• Nuclear Medicine and Molecular Imaging
• /
• v.40 no.5
• /
• pp.263-270
• /
• 2006

Purpose: Several radioisotope-labeled thymidine derivatives such as $[^{11}C]$thymidine was developed to demonstrate cell proliferation in tumor. But it is difficult to track metabolism with $[^{11}C]$thymidine due to rapid in vivo degradation and its short physical half-life. 3'-$[^{18}F]$fluoro-3'-deoxythymidine ($[^{18}F]$FLT) was reported to have the longer half life of fluorine-18 and the lack of metabolic degradation in vivo. Here, we described the synthesis of the 3'-$[^{18}F]$fluoro-3'-deoxythymidine ($[^{18}F]$FLT) and compared with $([^{18}F]FET)\;and\;([^{18}F]FDG)$ in cultured 9L cell and obtained the biodistribution and PET image in 9L tumor hearing rats. Material and Methods: For the synthesis of $[^{18}F]$FLT, 3-N-tert-butoxycarbonyl-(5'-O-(4,4'-dimet hoxytriphenylmethyl)-2'-deoxy-3'-O-(4-nitrobenzenesulfonyl)-${\beta}$-D-threopentofuranosyl)thymine was used as a FLT precursor, on which the tert-butyloxycarbonyl group was introduced to protect N3-position and nitrobenzenesulfonyl group. Radiolabeling of nosyl substitued precursor with $^{18}F$ was performed in acetonitrile at $120^{\circ}C$ and deproteced with 0.5 N HCI. The cell uptake was measured in cultured 9L glioma cell. The biodistribution was evaluated in 9L tumor bearing rats after intravenous injection at 10 min, 30 min, 60 min and 120 min and obtained PET image 60 minutes after injection. Results: The radiochemical yield was about 20-30% and radiochemical purity was more than 95% after HPLC purification. Cellular uptake of $[^{18}F]$FLT was increased as time elapsed. At 120 min post-injection, the ratios of tumor/blood, tumor/muscle and tumor/brain were $1.61{\pm}0.34,\;1.70{\pm}0.30\;and\;9.33{\pm}2.22$, respectively. The 9L tumor was well visualized at 60 min post injection in PET image. Conclusion: The uptake of $[^{18}F]$FLT in tumor was higher than in normal brain and PET image of $[^{18}F]$FLT was acceptable. These results suggest the possibility of $[^{18}F]$FLT at an imaging agent for brain tumor.

• Korean Journal of Poultry Science
• /
• v.36 no.3
• /
• pp.207-213
• /
• 2009

Adenylosuccinate lyase (ADSL) deficiency is a disease of purine metabolism which affects patients both biochemicall and behaviorally. An obstacle of this purine nucleotide cycle(PNC) can be caused brain functional disorder and growth disorder. So ADSL deficiency, which is associated with sever mental retardation, autistic features and energy metabolism. This study was performed to identify SNP on ADSL gene in chicken. The nucleotides were observed as T to C ($7724^{th}$ nucleotide), C to T ($7732^{nd}$ nucleotide), G to T ($10108^{th}$ nucleotide), A to T ($10356^{th}$ nucleotide), G to A($10375^{th}$ nucleotide), A to C ($10402^{nd}$ nucleotide), A to T ($12716^{th}$ nucleotide), T to A ($12717^{th}$ nucleotide), C to T ($15491^{st}$ nucleotide), C to T ($15542^{nd}$ nucleotide) and C to T ($15550^{th}$ nucleotide). The nucleotide substitutions at $15542^{nd}$ and $15550^{th}$ (GeneBank accession no. AY665559) were found as missense mutation (alanine$\rightarrow$valine, proline$\rightarrow$serine, respectively). This study will be useful for farther researches for identifying association between these SNPs and energy metabolism in chicken. The C15550T SNP showed three genotypes, CC, CT, TT by digestion with the genotype TT had significantly faster the first lay day (150.0) than CT (162.0, P<0.05) and genotype TT (150.0, P<0.05) had significantly higher the egg production rate than CT (172.4, P<0.05). According to result of this study, a C15550T was found to have a significantly effect first lay day and mean egg production. It will be possible to use SNP marker on selecting chicken to improve important economic traits, which is the first lay day and mean egg production.

