• Molecules and Cells
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• v.38 no.4
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• pp.373-379
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• 2015

Pyruvate kinase M2 isoform (PKM2), a rate-limiting enzyme in the final step of glycolysis, is known to be associated with the metabolic rewiring of cancer cells, and considered an important cancer therapeutic target. Herein, we report a novel PKM2 activator, PA-12, which was identified via the molecular docking-based virtual screening. We demonstrate that PA-12 stimulates the pyruvate kinase activity of recombinant PKM2 in vitro, with a half-maximal activity concentration of $4.92{\mu}M$, and effectively suppresses both anchorage-dependent and -independent growth of lung cancer cells in non-essential amino acid-depleted medium. In addition, PA-12 blocked the nuclear translocalization of PKM2 in lung cancer cells, resulting in the inhibition of hypoxia response element (HRE)-mediated reporter activity as well as hypoxia-inducible factor 1 (HIF-1) target gene expression, eventually leading to the suppression of cell viability under hypoxia. We also verified that the effects of PA-12 were dependent on PKM2 expression in cancer cells, demonstrating the specificity of PA-12 for PKM2 protein. Taken together, our data suggest that PA-12 is a novel and potent PKM2 activator that has therapeutic implications for lung cancer.

• Korean Journal of Exercise Nutrition
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• v.16 no.2
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• pp.65-71
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• 2012

Oxygen is the final acceptor of electron transport from fat and carbohydrate oxidation, which is the rate-limiting factor for cellular ATP production. Under altitude hypoxia condition, energy reliance on anaerobic glycolysis increases to compensate for the shortfall caused by reduced fatty acid oxidation [1]. Therefore, training at altitude is expected to strongly influence the human metabolic system, and has the potential to be designed as a non-pharmacological or recreational intervention regimen for correcting diabetes or related metabolic problems. However, most people cannot accommodate high altitude exposure above 4500 M due to acute mountain sickness (AMS) and insulin resistance corresponding to a increased levels of the stress hormones cortisol and catecholamine [2]. Thus, less stringent conditions were evaluated to determine whether glucose tolerance and insulin sensitivity could be improved by moderate altitude exposure (below 4000 M). In 2003, we and another group in Austria reported that short-term moderate altitude exposure plus endurance-related physical activity significantly improves glucose tolerance (not fasting glucose) in humans [3,4], which is associated with the improvement in the whole-body insulin sensitivity [5]. With daily hiking at an altitude of approximately 4000 M, glucose tolerance can still be improved but fasting glucose was slightly elevated. Individuals vary widely in their response to altitude challenge. In particular, the improvement in glucose tolerance and insulin sensitivity by prolonged altitude hiking activity is not apparent in those individuals with low baseline DHEA-S concentration [6]. In addition, hematopoietic adaptation against altitude hypoxia can also be impaired in individuals with low DHEA-S. In short-lived mammals like rodents, the DHEA-S level is barely detectable since their adrenal cortex does not appear to produce this steroid [7]. In this model, exercise training recovery under prolonged hypoxia exposure (14-15% oxygen, 8 h per day for 6 weeks) can still improve insulin sensitivity, secondary to an effective suppression of adiposity [8]. Genetically obese rats exhibit hyperinsulinemia (sign of insulin resistance) with up-regulated baseline levels of AMP-activated protein kinase and AS160 phosphorylation in skeletal muscle compared to lean rats. After prolonged hypoxia training, this abnormality can be reversed concomitant with an approximately 50% increase in GLUT4 protein expression. Additionally, prolonged moderate hypoxia training results in decreased diffusion distance of muscle fiber (reduced cross-sectional area) without affecting muscle weight. In humans, moderate hypoxia increases postprandial blood distribution towards skeletal muscle during a training recovery. This physiological response plays a role in the redistribution of fuel storage among important energy storage sites and may explain its potent effect on changing body composition. Conclusion: Prolonged moderate altitude hypoxia (rangingfrom 1700 to 2400 M), but not acute high attitude hypoxia (above 4000 M), can effectively improve insulin sensitivity and glucose tolerance for humans and antagonizes the obese phenotype in animals with a genetic defect. In humans, the magnitude of the improvementvaries widely and correlates with baseline plasma DHEA-S levels. Compared to training at sea-level, training at altitude effectively decreases fat mass in parallel with increased muscle mass. This change may be associated with increased perfusion of insulin and fuel towards skeletal muscle that favors muscle competing postprandial fuel in circulation against adipose tissues.

