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1.
FASEB J ; 30(3): 1207-17, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26644352

ABSTRACT

Although mutations in the Wnt/ß-catenin signaling pathway are linked with the metabolic syndrome and type 2 diabetes in humans, the mechanism is unclear. High-fat-fed male C57BL/6 mice were treated for 4 wk with a 2'-O-methoxyethyl chimeric antisense oligonucleotide (ASO) to decrease hepatic and adipose expression of ß-catenin. ß-Catenin mRNA decreased by ≈80% in the liver and by 70% in white adipose tissue relative to control ASO-treated mice. ß-Catenin ASO improved hepatic insulin sensitivity and increased insulin-stimulated whole body glucose metabolism, as assessed during hyperinsulinemic-euglycemic clamp in awake mice. ß-Catenin ASO altered hepatic lipid composition in high-fat-fed mice. There were reductions in hepatic triglyceride (44%, P < 0.05) and diacylglycerol content (60%, P < 0.01) but a 30% increase in ceramide content (P < 0.001). The altered lipid content was attributed to decreased expression of sn-1,2 diacylglycerol acyltransferase and mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase and an increase in serine palmitoyl transferase. The decrease in cellular diacyglycerol was associated with a 33% decrease in PKCε activation (P < 0.05) and 64% increase in Akt2 phosphorylation (P < 0.05). In summary, Reducing ß-catenin expression decreases expression of enzymes involved in hepatic fatty acid esterification, ameliorates hepatic steatosis and lipid-induced insulin resistance.


Subject(s)
Fatty Liver/prevention & control , Insulin Resistance/physiology , Oligonucleotides, Antisense/pharmacology , beta Catenin/metabolism , Adipose Tissue, White/drug effects , Adipose Tissue, White/metabolism , Animals , Dietary Fats/metabolism , Diglycerides/metabolism , Fatty Acids/metabolism , Fatty Liver/drug therapy , Fatty Liver/genetics , Fatty Liver/metabolism , Glucose/metabolism , Insulin/metabolism , Lipids/physiology , Liver/drug effects , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Oligonucleotides, Antisense/genetics , Protective Agents/pharmacology , Triglycerides/metabolism
2.
J Lipid Res ; 56(3): 526-536, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25548259

ABSTRACT

ApoA5 has a critical role in the regulation of plasma TG concentrations. In order to determine whether ApoA5 also impacts ectopic lipid deposition in liver and skeletal muscle, as well as tissue insulin sensitivity, we treated mice with an antisense oligonucleotide (ASO) to decrease hepatic expression of ApoA5. ASO treatment reduced ApoA5 protein expression in liver by 60-70%. ApoA5 ASO-treated mice displayed approximately 3-fold higher plasma TG concentrations, which were associated with decreased plasma TG clearance. Furthermore, ApoA5 ASO-treated mice fed a high-fat diet (HFD) exhibited reduced liver and skeletal muscle TG uptake and reduced liver and muscle TG and diacylglycerol (DAG) content. HFD-fed ApoA5 ASO-treated mice were protected from HFD-induced insulin resistance, as assessed by hyperinsulinemic-euglycemic clamps. This protection could be attributed to increases in both hepatic and peripheral insulin responsiveness associated with decreased DAG activation of protein kinase C (PKC)-ε and PKCθ in liver and muscle, respectively, and increased insulin-stimulated AKT2 pho-sphory-lation in these tissues. In summary, these studies demonstrate a novel role for ApoA5 as a modulator of susceptibility to diet-induced liver and muscle insulin resistance through regulation of ectopic lipid accumulation in liver and skeletal muscle.


