic Encephalopathy ; Humans ; Liver Cirrhosis* ; Liver* ; Mass Screening ; Multivariate Analysis ; Platelet Count ; Prothrombin ; Prothrombin Time ; Retrospective Studies ; Splenomegaly ; Varicose Veins

BACKGROUND: Minimal (subclinical) hepatic encephalopathy (mHE) currently diagnosed by psychometric tests or neurophysiological test adversely affects daily functioning. In view of its sociomedical relevance, simple and reproducible tests for routine diagnosis are required. The aims of this study are to evaluate cognitive function of patients with chronic liver disease by computerized neuropsychological test (STIM), and the difference of cognitive function according to Child classification. METHODS: Between June, 2002 and February, 2003 We enrolled 61 randomized consecutive patients diagnosed with chronic liver disease by biochemical tests, ultrasonographic finding or histology. This study used finger tapping, visual CPT, spatial memory test, Wisconsin card sorting test chosen from Neuscan and STIM system (Neurosoft company, U.S.A) and global-local processing test. RESULTS: In the present study, significant correlation was found between neurologic abnormalities and the degree of liver disease. The result of neuropsychological test showed that cognitive function was decreased according to the severity of chronic liver disease, especially liver cirrhosis. Cirrhotic patients, especially Child C group, exhibited selective deficits in complex attentional and fine motor skills, visuospatial perception, with preservation of memory. CONCLUSION: The STIM in this study is simple, objective and reproducible method because it can subdivide evaluation of cognitive function and computerize the measurement of response. We assume that STIM may be used early detection method of mHE if the study will be in a large scale. Because psychomotor deficits found in mHE could have a disadvanting influence on daily functioning of patients, e.g., driving abilty of a car or performance at work, we concluded early detection of mHE and aggressive treatment of mHE in clinically asymptomatic cirrhotic patients is necessary for improvement of their quality of life.
Child ; Classification ; Diagnosis ; Fingers ; Hepatic Encephalopathy ; Humans ; Liver Cirrhosis ; Liver Diseases* ; Liver* ; Memory ; Motor Skills ; Neuropsychological Tests* ; Psychometrics ; Quality of Life ; Wisconsin

BACKGROUND: Electromyography and acceleromyography are common neuromuscular monitoring devices. However, questions still remain regarding the use of acceleromyography in children. This study compared the calibration success rates and intubation conditions in children after obtaining the maximal blockade depending on each of the devices METHODS: Children, 3 to 6 years old, were randomly allocated to the TOF-Watch SX acceleromyography group or the NMT electromyography group. The induction was performed with propofol, fentanyl, and rocuronium. The bispectral index and 1 Hz single twitch were monitored during observation. The calibration of the each device was begun when the BIS dropped to 60. After successful calibration, rocuronium 0.6 mg/kg was injected. A tracheal intubation was performed when the twitch height suppressed to 0. The rocuronium onset time (time from administration to the maximal depression of twitch height) and intubating conditions were rated in a blinded manner. RESULTS: There was no difference in the calibration success rates between the two groups; and the calibration time in the electromyography group (16.7 +/- 11.0 seconds) was shorter than the acceleromyography group (28.1 +/- 13.4 seconds, P = 0.012). The rocuronium onset time of the electromyography group (73.6 +/- 18.9 seconds) was longer than the acceleromyography group (63.9 +/- 18.8 seconds, P = 0.042) and the intubation condition of the electromyography group (2.27 +/- 0.65) was better than the acceleromyography group (1.86 +/- 0.50, P = 0.007). CONCLUSIONS: Electromyography offers a better compromise than acceleromyography with respect to the duration of calibration process and surrogate for the optimal time of tracheal intubation in children.
Anesthesia, General* ; Calibration ; Child* ; Child, Preschool ; Depression ; Electromyography* ; Fentanyl ; Humans ; Intubation ; Neuromuscular Monitoring ; Propofol ; Prospective Studies*

BACKGROUND/AIMS: Follicular thyroid carcinoma (FTC) and Hurthle cell carcinoma (HCC) of the thyroid are relatively uncommon thyroid malignancies in iodine-sufficient areas. In this study we evaluated the clinical behavior, prognostic factors and treatment outcomes of FTC and HCC in Korea. METHODS: This multicenter study included 483 patients with FTC and 80 patients with HCC who underwent an initial surgery between 1995 and 2006 in one of the four tertiary referral hospitals in Korea. We evaluated clinicopathological factors associated with distant metastases and recurrence during a median of 6 years of follow-up. RESULTS: HCC patients were significantly older (49 years vs. 43 years; p < 0.001) and had more lymphovascular invasions (22% vs. 14%; p = 0.03) compared with FTC patients. Distant metastases were confirmed in 40 patients (8%) in the FTC group and in two patients (3%) in the HCC group (p = 0.07). Distant metastases were significantly associated with older age, widely invasive cancer and extrathyroidal invasion. Only 14 patients (3%) had recurrent disease and there was no significant difference between FTC and HCC groups (p = 0.38). Recurrence was associated with larger tumor size and cervical lymph node metastasis. CONCLUSIONS: HCC patients were older and had more lymphovascular invasions than FTC patients. However, FTC and HCC patients had similar initial clinicopathological features. Older age, wide invasiveness and extrathyroidal invasion were independent risk factors for predicting distant metastases in FTC and HCC patients.
Adenocarcinoma, Follicular/*epidemiology/secondary/surgery ; Adult ; Age Factors ; *Diet ; Female ; Humans ; *Iodine ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Recurrence, Local ; *Nutritional Status ; Republic of Korea/epidemiology ; Retrospective Studies ; Risk Factors ; Tertiary Care Centers ; Thyroid Neoplasms/*epidemiology/pathology/surgery ; Thyroidectomy ; Time Factors ; Treatment Outcome

