In the well-fed state a relatively high activity of the pyruvate dehydrogenase complex (PDC) reduces blood glucose levels by directing the carbon of pyruvate into the citric acid cycle. In the fasted state a relatively low activity of the PDC helps maintain blood glucose levels by conserving pyruvate and other three carbon compounds for gluconeogenesis. The relative activities of the pyruvate dehydrogenase kinases (PDKs) and the opposing pyruvate dehydrogenase phosphatases determine the activity of PDC in the fed and fasted states. Up regulation of PDK4 is largely responsible for inactivation of PDC in the fasted state. PDK4 knockout mice have lower fasting blood glucose levels than wild type mice, proving that up regulation of PDK4 is important for normal glucose homeostasis. In type 2 diabetes, up regulation of PDK4 also inactivates PDC, which promotes gluconeogenesis and thereby contributes to the hyperglycemia characteristic of this disease. When fed a high fat diet, wild type mice develop fasting hyperglycemia but PDK4 knockout mice remain euglycemic, proving that up regulation of PDK4 contributes to hyperglycemia in diabetes. These finding suggest PDK4 inhibitors might prove useful in the treatment of type 2 diabetes.
Animals ; Blood Glucose ; Carbon ; Citric Acid Cycle ; Diet, High-Fat ; Fasting ; Gluconeogenesis ; Glucose ; Homeostasis ; Hyperglycemia ; Ketone Bodies ; Mice ; Mice, Knockout ; Oxidoreductases ; Phosphoric Monoester Hydrolases ; Phosphotransferases ; Protein Kinases ; Protein-Serine-Threonine Kinases ; Pyruvate Dehydrogenase Complex ; Pyruvic Acid ; Up-Regulation

O-Linked beta-N-acetyl glucosaminylation (O-GlcNAcylation) is a dynamic post-translational modification that occurs on serine and threonine residues of cytosolic and nuclear proteins in all cell types, including those involved in the cardiovascular system. O-GlcNAcylation is thought to act in a manner analogous to protein phosphorylation. O-GlcNAcylation rapidly cycles on/off proteins in a time scale similar to that for phosphorylation/dephosphorylation of proteins. Several studies indicate that O-GlcNAc might induce nuclear localization of some transcription factors and may affect their DNA binding activities. However, at the cellular level, it has been shown that O-GlcNAc levels increase in response to stress and augmentation of this response suppresses cell survival. Increased levels of O-GlcNAc have been implicated as a pathogenic contributor to glucose toxicity and insulin resistance, which are major hallmarks of type 2 diabetes and diabetes-related cardiovascular complications. Thus, O-GlcNAc and its metabolic functions are not yet well-understood; focusing on the role of O-GlcNAc in the cardiovascular system is a viable target for biomedical investigation. In this review, we summarize our current understanding of the role of O-GlcNAc on the regulation of cell function and survival in the cardiovascular system.
Acetylglucosaminidase ; Cardiovascular Diseases ; Cardiovascular System ; Cell Survival ; Cytosol ; Diabetes Mellitus, Type 2 ; DNA ; Friends ; Glucose ; Humans ; Insulin Resistance ; Nuclear Proteins ; Phosphorylation ; Protein Processing, Post-Translational ; Proteins ; Serine ; Threonine ; Transcription Factors ; Vascular Diseases

