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3.
J Nutr Biochem ; 23(4): 313-9, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22423897

ABSTRACT

Type 2 diabetes is often associated with obesity, dyslipidemia and cardiovascular anomalies and is a major health problem approaching global epidemic proportions. Insulin resistance, a prediabetic condition, precedes the onset of frank type 2 diabetes and offers potential avenues for early intervention to treat the disease. Although lifestyle modifications and exercise can reduce the incidence of diabetes, compliance has proved to be difficult, warranting pharmacological interventions. However, most of the currently available drugs that improve insulin sensitivity have adverse effects. Therefore, attractive strategies to alleviate insulin resistance include dietary supplements. One such supplement is chromium, which has been shown to reduce insulin resistance in some, but not all, studies. Furthermore, the molecular mechanisms of chromium in alleviating insulin resistance remain elusive. This review examines emerging reports on the effect of chromium, as well as molecular and cellular mechanisms by which chromium may provide beneficial effects in alleviating insulin resistance.


Subject(s)
Chromium/therapeutic use , Dietary Supplements , Insulin Resistance , Diabetes Mellitus, Type 2/drug therapy , Early Medical Intervention , Exercise , Humans , Life Style , Obesity/complications , Obesity/drug therapy , Phosphorylation/drug effects , Randomized Controlled Trials as Topic , Receptor, Insulin/metabolism
4.
J Inorg Biochem ; 106(1): 32-42, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22112837

ABSTRACT

Gold(III) compounds have been recognized as anticancer agents due to their structural and electronic similarities with currently employed platinum(II) species. An added benefit to gold(III) agents is the ability to overcome cisplatin resistance. This work identified four gold(III) compounds, [Au(Phen)Cl(2)]PF(6), [Au(DPQ)Cl(2)]PF(6), [Au(DPPZ)Cl(2)]PF(6), and [Au(DPQC)Cl(2)]PF(6), (Phen = 1,10-phenanthroline, DPQ = dipyrido[3,2-d:2',3'-f]quinoxaline, DPPZ = dipyrido[3,2-a:2',3'-c] phenazine, DPQC = dipyrido[3,2-d:2',3'-f] cyclohexyl quinoxaline) that exhibited anticancer activity in both cisplatin sensitive and cisplatin resistant ovarian cancer cells. Two of these compounds, [Au(DPQ)Cl(2)]PF(6) (AQ) and [Au(DPPZ)Cl(2)]PF(6) (AZ), displayed exceptional anticancer activity and were the focus of more intensive mechanistic study. At the molecular level, AQ and AZ formed DNA adducts, generated free radicals, and upregulated pro-apoptotic signaling molecules (p53, caspases, PARP, death effectors). Taken together, these two novel gold(III) polypyridyl complexes exhibit potent antitumor activity in cisplatin resistant cancer cells. These activities may be mediated, in part, by the activation of apoptotic signaling.


Subject(s)
Antineoplastic Agents/chemistry , Cisplatin/chemistry , Gold/chemistry , Organometallic Compounds/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Blotting, Western , Caspases/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Circular Dichroism , Cisplatin/pharmacology , DNA Adducts/chemistry , DNA, Neoplasm/chemistry , Drug Resistance, Neoplasm/drug effects , Female , Humans , Inhibitory Concentration 50 , Molecular Mimicry , Molecular Structure , Organometallic Compounds/pharmacology , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Poly(ADP-ribose) Polymerases/metabolism , Reactive Oxygen Species/metabolism , Tumor Suppressor Protein p53/metabolism
5.
J Mol Cell Cardiol ; 50(1): 107-16, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21035453

