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1.
Diabetes Metab J ; 46(2): 337-348, 2022 03.
Article in English | MEDLINE | ID: mdl-35052026

ABSTRACT

BACKGROUND: We investigated the antidiabetic effects of DA-1241, a novel G protein-coupled receptor (GPR) 119 agonist, in vitro and in vivo. METHODS: DA-1241 was administrated to high-fat diet (HFD)-fed C57BL/6J mice for 12 weeks after hyperglycaemia developed. Oral/intraperitoneal glucose tolerance test and insulin tolerance test were performed. Serum insulin and glucagon-like peptide-1 (GLP-1) levels were measured during oral glucose tolerance test. Insulinoma cell line (INS-1E) cells and mouse islets were used to find whether DA-1241 directly stimulate insulin secretion in beta cell. HepG2 cells were used to evaluate the gluconeogenesis and autophagic process. Autophagic flux was evaluated by transfecting microtubule-associated protein 1 light chain 3-fused to green fluorescent protein and monomeric red fluorescent (mRFP-GFP-LC3) expression vector to HepG2 cells. RESULTS: Although DA-1241 treatment did not affect body weight gain and amount of food intake, fasting blood glucose level decreased along with increase in GLP-1 level. DA-1241 improved only oral glucose tolerance test and showed no effect in intraperitoneal glucose tolerance test. No significant effect was observed in insulin tolerance test. DA-1241 did not increase insulin secretion in INS-1E cell and mouse islets. DA-1241 reduced triglyceride content in the liver thereby improved fatty liver. Additionally, DA-1241 reduced gluconeogenic enzyme expression in HepG2 cells and mouse liver. DA-1241 reduced autophagic flow in HepG2 cells. CONCLUSION: These findings suggested that DA-1241 augmented glucose-dependent insulin release via stimulation of GLP-1 secretion, and reduced hepatic gluconeogenesis, which might be associated with autophagic blockage, leading to improved glycaemic control.


Subject(s)
Diabetes Mellitus, Experimental , Hyperglycemia , Animals , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Glucagon-Like Peptide 1 , Gluconeogenesis , Hyperglycemia/drug therapy , Hyperglycemia/metabolism , Insulin , Insulin Secretion , Liver/metabolism , Mice , Mice, Inbred C57BL
2.
Life Sci ; 288: 120151, 2022 Jan 01.
Article in English | MEDLINE | ID: mdl-34801515

ABSTRACT

Obesogens are a type of endocrine-disrupting chemicals (EDCs) that disrupt the human endocrine system, resulting in obesity and metabolic disease. Several obesogens, including bisphenol A, tolylfluanid, and some pesticides, have been identified and studied previously; however, the underlying molecular mechanisms by which obesogens interfere with adipogenesis and induce insulin resistance in adipocyte remain unknown. This study aims to determine which type of chemical is the most potent obesogen and to investigate its effect on adipogenesis-related gene expressions. 3T3-L1, a pre adipocyte cell line, was differentiated into mature adipocytes with either vehicle or various obesogens, including bisphenol A, tolylfluanid, and endrin, as well as corticosterone, at the same dose. Subsequently, intracellular and secreted triglyceride levels were measured, and the expression of genes and proteins involved in adipogenesis and lipogenesis was investigated. We found that endrin was the most potent regulator of adipogenic differentiation, as compared to tolylfluanid, bisphenol A, and corticosterone. Endrin increased intracellular and secreted triglyceride levels and enhanced the expression of adipogenic transcription factors as well as the terminal differentiation marker in a dose-dependent manner. During the early stages of differentiation, endrin enhanced mammalian target of rapamycin (mTOR) activity, which was suppressed by the pharmacological blockade of the protein kinase B-mTOR pathway, with repressed adipogenic differentiation. However, endrin did not change the expression levels of the downstream members of the mTOR signaling pathway or proteins related to lipolysis in response to insulin. Thus, we suggest that endrin potentiates early-stage adipogenic differentiation by activating the mTOR pathway.