Subject(s)
Apolipoproteins/metabolism , Dietary Fats/pharmacology , Insulin Resistance , Liver/metabolism , Muscle, Skeletal/metabolism , Triglycerides/metabolism , Animals , Apolipoprotein A-V , Apolipoproteins/genetics , Gene Knockdown Techniques , Male , Mice , Protein Kinase C-epsilon/genetics , Protein Kinase C-epsilon/metabolism , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Triglycerides/genetics
3.
Diabetologia ; 57(6): 1232-41, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24718953

ABSTRACT

AIMS/HYPOTHESIS: Aerobic exercise increases muscle glucose and improves insulin action through numerous pathways, including activation of Ca(2+)/calmodulin-dependent protein kinases (CAMKs) and peroxisome proliferator γ coactivator 1α (PGC-1α). While overexpression of PGC-1α increases muscle mitochondrial content and oxidative type I fibres, it does not improve insulin action. Activation of CAMK4 also increases the content of type I muscle fibres, PGC-1α level and mitochondrial content. However, it remains unknown whether CAMK4 activation improves insulin action on glucose metabolism in vivo. METHODS: The effects of CAMK4 activation on skeletal muscle insulin action were quantified using transgenic mice with a truncated and constitutively active form of CAMK4 (CAMK4([Symbol: see text])) in skeletal muscle. Tissue-specific insulin sensitivity was assessed in vivo using a hyperinsulinaemic-euglycaemic clamp and isotopic measurements of glucose metabolism. RESULTS: The rate of insulin-stimulated whole-body glucose uptake was increased by ∼25% in CAMK4([Symbol: see text]) mice. This was largely attributed to an increase of ∼60% in insulin-stimulated glucose uptake in the quadriceps, the largest hindlimb muscle. These changes were associated with improvements in insulin signalling, as reflected by increased phosphorylation of Akt and its substrates and an increase in the level of GLUT4 protein. In addition, there were extramuscular effects: CAMK4([Symbol: see text]) mice had improved hepatic and adipose insulin action. These pleiotropic effects were associated with increased levels of PGC-1α-related myokines in CAMK4([Symbol: see text]) skeletal muscle. CONCLUSIONS/INTERPRETATION: Activation of CAMK4 enhances mitochondrial biogenesis in skeletal muscle while also coordinating improvements in whole-body insulin-mediated glucose.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinase Type 4/metabolism , Glucose/metabolism , Insulin/metabolism , Muscle, Skeletal/enzymology , Animals , Calcium-Calmodulin-Dependent Protein Kinase Type 4/genetics , Female , Male , Mice , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Transcription Factors/genetics
4.
Bioorg Med Chem Lett ; 23(9): 2560-5, 2013 May 01.
Article in English | MEDLINE | ID: mdl-23528296

ABSTRACT

The discovery and optimization of a novel series of FATP1 inhibitors are described. Through the derivatization process, arylpiperazine derivatives 5k and 12a were identified as possessing potent in vitro activity against human and mouse FATP1s as well as excellent pharmacokinetic properties. In vivo evaluation of triglyceride accumulation in the liver, white gastrocnemius muscle and soleus is also described.


Subject(s)
Fatty Acid Transport Proteins/antagonists & inhibitors , Piperazines/chemistry , Animals , Fatty Acid Transport Proteins/metabolism , Half-Life , Humans , Liver/metabolism , Mice , Muscle, Skeletal/metabolism , Piperazines/chemical synthesis , Piperazines/pharmacokinetics , Protein Binding , Structure-Activity Relationship , Triglycerides/metabolism
5.
Endocrinology ; 154(3): 1021-8, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23364948