BACKGROUND: There are many studies regarding the effects of insulin on bone metabolism and changes in bone mineral density (BMD) in the setting of diabetes. The effect of prediabetes on BMD is not known. METHODS: A total of 802 men participated in the Korea Rural Genomic Cohort Study (in Geumsan County). According to the results of an oral glucose tolerance test, subjects were classified into normal, prediabetic, and diabetic categories. One hundred twenty-four subjects diagnosed with type 2 diabetes were excluded, leaving 678 subjects for the study inclusion. BMD was estimated with a quantitative ultrasonometer. RESULTS: The average BMD T scores of normal and prediabetic subjects were -1.34 +/- 1.42 and -1.33 +/- 1.30, respectively; there was no significant difference in the BMD T scores between these groups. The BMD T score was inversely associated with age and positively correlated with body weight, body mass index, total cholesterol, low density lipoprotein cholesterol, and HbA1c. On multiple linear regression analysis, low density lipoprotein cholesterol was the only statistically significant variable for prediabetes (beta = 0.007, P = 0.005). On the stepwise regression analysis, age (beta = -0.026, P < 0.001), the body mass index (beta = 0.079, P < 0.001), and low density lipoprotein cholesterol (beta = 0.004, P = 0.016) were significant variables for prediabetes. CONCLUSIONS: There was no significant difference in the BMD T score between the normal and prediabetic subjects. Further studies are needed regarding the association of fracture risk and changes in BMD with the development of overt diabetes.
Body Mass Index ; Body Weight ; Bone Density ; Cholesterol ; Cholesterol, LDL ; Cohort Studies ; Glucose Tolerance Test ; Humans ; Insulin ; Korea ; Linear Models ; Lipoproteins ; Male ; Prediabetic State

Previous studies have demonstrated that rottlerin, a specific PKCdelta inhibitor, potentiates death receptor- mediated apoptosis through a cytochrome c-dependent or -independent pathway. However, its ability to regulate necrotic cell death, as well as the underlying mechanism, remains unknown. We found that in murine fibrosarcoma L929 cells, treatment with rottlerin protected the cells against TNF-induced necrosis, whereas it sensitized the cells to apoptosis induced by co-treatment with Hsp90 inhibitor geldanamycin and TNF, in a manner independent of its ability to inhibit PKC-delta. TNF treatment induced rapid accumulation of mitochondrial superoxide (O2") through the Nox1 NADPH oxidase when cells undergo necrosis. Moreover, pretreatment with rottlerin failed to induce the GTP-bound form of small GTPase Rac1 by TNF treatment, and subsequently suppressed mitochondrial O2(-) production and poly(ADP-ribose) polymerase activation, thus inhibiting necrotic cell death. Therefore, our study suggests that Nox1 NADPH oxidase is a new molecular target for anti-necrotic activity of rottlerin upon death-receptor ligation.
Acetophenones/*pharmacology ; Animals ; Benzopyrans/*pharmacology ; Cell Death/*drug effects ; Cell Line, Tumor ; Mice ; Protein Kinase Inhibitors/*pharmacology ; Superoxides/metabolism ; Tumor Necrosis Factor-alpha/*antagonists & inhibitors/pharmacology

Activation of c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase family, is an important cellular response that modulates the outcome of the cells which are exposed to the tumor necrosis factor (TNF) or the genotoxic stress including DNA damaging agents. Although it is known that JNK is activated in response to genotoxic stress, neither the pathways to transduce signals to activate JNK nor the primary sensors of the cells that trigger the stress response have been identified. Here, we report that the receptor interacting protein (RIP), a key adaptor protein of TNF signaling, was required to activate JNK in the cells treated with certain DNA damaging agents such as adriamycin (Adr) and 1-beta-D-arabinofuranosylcytosine (Ara-C) that cause slow and sustained activation, but it was not required when treated with N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and short wavelength UV, which causes quick and transient activation. Our findings revealed that this sustained JNK activation was not mediated by the TNF (tumor necrosis factor) receptor signaling, but it required a functional ATM (ataxia telangiectasia) activity. In addition, JNK inhibitor SP-600125 significantly blocked the Adr-induced cell death, but it did not affect the cell death induced by MNNG. These findings suggest that the sustained activation of JNK mediated by RIP plays an important role in the DNA damage-induced cell death, and that the duration of JNK activation relays a different stress response to determine the cell fate.
Cell Death ; DNA ; DNA Damage ; Doxorubicin ; Humans ; JNK Mitogen-Activated Protein Kinases ; Methylnitronitrosoguanidine ; Necrosis ; Protein Kinases ; Tumor Necrosis Factor-alpha