Hyperactivation of phosphoinositol 3-kinase (PI3K) has been suggested to be a potential mechanism for endoplasmic reticulum (ER) stress-enhanced airway hyperresponsiveness, and PI3K inhibitors have been examined as asthma therapeutics. However, the regulatory mechanism linking PI3K to ER stress and related pathological signals in asthma have not been defined. To elucidate these pathogenic pathways, we investigated the influence of a selective PI3Kδ inhibitor, IC87114, on airway inflammation in an ovalbumin/lipopolysaccharide (OVA/LPS)-induced asthma model. In OVA/LPS-induced asthmatic mice, the activity of PI3K, downstream phosphorylation of AKT and activation of nuclear factor-κB (NF-κB) were all significantly elevated; these effects were reversed by IC87114. IC87114 treatment also reduced the OVA/LPS-induced ER stress response by enhancing the intra-ER oxidative folding status through suppression of protein disulfide isomerase activity, ER-associated reactive oxygen species (ROS) accumulation and NOX4 activity. Furthermore, inositol-requiring enzyme-1α (IRE1α)-dependent degradation (RIDD) of IRE1α was reduced by IC87114, resulting in a decreased release of proinflammatory cytokines from bronchial epithelial cells. These results suggest that PI3Kδ may induce severe airway inflammation and hyperresponsiveness by activating NF-κB signaling through ER-associated ROS and RIDD–RIG-I activation. The PI3Kδ inhibitor IC87114 is a potential therapeutic agent against neutrophil-dominant asthma.

PURPOSE: Hirschsprung’s disease (HD) is a congenital intestinal disorder with absence of ganglion cells in the intestinal muscle and submucosa. Diagnosis is based on histopathological study such as H&E, and acetylcholinesterase (AchE) immunohistochemistry. Calretinin immunohistochemistry was introduced as a new diagnostic method against limitations of other staining. The aim of this study is to investigate the usefulness of calretinin immunohistochemistry for the diagnosis of HD compared to H&E and AchE. METHODS: Ten patients with HD and 22 non-HD patients were included in the study. H&E staining, AchE and calretinin immunohistochemistry were performed in all 32 patients. All slides were evaluated by same single pathologist and the diagnostic value was calculated for each H&E stain, AchE immunohistochemical staining, and calretinin immunohistochemical staining. RESULTS: Calretinin method had sensitivity of 100% and specificity of 100% for diagnosis of HD. Its diagnostic accuracy was 100%. AchE staining showed 100% of specificity and 80% of sensitivity. Diagnostic accuracy of H&E staining was 56.3%. CONCLUSION: We concluded that calretinin immunohistochemistry is a very useful and valuable method to diagnosis HD patient.
Acetylcholinesterase ; Biopsy* ; Calbindin 2* ; Diagnosis ; Ganglion Cysts ; Hematoxylin ; Hirschsprung Disease ; Humans ; Immunohistochemistry* ; Sensitivity and Specificity ; Suction*

Numerous studies have established a link between autophagy and aging; however, the relationship has not been clearly defined. Aging is a very complex process caused by the accumulation of various factors due to the gradual failure of cellular maintenance. Recent studies have shown that autophagy reduces the stress responses induced by starvation, reactive oxygen species, and the accumulation of intracellular proteins and organelles through cytoprotection, clearance of damaged mitochondria, and lysosomal degradation. Here, we summarize our current understanding of the relationship between autophagy and the aging process.
Aging* ; Autophagy* ; Caloric Restriction ; Cytoprotection ; Mitochondria ; Organelles ; Proteins ; Reactive Oxygen Species ; Starvation

Numerous studies have established a link between autophagy and aging; however, the relationship has not been clearly defined. Aging is a very complex process caused by the accumulation of various factors due to the gradual failure of cellular maintenance. Recent studies have shown that autophagy reduces the stress responses induced by starvation, reactive oxygen species, and the accumulation of intracellular proteins and organelles through cytoprotection, clearance of damaged mitochondria, and lysosomal degradation. Here, we summarize our current understanding of the relationship between autophagy and the aging process.
Aging* ; Autophagy* ; Caloric Restriction ; Cytoprotection ; Mitochondria ; Organelles ; Proteins ; Reactive Oxygen Species ; Starvation