• Korean Journal of Radiology
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• v.22 no.3
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• pp.425-434
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• 2021

Objective: To investigate the potential value of ¹⁸F-fluorodeoxyglucose (FDG) PET/CT in predicting the survival of patients with primary tracheal malignant tumors. Materials and Methods: An analysis of FDG PET/CT findings in 37 primary tracheal malignant tumor patients with a median follow-up period of 43.2 months (range, 10.8-143.2 months) was performed. Cox proportional hazards regression analyses were used to assess the associations between quantitative ¹⁸F-FDG PET/CT parameters, other clinic-pathological factors, and overall survival (OS). A risk prognosis model was established according to the independent prognostic factors identified on multivariate analysis. A survival curve determined by the Kaplan-Meier method was used to assess whether the prognosis prediction model could effectively stratify patients with different risks factors. Results: The median survival time of the 37 patients with tracheal tumors was 38.0 months, with a 95% confidence interval of 10.8 to 65.2 months. The 3-year, 5-year and 10-year survival rate were 54.1%, 43.2%, and 16.2%, respectively. The metabolic tumor volume (MTV), total lesion glycolysis (TLG), maximum standardized uptake value, age, pathological type, extension categories, and lymph node stage were included in multivariate analyses. Multivariate analysis showed MTV (p = 0.011), TLG (p = 0.020), pathological type (p = 0.037), and extension categories (p = 0.038) were independent prognostic factors for OS. Additionally, assessment of the survival curve using the Kaplan-Meier method showed that our prognosis prediction model can effectively stratify patients with different risks factors (p < 0.001). Conclusion: This study shows that ¹⁸F-FDG PET/CT can predict the survival of patients with primary tracheal malignant tumors. Patients with an MTV > 5.19, a TLG > 16.94 on PET/CT scans, squamous cell carcinoma, and non-E1 were more likely to have a reduced OS.

• Applied Biological Chemistry
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• v.7
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• pp.21-27
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• 1966

This experiment was performed to investigate the effect of the frequency of meals on the metatolism and the body composition of rats when equal amount of purified diet was ingested. Thirty approximately days old rats weighing 290 g and thirty-two about 40 days old rats weighing 180 g were employed for the period of 34 days. Rats fed ad libitum (10 to 15 meals per day) and two-meal per day were pair-fed and equal amount of diet was fed to each rat in pair. The experimental results obtained are summarized as follows: 1. Frequency of meal did not exert any effect on the body weight gain. However, rats fed two-meal per· day gained significantly (p <0.005) more fat and energy than ad libitum group. The rate of gain of protein in ad libitum group was higher than that of two-meal group. No difference was observed for the mineral deposition of rat body. 2. From the preperation of rat liver it was found that the activity of glucose-6-phosphate dehydrogenase was much higher for the rats fed two-meals per day than those fed ad libitum. Therefore, it is suggested that the metabolic pathway of carbohydrate for two-meal group has been shifted from glycolysis to Hexose Monophosphate Shunt and produced more NADPH which would be the essential cofactor of fatty acids synthesis. 3. The rate of excretion of urinary nitrogen for two-meal group was significantly (p<0.005) higher than that of ad libitum group. It is apparent that considerable amount of over-loaded amino acids by feeding two-big-meal daily· could not be used for the protein biosynthesis all at once and excreted following deamination through urine. The residual carbon chain could be served as a precursor of fatty acids synthesis. 4. The heat production rate of rats fed two-meal group was significantly (p<0.005) lower than that of ad libitum group. It seems possible that the activity of thyroid gland (and consequently BMR) can be depressed by the frequency of meal.