• Journal of the Korean Society of Food Science and Nutrition
• /
• v.37 no.10
• /
• pp.1238-1243
• /
• 2008

The root of Adenophora triphylla is widely used as traditional herbal medicine in Korea. We studied its effects on sodium nitroprusside (SNP) cytotoxicity and antioxidant genes expression in HepG2 cells. To study whether Adenophora triphylla ethylacetate extract (ATea) inhibited NO-induced cell death, HepG2 cells were preincubated for 24 hr with 50 and 100 $\mu$g/mL ATea followed by 24-hr exposure to 0.5 mM SNP (exogenous NO donor). No-induced cytotoxicity was inhibited by pretreatment of ATea, as assessed by mitochondrial dehydrogenase activity (MTT assay). We further investigated the effects of ATea on mRNA levels of various enzymes of the antioxidant system such as Cu, Zn superoxide dismutase (SOD 1), Mn SOD (SOD 2), glutathione peroxidase (GPx), catalase and several enzymes of the glutathione metabolism [glutathione reductase (GR), $\gamma$-glutamyl-cystein synthetase (GCS), glutathione-S-transferase (GST), $\gamma$-glutamyltranspeptidase ($\gamma$-GT), glucose-6-phosphate dehydrogenase (G6PD)] by RT-PCR. CAT, GCS, GR and G6PD mRNA levels were increased after treatment with ATea. The SOD 1, SOD 2, GPx, GST and $\gamma$-GT mRNA levels were not affected in ATea-treated HepG2 cells. We concluded that ATea have an indirect antioxidant effects, perhaps via induction of CAT, GCS, GR and G6PD.

• Nuclear Medicine and Molecular Imaging
• /
• v.41 no.4
• /
• pp.280-290
• /
• 2007

Purpose: Gender differences in personality are considered to have biological bases. In an attempt to understand the gender differences of personality on neurobiological bases, we conducted correlation analyses between regional brain glucose metabolism and temperament factors of personality in males and females. Materials and Methods: Thirty-six healthy right-handed volunteers (18 males, 33.8$\pm$17.6 y; 18 females, 36.2$\pm$20.4 y) underwent FDG PET at resting state. Three temperament factors of personality (novelty seeking (NS), harm avoidance (HA), reward dependence (RD)) were assessed using Cloninger's 240-item Temperament and Character Inventory (TCD within 10 days of FOG PET scan. Correlation between regional glucose metabolism and each temperament factor was tested using SPM2. Results: In males, a significant negative correlation between NS score and glucose metabolism was observed in the bilateral superior temporal gyri, the hippocampus and the insula, while it was found in the bilateral middle frontal gyri, the right superior temporal gyrus and the left cingulate cortex and the putamen in females. A positive HA correlation was found in the right midbrain and the left cingulate gyrus in males, but in the bilateral basal ganglia in females. A negative RD correlation was observed in the right middle frontal and the left middle temporal gyri in males, while the correlation was found in the bilateral middle frontal gyri and the right basal ganglia and the superior temporal gyrus in females. Conclusion: These data demonstrate different cortical and subcortical metabolic correlates of temperament factors of personality between males and females. These results may help understand biological substrate of gender differences in personality and susceptibility to neuropsychiatric illnesses.

