• Title/Summary/Keyword: First-in-human dose

Search Result 161, Processing Time 0.033 seconds

Effects of Compound K on Insulin Secretion and Carbohydrate Metabolism (Compound K의 인슐린분비 및 탄수화물 대사에 미치는 영향)

  • Choi, Yun-Suk;Han, Gi-Cheol;Han, Eun-Jung;Park, Kum-Ju;Sung, Jong-Hwan;Chung, Sung-Hyun
    • Journal of Ginseng Research
    • /
    • v.31 no.2
    • /
    • pp.79-85
    • /
    • 2007
  • Compound K (CK) is a final metabolite of panaxadiol ginsenosides. Although panax ginseng is known to have anti-diabetic activity, the active ingredient is not yet fully identified. Therefore, it would be interesting to know whether and how CK has an anti-diabetic activity. First, insulin secretion-stimulating activity of CK was examined using RIN-m5F cell line and primary cultured islets. CK enhanced the insulin secretion in a concentration dependent manner. This effect, however, was almost completely abolished in the presence of diazoxide, $K^+$ channel opener, indicating that the insulin secretion-stimulating activity of CK is presumably due to blockade of ATP sensitive $K^+$ channel. In addition, effects of CK on gene expressions of hepatic enzymes (phosphoenolpyruvate carboxykinase[PEPCK], glucose-6-phos-phatase[G6Pase]) and on adipocyte differentiation in H4IIE and 3T3-Ll cells, respectively, were examined. CK suppressed the induction of PEPCK and G6Pase mRNA expressions under the dexamethasone/cAMP stimulation condition. CK also reduced the $PPAR-{\gamma}$ mRNA expression and triglyceride accumulation in a dose dependent manner as compared to the control. The present study suggests that CK deserves to examine whether it shows an anti-diabetic activity in animal and human studies.

Anti-proliferative and Pro-apoptotic Effects by Lees Extracts of Ehwa Makgeolli Containing Oriental Herbs (한방이화주 주박 추출물에 의한 암세포 항성장 및 세포사멸 기전 연구)

  • Kwon, Min-Jeong;Lee, Seung Hoon;Chung, Chung Wook;Sohn, Ho-Yong;Shin, Woo-Chang;Kim, Jong-Sik
    • Journal of Life Science
    • /
    • v.26 no.2
    • /
    • pp.241-246
    • /
    • 2016
  • In the present study, ethanol extracts and their subsequent organic solvent fractions were extracted from the lees of Ehwa Makgeolli containing oriental herbs, a commercialized traditional Korean rice wine, and the prepared lees samples were designated as from KSD-E3-1 to KSD-E3-5. First, their effects on cell viability and on the expression of pro-apoptotic ATF3 and NAG-1 genes in human colorectal HCT116 cells were investigated. Among the treated lees samples, the hexane fraction (KSD-E3-2) and the ethyl acetate fraction (KSD-E3-3) of lees extracts from Ehwa Makgeolli significantly reduced cell viabilities, in a dose dependent manner. The treatment with KSD-E3-2 and KSD-E3-3 also increased the expression of pro-apoptotic NAG-1 and ATF-3 genes and their proteins, which were detected with RT-PCR and Western blot analysis, respectively. In addition, poly-(ADP-ribose) polymerase (PARP) cleavage was detected by treatment with the fraction KSD-E3-3, indicating that KSD-E3-3 could induce apoptosis in HCT116 cells. Interestingly, this PARP cleavage was recovered by transfection of NAG-1 small interfering RNA. The results indicate that NAG-1 is one of the genes responsible for apoptosis induced by the fraction KSD-E3-3 from Ehwa Makgeolli. Overall, the findings may help in understanding the molecular mechanisms of the anti-proliferative and pro-apoptotic activities mediated by the lees of Ehwa Makgeolli.

