• Journal of Physiology & Pathology in Korean Medicine
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• v.32 no.3
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• pp.157-164
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• 2018

This study was designed to investigate the mechanism of the synergistic anticancer effect of Astragalus membranaceus (AM) and Adenophora triphylla var. japonica (AT) in H1299 human lung carcinoma cells. A combined treatment of ethanol extract of AM (EAM) and AT (EAT) explosively increased the reactive oxygen species (ROS) generation in H1299 cells compared to the single treatment of each of them. Co-treatment of N-acetyl-L-cysteine (NAC) with EAM and EAT markedly enhanced the cell viability and suppressed apoptosis in H1299 cells, suggesting that ROS generation contributed to the anticancer effect of EAM and EAT. Interestingly, the combined treatment of EAM and EAT down-regulated p-AKT in H1299 cells, which was abrogated by NAC treatment. These results clearly indicated that ROS generation mediated the inactivation of AKT. Co-treatment of LY294002 with EAM and EAT significantly reduced the cell viability at a concentration which EAM and EAT didn't show any cytotoxicity. In addition, the recovery of cell viability by co-treatment of NAC with EAM and EAT was quite reversed by LY294002 treatment, which confirmed that the inactivation of AKT played a pivotal role in ROS-mediated apoptosis. Taken together, our results demonstrated that the synergistic anticancer effect of EAM and EAT was mediated by ROS generation and inactivation of AKT. We provide a valuable preclinical data for the development of more effective combination of AM and AT to treat lung cancer.

• Biomolecules & Therapeutics
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• v.24 no.3
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• pp.207-243
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• 2016

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication impairments, as well as repetitive and restrictive behaviors. The phenotypic heterogeneity of ASD has made it overwhelmingly difficult to determine the exact etiology and pathophysiology underlying the core symptoms, which are often accompanied by comorbidities such as hyperactivity, seizures, and sensorimotor abnormalities. To our benefit, the advent of animal models has allowed us to assess and test diverse risk factors of ASD, both genetic and environmental, and measure their contribution to the manifestation of autistic symptoms. At a broader scale, rodent models have helped consolidate molecular pathways and unify the neurophysiological mechanisms underlying each one of the various etiologies. This approach will potentially enable the stratification of ASD into clinical, molecular, and neurophenotypic subgroups, further proving their translational utility. It is henceforth paramount to establish a common ground of mechanistic theories from complementing results in preclinical research. In this review, we cluster the ASD animal models into lesion and genetic models and further classify them based on the corresponding environmental, epigenetic and genetic factors. Finally, we summarize the symptoms and neuropathological highlights for each model and make critical comparisons that elucidate their clinical and neurobiological relevance.

• Korean Journal of Clinical Pharmacy
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• v.14 no.2
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• pp.61-70
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• 2004

Heptaplatin is a new platinum derivative with antitumor activity against gastric cancer. Preclinical studies showed that it is less toxic than other platinum analogues. The purpose of this study is to evaluate the efficacy and toxicity of the combination therapy of heptaplatin and 5-fluorouracil in Korean advanced gastric cancer patients. This study was investigated retrospectively. The patients group consisted of 65 advanced gastric cancer patients with no prior radiotherapy. All patients received heptaplatin $400\;mg/m^2$ by 2-3 hour infusion on Day 1 and 5-FU $1000\;mg/m^2by 12-24 hour continuous infusion for 5 days. After the first cycle, subsequent doses were adjusted according to the toxicity. Courses were repeated every 28 days. As results, objective response occurred in 16 patients $(24.6\%)$. Two were complete and 14 were partial response. Median progression free survival was 32 weeks with $29\%$ of patients progression free at 1 year. The most common hematologic toxicity was anemia. Grade 3 or 4 anemia was seen at $2.7\%$ of treatment cycles. Grade 3 or higher leucopenia was seen at $1.2\%$ of cycles. Grade 3 or 4 neutropenia and thrombocytopenia occurred at $6.1\%\;and\;1.5\%$ of cycles, respectively. The most common nonhematologic toxicity was proteinuria. Though no patients experienced grade 3 or 4 proteinuria, proteinuria was a considerable factor for this chemotherapy. Grade 3 or higher gastrointestinal toxicities were nausea and vomiting ($4.6\%$ of patients) and diarrhea ($1.5\%$ of patients). Grade 2 renal toxicity with elevation of serum creatinine was seen in $0.3\%$ of cycles, which is less than that of other platinum analogues. This study showed that combination therapy of heptaplatin and 5-FU have modest antitumor activity against advanced gastric cancer without severe renal toxicity.