ABSTRACT

ER stress is involved in the pathophysiology of obesity although little is known about the role of ER stress on obesity-associated cardiac dysfunction. This study was designed to examine the effect of ER chaperone tauroursodeoxycholic acid (TUDCA) on obesity-induced myocardial dysfunction. Adult lean and ob/ob obese mice were treated with TUDCA (50mg/kg/day, p.o.) or vehicle for 5 weeks. Oral glucose tolerance test (OGTT) was performed. Echocardiography, cardiomyocyte contractile and intracellular Ca(2+) properties were assessed. Sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) activity and protein expression of intracellular Ca(2+) regulatory proteins were measured using (45)Ca(2+) uptake and Western blot analysis, respectively. Insulin signaling, ER stress markers and HSP90 were evaluated. Our results revealed that chronic TUDCA treatment lowered systolic blood pressure and lessened glucose intolerance in obese mice. Obesity led to increased diastolic diameter, cardiac hypertrophy, compromised fractional shortening, cardiomyocyte contractile (peak shortening, maximal velocity of shortening/relengthening, and duration of contraction/relaxation) and intracellular Ca(2+) properties, all of which were significantly attenuated by TUDCA. TUDCA reconciled obesity-associated decrease in SERCA activity and expression, and increase in serine phosphorylation of IRS, total and phosphorylated cJun, ER stress markers Bip, peIF2α and pPERK. Obesity-induced changes in phospholamban and HSP90 were unaffected by TUDCA. In vitro finding revealed that TUDCA ablated palmitic acid-induced cardiomyocyte contractile dysfunction. In summary, these data depicted a pivotal role of ER stress in obesity-associated cardiac contractile dysfunction, suggesting the therapeutic potential of ER stress as a target in the management of cardiac dysfunction in obesity.


Subject(s)
Endoplasmic Reticulum/metabolism , Myocardial Contraction/drug effects , Myocytes, Cardiac/drug effects , Obesity/physiopathology , Taurochenodeoxycholic Acid/pharmacology , Animals , Blood Pressure/drug effects , Blotting, Western , Calcium/metabolism , Cells, Cultured , Echocardiography , Glucose Tolerance Test , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Myocytes, Cardiac/metabolism , Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism
6.
J Inorg Biochem ; 105(1): 58-62, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21134603

ABSTRACT

High-fat diet has been implicated as a major cause of insulin resistance and dyslipidemia. The objective of this study was to evaluate the impact of dietary-supplementation of chromium (D-phenylalanine)(3) [Cr(D-Phe)(3)] on glucose and insulin tolerance in high-fat diet fed mice. C57BL/6-mice were randomly assigned to orally receive vehicle or Cr(D-Phe)(3) (45 µg of elemental chromium/kg/day) for 8-weeks. High-fat-fed mice exhibited impaired whole-body-glucose and -insulin tolerance and elevated serum triglyceride levels compared to normal chow-fed mice. Insulin-stimulated glucose up-take in the gastrocnemius muscles, assessed as 2-[(3)H-deoxyglucose] incorporation was markedly diminished in high-fat fed mice compared to control mice. Treatment with chromium reconciled the high-fat diet-induced alterations in carbohydrate and lipid metabolism. Treatment of cultured, differentiated myotubes with palmitic acid evoked insulin resistance as evidenced by lower levels of insulin-stimulated Akt-phosphorylation, elevated JNK-phosphorylation, (assessed by Western blotting), attenuation of phosphoinositol-3-kinase activity (determined in the insulin-receptor substrate-1-immunoprecipitates by measuring the extent of phosphorylation of phosphatidylinositol by γ-(32)P-ATP), and impairment in cellular glucose up-take, all of which were inhibited by Cr(d-Phe)(3). These results suggest a beneficial effect of chromium-supplementation in insulin resistant conditions. It is likely that these effects of chromium may be mediated by augmenting downstream insulin signaling.


Subject(s)
Dietary Fats/adverse effects , Insulin Resistance/physiology , Lipid Metabolism/drug effects , Organometallic Compounds/pharmacology , Phenylalanine/analogs & derivatives , Animals , Blood Glucose/drug effects , Blotting, Western , Cell Line , Male , Mice , Mice, Inbred C57BL , Phenylalanine/pharmacology , Random Allocation , Signal Transduction/drug effects
7.
Toxicol Mech Methods ; 20(6): 321-33, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20515439

ABSTRACT

Chromium(III) is an essential trace element required for normal protein, fat and carbohydrate metabolism. It also helps in energy production and increasing lean body mass. Chromium(III) dinicocysteinate (CDNC) is a unique form of bioavailable chromium(III). This study was focused on determining the broad spectrum safety of CDNC. Acute oral, acute dermal, primary dermal and eye irritation studies, Ames' bacterial reverse mutation assay, mammalian erythrocyte micronucleus test, and a 90-day dose-dependent oral toxicity study were conducted. Acute oral and dermal LD(50) of CDNC was found to be greater than 2000 mg/kg in Sprague-Dawley rats. A primary skin irritation study in New Zealand Albino rabbits demonstrated CDNC as slightly irritating. An eye irritation study exhibited that CDNC is moderately irritating. Ames' bacterial reverse mutation assay and mammalian erythrocyte micronucleus test demonstrated CDNC as non-mutagenic. A dose-dependent 90-day oral toxicity study demonstrated no significant toxicity of CDNC. Body weight, food and water consumption, selected organ weights (expressed as percentages of body or brain weights), ocular health, hematology, blood chemistry, and histopathology showed no abnormal changes. Clinical and histopathological evaluation of CDNC identified a dose level of 5.7 mg/kg/day as the no observed adverse effect level (NOAEL). Overall, these results demonstrate the broad spectrum safety of CDNC.