Increased Frequency of Sister Chromatid Exchanges After $^{131}I$ Therapy in Lymphocytes of Thyroid Cancer Patients (갑상선암 환자에서 방사성옥소($^{131}I$) 치료로 인한 림프구의 자매염색분체교환(SCE) 빈도증가)

  • Choi, Keun-Hee;Bom, Hee-Seung;Kim, Kwang-Yoon;Kim, Ji-Yeul;Yoon, Jung-Han;JaeGal, Young-Jong;Kim, Jae-Min
    • The Korean Journal of Nuclear Medicine
    • /
    • v.27 no.1
    • /
    • pp.118-122
    • /
    • 1993
  • To evaluate the genotoxic effect of $^{131}I$, lymphocytes from 9 patients who underwent large dose (150 mCi) $^{131}I$ therapy after total thyroidectomy were studied for sister chromatid exchanges (SCE) before and after their first radioiodine treatments. Frequency of SCE (FSCE) was counted in chromosomes of 30 lymphocytes in each patients, and was expressed as numbers of SCE per cell. Numbers of leukocytes were also observed during $^{131}I$ therapy. Pretreatment FSCE ($4.2{\pm}0.7$) was not different from the control ($3.8{\pm}0.4$, p=0.17). However, the frequency was significantly elevated after $^{131}I$ administration (at the second day, $7.9{\pm}0.8$, p<0.001) and was diminished but still significantly elevated after a week (at 9th day, $6.4{\pm}0.6$, p<0.001). While counts of leukocytes in the peripheral blood showed no change (p> 0.05). In conclusion, chromatids of human lymphocytes were significantly damaged after $^{131}I$ treatment without any bone marrow supression. And the repair of SCE was not complete within one week.

  • PDF

Taxol Produced from Endophytic Fungi Induces Apoptosis in Human Breast, Cervical and Ovarian Cancer Cells

  • Wang, Xin;Wang, Chao;Sun, Yu-Ting;Sun, Chuan-Zhen;Zhang, Yue;Wang, Xiao-Hua;Zhao, Kai
    • Asian Pacific Journal of Cancer Prevention
    • /
    • v.16 no.1
    • /
    • pp.125-131
    • /
    • 2015
  • Currently, taxol is mainly extracted from the bark of yews; however, this method can not meet its increasing demand on the market because yews grow very slowly and are a rare and endangered species belonging to first-level conservation plants. Recently, increasing efforts have been made to develop alternative means of taxol production; microbe fermentation would be a very promising method to increase the production scale of taxol. To determine the activities of the taxol extracted from endophytic fungus N. sylviforme HDFS4-26 in inhibiting the growth and causing the apoptosis of cancer cells, on comparison with the taxol extracted from the bark of yew, we used cellular morphology, cell counting kit (CCK-8) assay, staining (HO33258/PI and Giemsa), DNA agarose gel electrophoresis and flow cytometry (FCM) analyses to determine the apoptosis status of breast cancer MCF-7 cells, cervical cancer HeLa cells and ovarian cancer HO8910 cells. Our results showed that the fungal taxol inhibited the growth of MCF-7, HeLa and HO8910 cells in a dose-and time-dependent manner. IC50 values of fungal taxol for HeLa, MCF-7 and HO8910 cells were $0.1-1.0{\mu}g/ml$, $0.001-0.01{\mu}g/ml$ and $0.01-0.1{\mu}g/ml$, respectively. The fungal taxol induced these tumor cells to undergo apoptosis with typical apoptotic characteristics, including morphological changes for chromatin condensation, chromatin crescent formation, nucleus fragmentation, apoptotic body formation and G2/M cell cycle arrest. The fungal taxol at the $0.01-1.0{\mu}g/ml$ had significant effects of inducing apoptosis between 24-48 h, which was the same as that of taxol extracted from yews. This study offers important information and a new resource for the production of an important anticancer drug by endofungus fermentation.

A Study on the Development of a Health Risk Assessment Method for the Management of the Health Environment of Residents Living Around Areas Affected by Chemical Accidents (화학사고 주변 지역 거주자의 보건환경 관리를 위한 건강위해성 평가 방법 개발에 관한 연구)