• Nutrition Research and Practice
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• v.14 no.2
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• pp.95-101
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• 2020

BACKGROUND/OBJECTIVES: Folate plays a critical role in DNA synthesis and methylation. Intracellular folate homeostasis is maintained by the enzymes folylpolyglutamate synthase (FPGS) and γ-glutamyl hydrolase (GGH). FPGS adds glutamate residues to folate upon its entry into the cell through a process known as polyglutamylation to enhance folate retention in the cell and to maintain a steady supply of utilizable folate derivatives for folate-dependent enzyme reactions. Thereafter, GGH catalyzes the hydrolysis of polyglutamylated folate into monoglutamylated folate, which can subsequently be exported from the cell. The objective of this review is to summarize the scientific evidence available on the effects of intracellular folate homeostasis-associated enzymes on cancer chemotherapy. METHODS: This review discusses the effects of FPGS and GGH on chemosensitivity to cancer chemotherapeutic agents such as antifolates, such as methotrexate, and 5-fluorouracil. RESULTS AND DISCUSSION: Polyglutamylated (anti)folates are better substrates for intracellular folate-dependent enzymes and retained for longer within cells. In addition to polyglutamylation of (anti)folates, FPGS and GGH modulate intracellular folate concentrations, which are an important determinant of chemosensitivity of cancer cells toward chemotherapeutic agents. Therefore, FPGS and GGH affect chemosensitivity to antifolates and 5-fluorouracil by altering intracellular retention status of antifolates and folate cofactors such as 5,10-methylenetetrahydrofolate, subsequently influencing the cytotoxic effects of 5-fluorouracil, respectively. Generally, high FPGS and/or low GGH activity is associated with increased chemosensitivity of cancer cells to methotrexate and 5-fluorouracil, while low FPGS and/or high GGH activity seems to correspond to resistance to these drugs. Further preclinical and clinical studies elucidating the pharmocogenetic ramifications of these enzyme-induced changes are warranted to provide a framework for developing rational, effective, safe, and customized chemotherapeutic practices.

• Radiation Oncology Journal
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• v.8 no.2
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• pp.151-154
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• 1990

The acute effects of variable dos rates to total body irradiation (TBI) were investigaed with 600 cGy of single exposure in the mice as a preclinical model. Total 80 mice (ICR) were used. Twenty of which sewed as controls, receiving no irradiation. All irradiated mice showed a universal decline in their weight and white blood cell count. The degree of weight loss and leukopenia were similar at 3 different dos rate but slightly prominent with 15 cGy/minute group. The degree of recovery among the groups showed no dose rate dependence. Our results suggest that TBI with 15 cGy/mimute may be applicable for clinical therapy with careful evaluation of patient's condition.

• Korean Journal of Clinical Laboratory Science
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• v.43 no.4
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• pp.179-187
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• 2011

Animal models are important tools in thrombosis research and preclinical drug development. In recent studies, ferric chloride ($FeCl_3$) has been widely used to induce arterial thrombosis in a variety of species. The purpose of this study was to find an optimal concentration of $FeCl_3$ and validate this model suited better for thrombosis research. A small piece of filter paper, soaked in $FeCl_3$ solution (10, 20 or 35%, v/v, in distilled water) was topically applied on the carotid artery of SD rats to measure the time to occlusion (TTO) and thrombus weight (TW) to ascertain 35%, as an optimal $FeCl_3$ concentration ($8.63{\pm}0.92min$; p =0.000, $0.79{\pm}0.03mg/mm$; p =0.000, respectively). To validate this experimental model, Ginkgo biloba special extract EGb761 (5, 10 or 30 mg/kg) as a reference agent administered by peritoneal route for 1h prior to the induction of thrombosis, showed significantly delayed TTO in a dose dependent manner ($18.50{\pm}2.17$, $29.17{\pm}1.83$, and $38.00{\pm}1.79min$, respectively) and significantly reduced TW and repaired collagen fibre in the injured vessel compare to vehicle group. Our results provide a simple, reproducible and well controlled in vivo screening system to induce thrombosis in rats by the topical application of 35% $FeCl_3$ to assess the efficacy of the new anti-thrombotic agents.

• Journal of Microbiology and Biotechnology
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• v.23 no.8
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• pp.1176-1184
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• 2013

Anti-hepatocyte growth factor (anti-HGF) monoclonal antibodies (mAbs) are potential therapeutics against various cancers. Screening for high-producer clones is a time-consuming and complex process and is a major hurdle in the development of therapeutic mAbs. Here, we describe an efficient approach that allows the selection of high-producer Chinese hamster ovary (CHO) cell lines producing the novel anti-HGF mAb SFN68, which was generated previously by immunizing HGF bound to its receptor c-Met. We selected an SFN68-producing parental cell line via transfection of the dihydrofolate reductase-deficient CHO cell line DG44, which was preadapted to serum-free suspension culture, with an SFN68-expression vector. Subsequent gene amplification via multiple passages of the parental cell line in a methotrexate-containing medium over 4 weeks, followed by clonal isolation, enabled us to isolate two cell lines, 2F7 and 2H4, with 3-fold higher specific productivity. We also screened 72 different media formulated with diverse feed and basal media to develop a suboptimized medium. In the established suboptimized medium, the highest anti-HGF mAb yields of the 2F7 and 2H4 clones were 842 and 861 mg/l, respectively, which were about 10.5-fold higher than that of the parental cell line in a non-optimized basal medium. The selected CHO cell lines secreting high titers of SFN68 would be useful for the production of sufficient amounts of antibodies for efficacy evaluation in preclinical and early clinical studies.