Subject(s)
Chromium/toxicity , Consumer Product Safety , Cysteine/toxicity , Toxicity Tests/methods , Animals , Body Weight/drug effects , Cysteine/analogs & derivatives , Eye/drug effects , Female , Male , Motor Activity/drug effects , Mutagenicity Tests , Organ Size/drug effects , Organ Specificity/drug effects , Rabbits , Rats , Rats, Sprague-Dawley , Sex Factors , Skin/drug effects , Skin Irritancy Tests , Toxicity Tests, Acute , Toxicity Tests, Chronic
8.
Biochem Biophys Res Commun ; 395(1): 146-51, 2010 Apr 23.
Article in English | MEDLINE | ID: mdl-20361929

ABSTRACT

AMP-activated protein kinase (AMPK) is a key regulator of energy metabolism; its activity is regulated by a plethora of physiological conditions, exercises and many anti-diabetic drugs. Recent studies show that AMPK involves in cell differentiation but the underlying mechanism remains undefined. Wingless Int-1 (Wnt)/beta-catenin signaling pathway regulates the differentiation of mesenchymal stem cells through enhancing beta-catenin/T-cell transcription factor 1 (TCF) mediated transcription. The objective of this study was to determine whether AMPK cross-talks with Wnt/beta-catenin signaling through phosphorylation of beta-catenin. C3H10T1/2 mesenchymal cells were used. Chemical inhibition of AMPK and the expression of a dominant negative AMPK decreased phosphorylation of beta-catenin at Ser 552. The beta-catenin/TCF mediated transcription was correlated with AMPK activity. In vitro, pure AMPK phosphorylated beta-catenin at Ser 552 and the mutation of Ser 552 to Ala prevented such phosphorylation, which was further confirmed using [gamma-(32)P]ATP autoradiography. In conclusion, AMPK phosphorylates beta-catenin at Ser 552, which stabilizes beta-catenin, enhances beta-catenin/TCF mediated transcription, expanding AMPK from regulation of energy metabolism to cell differentiation and development via cross-talking with the Wnt/beta-catenin signaling pathway.


Subject(s)
Protein Kinases/metabolism , Wnt1 Protein/metabolism , beta Catenin/metabolism , AMP-Activated Protein Kinase Kinases , Animals , Cell Line , Mesenchymal Stem Cells/metabolism , Mice , Phosphorylation , Protein Kinases/genetics , Serine/genetics , Serine/metabolism , Transcription, Genetic , beta Catenin/genetics
9.
Biochem Pharmacol ; 79(4): 623-31, 2010 Feb 15.
Article in English | MEDLINE | ID: mdl-19769946

ABSTRACT

Type-2 diabetes is growing at epidemic proportions world-wide. This report describes the effect of a novel, synthetic, small molecule 2-(3,4-dihydro-2H-pyrrolium-1-yl)-3oxoindan-1-olate (DHPO), on metabolic abnormalities in genetic and dietary mouse models of type-2 diabetes. DHPO (20mg/kg/d i.p. for 21 days) attenuated fasting blood glucose, improved glucose disposal and corrected dyslipidemia in genetic (leptin deficient, ob/ob) and dietary (high-fat-fed) mouse models of insulin resistance. In addition, DHPO augmented 2-deoxy-d-glucose (2DG) uptake in gastrocnemius muscles of wild-type mice and in cultured myotubes. The increase in 2DG-uptake was associated with an increase in the phosphorylation of AMPK (thr-172) and its downstream effector acetyl-CoA carboxylase without any changes in the phosphorylation of Akt of insulin receptor. The AMPK inhibitor, compound C attenuated DHPO-induced glucose-uptake whereas the PI3-kinase inhibitor Wortmannin was less effective. In addition, DHPO failed to augment glucose-uptake in the gastrocnemius muscle from AMPK-alpha2-transgenic (kinase-dead) mice. Taken together, these results suggest that DHPO is a novel small molecule that alleviates impaired glucose tolerance and lipid abnormalities associated with type-2 diabetes.