Autophagy is a self-degradation system of cellular components through an autophagosomal-lysosomal pathway. Over the last 15 yr, yeast genetic screens led to the identification of a number of genes involved in the autophagic pathway. Most of these autophagy genes are present in higher eukaryotes and regulate autophagy process for cell survival and homeostasis. Significant progress has recently been made to better understand the molecular mechanisms of the autophagy machinery. Especially, autophagy process, including the regulation of autophagy induction through mTOR and the nucleation and elongation in autophagosome formation through class III phosphatidylinositol 3-kinase complex and ubiquitin-like conjugation systems, became evident. While many unanswered questions remain to be answered, here, we summarize the recent process of autophagy with emphasis on molecules and their protein complexes along with advanced molecular mechanisms that regulate the autophagy machinery.
Autophagy/genetics/*physiology ; Carrier Proteins/genetics/metabolism ; Class III Phosphatidylinositol 3-Kinases/genetics/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Membrane Proteins/genetics/metabolism ; Microtubule-Associated Proteins/genetics/metabolism ; Models, Biological ; Protein-Serine-Threonine Kinases/genetics/metabolism ; Small Ubiquitin-Related Modifier Proteins/genetics/metabolism

The onset, severity, and ultimate outcome of malaria infection are influenced by parasite-expressed virulence factors as well as by individual host responses to these determinants. In both humans and mice, liver injury follows parasite entry, persisting to the erythrocytic stage in the case of infection with the fatal strain of Plasmodium falciparum. Hepatic nuclear factor (HNF)-1alpha is a master regulator of not only the liver damage and adaptive responses but also diverse metabolic functions. In this study, we analyzed the expression of host HNF-1alpha in relation to malaria infection and evaluated its interaction with the 5'-untranslated region of subtilisin-like protease 2 (subtilase, Sub2). Recombinant human HNF-1alpha expressed by a lentiviral vector (LV HNF-1alpha) was introduced into mice. Interestingly, differences in the activity of the 5'-untranslated region of the Pf-Sub2 promoter were detected in 293T cells, and LV HNF-1alpha was observed to influence promoter activity, suggesting that host HNF-1alpha interacts with the Sub2 gene.
5' Untranslated Regions/*genetics ; Animals ; Cell Line ; DNA, Protozoan/genetics ; Gene Expression Regulation/*genetics ; Genetic Vectors ; Hepatocyte Nuclear Factor 1-alpha/administration & dosage/genetics/*metabolism ; Host-Parasite Interactions ; Humans ; Injections, Intravenous ; Lentivirus/genetics ; Malaria, Falciparum/metabolism/*parasitology/pathology ; Mice ; Plasmodium falciparum/drug effects/*genetics ; Promoter Regions, Genetic/genetics ; RNA, Messenger/genetics ; RNA, Protozoan/genetics ; Recombinant Proteins ; Signal Transduction ; Subtilisins/*genetics/metabolism

BACKGROUND/AIMS: The aim of our study was to define the potential role of virologic response at 12 months of treatment (VR12) in predicting subsequent virologic and clinical outcomes in adefovir (ADV)-treated lamivudine-resistant chronic hepatitis B. METHODS: Two hundred and four patients with lamivudine-resistant chronic hepatitis B virus (HBV) treated with ADV monotherapy were included. Serum HBV DNA was quantified by real-time polymerase chain reactions. VR12 was defined as a HBV DNA level of less than 4 log10 copies/mL after 12 months of ADV treatment. RESULTS: VR12 was observed in 110 of the 204 patients (54%). The mean HBV DNA reductions from baseline after 12 months of ADV treatment were 3.8 and 1.9 log10 copies/mL in patients with and without VR12, respectively (p<0.001). The hepatitis B "e" antigen (HBeAg) seroconversion rates in patients with and without VR12 were 32% and 14% at 12 months treatment, respectively (p=0.018), and 40% and 27% at 24 months of treatment (p=0.032). The genotypic mutation rates to ADV in patients with and without VR12 were 0% and 6% at 12 months of treatment, respectively (p=0.033), and 21% and 42% at 24 months (p=0.012). The rates of viral breakthrough in patients with and without VR12 were 0% and 7% at 12 months of treatment, respectively (p=0.072), and 9% and 25% at 24 months (p=0.006). CONCLUSIONS: Patients without VR12 may need to switch to or add on other potent antiviral drugs in their medical regimens.
Adenine ; Antiviral Agents ; DNA ; Drug Resistance ; Hepatitis B ; Hepatitis B, Chronic ; Hepatitis, Chronic ; Humans ; Mutation Rate ; Organophosphonates ; Polymerase Chain Reaction ; Viruses