Subject(s)
Adipocytes/cytology , Adipogenesis , Cell Differentiation , Endrin/pharmacology , Gene Expression Regulation/drug effects , Proto-Oncogene Proteins c-akt/metabolism , TOR Serine-Threonine Kinases/metabolism , 3T3-L1 Cells , Adipocytes/drug effects , Adipocytes/metabolism , Animals , Insecticides/pharmacology , Mice , Proto-Oncogene Proteins c-akt/genetics , TOR Serine-Threonine Kinases/genetics
3.
J Atheroscler Thromb ; 27(5): 429-440, 2020 May 01.
Article in English | MEDLINE | ID: mdl-31527323

ABSTRACT

AIM: Most statins increase the risk of new-onset diabetes. Unlike other statins, pitavastatin is reported to exert neutral effects on serum glucose level, but the precise mechanism is unknown. METHODS: Eight-week-old male C57BL/6J mice (n=26) were fed high-fat diet (HFD, 45% fat) with 0.01% placebo, rosuvastatin, or pitavastatin for 12 weeks. Cultured HepG2, C2C12, and 3T3-L1 cells and visceral adipocytes from HFD-fed mice were treated with vehicle or 10 µM statins for 24 h. The effects of pitavastatin and rosuvastatin on intracellular insulin signaling and glucose transporter 4 (GLUT4) translocation were evaluated. RESULTS: After 12 weeks, the fasting blood glucose level was significantly lower in pitavastatin-treated group than in rosuvastatin-treated group (115.2±7.0 versus 137.4±22.3 mg/dL, p=0.024). Insulin tolerance significantly improved in pitavastatin-treated group as compared with rosuvastatin-treated group, and no significant difference was observed in glucose tolerance. Although plasma adiponectin and insulin levels were not different between the two statin treatment groups, the insulin-induced protein kinase B phosphorylation was weakly attenuated in pitavastatin-treated adipocytes than in rosuvastatin-treated adipocytes. Furthermore, minor attenuation in insulin-induced GLUT4 translocation to the plasma membrane of adipocytes was observed in pitavastatin-treated group. CONCLUSION: Pitavastatin showed lower diabetogenic effects than rosuvastatin in mice that may be mediated by minor attenuations in insulin signaling in adipocytes.


Subject(s)
Adipocytes , Blood Glucose , Diabetes Mellitus , Quinolines/pharmacology , Rosuvastatin Calcium/pharmacology , Adipocytes/drug effects , Adipocytes/metabolism , Adiponectin/blood , Adiponectin/metabolism , Animals , Anticholesteremic Agents/pharmacology , Blood Glucose/analysis , Blood Glucose/metabolism , Cells, Cultured , Correlation of Data , Diabetes Mellitus/blood , Diabetes Mellitus/chemically induced , Diabetes Mellitus/diagnosis , Glucose Transporter Type 4/metabolism , Humans , Insulin/blood , Insulin/metabolism , Intra-Abdominal Fat/drug effects , Intra-Abdominal Fat/metabolism , Mice , Mice, Inbred C57BL , Signal Transduction/drug effects
4.
Chronobiol Int ; 34(8): 1057-1066, 2017.
Article in English | MEDLINE | ID: mdl-28650669

ABSTRACT

Increasing evidence suggests a close interrelationship between disrupted circadian rhythms and obesity and metabolic disturbances. In particular, abdominal obesity, which contributes to the pathogenesis of metabolic disease, is associated with disrupted clock gene expression. However, little is known about the relationship between clock gene expression and accurate computed tomography (CT)-based measurements of visceral adiposity. Therefore, we examined the relationship between expression of clock genes in peripheral blood mononuclear cells (PBMCs) with visceral and subcutaneous adiposity in 75 healthy overweight or obese individuals. PBMCs were obtained from blood samples collected at 8 AM, and gene expression was analyzed by real-time reverse transcription polymerase chain reaction. Visceral and subcutaneous adiposity were measured by CT. Our results showed that visceral fat area was significantly positively correlated with BMAL1 and CRY1 mRNA levels and significantly negatively correlated with CLOCK, PER2, PER3 and CRY2 mRNA levels. In contrast, subcutaneous fat area was not correlated with the expression of any of the clock genes analyzed. After adjusting for multiple variables, visceral fat area was significantly associated with the expression of BMAL1, PER2 and CRY1. Taken together, our results indicate that visceral adiposity, but not subcutaneous adiposity, correlates with expression of clock genes in PBMCs.