  • Park, Sihyun;Park, Sejung;Park, Taehyun;Yoon, Danki;Jung, Jonghyeon;Gang, Sungkyu;Lee, Dongsoo;Seo, Youngrok;An, Yeonsoon;Lee, Cheolmin
    • Journal of Korean Society of Occupational and Environmental Hygiene
    • /
    • v.28 no.1
    • /
    • pp.1-17
    • /
    • 2018
  • Objectives: This research is part of a study to be conducted over five years starting from 2017 by the Ministry of Environment on the development of technologies to evaluate the impact of chemical accidents on the human body. Methods: For this research, a five-stage specific study method was developed. Results: In brief, the developed health risk assessment method can be summarized as follows. First, a health risk assessment system was built based on the guidelines set forth by the USA NRC/NAS. Second, based on the disease manifestation theory, the health risk assessment method was divided into 1) a carcinogenic health risk assessment method focused on all carcinogens except non-genotoxic carcinogens and 2) a non-carcinogenic health risk assessment method focused on noncarcinogens including non-genotoxic carcinogens. Third, the detailed contents of the health risk assessment method were developed in four stages(hazard identification, dose-response assessment, exposure assessment, and risk determination) through theoretical consideration of the assessment of the level of health risk related to chemical exposure. Finally, a health risk assessment methodology, classified into stages to address acute, subacute/subchronic, and chronic conditions was developed after considering the physicochemical behavior of hazardous chemicals upon implementation of countermeasures after a chemical accident. Conclusions: A method to evaluate the health risks related to toxic chemicals generated by chemical accidents was developed. This study was performed with the purpose of developing a mathematical health risk assessment method to evaluate the health effects of exposure to hazardous chemicals upon implementation of emergency countermeasures after chemical accidents.

Construction and In vitro Study of a Prx 6/Luc Vector System for Screening Antioxidant Compounds in the Transgenic Mice (항산화반응을 유발하는 물질의 검색에 적용할 수 있는 형질전환 마우스 생산을 위한 새로운 Prx 6/Luc 벡터시스템의 제조 및 폐암세포주에서 반응성 확인)

  • Lee, Young Ju;Nam, So Hee;Kim, Ji Eun;Hwang, In Sik;Lee, Hye Ryun;Choi, Sun Il;Kwak, Moon Hwa;Lee, Jae Ho;Jung, Young Jin;An, Beum Soo;Hwang, Dae Youn
    • Journal of Life Science
    • /
    • v.23 no.2
    • /
    • pp.167-174
    • /
    • 2013
  • Peroxiredoxin 6 (Prx 6) is a member of the thiol-specific antioxidant protein family, which may play a role in protection against oxidative stress and in regulating phospholipid turnover. The aim of this study was to determine whether a human Prx 6/Luc vector was stably expressed and responded to antioxidants in a lung cell line (NCI-H460). To achieve this, the luciferase signal, hPrx 6 mRNA expression, and superoxide dismutase (SOD) activity were measured in transfectants with a hPrx 6/Luc plasmid after treatment with four antioxidant extracts, including Korea white ginseng (KWG), Korea red ginseng (KRG), Liriope platyphylla (LP), and red Liriope platyphylla (RLP). First, the hPrx 6/Luc plasmid was successfully constructed with DNA fragments of human Prx 6 promoter, amplified by PCR using genomic DNA isolated from NCI-H460 cells, and cloned into the pTransLucent reporter vector. The orientation and sequencing of the hPrx 6/Luc plasmid were identified with restriction enzyme and automatic sequencing. A luciferase assay revealed significant enhancement of luciferase activity in the four treatment groups compared with a vehicle-treated group, although the ratio of the increase was different within each group. The KRG- and LP-treated groups showed higher activity than the KWG- and RLP-treated groups. Furthermore, the luciferase activity against RLP occurred roughly in a dose-dependent manner. However, the level of endogenous hPrx 6 mRNA did not change in any group treated with the four extracts. The SOD activity was in agreement with the luciferase activity. Therefore, these results indicate that the hPrx 6/Luc vector system may successfully express and respond to antioxidant compounds in NCI-H460 cells. The data also suggest that the Prx 6/Luc vector system may be effectively applied in screening the response of hPrx 6 to antioxidant compounds in transgenic mice.

Value of the Serum Thyroglobulin Level Alteration at the First High Dose Radioiodine Treatment in Patients with Differentiated Thyroid Carcinoma (분화성갑상선암에서 최초 고용량 방사성요오드 치료시 혈청 갑상선글로불린 수치 변화의 의의)