• Journal of Pharmaceutical Investigation
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• v.36 no.6
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• pp.363-369
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• 2006

Granisetron is a selective 5-HT3 receptor antagonist that is used therapeutically for the prevention of vomiting and nausea associated with emetogenic cancer chemotherapy. Although this drug is commercially available for intravenous and oral dosage, there is a need for intranasal delivery formulations in specific patient populations in which the use of these dosage forms may be unfeasible and/or inconvenient. A rapid and specific high-performance liquid chromatography method with mass spectrometric detection(LC-MS) was developed and validated for the analysis of granisetron in plasma after nasal administration in rats. This method has been validated for concentrations ranging from 5 to 1000 ng/ml with simple treatment. This technique has high level reproducibility, accuracy, and sensitivity. The method described was found to be suitable for the analysis of all samples collected during preclinical pharmacokinetic investigations of granisetron in rats after nasal administration. This study was aimed to investigate the feasibility of nasal delivery of granisetron for the elimination of vomiting. The effects of osmolarity, dosage volume at the same dose and applied dose on the nasal absorption of granisetron in rats were observed. No significant difference in the effect of osmolarity and dosage volume at the same dose was observed. As the applied dose of granisetron in nasal formulation increased, the absorption increased linearly. Based on these results it appears that only the applied dose(drug mass) determines the nasal absorption of granisetron. The bioavailability of granisetron on nasal administration of 4 mg/kg appeared to be comparable to that of intravenous administration of the same dose. These results suggest that granisetron can be efficiently delivered nasally and the development of nasal formulation will be feasible.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.16
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• pp.6863-6869
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• 2014

Objectives: Several preclinical and observational studies have shown that anti-diabetic medications (ADMs) may modify the risk of lung cancer. We performed a systematic review and meta-analysis evaluating the effect of metformin, sulfonylureas (SUs), thiazolidinediones (TZDs), and insulin on the risk of lung cancer in patients with diabetes mellitus (DM). Materials and Methods: We conducted a systematic search of Pubmed and Web of Science, up to August 20, 2013. We also searched the Conference Proceedings Citation Index (CPCI) and China National Knowledge Infrastructure (CNKI) for abstracts from major meetings. Fixed or random effect pooled measures were selected based on heterogeneity among studies, which was evaluated using Q test and the I2 of Higgins and Thompson. Meta-regression was used to explore the sources of between-study heterogeneity. Publication bias was analyzed by Begg's funnel plot and Egger's regression test. Associations were assessed by odds ratios (ORs) with 95% confidence intervals (CIs). Results: A total of 15 studies (11 cohort, 4 case-control) were included in this meta-analysis. In observational studies no significant association between metformin (n=11 studies; adjusted OR=0.99, 95%CI: 0.87-1.12), SUs (n=5 studies; adjusted OR=0.98, 95%CI: 0.79-1.22), or TZDs (n=7 studies; adjusted OR=0.92, 95%CI: 0.75-1.13), insulin (n=6 studies; adjusted OR=1.13, 95%CI: 0.79-1.62) use and risk of developing lung cancer was noted. There was considerable inherent heterogeneity between studies not explained by study design, setting, or location. Conclusions: Meta-analysis of existing studies does not support a protective or harmful association between ADMs use and risk of lung cancer in patients with DM. There was considerable heterogeneity across studies, and future, well-designed, prospective studies would be required for better understanding of any association.

• The Korean Journal of Physiology and Pharmacology
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• v.21 no.1
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• pp.107-115
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• 2017

Over the last decade, physiologically based pharmacokinetics (PBPK) application has been extended significantly not only to predicting preclinical/human PK but also to evaluating the drug-drug interaction (DDI) liability at the drug discovery or development stage. Herein, we describe a case study to illustrate the use of PBPK approach in predicting human PK as well as DDI using in silico, in vivo and in vitro derived parameters. This case was composed of five steps such as: simulation, verification, understanding of parameter sensitivity, optimization of the parameter and final evaluation. Caffeine and ciprofloxacin were used as tool compounds to demonstrate the "fit for purpose" application of PBPK modeling and simulation for this study. Compared to caffeine, the PBPK modeling for ciprofloxacin was challenging due to several factors including solubility, permeability, clearance and tissue distribution etc. Therefore, intensive parameter sensitivity analysis (PSA) was conducted to optimize the PBPK model for ciprofloxacin. Overall, the increase in $C_{max}$ of caffeine by ciprofloxacin was not significant. However, the increase in AUC was observed and was proportional to the administered dose of ciprofloxacin. The predicted DDI and PK results were comparable to observed clinical data published in the literatures. This approach would be helpful in identifying potential key factors that could lead to significant impact on PBPK modeling and simulation for challenging compounds.