Subject(s)
Adiposity/physiology , CLOCK Proteins/genetics , Circadian Rhythm/genetics , Leukocytes, Mononuclear/metabolism , Adult , Aged , CLOCK Proteins/metabolism , Female , Gene Expression/physiology , Humans , Male , Middle Aged , Obesity/genetics , Obesity/metabolism , Obesity, Abdominal/genetics , Period Circadian Proteins/genetics , Pilot Projects , Young Adult
5.
Biochem Biophys Res Commun ; 446(4): 822-9, 2014 Apr 18.
Article in English | MEDLINE | ID: mdl-24569072

ABSTRACT

Obesity is associated with certain types of cancer, including gastric cancer. However, it is still unclear whether obesity-related cytokine, leptin, is implicated in gastric cancer. Therefore, we aimed to investigate the role of leptin in gastric cancer. The expression of leptin and its receptor, Ob-R, was assessed by immunohistochemical staining and was compared in patients with gastric adenoma (n=38), early gastric cancer (EGC) (n=38), and advanced gastric cancer (AGC) (n=38), as a function of their clinicopathological characteristics. Gastric cancer cell lines were studied to investigate the effects of leptin on the signal transducer and activator of transcription-3 (STAT3) and extracellular receptor kinase 1/2 (ERK1/2) signaling pathways using MTT assays, immunoblotting, and inhibition studies. Leptin was expressed in gastric adenomas (42.1%), EGCs (47.4%), and AGCs (43.4%). Ob-R expression tended to increase from gastric adenoma (2%), through EGC (8%), to AGC (18%). Leptin induced the proliferation of gastric cancer cells by activating STAT3 and ERK1/2 and up-regulating the expression of vascular endothelial growth factor (VEGF). Blocking Ob-R with pharmacological inhibitors and by RNAi decreased both the leptin-induced activation of STAT3 and ERK1/2 and the leptin-induced expression of VEGF. Leptin plays a role in gastric cancer by stimulating the proliferation of gastric cancer cells via activating the STAT3 and ERK1/2 pathways.


Subject(s)
Adenoma/pathology , Leptin/analysis , Leptin/metabolism , Stomach Neoplasms/pathology , Stomach/pathology , Adenoma/etiology , Adenoma/metabolism , Adult , Aged , Aged, 80 and over , Cell Line, Tumor , Cell Proliferation , Female , Gastric Mucosa/metabolism , Humans , Immunohistochemistry , MAP Kinase Signaling System , Male , Middle Aged , Obesity/complications , Receptors, Leptin/analysis , Receptors, Leptin/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction , Stomach Neoplasms/etiology , Stomach Neoplasms/metabolism , Vascular Endothelial Growth Factor A/metabolism
6.
Endocr J ; 60(11): 1269-73, 2013.
Article in English | MEDLINE | ID: mdl-23933590

ABSTRACT

Sirtuin1 (SIRT1) is activated during calorie restriction and appears to be related to energy balance through glucose or lipid metabolism and insulin signaling. These findings suggest that SIRT1 may play a role in the pathophysiology of visceral obesity. Therefore, we investigated the relationship between SIRT1 gene expression in circulating peripheral blood mononuclear cells (PBMCs) and abdominal visceral adiposity as measured by computed tomography. We recruited 43 men and women without history of diabetes or cardiovascular disease Biomarkers of metabolic disease and body composition by computed tomography were assessed. SIRT1 gene expression was determined using isolated PBMCs. SIRT1 expression levels negatively correlated with body mass index, waist circumference, abdominal visceral fat area, and homeostasis model of assessment of insulin resistance (HOMA-IR) and positively correlated with adiponectin levels. Results of step-wise multiple regression analysis revealed that abdominal visceral fat area and HOMA-IR were independently associated with SIRT1 expression. The significant association between abdominal visceral fat accumulation and SIRT1 gene expression in PBMCs suggests that SIRT1 may be a new therapeutic target for the prevention of disease related to obesity, especially visceral obesity.


