• Biomolecules & Therapeutics
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• v.20 no.3
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• pp.245-255
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• 2012

Amyloid-${\beta}$ peptide ($A{\beta}$) is still best known as a molecule to cause Alzheimer's disease (AD) through accumulation and deposition within the frontal cortex and hippocampus in the brain. Thus, strategies on developing AD drugs have been focused on the reduction of $A{\beta}$ in the brain. Since accumulation of $A{\beta}$ depends on the rate of its synthesis and clearance, the metabolic pathway of $A{\beta}$ in the brain and the whole body should be carefully explored for AD research. Although the synthetic pathway of $A{\beta}$ is equally important, we summarize primarily the clearance pathway in this paper because the former has been extensively reviewed in previous studies. The clearance of $A{\beta}$ from the brain is accomplished by several mechanisms which include non-enzymatic and enzymatic pathways. Nonenzymatic pathway includes interstitial fluid drainage, uptake by microglial phagocytosis, and transport across the blood vessel walls into the circulation. Multiple $A{\beta}$-degrading enzymes (ADE) implicated in the clearance process have been identified, which include neprilysin, insulin-degrading enzyme, matrix metalloproteinase-9, glutamate carboxypeptidase II and others. A series of studies on $A{\beta}$ clearance mechanism provide new insight into the pathogenesis of AD at the molecular level and suggest a new target for the development of novel therapeutics.

• Biomolecules & Therapeutics
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• v.27 no.3
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• pp.283-289
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• 2019

Brain aging induces neuropsychological changes, such as decreased memory capacity, language ability, and attention; and is also associated with neurodegenerative diseases. However, most of the studies on brain aging are focused on neurons, while senescence in astrocytes has received less attention. Astrocytes constitute the majority of cell types in the brain and perform various functions in the brain such as supporting brain structures, regulating blood-brain barrier permeability, transmitter uptake and regulation, and immunity modulation. Recent studies have shown that SIRT1 and SIRT2 play certain roles in cellular senescence in peripheral systems. Both SIRT1 and SIRT2 inhibitors delay tumor growth in vivo without significant general toxicity. In this study, we investigated the role of tenovin-1, an inhibitor of SIRT1 and SIRT2, on rat primary astrocytes where we observed senescence and other functional changes. Cellular senescence usually is characterized by irreversible cell cycle arrest and induces senescence- associated ${\beta}$-galactosidase (SA-${\beta}$-gal) activity. Tenovin-1-treated astrocytes showed increased SA-${\beta}$-gal-positive cell number, senescence-associated secretory phenotypes, including IL-6 and IL-$1{\beta}$, and cell cycle-related proteins like phospho-histone H3 and CDK2. Along with the molecular changes, tenovin-1 impaired the wound-healing activity of cultured primary astrocytes. These data suggest that tenovin-1 can induce cellular senescence in astrocytes possibly by inhibiting SIRT1 and SIRT2, which may play particular roles in brain aging and neurodegenerative conditions.

• Bulletin of the Korean Chemical Society
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• v.32 no.4
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• pp.1282-1292
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• 2011

The biotin-attached G8 molecular transporter (5) was synthesized and used together with quantum dots in preparing the complexes (QD-MT). The QD-MT complexes were studied in terms of the cellular uptake and the internalization mechanism in live HeLa cells with the aid of various known endocytosis inhibitors. It has been concluded that the QD-MT complex is internalized largely by macropinocytosis. The mouse tissue distribution of the QD-MT complex by i.p. and i.v. routes showed some organ selectivity and a good ability to cross the BBB.