ABSTRACT

Estrogen replacement therapy reduces the incidence of type 2 diabetes in postmenopausal women; however, the mechanism is unknown. Therefore, the aim of this study was to evaluate the metabolic effects of estrogen replacement therapy in an experimental model of menopause. At 8 weeks of age, female mice were ovariectomized (OVX) or sham (SHAM) operated, and OVX mice were treated with vehicle (OVX) or estradiol (E2) (OVX+E2). After 4 weeks of high-fat diet feeding, OVX mice had increased body weight and fat mass compared with SHAM and OVX+E2 mice. OVX mice displayed reduced whole-body energy expenditure, as well as impaired glucose tolerance and whole-body insulin resistance. Differences in whole-body insulin sensitivity in OVX compared with SHAM mice were accounted for by impaired muscle insulin sensitivity, whereas both hepatic and muscle insulin sensitivity were impaired in OVX compared with OVX+E2 mice. Muscle diacylglycerol (DAG), content in OVX mice was increased relative to SHAM and OVX+E2 mice. In contrast, E2 treatment prevented the increase in hepatic DAG content observed in both SHAM and OVX mice. Increases in tissue DAG content were associated with increased protein kinase Cε activation in liver of SHAM and OVX mice compared with OVX+E2 and protein kinase Cθ activation in skeletal muscle of OVX mice compared with SHAM and OVX+E2. Taken together, these data demonstrate that E2 plays a pivotal role in the regulation of whole-body energy homeostasis, increasing O(2) consumption and energy expenditure in OVX mice, and in turn preventing diet-induced ectopic lipid (DAG) deposition and hepatic and muscle insulin resistance.


Subject(s)
Diet, High-Fat/adverse effects , Estradiol/metabolism , Estradiol/pharmacology , Insulin Resistance/physiology , Liver/drug effects , Liver/metabolism , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Animals , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/prevention & control , Eating/drug effects , Energy Metabolism/drug effects , Estradiol/deficiency , Estrogen Replacement Therapy , Female , Glucose/metabolism , Homeostasis/drug effects , Humans , Lipid Metabolism/drug effects , Menopause/metabolism , Mice , Models, Animal , Ovariectomy , Protein Kinase C/metabolism
6.
Bioorg Med Chem Lett ; 22(15): 5067-70, 2012 Aug 01.
Article in English | MEDLINE | ID: mdl-22749869

ABSTRACT

The discovery, optimization and structure-activity relationship of novel FATP1 inhibitors have been described. The detailed SAR studies of each moiety of the inhibitors combined with metabolite analysis led to the identification of the potent inhibitors 11p and 11q with improved blood stability.


Subject(s)
Benzoxazoles/chemistry , Fatty Acid Transport Proteins/antagonists & inhibitors , Triazoles/chemistry , Administration, Oral , Animals , Benzoxazoles/chemical synthesis , Benzoxazoles/pharmacokinetics , Drug Evaluation, Preclinical , Fatty Acid Transport Proteins/metabolism , Humans , Injections, Intravenous , Mice , Rats , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/pharmacokinetics
7.
Biol Pharm Bull ; 34(7): 1094-104, 2011.
Article in English | MEDLINE | ID: mdl-21720019

ABSTRACT

Peroxisome proliferator-activated receptor γ (PPARγ; NR1C3) is known as a key regulator of adipocytogenesis and the molecular target of thiazolidinediones (TZDs), also known as antidiabetic agents. Despite the clinical benefits of TZDs, their use is often associated with adverse effects including peripheral edema, congestive heart failure, and weight gain. Here we report the identification and characterization of a non-thiazolidinedione PPARγ partial agonist, Cerco-A, which is a derivative of the natural product, (-)-cercosporamide. Cerco-A was found to be a binder of the PPARγ ligand-binding domain in a ligand competitive binding assay and showed a unique cofactor recruitment profile compared to rosiglitazone. A crystal structure analysis revealed that Cerco-A binds to PPARγ without direct hydrogen bonding to helix12. In PPARγ transcriptional activation assay and an adipocyte differentiation assay, Cerco-A was a potent partial agonist of PPARγ. After a 14-day oral administration, once per day of Cerco-A in Zucker diabetic fatty (ZDF) rats, an apparent decrease of plasma glucose and triglyceride was observed, as with pioglitazone. To evaluate drug safety, Cerco-A was administered for 13 days orally in non-diabetic Zucker fatty (ZF) rats. Each of the hemodilution parameters (hematocrit, red blood cells number, and hemoglobin), which are considered as undesirable effects of TZDs, was improved significantly compared to pioglitazone. While Cerco-A showed body weight gain, as with pioglitazone, Cerco-A had significantly lower effects on heart and white adipose tissues weight gain. The results suggest that Cerco-A offers beneficial effects on glycemic control with attenuated undesirable side effects.