Subject(s)
Adiposity/genetics , Intra-Abdominal Fat/metabolism , Leukocytes, Mononuclear/metabolism , Sirtuin 1/genetics , Sirtuin 1/metabolism , Adiponectin/blood , Adult , Body Mass Index , Cross-Sectional Studies , Female , Gene Expression , Healthy Volunteers , Humans , Intra-Abdominal Fat/diagnostic imaging , Lipid Metabolism , Male , Pilot Projects , RNA, Messenger/metabolism , Regression Analysis , Tomography, X-Ray Computed , Waist Circumference
7.
APMIS ; 120(10): 836-45, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22958292

ABSTRACT

(±) trans-Dihydronarciclasine, isolated from Chinese medicinal plant Zephyranthes candida, has been shown to possess quite potent anti-tumoral effect against selected human cancer cell lines. However, little is known about the anti-tumoral effect of (±) trans-dihydronarciclasine in acute myeloid leukemia (AML). This study was performed to investigate the effect of a novel synthetic (±) trans-dihydronarciclasine (code name; HYU-01) in AML. The HYU-01 inhibited the proliferation of various AML cell lines including HL-60 as well as primary leukemic blasts in a dose-dependent manner. To investigate the mechanism of the anti-proliferative effect of HYU-01, cell-cycle analysis was attempted in HL-60 cells, resulting in G1 arrest. The expression levels of CDK2, CDK4, CDK6, cyclin E, and cyclin A were decreased in a time-dependent manner. In addition, HYU-01 up-regulated the expression of the p27, and markedly enhanced the binding of p27 with CDK2, 4, and 6, ultimately resulting in the decrease of their kinase activities. Furthermore, HYU-01 induced the apoptosis through the induction of proapoptotic molecules and reduction of antiapoptotic molecules in association with the activation of caspase-3, -8, and -9. These results suggest that HYU-01 may inhibit the proliferation of HL-60 cells, via apoptosis, as well as G1 block in association with the induction of p27.


Subject(s)
Alkaloids/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Alkaloids/chemical synthesis , Antineoplastic Agents, Phytogenic/chemical synthesis , Apoptosis/genetics , Caspases/genetics , Caspases/metabolism , Cell Cycle Checkpoints/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin-Dependent Kinases/genetics , Cyclin-Dependent Kinases/metabolism , Cyclins/genetics , Cyclins/metabolism , Dose-Response Relationship, Drug , Gene Expression Regulation, Neoplastic/drug effects , HL-60 Cells , Humans , Leukemia, Myeloid, Acute , Proliferating Cell Nuclear Antigen/genetics , Proliferating Cell Nuclear Antigen/metabolism , Protein Binding , Signal Transduction/drug effects , Signal Transduction/genetics
8.
Oncol Rep ; 23(5): 1369-74, 2010 May.
Article in English | MEDLINE | ID: mdl-20372853

ABSTRACT

Leptin acts as a growth factor in normal cells as well as in various types of cancer cells. We investigated the effects of leptin on human acute myelogenous leukemia (AML) cells. Leptin stimulated the proliferation of HEL cells through the phosphorylation of STAT3 and ERK1/2. The blocking of STAT3 phosphorylation with the specific inhibitor, AG490, significantly reduced leptin-induced ERK1/2 phosphorylation and cellular proliferation, whereas the blocking of ERK1/2 activation by the specific ERK1/2 inhibitor, PD98059, did not affect the STAT3 phosphorylation or leptin-induced proliferation in HEL cells. Furthermore, knockdown of leptin receptor (OB-R) expression with stealth RNA interference (RNAi) reduced the leptin-induced proliferation of HEL cells and also significantly attenuated leptin-induced STAT3 and ERK1/2 activation. These results suggest that leptin promotes AML cell growth by activating STAT3 and MAPK, although not directly dependent on ERK.


