• BMB Reports
• /
• v.39 no.5
• /
• pp.469-478
• /
• 2006

Vascular endothelial growth factor (VEGF)-A, a major regulator for angiogenesis, binds and activates two tyrosine kinase receptors, VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk-1). These receptors regulate physiological as well as pathological angiogenesis. VEGFR2 has strong tyrosine kinase activity, and transduces the major signals for angiogenesis. However, unlike other representative tyrosine kinase receptors which use the Ras pathway, VEGFR2 mostly uses the Phospholipase-$C{\gamma}$-Protein kinase-C pathway to activate MAP-kinase and DNA synthesis. VEGFR2 is a direct signal transducer for pathological angiogenesis including cancer and diabetic retinopathy, thus, VEGFR2 itself and the signaling appear to be critical targets for the suppression of these diseases. VEGFR1 plays dual role, a negative role in angiogenesis in the embryo most likely by trapping VEGF-A, and a positive role in adulthood in a tyrosine kinase-dependent manner. VEGFR1 is expressed not only in endothelial cells but also in macrophage-lineage cells, and promotes tumor growth, metastasis, and inflammation. Furthermore, a soluble form of VEGFR1 was found to be present at abnormally high levels in the serum of preeclampsia patients, and induces proteinurea and renal dysfunction. Therefore, VEGFR1 is also an important target in the treatment of human diseases. Recently, the VEGFR2-specific ligand VEGF-E (Orf-VEGF) was extensively characterized. Interestingly, the activation of VEGFR2 via VEGF-E in vivo results in a strong angiogenic response in mice with minor side effects such as inflammation compared with VEGF-A, suggesting VEGF-E to be a novel material for pro-angiogenic therapy.

• BMB Reports
• /
• v.45 no.1
• /
• pp.51-56
• /
• 2012

The purpose of this study was to determine the effects of duration and timing of glucocorticoid treatment on the expansion and differentiation of porcine neonatal pancreas cell clusters (NPCCs) into ${\beta}$-cells. After transplantation of NPCCs, the ductal cyst area and ${\beta}$-cell mass in the grafts both showed positive and negative correlations with duration of dexamethasone (Dx) treatment. Pdx-1 and HNF-3${\beta}$ gene expression was significantly downregulated following Dx treatment, whereas PGC-1${\alpha}$ expression increased. Pancreatic duct cell apoptosis significantly increased following Dx treatment, whereas proliferation did not change. Altogether, transdifferentiation of porcine NPCCs into ${\beta}$-cells was influenced by the duration of Dx treatment, which might have been due to the suppression of key pancreatic transcription factors. PGC-1${\alpha}$ plays an important role in the expansion and transdifferentiation of porcine NPCCs, and the initial 2 weeks following transplantation of porcine NPCCs is a critical period in determining the final ${\beta}$-cell mass in grafts.

• Journal of Physiology & Pathology in Korean Medicine
• /
• v.23 no.4
• /
• pp.888-894
• /
• 2009

It has been reported that silibinin, a natural polyphenolic flavonoid, induces cell death in various cancer cell types. However, the underlying mechanisms by which silibinin induces apoptosis in human glioma cells are poorly understood. The present study was therefore undertaken to examine the effect of silibinin on glioma cell apoptosis and to determine its underlying mechanism in human glioma cells. Apoptosis was estimated by FACS analysis. Reactive oxygen species (ROS) generation and mitochondrial membrane potential (${\Psi}m$) were measured using fluorescence dyes DCFH-DA and $DiOC_6$(3), respectively. Cytochrome c release from mitochondria and caspase-3 activation were estimated by Western blot analysis using specific antibodies. Exposure of cells to 30 mM silibinin induced apoptosis starting at 6 h, with increasing effects after 12-48h in a time-dependent manner. Silibinin caused ROS generation and disruption of ym, which were associated with the silibinin-induced apoptosis. The silibinin-induced ROS generation and disruption in ym were prevented by inhibitors of mitochondrial electron transport chain. The hydrogen peroxide scavenger catalase blocked ROS generation and apoptosis induced by silibinin. Silibinin induced cytochrome c release into cytosolic fraction and its effect was prevented by catalase and cyclosporine A. Silibinin treatment caused caspase-3 activation, which was inhibited by DVED-CHO and cyclosporine A. Pretreatment of caspase inhibitors also protected against the silibinin-induced apoptosis. These findings indicate that ROS generation plays a critical role in the initiation of the silibinin-induced apoptotic cascade by mediation of the mitochondrial apoptotic pathway including the disruption of ${\Psi}m$, cytochrome c release, and caspase-3 activation.