Impaired glucose homeostasis is one of the risk factors for causing metabolic diseases including obesity, type 2 diabetes, and cancers. In glucose metabolism, pyruvate dehydrogenase complex (PDC) mediates a major regulatory step, an irreversible reaction of oxidative decarboxylation of pyruvate to acetyl-CoA. Tight control of PDC is critical because it plays a key role in glucose disposal. PDC activity is tightly regulated using phosphorylation by pyruvate dehydrogenase kinases (PDK1 to 4) and pyruvate dehydrogenase phosphatases (PDP1 and 2). PDKs and PDPs exhibit unique tissue expression patterns, kinetic properties, and sensitivities to regulatory molecules. During the last decades, the up-regulation of PDKs has been observed in the tissues of patients and mammals with metabolic diseases, which suggests that the inhibition of these kinases may have beneficial effects for treating metabolic diseases. This review summarizes the recent advances in the role of specific PDK isoenzymes on the induction of metabolic diseases and describes the effects of PDK inhibition on the prevention of metabolic diseases using pharmacological inhibitors. Based on these reports, PDK isoenzymes are strong therapeutic targets for preventing and treating metabolic diseases.
Acetyl Coenzyme A ; Decarboxylation ; Diabetes Mellitus, Type 2 ; Glucose ; Homeostasis ; Humans ; Isoenzymes ; Mammals ; Metabolic Diseases ; Metabolism ; Obesity ; Oxidoreductases* ; Phosphoric Monoester Hydrolases ; Phosphorylation ; Phosphotransferases* ; Pyruvate Dehydrogenase Complex ; Pyruvic Acid* ; Risk Factors ; Up-Regulation

Cryptotanshinone is known for its inhibitory activity against tumorigenesis in various human cancer cells. However, exact mechanisms underlying the anticancer effects of cryptotanshinone are not fully elucidated. Here, we propose a plausible molecular mechanism, wherein cryptotanshinone represses rapamycin-sensitive mTORC1/S6K1 mediated cancer cell growth and cell transformation. We investigated the various effects of cryptotanshinone on the mTORC1/S6K1 axis, which is associated with the regulation of cell growth in response to nutritional and growth factor signals. We found that cryptotanshinone specifically inhibited the mTORC1-mediated phosphorylation of S6K1, which consequently suppressed the clonogenicity of SK-Hep1 cells and the neoplastic transformation of JB6 Cl41 cells induced by insulin-like growth factor-1. Finally, we observed that cryptotanshinone prevented S6K1 from binding to the Raptor/mTOR complex, rather than regulating mTOR and its upstream pathway. Overall, our findings provide a novel mechanism underlying anti-cancer effects cryptotanshinone targeting mTORC1 signaling, contributing to the development of anticancer agents involving metabolic cancer treatment.

Cryptotanshinone is known for its inhibitory activity against tumorigenesis in various human cancer cells. However, exact mechanisms underlying the anticancer effects of cryptotanshinone are not fully elucidated. Here, we propose a plausible molecular mechanism, wherein cryptotanshinone represses rapamycin-sensitive mTORC1/S6K1 mediated cancer cell growth and cell transformation. We investigated the various effects of cryptotanshinone on the mTORC1/S6K1 axis, which is associated with the regulation of cell growth in response to nutritional and growth factor signals. We found that cryptotanshinone specifically inhibited the mTORC1-mediated phosphorylation of S6K1, which consequently suppressed the clonogenicity of SK-Hep1 cells and the neoplastic transformation of JB6 Cl41 cells induced by insulin-like growth factor-1. Finally, we observed that cryptotanshinone prevented S6K1 from binding to the Raptor/mTOR complex, rather than regulating mTOR and its upstream pathway. Overall, our findings provide a novel mechanism underlying anti-cancer effects cryptotanshinone targeting mTORC1 signaling, contributing to the development of anticancer agents involving metabolic cancer treatment.