Subject(s)
Cell Proliferation , Leptin/metabolism , Leukemia, Myeloid, Acute/metabolism , Signal Transduction , Cell Proliferation/drug effects , Flavonoids/pharmacology , HL-60 Cells , Humans , K562 Cells , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Mitogen-Activated Protein Kinase 3/metabolism , Phosphorylation , Protein Kinase Inhibitors/pharmacology , RNA Interference , Receptors, Leptin/genetics , Receptors, Leptin/metabolism , Recombinant Proteins/metabolism , STAT3 Transcription Factor/antagonists & inhibitors , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , Tyrphostins/pharmacology
9.
Int J Oncol ; 33(3): 493-501, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18695878

ABSTRACT

This study investigated whether advanced glycation end products (AGE) and RAGE (receptor for AGE) are involved in the proliferation of leukemia cells. AGE strongly induced the proliferation of primary acute myeloid leukemia (AML) cells and cell lines. MAP kinase, PI3K and JAK/STAT pathways were involved in cellular proliferation of HEL cells by AGE. RAGE antisense S-ODN effectively inhibited cell growth, induced apoptosis and reversed AGE-induced expression of targeting molecules in HEL cells. The study demonstrated for the first time that AGE directly induced human AML cell proliferation via the MAPK, PI3K and JAK/STAT pathways.


Subject(s)
Cell Proliferation , Glycation End Products, Advanced/metabolism , Leukemia, Myeloid, Acute/metabolism , Receptors, Immunologic/metabolism , Signal Transduction/physiology , Blotting, Western , Extracellular Signal-Regulated MAP Kinases/metabolism , Flow Cytometry , Humans , Immunoprecipitation , Phosphatidylinositol 3-Kinases/metabolism , Receptor for Advanced Glycation End Products , Reverse Transcriptase Polymerase Chain Reaction , STAT Transcription Factors/metabolism , Tumor Cells, Cultured
10.
J Am Chem Soc ; 130(6): 2062-6, 2008 Feb 13.
Article in English | MEDLINE | ID: mdl-18205362

ABSTRACT

Various electron-donating and -withdrawing groups in aromatic and aliphatic backbones of solvent have been introduced to tailor the electronic structures of single-walled carbon nanotubes (SWCNTs). In the case of solvent with a withdrawing group, electrons were extracted mainly from metallic SWCNTs, whereas small charge transfer was also observed in semiconducting SWCNTs. On the other hand, in the case of solvent with a donating group, electrons were donated to both metallic and semiconducting SWCNTs. This effect was less prominent in solvent with an aliphatic backbone than that with an aromatic backbone. The strong correlation between the sheet resistance and electronic structures of nanotubes is further discussed in conjunction with a modulation of Schottky barrier height.


Subject(s)
Electrons , Nanotubes, Carbon/chemistry , Chemical Phenomena , Chemistry, Physical , Solvents/chemistry , Spectrophotometry , X-Rays
11.
Int J Oncol ; 32(2): 387-96, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18202761

ABSTRACT

1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] is capable of inhibiting the proliferation of acute myelogenous leukemia (AML). However, toxicity of hypercalcemia has limited the use of 1,25(OH)2D3 in clinical trials. We have evaluated 11 synthesized vitamin D3 analogs for their ability to inhibit clonal growth of HL-60 myeloid leukemic cells. Among the 11 vitamin D3 analogs, HY-11 (code name) showed the most potent antileukemic activity with 2.5x10(-6) M of IC50, however, it did not affect the cellular growth of normal peripheral blood mononuclear cells until 10(-6) M. Flow cytometric analysis indicated that HY-11 induced the G1 arrest in a dose-dependent manner, which was mediated via inactivation of CDK4 and CDK6 in association with up-regulation of CDKI (cyclin-dependent kinase inhibitor), p27 and Rb protein. Induction of apoptosis was mediated via caspase-3 pathway in HY-11-treated HL-60. In addition, HY-11 enhanced the expression of TGF-beta1, TGF-beta receptor type I and II and vitamin D3 receptor (VDR). VDR expression was increased by TGF-beta1, suggesting that TGF-beta1 might be involved in the antiproliferative effect of HY-11 on HL-60 cells by autocrine and paracrine regulation. Serum calcium levels were within normal limit when HY-11 was given intraperitoneally (i.p.) every other day for 5 weeks to BALB/c mice at the doses of 10(-7), 10(-6)and 10(-5) M. HY-11 inhibited the growth of WEHI-3BD+ mouse leukemic cells in vitro, and syngeneic BALB/c mice that received WEHI-3BD+ mouse leukemic cells and HY-11 had a significantly longer survival without producing hypercalcemia compared to control group. In summary, HY-11 is a vitamin D3 analog that inhibited the proliferation of human AML cell line, HL-60, through induction of cell cycle arrest, triggering apoptosis as well as modulation of TGF-beta1 and its receptors. In particular, HY-11 significantly increased the survival of mice that had myeloid leukemia without producing hypercalcemia.