• Molecular & Cellular Toxicology
• /
• v.1 no.2
• /
• pp.137-141
• /
• 2005

The critical role of folate in the remethylation pathway for methionine synthesis from homocysteine has been well documented. Hyperhomocysteinemia resulting from inadequate folate nutrition has been implicated in increased incidence of macrovascular diseases, colorectal cancer, neural tube defects, etc. Chronic exposure to ethanol impairs folate nutrition and one-carbon metabolism in the liver, which often results in fatty liver due to a defective remetylation process. This study was carried out to investigate the chronic effects of moderate levels of alcohol and dietary folate on plasma homocysteine levels, and on histopathology and biochemical functions of the liver. Rats were raised on experimental diets with three levels of folate (0, 2, 8 mg/kg diet), and 50% ethanol (1.8 ml/kg body weight) was administered intragastically by intubation tubes three times a week for 10 weeks. Plasma homocysteine concentrations were found to be significantly influenced by dietary folate intake and alcohol administration. Among all treatment groups, plasma homocysteine levels were the highest in the animals receiving a combined treatment of folate deficient diet and alcohol administration. Plasma homocysteine concentrations were negatively correlated with folate concentration in the plasma (p<0.01) and liver (p<0.05). Among alcohol treated rats, increase in plasma homocysteine values due to macrovascular and microvascular fatty changes and spotted necrosis were observed more frequently in folate-deficient animals diet than those on folate-adequate and folate supplemented diets in alcohol-treated rats. These results indicate that folate supplementation above the recommended level might be beneficial in the prevention of alcohol-related hyperhomocysteinemia and abnormal histologic changes in the liver.

• The Korean Journal of Nuclear Medicine
• /
• v.36 no.1
• /
• pp.74-79
• /
• 2002

In addition to the well-established use of positron emission tomography (PET) in clinical oncology, novel roles for PET are rapidly emerging in the field of gene therapy. Methods for controlled gene delivery to living bodies, made available through advances in molecular biology, are currently being employed in animals for research purposes and in humans to treat diseases such as cancer. Although gene therapy is still in its early developmental stage, it is perceived that many serious illnesses could be treated successfully by the use of therapeutic gene delivery. A major challenge for the widespread use of human gene therapy is to achieve a controlled and effective delivery of foreign genes to target cells and subsequently, adequate levels of expression. As such, the availability of noninvasive imaging methods to accurately assess the location, duration, and level of transgene expression is critical for optimizing gene therapy strategies. Current endeavors to achieve this goal include methods that utilize magnetic resonance imaging, optical imaging, and nuclear imaging techniques. As for PET, reporter systems that utilize genes encoding enzymes that accumulate positron labeled substrates and those transcribing surface receptors that bind specific positron labeled ligands have been successfully developed. More recent advances in this area include improved reporter gene constructs and radiotracers, introduction of potential strategies to monitor endogenous gene expression, and human pilot studies evaluating the distribution and safety of reporter PET tracers. The remarkably rapid progress occurring in gene imaging technology indicates its importance and wide range of application. As such, gene imaging is likely to become a major and exciting new area for future application of PET technology.