STUDY DESIGN: Retrospective radiologic assessment OBJECTIVES: To assess the clinical importance of MRI for the diagnosis of posterior spinal ligament complex injuries in thoracolumbar fractures. SUMMARY OF LITERATURE REVIEW: Evaluation of spinal instability is important in thoracolumbar fractures. When simple radiography and CT alone are performed, spinal instability may be missed, especially that involving the posterior spinal ligament complex. MATERIALS AND METHODS: Eighty-seven patients who were evaluated using simple radiography, computed tomography (CT), and magnetic resonance imaging (MRI) between March 1994 and March 2003 were included in the study. The local kyphotic angle was measured on lateral radiography, and it was then compared to the fracture pattern on MRI. Statistical analysis was performed using ANOVA. RESULTS: There was no correlation between the local kyphotic angle on radiography and fracture involvement on MRI (p=0.106). In 41 patients who were found to have involvement of the anterior column on CT, 25 had anterior column involvement, 4 had middle column involvement, and 12 had posterior column involvement on MRI. In 36 patients who were found to have involvement of the middle column on CT, 17 had involvement of the middle column and 19 had involvement of the posterior column on MRI. The fractures of the ten patients who were found to have posterior column involvement on CT were all seen on MRI. The coincidence of fracture patterns between CT and MRI, which was evaluated using Cohen's Kappa analysis, was 0.434. The sensitivity of CT compared with MRI was 0.741 in the middle column and 0.243 in the posterior column. CONCLUSIONS: Many thoracolumbar fractures are missed on both simple radiography and CT. MRI is essential for accurate diagnosis of posterior spinal ligament complex injuries, especially when there is involvement above the middle column, or when canal encroachment is seen on CT.
Humans ; Ligaments ; Magnetic Resonance Imaging ; Retrospective Studies ; Spinal Fractures

PURPOSE: To analyze the changes of astigmatism and keratometric cylinder by using the scalar and vector analysis method in children who had undergone surgery for epiblepharon or ptosis. METHODS: The study subjects were 142 eyes of 79 patients who had undergone surgery for epiblepharon or ptosis. We examined the cycloplegic refractive error and keratometric astigmatism by auto-refractometry before and 2 months after surgery. Astigmatic changes were analyzed through the scalar and vector analysis method. RESULTS: The mean age of the patients was 5.27+/-2.18 years of age, and the male to female ratio was 35: 44. There were 98 eyes of 49 patients in the epiblepharon surgery group, 28 eyes of 22 patients in the ptosis surgery group, and 16 eyes of 8 patients in the epiblepharon and ptosis surgery (combined surgery) group. The epiblepharon surgery group demonstrated a decrease in with-the-rule astigmatism, and the changes in magnitude (p<0.001) and vector (p<0.05) of keratometric cylinder were statistically significant. The ptosis surgery group demonstrated an increase in with-the-rule astigmatism and the changes in magnitude and vector of astigmatism were statistically significant (both p<0.01). The combined surgery group demonstrated an increase in with-the-rule astigmatism and the changes in vector of astigmatism and magnitude of keratometric cylinder were statistically significant (both p<0.05). CONCLUSIONS: Our results showed significant astigmatic change in eyes that underwent surgery for epiblepharon or ptosis. Therefore, careful cycloplegic refraction is necessary after epiblepharon or ptosis surgery.
Astigmatism* ; Child ; Female ; Humans ; Male ; Refractive Errors

The pyruvate dehydrogenase complex (PDC) activity is crucial to maintains blood glucose and ATP levels, which largely depends on the phosphorylation status by pyruvate dehydrogenase kinase (PDK) isoenzymes. Although it has been reported that PDC is phosphorylated and inactivated by PDK2 and PDK4 in metabolically active tissues including liver, skeletal muscle, heart, and kidney during starvation and diabetes, the precise mechanisms by which expression of PDK2 and PDK4 are transcriptionally regulated still remains unclear. Insulin represses the expression of PDK2 and PDK4 via phosphorylation of FOXO through PI3K/Akt signaling pathway. Several nuclear hormone receptors activated due to fasting or increased fat supply, including peroxisome proliferator-activated receptors, glucocorticoid receptors, estrogen-related receptors, and thyroid hormone receptors, also participate in the up-regulation of PDK2 and PDK4; however, the endogenous ligands that bind those nuclear receptors have not been identified. It has been recently suggested that growth hormone, adiponectin, epinephrine, and rosiglitazone also control the expression of PDK4 in tissue-specific manners. In this review, we discuss several factors involved in the expressional regulation of PDK2 and PDK4, and introduce current studies aimed at providing a better understanding of the molecular mechanisms that underlie the development of metabolic diseases such as diabetes.
Adenosine Triphosphate ; Adiponectin ; Blood Glucose ; Epinephrine ; Fasting ; Growth Hormone ; Heart ; Insulin ; Insulin Resistance ; Isoenzymes ; Kidney ; Ligands ; Liver ; Metabolic Diseases ; Muscle, Skeletal ; Oxidoreductases ; Peroxisome Proliferator-Activated Receptors ; Phosphorylation ; Phosphotransferases ; Protein-Serine-Threonine Kinases ; Pyruvate Dehydrogenase Complex ; Pyruvic Acid ; Receptors, Cytoplasmic and Nuclear ; Receptors, Glucocorticoid ; Receptors, Thyroid Hormone ; Starvation ; Thiazolidinediones ; Up-Regulation