  • Nam, Hyun-Yeol;Kim, In-Joo;Kim, Yong-Ki;Kim, Seong-Jang;Jun, Sung-Min;Kim, Bum-Soo
    • Nuclear Medicine and Molecular Imaging
    • /
    • v.43 no.4
    • /
    • pp.294-300
    • /
    • 2009
  • Purpose: The purpose of this study was to evaluate if short-term serum thyroglobulin (Tg) elevation after radioiodine administration can predict successful radioiodine remnant ablation (RRA) and whether comparable RRA effectiveness is exhibited between a group administered with recombinant human thyrotropin (rhTSH) and a group experiencing thyroid hormone withdrawal (THW), in preparation for RRA. Materials and Methods: A retrospective chart review was performed on 39 patients in the rhTSH group and 46 patients in the THW group. They were treated for differentiated thyroid carcinoma by total or near total thyroidectomy, and referred for RRA between 2003 and 2006 (the rhTSH group) and between January and June of 2006 (the THW group). They were assessed for serum Tg levels just before I-131 administration (TgD0), reassessed 9 days later (TgD9), and again 6-12 months later. Results: RRA was successful in 64 (37 from the THW group and 27 from the rhTSH group) of the total 85 patients. The success rates of RRA had no statistically significant differences between the two groups. In both groups, TgD9/TgD0 values were significantly higher in the RRA success group (the rhTSH group; P = 0.03, the THW group; P = 0.04). By combining cutoff values of TgD0 and TgD9/TgD0, the successful RRA value was determined to be 96.7% (29/30) with TgD0$\leq$5.28 ng/mL and TgD9/TgD0>4.37 in both groups (the rhTSH group; 100% (16/16), the THW group; 92.9% (13/14)). Using logistic multivariate analysis, only TgD0 was independently associated with successful RRA. Conclusion: We may predict successful ablation by evaluating short-term serum Tg elevation after I-131 administration for RRA, in both rhTSH and THW patients.

Antioxidant and Anticancer Activities of Euonymus porphyreus Extract in Human Lung Cancer Cells A549 (인체 폐암 세포주 A549에서 Euonymus porphyreus 추출물의 항산화 및 항암활성 분석)

  • Jin, Soojung;Oh, You Na;Son, Yu Ri;Bae, Soobin;Park, Jung-ha;Kim, Byung Woo;Kwon, Hyun Ju
    • Journal of Life Science
    • /
    • v.31 no.2
    • /
    • pp.199-208
    • /
    • 2021
  • Euonymus porphyreus, a species of plant in the Celastraceae family, is widely distributed in East Asia, especially in Southern China. The botanical characteristics of E. porphyreus have been reported, but its antioxidative and anticancer activities remain unclear. In this study, we evaluated the antioxidative and anticancer effects of ethanol extracts of E. porphyreus (EEEP) and the molecular mechanism of its anticancer activity in human lung adenocarcinoma A549 cells. The total polyphenol and flavonoid compound contents from EEEP were 115.42 mg/g and 23.07 mg/g, respectively. EEEP showed significant antioxidative effects with a concentration at 50% of the inhibition (IC50) value of 11.09 ㎍/ml, as measured by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. EEEP showed cytotoxic activity by increasing the SubG1 cell population of A549 cells in a dose-dependent manner. Apoptosis in A549 cells treated with EEEP was evident due to increased apoptotic cells and apoptotic bodies, as detected by Annexin V and 4,6-diamidino-2-phenylindole (DAPI) staining, respectively. EEEP-induced apoptosis resulted in increased expression of the First apoptosis signal (Fas), p53, and Bax, with decreased expression of Bcl-2 and subsequent activation of caspase-8, -9, and caspase-3, leading to cleavage of poly (ADP-ribose) polymerase (PARP). Collectively, these results suggest that EEEP may exert an anticancer effect by inducing apoptosis in A549 cells through both intrinsic and extrinsic pathways.

Degradation Kinetic and Mechanism of Methyl Tert-butyl Ether (MTBE) by the Modified Photo-Fenton Reaction (Modified Photo-Fenton Reaction을 이용한 Methyl Tert-butyl Ether (MTBE)의 분해 Kinetic 및 메커니즘 규명에 관한 연구)