• Archives of Pharmacal Research
• /
• v.28 no.3
• /
• pp.249-268
• /
• 2005

Drug metabolizing enzymes (DMEs) play central roles in the metabolism, elimination and detoxification of xenobiotics and drugs introduced into the human body. Most of the tissues and organs in our body are well equipped with diverse and various DMEs including phase I, phase II metabolizing enzymes and phase III transporters, which are present in abundance either at the basal unstimulated level, and/or are inducible at elevated level after exposure to xenobiotics. Recently, many important advances have been made in the mechanisms that regulate the expression of these drug metabolism genes. Various nuclear receptors including the aryl hydrocarbon receptor (AhR), orphan nuclear receptors, and nuclear factor-erythoroid 2 p45-related factor 2 (Nrf2) have been shown to be the key mediators of drug-induced changes in phase I, phase II metabolizing enzymes as well as phase III transporters involved in efflux mechanisms. For instance, the expression of CYP1 genes can be induced by AhR, which dimerizes with the AhR nuclear translocator (Arnt) , in response to many polycyclic aromatic hydrocarbon (PAHs). Similarly, the steroid family of orphan nuclear receptors, the constitutive androstane receptor (CAR) and pregnane X receptor (PXR), both heterodimerize with the ret-inoid X receptor (RXR), are shown to transcriptionally activate the promoters of CYP2B and CYP3A gene expression by xenobiotics such as phenobarbital-like compounds (CAR) and dexamethasone and rifampin-type of agents (PXR). The peroxisome proliferator activated receptor (PPAR), which is one of the first characterized members of the nuclear hormone receptor, also dimerizes with RXR and has been shown to be activated by lipid lowering agent fib rate-type of compounds leading to transcriptional activation of the promoters on CYP4A gene. CYP7A was recognized as the first target gene of the liver X receptor (LXR), in which the elimination of cholesterol depends on CYP7A. Farnesoid X receptor (FXR) was identified as a bile acid receptor, and its activation results in the inhibition of hepatic acid biosynthesis and increased transport of bile acids from intestinal lumen to the liver, and CYP7A is one of its target genes. The transcriptional activation by these receptors upon binding to the promoters located at the 5-flanking region of these GYP genes generally leads to the induction of their mRNA gene expression. The physiological and the pharmacological implications of common partner of RXR for CAR, PXR, PPAR, LXR and FXR receptors largely remain unknown and are under intense investigations. For the phase II DMEs, phase II gene inducers such as the phenolic compounds butylated hydroxyanisol (BHA), tert-butylhydroquinone (tBHQ), green tea polyphenol (GTP), (-)-epigallocatechin-3-gallate (EGCG) and the isothiocyanates (PEITC, sul­foraphane) generally appear to be electrophiles. They generally possess electrophilic-medi­ated stress response, resulting in the activation of bZIP transcription factors Nrf2 which dimerizes with Mafs and binds to the antioxidant/electrophile response element (ARE/EpRE) promoter, which is located in many phase II DMEs as well as many cellular defensive enzymes such as heme oxygenase-1 (HO-1), with the subsequent induction of the expression of these genes. Phase III transporters, for example, P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs), and organic anion transporting polypeptide 2 (OATP2) are expressed in many tissues such as the liver, intestine, kidney, and brain, and play crucial roles in drug absorption, distribution, and excretion. The orphan nuclear receptors PXR and GAR have been shown to be involved in the regulation of these transporters. Along with phase I and phase II enzyme induction, pretreatment with several kinds of inducers has been shown to alter the expression of phase III transporters, and alter the excretion of xenobiotics, which implies that phase III transporters may also be similarly regulated in a coordinated fashion, and provides an important mean to protect the body from xenobiotics insults. It appears that in general, exposure to phase I, phase II and phase III gene inducers may trigger cellular 'stress' response leading to the increase in their gene expression, which ultimately enhance the elimination and clearance of these xenobiotics and/or other 'cellular stresses' including harmful reactive intermediates such as reactive oxygen species (ROS), so that the body will remove the 'stress' expeditiously. Consequently, this homeostatic response of the body plays a central role in the protection of the body against 'environmental' insults such as those elicited by exposure to xenobiotics.