Subject(s)
Benzofurans/pharmacology , PPAR gamma/pharmacology , Adipocytes/cytology , Adipocytes/drug effects , Animals , Base Sequence , Benzofurans/administration & dosage , Benzofurans/chemistry , Cell Differentiation/drug effects , Cell Line, Tumor , DNA Primers , Fluorescence Polarization , Humans , Ligands , Molecular Structure , PPAR gamma/genetics , PPAR gamma/metabolism , Rats , Rats, Zucker
8.
Hepatology ; 54(5): 1650-60, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21793029

ABSTRACT

UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) and insulin resistance have recently been found to be associated with increased plasma concentrations of apolipoprotein CIII (APOC3) in humans carrying single nucleotide polymorphisms within the insulin response element of the APOC3 gene. To examine whether increased expression of APOC3 would predispose mice to NAFLD and hepatic insulin resistance, human APOC3 overexpressing (ApoC3Tg) mice were metabolically phenotyped following either a regular chow or high-fat diet (HFD). After HFD feeding, ApoC3Tg mice had increased hepatic triglyceride accumulation, which was associated with cellular ballooning and inflammatory changes. ApoC3Tg mice also manifested severe hepatic insulin resistance assessed by a hyperinsulinemic-euglycemic clamp, which could mostly be attributed to increased hepatic diacylglycerol content, protein kinase C-ϵ activation, and decreased insulin-stimulated Akt2 activity. Increased hepatic triglyceride content in the HFD-fed ApoC3Tg mice could be attributed to a ≈ 70% increase in hepatic triglyceride uptake and ≈ 50% reduction hepatic triglyceride secretion. CONCLUSION: These data demonstrate that increase plasma APOC3 concentrations predispose mice to diet-induced NAFLD and hepatic insulin resistance.


Subject(s)
Apolipoprotein C-III/blood , Apolipoprotein C-III/genetics , Fatty Liver/genetics , Fatty Liver/metabolism , Insulin Resistance/genetics , Animal Feed , Animals , Apolipoprotein B-100/metabolism , Blood Glucose/metabolism , Cholesterol, VLDL/metabolism , Dietary Fats/pharmacology , Diglycerides/metabolism , Female , Genetic Predisposition to Disease/genetics , Hyperinsulinism/metabolism , Male , Mice , Mice, Mutant Strains , Non-alcoholic Fatty Liver Disease , Postprandial Period/physiology , Protein Kinase C/metabolism , Triglycerides/metabolism , Triglycerides/pharmacokinetics
9.
Proc Natl Acad Sci U S A ; 108(14): 5748-52, 2011 Apr 05.
Article in English | MEDLINE | ID: mdl-21436037

ABSTRACT

Mice overexpressing acylCoA:diacylglycerol (DAG) acyltransferase 2 in the liver (Liv-DGAT2) have been shown to have normal hepatic insulin responsiveness despite severe hepatic steatosis and increased hepatic triglyceride, diacylglycerol, and ceramide content, demonstrating a dissociation between hepatic steatosis and hepatic insulin resistance. This led us to reevaluate the role of DAG in causing hepatic insulin resistance in this mouse model of severe hepatic steatosis. Using hyperinsulinemic-euglycemic clamps, we studied insulin action in Liv-DGAT2 mice and their wild-type (WT) littermate controls. Here, we show that Liv-DGAT2 mice manifest severe hepatic insulin resistance as reflected by decreased suppression of endogenous glucose production (0.8 ± 41.8 vs. 87.7 ± 34.3% in WT mice, P < 0.01) during the clamps. Hepatic insulin resistance could be attributed to an almost 12-fold increase in hepatic DAG content (P < 0.01) resulting in a 3.6-fold increase in protein kinase Cε (PKCε) activation (P < 0.01) and a subsequent 52% decrease in insulin-stimulated insulin receptor substrate 2 (IRS-2) tyrosine phosphorylation (P < 0.05), as well as a 64% decrease in fold increase pAkt/Akt ratio from basal conditions (P < 0.01). In contrast, hepatic insulin resistance in these mice was not associated with increased endoplasmic reticulum (ER) stress or inflammation. Importantly, hepatic insulin resistance in Liv-DGAT2 mice was independent of differences in body composition, energy expenditure, or food intake. In conclusion, these findings strengthen the link between hepatic steatosis and hepatic insulin resistance and support the hypothesis that DAG-induced PKCε activation plays a major role in nonalcoholic fatty liver disease (NAFLD)-associated hepatic insulin resistance.