• Journal of Korean Neurosurgical Society
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• v.63 no.5
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• pp.649-656
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• 2020

Objective : Unclear mental state is one of the major factors contributing to diagnostic failure of occult skeletal trauma in patients with traumatic brain injury (TBI). The aim of this study was to evaluate the overlooked co-occurring skeletal trauma through whole body bone scan (WBBS) in TBI. Methods : A retrospective study of 547 TBI patients admitted between 2015 and 2017 was performed to investigate their cooccurring skeletal injuries detected by WBBS. The patients were divided into three groups based on the timing of suspecting skeletal trauma confirmed : 1) before WBBS (pre-WBBS); 2) after the routine WBBS (post-WBBS) with good mental state and no initial musculoskeletal complaints; and 3) after the routine WBBS with poor mental state (poor MS). The skeletal trauma detected by WBBS was classified into six skeletal categories : spine, upper and lower extremities, pelvis, chest wall, and clavicles. The skeletal injuries identified by WBBS were confirmed to be simple contusion or fractures by other imaging modalities such as X-ray or computed tomography (CT) scans. Of the six categorizations of skeletal trauma detected as hot uptake lesions in WBBS, the lesions of spine, upper and lower extremities were further statistically analyzed to calculate the incidence rates of actual fractures (AF) and actual surgery (AS) cases over the total number of hot uptake lesions in WBBS. Results : Of 547 patients with TBI, 112 patients (20.4 %) were presented with TBI alone. Four hundred and thirty-five patients with TBI had co-occurring skeletal injuries confirmed by WBBS. The incidences were as follows : chest wall (27.4%), spine (22.9%), lower extremities (20.2%), upper extremities (13.5%), pelvis (9.4%), and clavicles (6.3%). It is notable that relatively larger number of positive hot uptakes were observed in the groups of post-WBBS and poor MS. The percentage of post-WBBS group over the total hot uptake lesions in upper and lower extremities, and spines were 51.0%, 43.8%, and 41.7%, respectively, while their percentages of AS were 2.73%, 1.1%, and 0%, respectively. The percentages of poor MS group in the upper and lower extremities, and spines were 10.4%, 17.4%, and 7.8%, respectively, while their percentages of AS were 26.7%, 14.2%, and 11.1%, respectively. There was a statistical difference in the percentage of AS between the groups of post-WBBS and poor MS (p=0.000). Conclusion : WBBS is a potential diagnostic tool in understanding the skeletal conditions of patients with head injuries which may be undetected during the initial assessment.

• The Korean Journal of Nuclear Medicine
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• v.29 no.1
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• pp.22-30
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• 1995

To predict preoperatively the safety of permanent occlusion of an internal carotid artery with $^{99m}Tc$-HMPAO brain single photon emission computed tomography(SPECT) from an objective point of view, Twenty-four patients underwent balloon test occlusion (BTO) of the internal carotid arteries because of neck and skull base tumors. The authors assessed the uptake of both middle cerebral artery territories before and during BTO with $^{99m}Tc$-HMPAO brain SPECT using semiquantitative analysis method and compared the results with other factors(neurologic examination, arterial stump pressure and electroenceph-alogram). Nineteen patients had not experienced neurological deteriorating or any problem during BTO. Their comparative uptakes of the middle cerebral artery territories were 95 to 101% of the pre-BTO state. The remaining five patients showed severe neurologic symptoms such as transient hemiplegia and unconsciousness. Their comparative uptake of the middle cerebral artery territories were 77 to 85% of the pre-BTO state, and were well matched with other factors. $^{99m}Tc$-HMPAO brain SPECT before and during BTO seems to be a simple and objective method for prediction of permanent neurologic deficits when the comparative uptake of middle cerebral artery territories during BTO is lower than 85% of that before BTO.

• The Korean Journal of Nuclear Medicine Technology
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• v.28 no.1
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• pp.41-47
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• 2024