• Progress in Medical Physics
• /
• v.9 no.3
• /
• pp.163-173
• /
• 1998

Nuclear medicine emission computed tomography(ECT) can be very useful to diagnose early stage of neuronal diseases and to measure theraputic results objectively, if we can quantitate energy metabolism, blood flow, biochemical processes, or dopamine receptor and transporter using ECT. However, physical factors including attenuation, scatter, partial volume effect, noise, and reconstruction algorithm make it very difficult to quantitate independent of type of SPECT. In this study, we quantitated the effects of attenuation and scatter using brain SPECT and three-dimensional brain phantom with and without applying their correction methods. Dual energy window method was applied for scatter correction. The photopeak energy window and scatter energy window were set to 140ke${\pm}$10% and 119ke${\pm}$6% and 100% of scatter window data were subtracted from the photopeak window prior to reconstruction. The projection data were reconstructed using Butterworth filter with cutoff frequency of 0.95cycles/cm and order of 10. Attenuation correction was done by Chang's method with attenuation coefficients of 0.12/cm and 0.15/cm for the reconstruction data without scatter correction and with scatter correction, respectively. For quantitation, regions of interest (ROIs) were drawn on the three slices selected at the level of the basal ganglia. Without scatter correction, the ratios of ROI average values between basal ganglia and background with attenuation correction and without attenuation correction were 2.2 and 2.1, respectively. However, the ratios between basal ganglia and background were very similar for with and without attenuation correction. With scatter correction, the ratios of ROI average values between basal ganglia and background with attenuation correction and without attenuation correction were 2.69 and 2.64, respectively. These results indicate that the attenuation correction is necessary for the quantitation. When true ratios between basal ganglia and background were 6.58, 4.68, 1.86, the measured ratios with scatter and attenuation correction were 76%, 80%, 82% of their true ratios, respectively. The approximate 20% underestimation could be partially due to the effect of partial volume and reconstruction algorithm which we have not investigated in this study, and partially due to imperfect scatter and attenuation correction methods that we have applied in consideration of clinical applications.

• The Korean Journal of Nuclear Medicine
• /
• v.18 no.2
• /
• pp.17-23
• /
• 1984

For nearly a century it has been known that chemical activity accompanies mental activity, but only recently has it been possible to begin to examine its exact nature. Positron-emitting radioactive tracers have made it possible to study the chemistry of the human mind in health and disease, using chiefly cyclotron-produced radionuclides, carbon-11, fluorine-18 and oxygen-15. It is now well established that measurable increases in regional cerebral blood flow, glucose and oxygen metabolism accompany the mental functions of perception, cognition, emotion and motion. On May 25, 1983 the first imaging of a neuroreceptor in the human brain was accomplished with carbon-11 methyl spiperone, a ligand that binds preferentially to dopamine-2 receptors, 80% of which are located in the caudate nucleus and putamen. Quantitative imaging of serotonin-2, opiate, benzodiazapine and muscarinic cholinergic receptors has subsequently been accomplished. In studies of normal men and women, it has been found that dopamine and serotonin receptor activity decreases dramatically with age, such a decrease being more pronounced in men than in women and greater in the case of dopamine receptors than serotonin-2 receptors. Preliminary studies in patients with neuropsychiatric disorders suggests that dopamine-2 receptor activity is diminished in the caudate nucleus of patients with Huntington's disease. Positron tomography permits quantitative assay of picomolar quantities of neuro-receptors within the living human brain. Studies of patients with Parkinson's disease, Alzheimer's disease, depression, anxiety, schizophrenia, acute and chronic pain states and drug addiction are now in progress. The growth of any scientific field is based on a paradigm or set of ideas that the community of scientists accepts. The unifying principle of nuclear medicine is the tracer principle applied to the study of human disease. Nineteen hundred and sixty-three was a landmark year in which technetium-99m and the Anger camera combined to move the field from its latent stage into a second stage characterized by exponential growth within the framework of the paradigm. The third stage, characterized by gradually declining growth, began in 1973. Faced with competing advances, such as computed tomography and ultrasonography, proponents and participants in the field of nuclear medicine began to search for greener pastures or to pursue narrow sub-specialties. Research became characterized by refinements of existing techniques. In 1983 nuclear medicine experienced what could be a profound change. A new paradigm was born when it was demonstrated that, despite their extremely low chemical concentrations, in the picomolar range, it was possible to image and quantify the distribution of receptors in the human body. Thus, nuclear medicine was able to move beyond physiology into biochemistry and pharmacology. Fundamental to the science of pharmacology is the concept that many drugs and endogenous substances, such as neurotransmitters, react with specific macromolecules that mediate their pharmacologic actions. Such receptors are usually identified in the study of excised tissues, cells or cell membranes, or in autoradiographic studies in animals. The first imaging and quantification of a neuroreceptor in a living human being was performed on May 25, 1983 and reported in the September 23, 1983 issue of SCIENCE. The study involved the development and use of carbon-11 N-methyl spiperone (NMSP), a drug with a high affinity for dopamine receptors. Since then, studies of dopamine and serotonin receptors have been carried out in over 100 normal persons or patients with various neuropsychiatric disorders. Exactly one year later, the first imaging of opitate receptors in a living human being was performed [1].