• Journal of Korean Society of Occupational and Environmental Hygiene
• /
• v.17 no.4
• /
• pp.282-288
• /
• 2007

그 동안 많은 역학연구를 통해서 금속가공유(metalworking fluid, MWFs) 노출과 여러 조직에서 암 발생 위험과의 관계를 밝혔지만, 금속가공유 종류(비수용성, 수용성, 합성, 준합성)별로 구분된 위험은 아직 완전하게 규명되지 않았다. 역학조사에서 금속가공유 노출을 대체할 수 있는 인자(surrogate)로서 정성적(qualitative), 명목적(ordinal) 혹은 준정량적인(semi-quantitative) 변수들(금속가공유에 대한 노출 유무, 노출 정도: 높음, 낮음 등, 직업 유무, 근무기간 등)을 이용하여 금속가공유 노출을 평가하였다. 이러한 노출평가방법은 기본적으로 금속가공유 노출 강도(intensity)가 고려되지 않을 뿐만 아니라 노출 분류 오류(misclassification)도 항상 존재할 수 있어 금속가공유 노출은 물론이고 종류별 위험을 밝히기 어렵다. 일부 역학연구에서 금속가공유 종류별 누적 노출양(cumulative exposure level)과 암위험과의 관계를 밝혔다. 이러한 연구결과들은 모두 금속가공유 종류별로 과거노출을 추정할 수 있는 자료(정량적인 노출평가자료, 과거직업력, 취급했던 금속가공유 종류 등)가 잘 기록되어 있는 1개의 대규모 자동차공장에서 나온 것들이다. 따라서 금속가공유에 대한 노출자료가 부족하고 사용특성에 대한 기록이 없거나 부족한 일반 인구나 산업을 대상으로 한 역학연구에서는 금속가공유의 종류별 위험을 밝히는것은 불가능하다. 금속가공유 종류별로 과거 노출에 대한 확률(probability)을 추정하는데 일반적으로 활용할 수 있는 노출확률 메트릭스를 개발하는 것이 필요하다.

• Nutrition Research and Practice
• /
• v.8 no.1
• /
• pp.46-53
• /
• 2014

Inorganic arsenic (iAs) is a toxic metalloid found ubiquitously in the environment. In humans, exposure to iAs can result in toxicity and cause toxicological manifestations. Arsenic trioxide ($As_2O_3$) has been used in the treatment for acute promyelocytic leukemia. The kidney is the critical target organ of trivalent inorganic As ($iAs^{III}$) toxicity. We examine if oral administration of astaxanthin (AST) has protective effects on nephrotoxicity and oxidative stress induced by $As_2O_3$ exposure (via intraperitoneal injection) in rats. Markers of renal function, histopathological changes, $Na^+-K^+$ ATPase, sulfydryl, oxidative stress, and As accumulation in kidneys were evaluated as indicators of $As_2O_3$ exposure. AST showed a significant protective effect against $As_2O_3$-induced nephrotoxicity. These results suggest that the mechanisms of action, by which AST reduces nephrotoxicity, may include antioxidant protection against oxidative injury and reduction of As accumulation. These findings might be of therapeutic benefit in humans or animals suffering from exposure to $iAs^{III}$ from natural sources or cancer therapy.