Subject(s)
Diacylglycerol O-Acyltransferase/metabolism , Fatty Liver/metabolism , Insulin Resistance/physiology , Liver/enzymology , Analysis of Variance , Animals , Blood Glucose , Cytokines/blood , Endoplasmic Reticulum/metabolism , Fatty Acids/blood , Immunoprecipitation , Insulin Receptor Substrate Proteins/metabolism , Mice , Micropore Filters , Phosphorylation , Protein Kinase C-epsilon/metabolism , Reverse Transcriptase Polymerase Chain Reaction
10.
J Pharmacol Sci ; 115(3): 329-35, 2011.
Article in English | MEDLINE | ID: mdl-21350313

ABSTRACT

Contributions of gluconeogenesis suppression in liver, kidney, and intestine as major gluconeogenic organs to the glucose-lowering effect of CS-917, a fructose 1,6-bisphosphatase inhibitor, was evaluated in overnight-fasted Goto-Kakizaki (GK) rats. CS-917 decreased plasma glucose by suppressing glucose release and lactate uptake from liver but not from kidney and intestine. These results suggest that hepatic gluconeogenesis suppression predominantly contributes to the glucose-lowering effect of CS-917 in GK rats. Moreover, the mechanism by which CS-917 decreased plasma glucose more in overnight-fasted GK rats than in non-fasted ones was investigated. Lactate uptake from liver was suppressed by 15 mg/kg of CS-917 in both states, but glucose release from liver and plasma glucose were decreased only in the overnight-fasted state. CS-917 at 30 mg/kg decreased hepatic glycogen content in both states and depleted it in the overnight-fasted state. In the non-fasted GK rats, co-administration of CS-917 with CP-91149, a glycogen phosphorylase inhibitor, suppressed hepatic glycogen reduction by CS-917 and decreased plasma glucose more than single administration of CS-917. These results suggest that gluconeogenesis suppression by CS-917 was counteracted by hepatic glycogenolysis especially in the non-fasted state and that combination therapy with CS-917 and CP-91149 is efficacious to decrease plasma glucose in GK rats.


Subject(s)
Alanine/analogs & derivatives , Amides/pharmacology , Blood Glucose/drug effects , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/drug therapy , Gluconeogenesis/drug effects , Glycogenolysis/drug effects , Hypoglycemic Agents/pharmacology , Indoles/pharmacology , Organophosphorus Compounds/pharmacology , Alanine/pharmacology , Animals , Drug Evaluation, Preclinical , Fasting/physiology , Glucose/metabolism , Lactic Acid/metabolism , Male , Organophosphonates , Peptide Hydrolases/metabolism , Rats
11.
J Pharmacol Sci ; 111(2): 155-66, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19809220

ABSTRACT

The pharmacological effects of rivoglitazone, a novel thiazolidinedione-derivative peroxisome proliferator-activated receptor (PPAR)-gamma agonist, were characterized in vitro and in vivo. Rivoglitazone activated human PPARgamma more potently compared with rosiglitazone and pioglitazone and had little effect on PPARalpha and PPARdelta activity in luciferase reporter assays. In Zucker diabetic fatty (ZDF) rats, 14-day administration of rivoglitazone decreased the plasma glucose and triglyceride (TG) levels in a dose-dependent manner. The glucose-lowering effect of rivoglitazone was much more potent than those of pioglitazone (ED(50): 0.19 vs. 34 mg/kg) and rosiglitazone (ED(50): 0.20 vs. 28 mg/kg). In addition, rivoglitazone showed potent antidiabetic effects in diabetic db/db mice. In Zucker fatty rats, rivoglitazone at a dose of 0.1 mg/kg clearly ameliorated insulin resistance and lowered plasma TG levels by accelerating the clearance of plasma TG. Gene expression analysis in the liver and heart of ZDF rats treated with rivoglitazone for 14 days suggested that rivoglitazone may reduce hepatic glucose production and modulate the balance of the cardiac glucose/fatty acid metabolism in diabetic animals. In summary, we showed that rivoglitazone is a potent and selective PPARgamma agonist and has a potent glucose-lowering effect via improvement of the insulin resistance in diabetic animal models.


Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/pharmacology , Obesity/drug therapy , PPAR gamma/agonists , Thiazolidinediones/pharmacology , Adiponectin/analysis , Adiponectin/metabolism , Animals , Blood Glucose/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Gene Expression Regulation/drug effects , Glucose/metabolism , Hypoglycemic Agents/therapeutic use , Inhibitory Concentration 50 , Insulin/analysis , Insulin/metabolism , Insulin Resistance/genetics , Liver/metabolism , Male , Metabolic Clearance Rate , Mice , Mice, Obese , Myocardium/metabolism , Pancreas/metabolism , Rats , Rats, Zucker , Sensitivity and Specificity , Time Factors , Triglycerides/blood
12.
Eur J Pharmacol ; 623(1-3): 141-7, 2009 Nov 25.
Article in English | MEDLINE | ID: mdl-19765581

ABSTRACT

Metformin is an anti-diabetic agent that has been reported to decrease plasma glucose by multiple mechanisms, such as decreasing hepatic glucose production and activating peripheral glucose utilization. In order to elucidate the primary glucose-lowering mechanism of metformin, the present study focused on a comparison of the acute effect between metformin and CS-917 as a direct gluconeogenesis inhibitor. We examined the effect of metformin and CS-917 on glucose turnover in intravenous glucose-loaded Goto-Kakizaki (GK) rats, and on gluconeogenesis and glucose utilization in rat hepatocytes. Moreover, the glucose-lowering effect of metformin and CS-917 was compared in a fed and a fasted state in GK rats. In intravenous glucose-loaded GK rats, metformin and CS-917 lowered plasma glucose by increasing the glucose disappearance rate and by decreasing the glucose appearance rate, respectively. In rat hepatocytes, CS-917 but not metformin suppressed gluconeogenesis (IC(50)=0.136microM). Instead, metformin dose-dependently increased glucose uptake and the following lactate production at 30 to 100microM. Metformin decreased plasma glucose more in a fed state than in a fasted state in GK rats. CS-917, however, decreased plasma glucose more in a fasted state. These results confirm that metformin primarily decreases plasma glucose not by gluconeogenesis inhibition but by activating glucose utilization in GK rats. Moreover, metformin and CS-917 have different glucose-lowering effects depending on the nutrient state, which may be related to differences in their mechanisms of action. Such differences in action may have implications for metformin and CS-917 in the treatment of type 2 diabetes patients.


Subject(s)
Alanine/analogs & derivatives , Diabetes Mellitus, Type 2/drug therapy , Fructose-Bisphosphatase/antagonists & inhibitors , Gluconeogenesis/drug effects , Glucose/metabolism , Hypoglycemic Agents/pharmacology , Metformin/pharmacology , Organophosphorus Compounds/pharmacology , Alanine/metabolism , Alanine/pharmacology , Animals , Blood Glucose/analysis , Blood Glucose/metabolism , Cells, Cultured , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Dose-Response Relationship, Drug , Glucose/pharmacokinetics , Hepatocytes/drug effects , Hepatocytes/metabolism , Hypoglycemic Agents/metabolism , Inhibitory Concentration 50 , Insulin/blood , Lactic Acid/metabolism , Male , Metformin/metabolism , Organophosphonates , Organophosphorus Compounds/metabolism , Radioisotope Dilution Technique , Rats , Rats, Mutant Strains , Rats, Wistar
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