• Journal of Biomedical Engineering Research
• /
• v.19 no.5
• /
• pp.455-468
• /
• 1998

For the objective interpretation of cerebral metabolic patterns in epilepsy patients, we developed computer-aided classifier using artificial neural network. We studied interictal brain FDG PET scans of 257 epilepsy patients who were diagnosed as normal(n=64), L TLE (n=112), or R TLE (n=81) by visual interpretation. Automatically segmented volume of interest (VOI) was used to reliably extract the features representing patterns of cerebral metabolism. All images were spatially normalized to MNI standard PET template and smoothed with 16mm FWHM Gaussian kernel using SPM96. Mean count in cerebral region was normalized. The VOls for 34 cerebral regions were previously defined on the standard template and 17 different counts of mirrored regions to hemispheric midline were extracted from spatially normalized images. A three-layer feed-forward error back-propagation neural network classifier with 7 input nodes and 3 output nodes was used. The network was trained to interpret metabolic patterns and produce identical diagnoses with those of expert viewers. The performance of the neural network was optimized by testing with 5~40 nodes in hidden layer. Randomly selected 40 images from each group were used to train the network and the remainders were used to test the learned network. The optimized neural network gave a maximum agreement rate of 80.3% with expert viewers. It used 20 hidden nodes and was trained for 1508 epochs. Also, neural network gave agreement rates of 75~80% with 10 or 30 nodes in hidden layer. We conclude that artificial neural network performed as well as human experts and could be potentially useful as clinical decision support tool for the localization of epileptogenic zones.

• The Korean Journal of Physiology
• /
• v.2 no.1
• /
• pp.23-30
• /
• 1968

Tissue homogenates of 12 kinds of human cancer tissues were incubated separately in medium containing $C^{14}-1-glucose$ and $C^{14}-6-glucose$ as a substrate in order to observe the oxidative pathway of glucose in the tumor tissues. At the end of 3 hours incubation in the Dubnuff metabolic shaking incubator, respiratory $CO_2$ samples trapped by alkaling which was placed in the center well of incubation flask were analysed for total $CO_2$ production rates and their radioactivities. The tissue homogenate samples after incubation were analyzed for their concentrations of glucose, lactate and pyruvate. Calculations were made on the glucose consumption rate and accumulation rates of lactate and pyruvate. Fractionation of oxidative pathway of glucose was carried out by calculating $C^{14}O_2 yields from C-1 and C-6 carbon of glucose. The following results were obtained. 1. In 12 kinds of human cancer, total $CO_2$ production rates were less than $8{\mu}M/gm$ except 2 cases. These lower values impressed that oxidative metabolism in the tumor tissues generally inhibited as compared with that in normal tissues. On the other hand, fractions of $CO_2$ derived from glucose to total $CO_2$ production rates (RSA) were less than 10% in every case. These facts showed that oxidation of glucose into $CO_2$ was remarkably inhibited in the tumor tissues. 2. Factions of glucose disappeared into $CO_2\;(RGD_{CO_2})$, lactate $(RGD_L)$, pyruvate $(RGD_P)$ to glucose consumption rates were as follows. $RGD_{CO_2}$ were less than 2% in cases of in this experiment and $RGD_L$ showed more than 5% except in 2 cases. These facts showed that anaerobic degradation of glucose into 3 carbon compounds was easily proceeded but further degradation into $CO_2$ via the TCA cycle was greatly inhibited resulting in accumulation of lactate. There are large variation in values of $RGD_P$ in different kinds of tumor tissue but relatively higher values in $RGD_{CO_2}$ were obtained in the tumor tissues as compared with those of normal tissues. 3. The oxidative pathway of glucose in tumor tissues were analyzed from the values of RSA which were obtained in $C^{14}-1\;and\;C^{14}-6-glucose$ incubation experiments. It was found that 3% of $CO_2$ derived from glucose were oxidized via the principal EMP-TCA cycle and the remainder were via alternate pathway such as HMP in the liver cancer and values in other cancer tissues were as follows; 4% in the tongue cancer, 6% in the colon cancer, 6% in the lung cancer, 9% in the stomach cancer, 11% in the ovarian cancer, 12% in the neck tumor, 22% in the uterine cancer, 22% in the bladder tumor, 32% in the spindle cell sarcoma and 65% in the brain tumor. These values except later 2 cases showed less than 30% which is the lowest value among the normal tissues. Even in the brain tumor in which showed highest value in the tumor group. It is reasonable to suppose that this fraction was remarkably decreased because values in normal brain tissue was more than 90%. From the above data, it was concluded that in tumor tissues, oxidation of glucose via TCA cycle was greatly inhibited but correlation between degree of inhibited oxidation of glucose via TCA cycle and malignancy of tumor were not clarified in this experiments.