• Tuberculosis and Respiratory Diseases
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• v.44 no.5
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• pp.1040-1050
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• 1997

Pulmonary rehabilitation has been known to improve dyspnea and exercise tolerance in patients with chronic lung disease, although it does not improve pulmonary function. The mechanism of this improvement is not clearly explained till now; however some authors suggested that the improvement in the skeletal muscle metabolism after the rehabilitation could be a possible mechanism. The metabolc changes in skeletal muscle in patients with COPD are characterized by impaired oxidative phosphorylation which causes early activation of anaerobic glycolysis and excess lactate production with exercise. In order to evaluate the change in the skeletal muscle metabolism as a possible cause of the improvement in the exercise tolerance after the rehabilitation, noninvasive $^{31}P$ magnetic resonance spectroscopy(MRS) of the forearm flexor muscle was performed before and after the exercise training in nine patients with chronic lung disease who have undertaken intensive pulmonary rehabilitation for 6 weeks. 31p MRS was studied during the sustained isometric contraction of the dominant forearm flexor muscles up to the exhaustion state and the recovery period. Maximal voluntary contraction(MVC) force of the muscle was measured before the isometric exercise, and then 30% of MVC force was constantly loaded to each patient during the isometric exercise. After the exercise training, exercise endurance of upper and lower extremities and 6 minute walking distance were significantly increased(p<0.05). There were no differences of baseline intracellular pH (pHi) and inorganic phosphate/phosphocreatine(Pi/PCr). After rehabilitation pHi at the exercise and the exhaustion state showed a significant increase($6.91{\pm}0.1$ to $6.99{\pm}0.1$ and $6.76{\pm}0.2$ to $6.84{\pm}0.2$ respectively, p<0.05). Pi/PCr at the exercise and the recovery rate of pHi and Pi/PCr did not show significant differences. These results suggest that the delayed intracellular acidosis of skeletal muscle may contribute to the improvement of exercise endurance after pulmonary rehabilitation.

• The Korean Journal of Nuclear Medicine
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• v.38 no.2
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• pp.180-189
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• 2004

Although the outcome of cancer patients after cytotoxic chemotherapy is related diverse mechanisms, multidrug resistance (MDR) for chemotherapeutic drugs due to cellular P-glycoprotein (Pgp) or multidrug-resistance associated protein (MRP) is most important factor in the chemotherapy failure to cancer. A large number of pharmacologic compounds, including verapamil, quinidine, tamoxifen, cyclosporin A and quinolone derivatives have been reported to overcome MDR. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are available for the detection of Pgp and MRP-mediated transporter. $^{99m}Tc$-MIBI and other $^{99m}Tc$-radiopharmaceuticals are substrates for Pgp and MRP, and have been used in clinical studies for tumor imaging, and to visualize blockade of PgP-mediated transport after modulation of Pgp pump. Colchicine, verapamil and daunorubicin labeled with $^{11}C$ have been evaluated for the quantification of Pgp-mediated transport with PET in vivo and reported to be feasible substrates with which to image Pgp function in tumors. Leukotrienes are specific substrates for MRP and $N-[^{11}C]acetyl-leukotriene$ E4 provides an opportunity to study MRP function non-invasively in vivo. SPECT and PET pharmaceuticals have successfully used to evaluate pharmacologic effects of MDR modulators. Imaging of MDR and reversal of MDR with bioluminescence in a living animal is also evaluated for future clinical trial. We have described recent advances in molecular imaging of MDR and reviewed recent publications regarding feasibility of SPECT and PET imaging to study the functionality of MDR transporters in vivo.