PURPOSE: Methylenetetrahydrofolate reductase (MTHFR) is the main regulatory enzyme for homocysteine metabolism. In the present study, we evaluated whether the MTHFR 677C>T and 1298A>C gene polymorphisms are associated with SBI and plasma homocysteine concentration in a Korean population. MATERIALS AND METHODS: We enrolled 264 patients with SBI and 234 healthy controls in South Korea. Fasting plasma total homocysteine (tHcy) concentrations were measured, and genotype analysis of the MTHFR gene was carried out. RESULTS: The plasma tHcy levels were significantly higher in patients with SBI than in healthy controls. Despite a significant association between the MTHFR 677TT genotype and hyperhomocysteinemia, the MTHFR 677C>T genotypes did not appear to influence susceptibility to SBI. However, odds ratios of the 1298AC and 1298AC + CC genotypes for the 1298AA genotype were significantly different between SBI patients and normal controls. The frequencies of 677C-1298A and 677C-1298C haplotypes were significantly higher in the SBI group than in the control group. CONCLUSION: This study demonstrates that the MTHFR 1298A>C polymorphism is a risk factor for SBI in a Korean population. The genotypes of 677C>T and 1298A>C polymorphisms interact additively, and increase the risk of SBI in Korean subjects.
Aged ; Asian Continental Ancestry Group ; Brain Infarction/*genetics/*metabolism ; Female ; Genotype ; Haplotypes ; Homocysteine/*metabolism ; Humans ; Male ; Methylenetetrahydrofolate Reductase (NADPH2)/*genetics ; Middle Aged ; Polymorphism, Genetic/*genetics

PURPOSE: To examine the relationship between weight gain and the success of VBAC by using body mass index (BMI). To examine the relationship between weight gain and the success of VBAC by using body mass index (BMI). METHODS: The study compared clinical features taken from 112 patients who tried VBAC at our institute from January 2001 through December 2006. There were divided into two GROUPS: 92 patients for the success (82.1%) and 20 patients for the failure group (17.9%). Excluding 36 patients with no BMI data, we constructed Receive-operating characteristics (ROC) curve to make the optimum BMI value for the prediction of success of VBAC. Based on the BMI 26 or more, two groups of patient were surveyed the interrelation between weight gain and success of VBAC. RESULTS: Between success and failure group, the weight gain during pregnancy showed significant differences which are 11.2+/-4 kg of the success group and 13.2+/-5 kg of the other one (p<0.05) A survey on the availability of the BMI date to estimate success of VBAC, the criteria with the standard BMI 26 is not statistically valuable (p=0.837). By comparing normal weight and overweight based on BMI 26, some factors showed statistically significant discrepancies: number of prenatal visit, maternal weight gain, maternal weight at the time of delivery, use of oxytocin and birth weight. CONCLUSION: BMI value of 26 has limitations in using as an estimate criteria on success of VBAC. Patients, however, who had relatively small scale of weight gain, showed significant clinical factors to increased success rate of VBAC.
Body Mass Index ; Humans ; Overweight ; Oxytocin ; Parturition ; Pregnancy ; Vaginal Birth after Cesarean ; Weight Gain

PURPOSE: To evaluate mortality and morbidity of very low birth weight infants(VLBW infants) born in the Busan area from 1996 to 2005. METHODS: A total of eight neonatal intensive care units (4 university hospitals and 4 general hospitals) in Busan participated in this study. A total of 1,414 VLBW infants were divided into three groups: period I, 1996 to 2000; period II, 1999 to 2002; period III, 2003 to 2005, based on date of birth. We performed a retrospective review of medical records of VLBWinfants and compared the survival rate, morbidity and mortality over the three periods. RESULT: The number of VLBW infants admitted to 8 NICUs in 1996-2005 was a total of 1,414 (1.3% incidence, mean gestational age 29.1+/-2.7 wk, mean birth weight 1158+/-235 g), including 361 (24.7%) extremely low birth weight infants (ELVW infants) who were less than 1,000 g at birth weight. Overall survival rate of VLBW infants was 66.1%. The survival rate of VLBW infants increased significantly over the three periods (period I:57.6%, period II:67.8%, period III:75.7%, P<0.01). Overall survival rate of ELBW infants was 33.8%, and increased from 26.4% in period I to 44.2% in period III (P<0.01). The incidence of respiratory distress syndrome was 45.1%; patent ductus arteriosus, 16.4%; bronchopulmonary dysplasia, 13.1%; blood culture positive sepsis, 12.7%; necrotizing enterocolitis, 6.6%; severe intracranial hemorrhage, 6.5%; and severe retinopathy of prematurity, 5.9%. The main causes of death were respiratory distress syndrome and sepsis. CONCLUSION: Overall survival rate of very low birth weight infant in Busan area during the last 10 years was 66.1%, and increased significantly over the three periods.
Birth Weight ; Bronchopulmonary Dysplasia ; Busan* ; Cause of Death ; Ductus Arteriosus, Patent ; Enterocolitis, Necrotizing ; Gestational Age ; Hospitals, University ; Humans ; Incidence ; Infant* ; Infant, Low Birth Weight ; Infant, Newborn ; Infant, Very Low Birth Weight* ; Intensive Care Units, Neonatal ; Intracranial Hemorrhages ; Medical Records ; Mortality ; Parturition ; Retinopathy of Prematurity ; Retrospective Studies ; Sepsis ; Survival Rate