  • Kim, Min-Kyoung;Kong, Sung-Ho
    • Journal of Soil and Groundwater Environment
    • /
    • v.11 no.6
    • /
    • pp.69-75
    • /
    • 2006
  • Improper disposal of petroleum and spills from underground storage tanks have created large areas with highly toxic contamination of the soil and groundwater. Methyl tert-butyl ether (MTBE) is widely used as a fuel additive because of its advantageous properties of increasing the octane value and reducing carbon monoxide and hydrocarbon exhausts. However, MTBE is categorized as a possible human carcinogen. This research investigated the Modified Photo-Fenton system which is based on the Modified Fenton reaction and UV light irradiation. The Modified Fenton reaction is effective for MTBE degradation near a neutral pH, using the ferric ion complex composed of a ferric ion and environmentally friendly organic chelating agents. This research was intended to treat high concentrations of MTBE; thus, 1,000 mg/L MTBE was chosen. The objectives of this research are to find the optimal reaction conditions and to elucidate the kinetic and mechanism of MTBE degradation by the Modified Photo-Fenton reaction. Based on the results of experiments, citrate was chosen among eight chelating agents as the candidate for the Modified Photo-Fenton reaction because it has a relatively higher final pH and MTBE removal efficiency than the others, and it has a relatively low toxicity and is rapidly biodegradable. MTBE degradation was found to follow pseudo-first-order kinetics. Under the optimum conditions, [$Fe^{3+}$] : [Citrate] = 1 mM: 4 mM, 3% $H_2O_2$, 17.4 kWh/L UV dose, and initial pH 6.0, the 1000 ppm MTBE was degraded by 86.75% within 6 hours and 99.99% within 16 hours. The final pH value was 6.02. The degradation mechanism of MTBE by the Modified Photo-Fenton Reaction included two diverse pathways and tert-butyl formate (TBF) was identified to be the major degradation intermediate. Attributed to the high solubility, stability, and reactivity of the ferric-citrate complexes in the near neutral condition, this Modified Photo-Fenton reaction is a promising treatment process for high concentrations of MTBE under or near a neutral pH.

Biodistribution and Hepatic Metabolism of Galactosylated $^{111}In-Antibody-Chelator$ Conjugates: Comparison with $^{111}In-Antibody-Chelator$ Conjugates ($^{111}In$-표지 갈락토즈 접합 항체의 체내분포 및 간에서의 대사 : $^{111}In$-표지 항체와의 비교연구)

  • Kwak, Dong-Suk;Jeong, Kyu-Sik;Ha, Jeoung-Hee;Ahn, Byeong-Cheol;Lee, Kyu-Bo;Paik, Chang-H.;Lee, Jae-Tae
    • The Korean Journal of Nuclear Medicine
    • /
    • v.37 no.6
    • /
    • pp.402-417
    • /
    • 2003
  • Purpose: To evaluate the use of monoclonal antibody (MoAb) as a carrier of the receptor-binding ligand the receptor mediated uptake into liver and subsequent metabolism of $^{111}In-labeled$ galactosylated MoAb-chelator conjugates were investigated and compared with those of $^{111}In$ labeled MoAb. Materials and Methods : T101 MoAb, $IgG_2$ against human lymphocytic leukemic cell, conjugated with cyclic DTPA dianhydride (DTPA) or 2-p-isothiocyanatobenzyl-6-methyl-DTPA (1B4M) was galactosylated with 2-imino-2-methoxyethyl-1-thio-${\beta}$-D-galactose and then radiolabeled with $^{111}In$. Biodistribution and metabolism study was peformed with two $^{111}In-conjugates$ in mice and rats. Results: $^{111}In-labeled$ T101 and its galactosylated conjugates were taken to the liver by the time, mostly within 10 min. However DTPA conjugate was retained longer in the liver than the 1B4M conjugate (55% vs 20% of injected dose at 44 hr). During this time, the radiornetabolite of DTPA conjugate was excreted similarly into urine (24%) and feces (17%). The radiometabolite of 1B4M was excreted primarily into feces (68%) rather than urine (8%). Size exclusion HPLC analysis of the bile and supernatant of liver homogenate showed two peaks the first (35%) with the retention time (Rt) identical to IgG and the second (65%) with Rt similar to free $^{111}In$ at 3 hr post-injection for the 1B4M conjugate, indicating that the metabolite is rapidly excreted through the biliary system. in contrast to DTPA conjugate, the small $^{111}In-DTPA-like$ metabolite was the major radioindium component (90%) in the liver homogenate as early as 3 hour post-injection, but the cumulative radioindium activity in feces was only 17% at 44 hour, indicating that the metabolite from DTPA conjugate does not clear readily through the biliary tract. Conclusion: The galactosylation of the MoAb conjugates resulted in higher hepatocyte uptake and enhanced metabolism, compared to those without galactosylation. Metabolism of the MoAb-conjugates is different between compounds radiolabled with different chelators due to different characteristics of radiometabolites generated in the liver.