• Journal of Life Science
• /
• v.20 no.2
• /
• pp.260-268
• /
• 2010

The lactate dehydrogenase (EC 1.1.1.27, LDH) isozymes in tissues from Channa argus were purified and characterized by biochemical, immunochemical and kinetic methods. The activity of LDH in skeletal muscle was the highest at 380.4 units and those in heart, eye and brain tissues were 13.4, 3,5 and 5.4 units, respectively. Citrate synthase (EC 4.1.3.7, CS) activity in heart tissue was the highest at 20.7 units. LDH/CS in skeletal muscle, heart, eye and brain tissues were 172.9, 0.6, 0.32 and 0.47. Protein concentration in skeletal muscle tissue was 14.7 mg/g and specific activities of LDH in skeletal muscle, heart, eye and brain tissues were 25.88, 0.79, 0.31 and 1.38 units/mg, respectively. Therefore, skeletal muscle tissue was anaerobic and heart tissue was aerobic. The LDH isozymes in tissues were identified by polyacrylamide gel electrophoresis, immunoprecipitation and Western blot with antiserum against $A_4$, $B_4$, and eye-specific $C_4$. LDH $A_4$, $A_3B$, $A_2B_2$. $AB_3$ and $B_4$ isozymes were detected in every tissue, $C_4$, $AC_3$, $A_2C_2$ and $A_3C$ were detected in eye tissue, and $A_3C$ was found in brain tissue. LDH $A_4$, $A_3B$, $A_2B_2$, $AB_3$, $B_4$, eye-specific $C_4$ isozymes were purified by affinity chromatography and Preparative PAGE Cells. The LDH $A_4$ isozyme was purified in the fraction from elution with $NAD^+$ containing buffer of affinity chromatography. Eye-specific $C_4$ isozyme was eluted right after $A_4$, after which $B_4$ isozyme was eluted with plain buffer. As a result, one part of molecular structures in $A_4$, $B_4$ and eye-specific $C_4$ were similar, but were different from each other in $B_4$ and $C_4$. Therefore the subunit A may be conservative in evolution, and the evolution of subunit B seems to be faster than that of subunit A. The activity of LDH $A_4$, $A_2B_2$, $B_4$, and eye-specific $C_4$ isozymes remained at 39.98, 21.28, 19.67 and 16.87% as a result of the inhibition by 10 mM of pyruvate, so the degree of inhibition was very high. The $Km^{PYR}$ values were 0.17, 0.27 and 0.133 mM in $A_4$, $B_4$ and eye-specific $C_4$ isozymes, respectively. The optimum pH of LDH $A_4$, $B_4$, eye-specific $C_4$, $A_2B_2$, $A_3B$, and $AB_3$ were pH 6.5, pH 8.5, pH 5.5, pH 6.0-6.5, pH 5.0 and pH 7.5. The $A_4$ and heterotetramer isozymes stabilized a broad range of pH. Especially, LDH activities in skeletal muscle tissue were high, resulting in a high degree of muscle activity.LDH metabolism in eye tissue seems to be converted faster from pyruvate to lactate by eye-specific $C_4$ isozyme as eye-specific $C_4$ have the highest affinity for pyruvate, and right after the conversion, oxidation of lactate was induced by $A_4$ isozyme. It was found that expression of Ldh-C, affinity to substrate and reaction time of $C_4$ isozyme were different according to the ecological environmental and feeding capturing patterns.