• BMB Reports
• /
• v.49 no.5
• /
• pp.245-246
• /
• 2016

The level and activity of critical regulatory proteins in cells are tightly controlled by several tiers of post-translational modifications. HIF-1α is maintained at low levels under normoxia conditions by the collaboration between PHD proteins and the VHL-containing E3 ubiquitin ligase complex. We recently identified a new physiologically relevant mechanism that regulates HIF-1α stability in the nucleus in response to cellular oxygen levels. This mechanism is based on the collaboration between the SET7/9 methyltransferase and the LSD1 demethylase. SET7/9 adds a methyl group to HIF-1α, which triggers degradation of the protein by the ubiquitin-proteasome system, whereas LSD1 removes the methyl group, leading to stabilization of HIF-1α under hypoxia conditions. In cells from knock-in mice with a mutation preventing HIF-1α methylation (Hif1α^KA/KA), HIF-1α levels were increased in both normoxic and hypoxic conditions. Hif1α^KA/KA knock-in mice displayed increased hematological parameters, such as red blood cell count and hemoglobin concentration. They also displayed pathological phenotypes; retinal and tumor-associated angiogenesis as well as tumor growth were increased in Hif1α^KA/KA knock-in mice. Certain human cancer cells exhibit mutations that cause defects in HIF-1α methylation. In summary, this newly identified methylation-based regulation of HIF-1α stability constitutes another layer of regulation that is independent of previously identified mechanisms.

• Korean Journal of Head & Neck Oncology
• /
• v.15 no.1
• /
• pp.66-69
• /
• 1999

Background and Objectives: It is critical to distinguish benign from malignant thyroid nodule and to select a patient for surgery. Even though the U/S study dose not make great contribution to diagnose a malignant thyroid nodule, it is widely used in the evaluation of anatomic feature of thyroid. The authors tried to estimate the efficacy of the U/S study in preoperative diagnosis of malignant thyroid nodule. Materials and Method: At the department of General Surgery of Ajou University, 75 patients who were operated after diagnosis with thyroid nodule by U/S study between July 1996 to June 1997 were retrospectively analyzed. By comparing the U/S impression that implies malignant thyroid nodule to FNAC and post-operative pathologic results ware as follows. Results: 1) Absence of cystic change, presence of internal hypoechogenicity, lobulation, calcification, thick and irregular halo, and nodule more than 4cm in diameter on U/S were considered significant statistically for the diagnosis of malignancy(Chi-square test, p<0.05) 2) Presence of internal hypoechogenicity or thick and irregular halo has the validity in Logistic regression analysis. 3) FNAC was done in 65 case. 19 case were malignant, 11 case were suspicious and 46 patients were benign (sensitivity 52.6%, specificity 87%). 4) The findings of U/S which are hypoechogenic and thick and irregular halo show 82% sensitivity and 97% specificity. In combination with the findings of FNAC that imply benign or suspicious lesions, the sensitivity was 100% and the specificity was 97%. Conclusion: This study suggest that the hypoechogenicity and thick and irregular halo on U/S are important information for the diagnosis of thyroid malignancy which were considered benign or suspicious after FNAC.

• Journal of Preventive Medicine and Public Health
• /
• v.53 no.3
• /
• pp.205-210
• /
• 2020

Objectives: Aging is assumed to be accompanied by greater health care expenditures. The objective of this retrospective, bottom-up micro-costing study was to identify and analyze the variables related to increased health care costs for the elderly from the provider's perspective. Methods: The analysis included all elderly inpatients who were admitted in 2017 to a hospital in Tehran, Iran. In total, 1288 patients were included. The Mann-Whitney and Kruskal-Wallis tests were used. Results: Slightly more than half (51.1%) of patients were males, and 81.9% had a partial recovery. The 60-64 age group had the highest costs. Cancer and joint/orthopedic diseases accounted for the highest proportion of costs, while joint/orthopedic diseases had the highest total costs. The surgery ward had the highest overall cost among the hospital departments, while the intensive care unit had the highest mean cost. No statistically significant relationships were found between inpatient costs and sex or age group, while significant associations (p<0.05) were observed between inpatient costs and the type of ward, length of stay, type of disease, and final status. Regarding final status, costs for patients who died were 3.9 times higher than costs for patients who experienced a partial recovery. Conclusions: Sex and age group did not affect hospital costs. Instead, the most important factors associated with costs were type of disease (especially chronic diseases, such as joint and orthopedic conditions), length of stay, final status, and type of ward. Surgical services and medicine were the most important cost items.