No abstract available.
Stomach Neoplasms*

Objective: The endothelial inflammatory response plays an important role in atherogenesis by inducing nuclear factor (NF)κB-dependent cell adhesion molecule expression and monocyte recruitment. Here, we screened for natural ligands and investigated the ability of shinjulactone A to inhibit interleukin-1β (IL-1β)-induced endothelial inflammatory signaling. Methods: The natural compound library included 880 single compounds isolated from medicinal plants by the Korean Medicinal Material Bank. Primary endothelial cells were pretreated with single compounds before stimulation with IL-1β to induce endothelial inflammation. Endothelial inflammation was measured by assaying NFκB activation and monocyte adhesion. The endothelial-mesenchymal transition (EndMT) was evaluated using cell type-specific marker protein expression and morphology. Results: Shinjulactone A was identified as an efficient blocker of IL-1β -induced NFκB activation, with a half-maximal inhibitory concentration of approximately 1 µM, and monocyte recruitment in endothelial cells. However, it did not affect lipopolysaccharideinduced NFκB activation in macrophages. Compared to Bay 11-782, a well-known NFκB inhibitor that shows considerable cytotoxicity during long-term treatment, shinjulactone A did not affect endothelial cell viability. Furthermore, it also significantly inhibited the EndMT, which is known to promote atherosclerosis and plaque instability. Conclusion We suggest that shinjulactone A may be an effective and safe drug candidate for atherosclerosis because it targets and inhibits both endothelial inflammation and the EndMT, without impairing NFκB-dependent innate immunity in macrophages.

Primary hyperparathyroidism (PHPT) is imbalance of calcium, phosphate, and bone metabolism attributed to an increased secretion of parathyroid hormone (PTH). Although PHPT is mainly associated with musculoskeletal and kidney dysfunction, variable symptoms can be presented in the elderly patients. A 75-year-old man presented with rapidly progressive dementia (RPD). Through etiological work-up of hypercalcemia and increased PTH, parathyroid adenoma was found. Subtotal parathyroidectomy resulted in recovery of cognitive impairment. Primary hyperparathyroidism should be considered in a differential diagnosis of RPD.
Aged ; Calcium ; Cognition Disorders ; Dementia* ; Diagnosis, Differential ; Humans ; Hypercalcemia ; Hyperparathyroidism ; Hyperparathyroidism, Primary* ; Kidney ; Metabolism ; Parathyroid Hormone ; Parathyroid Neoplasms ; Parathyroidectomy

No abstract available.
Animals ; Antibodies, Neutralizing* ; Immunization* ; Mice*

Steroid sulfatase (STS) is an enzyme responsible for the hydrolysis of aryl and alkyl sulfates. STS plays a pivotal role in the regulation of estrogens and androgens that promote the growth of hormone-dependent tumors, such as those of breast or prostate cancer. However, the molecular function of STS in tumor growth is still not clear. To elucidate the role of STS in cancer cell proliferation, we investigated whether STS is able to regulate the integrin signaling pathway. We found that overexpression of STS in HeLa cells increases the protein and mRNA levels of integrin β1 and fibronectin, a ligand of integrin α5β1. Dehydroepiandrosterone (DHEA), one of the main metabolites of STS, also increases mRNA and protein expression of integrin β1 and fibronectin. Further, STS expression and DHEA treatment enhanced phosphorylation of focal adhesion kinase (FAK) at the Tyr 925 residue. Moreover, increased phosphorylation of ERK at Thr 202 and Tyr 204 residues by STS indicates that STS activates the MAPK/ERK pathway. In conclusion, these results suggest that STS expression and DHEA treatment may enhance MAPK/ERK signaling through up-regulation of integrin β1 and activation of FAK.
Androgens ; Breast ; Cell Proliferation ; Dehydroepiandrosterone ; Estrogens ; Fibronectins ; Focal Adhesion Protein-Tyrosine Kinases ; HeLa Cells ; Humans* ; Hydrolysis ; Phosphorylation ; Prostatic Neoplasms ; RNA, Messenger ; Steryl-Sulfatase* ; Sulfates ; Up-Regulation ; Uterine Cervical Neoplasms*