Subject(s)
Antineoplastic Agents/pharmacology , Cholecalciferol/analogs & derivatives , Cholecalciferol/chemistry , Hypercalcemia/prevention & control , Leukemia, Myeloid/drug therapy , Animals , Calcium/metabolism , Cell Line, Tumor , Cell Proliferation , Cholecalciferol/pharmacology , HL-60 Cells , Humans , Male , Mice , Mice, Inbred BALB C , Models, Chemical , Neoplasm Transplantation
12.
Oncol Rep ; 13(6): 1177-83, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15870940

ABSTRACT

The purpose of this study was to investigate the radioprotective effect of HGFs (GM-CSF, IL-3 and SCF) in irradiated human peripheral blood mononuclear cells (PBMCs) in vitro, and the survival effect of lethally irradiated C3H mice in vivo. The irradiation of human PBMCs using a (137)Cs irradiator showed a dose-dependent inhibition of cell growth up to a dose of 5 Gy. This cell growth inhibition induced apoptosis, which was associated with the down-regulation of Bcl-2, up-regulation of Bax, depolarization of mitochondrial transmembrane potential (Delta psi m), and caspase-3 and -9 activation. Following gamma-irradiation at 2 Gy, IL-3 (10 ng/ml) alone or combined with SCF (50 ng/ml) reduced the apoptotic portion of human PBMCs by 15 and 20% of the cell population, respectively, showing no activation of caspase-3 compared to the control group. To examine the in vivo effect of gamma-irradiation and cytokines, we investigated the survival rate and recovery of peripheral blood cells in C3H mice. C3H mice subjected to total body irradiation (TBI) at a dose of 7 Gy (lethal dose 83% at 30 days) showed time-dependent decreases in RBC, WBC and platelet counts, with the nadir occurring at 12 to 15 days. However, treatment with recombinant murine (rm) SCF (2 microg/day s.c.), rmIL-3 (2 microg/day s.c.), or rmG-CSF (2.5 microg/day s.c.) 24 h before and after irradiation did not promote hematologic recovery or survival in the lethally irradiated C3H mice. These findings indicate that the combined treatment of IL-3 and SCF prevents the apoptosis induced in PBMCs by gamma-irradiation in vitro, but it does not afford any in vivo radioprotective effect in lethally irradiated C3H mice.


Subject(s)
Apoptosis/drug effects , Apoptosis/radiation effects , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Interleukin-3/pharmacology , Radiation-Protective Agents/pharmacology , Stem Cell Factor/pharmacology , Animals , Caspase 3 , Caspases/metabolism , Enzyme Activation/drug effects , Enzyme Activation/radiation effects , Female , Gamma Rays , Granulocyte-Macrophage Colony-Stimulating Factor/blood , Interleukin-3/blood , Membrane Potentials/drug effects , Membrane Potentials/radiation effects , Mice , Mice, Inbred C3H , Proto-Oncogene Proteins c-bcl-2/metabolism , Radiation Injuries, Experimental/metabolism , Radiation Injuries, Experimental/pathology , Stem Cell Factor/blood , Survival Rate , Whole-Body Irradiation , bcl-2-Associated X Protein
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