Purpose: ¹⁸F-FET, a radiopharmaceutical based on a Tyrosine amino acid derivative using the Sodium-Potassium Pump-independent Transporter (System L) for non-invasive evaluation of primary, recurrent, and metastatic brain tumors, exhibits distinct characteristics. Unlike the widely absorbed ¹⁸F-FDG in both tumor and normal brain tissues, ¹⁸F-FET demonstrates specific uptake only in tumor tissue while almost negligible uptake in normal brain tissue. This study aims to compare and evaluate the usefulness of ¹⁸F-FDG and ¹⁸F-FET Brain PET/CT quantitative analysis in brain tumor diagnosis. Materials and Methods: In 46 patients diagnosed with brain gliomas (High Grade: 34, Low Grade: 12), Brain PET/CT scans were performed at 40 minutes after ¹⁸F-FDG injection and at 20 minutes (early) and 80 minutes (delay) after ¹⁸F-FET injection. SUV_max and SUV_peak of tumor areas corresponding to MRI images were measured in each scan, and the SUV_max-to-SUV_peak ratio, an indicator of tumor prognosis, was calculated. Differences in SUV_max, SUV_peak, and SUV_max-to-SUV_peak ratio between ¹⁸F-FDG and ¹⁸F-FET early/delay scans were statistically verified using SPSS (ver.28) package program. Results: SUV_max values were 3.72±1.36 for ¹⁸F-FDG, 4.59±1.55 for ¹⁸F-FET early, and 4.12±1.36 for ¹⁸F-FET delay scans. The highest SUV_max was observed in ¹⁸F-FET early scans, particularly in HG tumors (4.85±1.44), showing a slightly more significant difference (P<0.0001). SUV_peak values were 3.33±1.13 for ¹⁸F-FDG, 3.04±1.11 for ¹⁸F-FET early, and 2.80±0.96 for ¹⁸F-FET delay scans. The highest SUV_peak was in ¹⁸F-FDG scans, while the lowest was in ¹⁸F-FET delay scans, with a more significant difference in HG tumors (P<0.001). SUV_max-to-SUV_peak ratio values were 1.11±0.09 for ¹⁸F-FDG, 1.54±0.22 for ¹⁸F-FET early, and 1.48±0.17 for ¹⁸F-FET delay scans. This ratio was higher in ¹⁸F-FET scans for both HG and LG tumors (P<0.0001), but there was no statistically significant difference between ¹⁸F-FET early and delay scans. Conclusion: This study confirms the usefulness of early and delay scans in ¹⁸F-FET Brain PET/CT examinations, particularly demonstrating the changes in objective quantitative metrics such as SUV_max, SUV_peak, and introducing the SUV_max-to-SUV_peak ratio as a new evaluation metric based on the degree of tumor malignancy. This is expected to further contributions to the quantitative analysis of Brain PET/CT images.

• Clinical and Experimental Pediatrics
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• v.59 no.sup1
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• pp.139-144
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• 2016

Encephalocraniocutaneous lipomatosis (ECCL) is a rare neurocutaneous syndrome that affects ectomesodermal tissues (skin, eyes, adipose tissue, and brain). The neurologic manifestations associated with ECCL are various including seizures. However, ECCL patients very rarely develop brain tumors that originate from the neuroepithelium. This is the first described case of ECCL in combination with dysembryoplastic neuroepithelial tumor (DNET) that presented with intractable seizures. A 7-year-old girl was admitted to our center because of ECCL and associated uncontrolled seizures. She was born with right anophthalmia and lipomatosis in the right temporal area and endured right temporal lipoma excision at 3 years of age. Seizures began when she was 3 years old, but did not respond to multiple antiepileptic drugs. Brain magnetic resonance (MR) imaging performed at 8 and 10 years of age revealed an interval increase of multifocal hyperintense lesions in the basal ganglia, thalamus, cerebellum, periventricular white matter, and, especially, the right temporal area. A nodular mass near the right hippocampus demonstrated the absence of N-acetylaspartate decrease on brain MR spectroscopy and mildly increased methionine uptake on brain positron emission tomography, suggesting low-grade tumor. Twenty-four-hour video electroencephalographic monitoring also indicated seizures originating from the right temporal area. Right temporal lobectomy was performed without complications, and the nodular lesion was pathologically identified as DNET. The patient has been seizure-free for 14 months since surgery. Although ECCL-associated brain tumors are very rare, careful follow-up imaging and surgical resection is recommended for patients with intractable seizures.