Human breast cancer cell line, MDA-MB-231, is highly invasive and aggressive, compared to less invasive cell line, MCF-7. To explore the genes that might influence the malignancy of MDA-MB-231, DNA microarray analysis was performed. The results showed that G0/G1 switch 2 (G0S2) was one of the most highly expressed genes among the genes upregulated in MDA-MB-231. Although G0S2 acts as a direct inhibitor of adipose triglyceride lipase, action of G0S2 in cancer progression is not yet understood. To investigate whether G0S2 affects invasiveness of MDA-MB-231 cells, G0S2 expression was inhibited using siRNA, which led to decreased cell proliferation, migration, and invasion of MDA-MB-231 cells. Consequently, G0S2 inhibition inactivated integrin-regulated FAK-Src signaling, which promoted Hippo signaling and inactivated ERK1/2 signaling. In addition, G0S2 downregulation decreased β-catenin expression, while E-cadherin expression was increased. It was demonstrated for the first time that G0S2 mediates the Hippo pathway and induces epithelial to mesenchymal transition (EMT). Taken together, our results suggest that G0S2 is a major factor contributing to cell survival and metastasis of MDA-MB-231 cells.
Breast Neoplasms ; Breast ; Cadherins ; Cell Line ; Cell Proliferation ; Cell Survival ; Down-Regulation ; Humans ; Lipase ; Neoplasm Metastasis ; Oligonucleotide Array Sequence Analysis ; RNA, Small Interfering ; Signal Transduction

This study was done to characterize the natural course of C-peptide levels in patients with type 1 diabetes and identify distinguishing characters among patients with lower rates of C-peptide decline. A sample of 95 children with type 1 diabetes was analyzed to retrospectively track serum levels of C-peptide, HbA1c, weight, BMI, and diabetic complications for the 15 yr after diagnosis. The clinical characteristics were compared between the patients with low and high C-peptide levels, respectively. The average C-peptide level among all patients was significantly reduced five years after diagnosis (P < 0.001). The incidence of diabetic ketoacidosis was significantly lower among the patients with high levels of C-peptide (P = 0.038). The body weight and BMI standard deviation scores (SDS) 15 yr after diagnosis were significantly higher among the patients with low C-peptide levels (weight SDS, P = 0.012; BMI SDS, P = 0.044). In conclusion, C-peptide level was significantly decreased after 5 yr from diagnosis. Type 1 diabetes patients whose beta-cell functions were preserved might have low incidence of diabetic ketoacidosis. The declines of C-peptide level after diagnosis in type 1 diabetes may be associated with changes of body weight and BMI.
Adolescent ; Body Mass Index ; Body Weight ; C-Peptide/*blood ; Child ; Child, Preschool ; Diabetes Complications ; Diabetes Mellitus, Type 1/blood/*diagnosis ; Diabetic Ketoacidosis/epidemiology ; Diabetic Retinopathy/epidemiology ; Female ; Follow-Up Studies ; Hemoglobin A, Glycosylated/analysis ; Humans ; Incidence ; Infant ; Male ; Peripheral Nervous System Diseases/epidemiology ; Retrospective Studies

Rheumatoid arthritis (RA) is an autoimmune disease that starts with decreased tolerance to modified self-antigens and eventually leads to synovitis and destruction of bone and cartilage. Age is a risk factor for developing RA. Major changes in the immune system come with age due to chronic oxidative stress on the deoxyribonucleic acid (DNA) damage pathway, somatic mutation, modifications of auto-antigens, T cell tolerance and activation of fibroblast-like synoviocytes (FLS). Reactive oxygen species (ROS) generated by nicotinamide adenine dinucleotide phosphate oxidase 2 (NADPH oxidase 2) suppress T cell receptor signaling. Sirtuin 1 (SIRT1) is a critical immune suppressor of T cell activation and a key regulator of oxidative stress. When oxidative stress reduces activity of SIRT1, the breakdown of tolerance to modified self-antigens is expected. Generation of ROS can be perpetuated by enhanced DNA damage and dysfunctional mitochondria in a feedback loop during the development of RA. Through major T cell loss and selective proliferation of peripheral T cells, pro-inflammatory T cell pools with abnormal features are established in the T cell compartment. Hypoxic and inflammatory condition in synovium perpetuates ROS generation, which leads to the activation of FLS. In both T cell and synovium compartment, oxidative stress reshapes the immune system into the development of pre-clinical RA.
Arthritis, Rheumatoid* ; Autoantigens ; Autoimmune Diseases ; Cartilage ; DNA ; DNA Damage ; Immune System ; Mitochondria ; NADP ; NADPH Oxidase ; Oxidative Stress ; Oxidoreductases ; Reactive Oxygen Species* ; Receptors, Antigen, T-Cell ; Risk Factors ; Sirtuin 1 ; Synovial Membrane ; Synovitis ; T-Lymphocytes