BACKGROUND AND OBJECTIVE: Malignant melanoma are developed from malignant transformation of the melanocyte. Mucosal malignant melanoma of the nasal cavity and paranasal sinuses is rare and fatal. The aim of this study is to evaluate the clinical characteristics and the treatment outcome of patients with mucosal malignant melanoma of the nasal cavity and paranasal sinuses. MATERIALS AND METHODS: From June 1989 to Dec. 1997, six patients with mucosal malignant melanoma of the nasal cavity and paranasal sinuses underwent surgical excision at Asan Medical Center. Their medical records were retrospectively reviewed with regard to age & sex, primary site, treatment modalities, recurrence, and survival. RESULTS: There were 3 men and 3 women. Their ages ranged from 38 to 55 years with a mean of 51 years. Two patients presented with primary tumors in septum, one in the lateral nasal wall, one in maxillary sinus, one in ethmoid sinus and one with unknown origin. The primary treatment modalities were wide surgical excision of primary site with or without postoperative radiotherapy. Up to the present, recurrence occurred in 4 of the 5 patients and the median time to recurrence was 4.8 months. Two patients died of local or regional disease and the median survival following the recurrence was 6.5 months. CONCLUSION: Mucosal malignant melanoma of the nose and paranasal sinuses have high recurrence rate and poor prognosis in spite of wide surgical excision and postoperative radiotherapy.
Chungcheongnam-do ; Ethmoid Sinus ; Female ; Humans ; Male ; Maxillary Sinus ; Medical Records ; Melanocytes ; Melanoma* ; Nasal Cavity* ; Nose ; Paranasal Sinuses* ; Prognosis ; Radiotherapy ; Recurrence ; Retrospective Studies ; Treatment Outcome

BACKGROUND: The prognostic impact of the presence of differentiating neuroblasts in bone marrow (BM) remains unclear in BM metastatic neuroblastoma (NB). We aimed to identify the prognostic impact of differentiating neuroblasts in BM at diagnosis and after chemotherapy. METHODS: A total of 51 patients diagnosed with BM metastatic NB at Asan Medical Center between January 1990 and July 2005 were enrolled. BM histology and laboratory data along with overall survival (OS) were compared with regard to the differentiation status of neuroblasts in BM at diagnosis and after chemotherapy. RESULTS: Among the 51 patients, 13 (25.5%) exhibited differentiating neuroblasts in BM at diagnosis and 17/51 (33.3%) exhibited them after chemotherapy. The only significant difference among patient groups was the improved OS in patients with differentiated neuroblasts in BM at diagnosis (P=0.021). In contrast, the differentiation status of neuroblasts in BM after chemotherapy did not affect OS (P=0.852). CONCLUSIONS: Our study is the first report describing the presence of differentiating neuroblasts in BM. The presence of differentiating neuroblasts in BM at diagnosis may be a favorable prognostic factor for patients with BM metastatic NB; however, the same phenomenon after chemotherapy is irrelevant to prognosis.
Adolescent ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Bone Marrow/*pathology ; Bone Marrow Cells/*cytology ; Bone Marrow Neoplasms/*diagnosis/secondary ; Cell Differentiation ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Karyotyping ; Male ; Neoplasm Grading ; Neuroblastoma/*diagnosis/drug therapy/pathology ; Prognosis ; Survival Analysis ; Young Adult