• Biomolecules & Therapeutics
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• v.20 no.2
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• pp.152-157
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• 2012

Docosahexaenoic acid (DHA) is the major polyunsaturated fatty acid (PUFA) in the brain and a structural component of neuronal membranes. Changes in DHA content of neuronal membranes lead to functional changes in the activity of receptors and other proteins which might be associated with synaptic function. Accumulating evidence suggests the beneficial effects of dietary DHA supplementation on neurotransmission. This article reviews the beneficial effects of DHA on the brain; uptake, incorporation and release of DHA at synapses, effects of DHA on synapses, effects of DHA on neurotransmitters, DHA metabolites, and changes in DHA with age. Further studies to better understand the metabolome of DHA could result in more effective use of this molecule for treatment of neurodegenerative or neuropsychiatric diseases.

• Journal of Pharmaceutical Investigation
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• v.29 no.2
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• pp.87-92
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• 1999

Drug delivery to the brain may be achieved by producing chimeric peptide, attaching the drug to protein 'vectors' which are transported into the brain from the blood by a receptor-mediated transcytosis through the blood-brain barrier (BBB). Since the BBB expresses high concentrations of transferrin receptor, and it was reported that anti-transferrin receptor mouse monoclonal antibody (OX26) undergoes transcytosis through the BBB, it is logical to assume that a drug delivery system via transferrin receptor-mediated transcytosis is a promising strategy. In the present study, therefore, we tested feasibility of several OX26 based vectors for the brain delivery of a model drug. Avidin-based delivery vectors such as OX26-streptavidin (OX26-SA), OX26-neutralite avidin (OX26-NLA) were chemically synthesized vectors and OX26 immunoglobulin G 3 type $C_{H}3$ fusion avidin $(OX26\;IgG3C_H3-AV)$ was genetically engineered. To improve the efficiency of producing chimeric peptide, we used avidin-biotin technology. Pharmacokinetics of $[^3H]biotin$ bound to OX26-SA, OX26-NLA and $OX26\;IgG3C_H3-AV$ was determined by intravenous injection technique, and their stabilities in plasma were analyzed using HPLC. The brain delivery of $[^3H]biotin$ bound to OX26-SA, OX26-NLA and OX26\;$IgG3C_{H}3-AV$ (expressed as %ID/g brain) was $0.22{\pm}0.01$, $0.18{\pm}0.01$ and $0.25{\pm}0.09$, respectively. The areas under the plasma concentration versus time curve (AUC) for OX26-SA, OX26-NLA, $OX26\;IgG3C_H3-AV$ from time zero to 60 min were $209{\pm}10$, $195{\pm}9$, $134{\pm}29\;%ID\;min/ml$ respectively and their total clearances $(CL_{tot})$ were $1.00{\pm}0.09$, $1.08{\pm}0.07$ and $1.54{\pm}0.29\;ml/min/kg$, espectively. These results showed that these vectors possess preferable pharmaceutical (e.g., resonable stability) and pharmacokinetics (e.g., significant brain uptake and enhanced AUC) for brain delivery. Therefore, these vectors may be broadly useful in the brain delivery of drugs that are not transported into the brain to a significant extent.

• The Korean Journal of Physiology and Pharmacology
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• v.9 no.6
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• pp.363-369
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• 2005

It is imperative to analyse brain injuries directly in real time, so as to find effective therapeutic compounds to protect brain injuries by stress. We established a system which could elucidate the real time $Ca^{2+}$ dynamics in an organotypic cultured hippocampal slice by the insults of artificial stress hormone, dexamethasone. The real time $Ca^{2+}$ dynamics could continuously be detected in cornus ammonis 3 (CA3) of the organotypic hippocampus for 8 hours under confocal microscopy. When dexamethasone concentration was increased, the $Ca^{2+}$ was also increased in a dose dependent manner at $1{\sim}100{\mu}M$ concentrations. Moreover, when the organotypic cultured hippocampal slice was treated with a glutamate receptor antagonist together with dexamethasone, the real time $Ca^{2+}$ dynamics were decreased. Furthermore, we confirmed by PI uptake study that glutamate receptor antagonist reduced the hippocampal tissue damage caused by dexamethasone treatment. Therefore, our new calcium ion dynamics system in organotypic cultured hippocampal slice after dexamethasone treatment could provide real time analysis method for investigation of brain injuries by stress.