HCMV infection can evoke the broad spectrum of symptoms, which may be caused by the infection of responsible cell types. It is important to identify the cell types to be infected and replicated with HCMV infection for characterizing the property of HCMV infection and symptoms. Bone marrow stroma consists of heterogeneous cells, which have many cellular functions. This study was performed to verify the infectivity of HCMV to osteoblasts using the osteogenic sarcoma cell line, Saos-2, and the effect of HCMV infection to them on the cellular function. Immediate-early antigens, IE1 and IE2, were detected from 1 day postinfection (d.p.i.), and early (ppUL44) and late (gB) antigen were detected from 2 d.p.i. by the immunoperoxidase staining. All the antigens were expressed as far as observed (9 days). It was found that the virus titer in the culture supernatant and the cell pellet were 150 to 2,200 pfu/ml and 50 to 800 pfu/ml, respectively, after 4 days when the cells were infected with 2 m.o.i. Alkaline phosphatase production in Saos-2 cells infected with the different amount of HCMV was decreased to 8 to 15%, 31 to 47%, and 11 to 52% on 4, 6, and 11 d.p.i., respectively, as compared with mock-infected cells. This result suggested that HCMV could replicate in some bone marrow stromal cells and disturb the cellular function such as production of alkaline phosphatase.
Alkaline Phosphatase* ; Bone Marrow ; Cell Line* ; Cytomegalovirus* ; Humans* ; Mesenchymal Stromal Cells ; Osteoblasts ; Osteosarcoma* ; Permissiveness ; Viral Load

BACKGROUND: To assess the cost-effectiveness of drug therapy to prevent osteoporotic fractures in postmenopausal women with osteopenia in Korea. METHODS: A Markov cohort simulation was conducted for lifetime with a hypothetical cohort of postmenopausal women with osteopenia and without prior fractures. They were assumed to receive calcium/vitamin D supplements only or drug therapy (i.e., raloxifene or risedronate) along with calcium/vitamin D for 5 years. The Markov model includes fracture-specific and non-fracture specific health states (i.e. breast cancer and venous thromboembolism), and all-cause death. Published literature was used to determine the model parameters. Local data were used to estimate the baseline incidence rates of fracture in those with osteopenia and the costs associated with each health state. RESULTS: From a societal perspective, the estimated incremental cost-effectiveness ratios (ICERs) for the base cases that had T-scores between -2.0 and -2.4 and began drug therapy at the age of 55, 60, or 65 years were $16,472, $6,741, and -$13,982 per quality-adjusted life year (QALY) gained, respectively. Sensitivity analyses for medication compliance, risk of death following vertebral fracture, and relaxing definition of osteopenia resulted in ICERs reached to $24,227 per QALY gained. CONCLUSIONS: ICERs for the base case and sensitivity analyses remained within the World Health Organization's willingness-to-pay threshold, which is less than per-capita gross domestic product in Korea (about $25,700). Thus, we conclude that drug therapy for osteopenia would be a cost-effective intervention, and we recommend that the Korean National Health Insurance expand its coverage to include drug therapy for osteopenia.
Bone Diseases, Metabolic* ; Breast Neoplasms ; Cohort Studies ; Cost-Benefit Analysis ; Drug Therapy ; Female ; Global Health ; Gross Domestic Product ; Humans ; Incidence ; Korea ; Medication Adherence ; National Health Programs ; Osteoporotic Fractures* ; Postmenopause ; Quality-Adjusted Life Years ; Raloxifene Hydrochloride ; Risedronate Sodium