Subject(s)
Drugs, Investigational/pharmacology , Indans/pharmacology , Insulin Resistance , Lipid Metabolism/drug effects , Pyrroles/pharmacology , Animals , Blood Glucose/metabolism , Cells, Cultured , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Drugs, Investigational/chemistry , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Indans/chemical synthesis , Indans/therapeutic use , Insulin Resistance/physiology , Lipid Metabolism/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Mice, Transgenic , Pyrroles/chemical synthesis , Pyrroles/therapeutic use
10.
J Cardiovasc Pharmacol ; 55(1): 49-55, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19834331

ABSTRACT

BACKGROUND/AIM: Recent evidence suggests that endoplasmic reticulum (ER) stress provoked under diabetic conditions augments the expression of scavenger receptors on macrophages, promoting the uptake of oxidized low-density lipoprotein uptake and atherogenesis. The aim of the present study was to test the hypothesis that the chemical chaperone tauroursodeoxycholic acid (TUDCA) attenuates lipid accumulation in macrophages subjected to ER stress. METHODS: Cultured human macrophages were subjected to ER stress by treating them with tunicamycin. Lipid uptake by macrophages subjected to ER stress in the presence or absence of TUDCA was assessed by oil red O staining and by assessing the cellular uptake of Dil-oxidized low-density lipoprotein by fluorescence measurement. Protein levels and phosphorylation status of ER stress markers, insulin-signaling molecules, and scavenger receptor were assessed by Western blotting. RESULTS: Treatment of cultured human macrophages with the ER stressor tunicamycin caused an increase in the protein levels of cluster of differentiation 36 (CD-36) and augmentation of lipid uptake both of which were inhibited by TUDCA. TUDCA treatment inhibited tunicamycin-induced ER stress as evidenced by the attenuation of phosphorylation of eukaryotic translation initiation factor-2a and glucose reactive protein-78. In addition, TUDCA improved insulin signaling in macrophages by augmenting Akt phosphorylation and blunting c-Jun N-terminal kinase activity. CONCLUSIONS: Inhibition of macrophage ER stress may represent a potential strategy in preventing atherogenesis under diabetic conditions.


Subject(s)
Endoplasmic Reticulum/drug effects , Lipid Metabolism/drug effects , Macrophages/drug effects , Taurochenodeoxycholic Acid/pharmacology , Blotting, Western , CD36 Antigens/metabolism , Cells, Cultured , Endoplasmic Reticulum/metabolism , Humans , Insulin/metabolism , Lipoproteins, LDL/drug effects , Lipoproteins, LDL/metabolism , Macrophages/metabolism , Phosphorylation/drug effects , Signal Transduction/drug effects , Tunicamycin/pharmacology
11.
J Nutr Biochem ; 20(12): 992-9, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19071005

ABSTRACT

Skeletal muscle atrophy and whole-body glucose intolerance are consequences of muscle disuse associated with conditions leading to prolonged bed rest. Nutritional supplementation with chromium has been shown to prevent weight loss and improve glucose tolerance in malnourished subjects on long-term total parenteral nutrition. The objective of this study was to evaluate the effect of oral supplementation with a novel chromium complex, chromium (d-phenylalanine)(3) [Cr(d-phe)(3)] at 45 microg/kg/day for 5 weeks, on skeletal muscle atrophy and glucose intolerance in a hindlimb suspension mouse model. Hindlimb-suspended mice exhibited reduced skeletal muscle fiber size and enhanced whole-body glucose intolerance, both of which were reversed by chromium treatment. The inhibition of skeletal muscle atrophy by chromium was associated with reductions in the ubiquitination ligase atrogin-1/muscle atrophy F-box, which is elevated in hindlimb-suspended mice. Neither hindlimb suspension nor chromium treatment altered the protein levels of the myostatin, phospho-Forkhead box O-1 and mammalian target of rapamycin. Chromium-treated animals exhibited elevated Akt (Homo sapiens v-akt murine thymoma viral oncogene homolog) phosphorylation in their skeletal muscle, with no change observed in the levels of activated JNK (c-Jun N-terminal kinase). Thus, these data suggest that nutritional supplementation with chromium may have potential therapeutic benefits in minimizing skeletal muscle atrophy associated with long periods of muscle disuse.


Subject(s)
Chromium/pharmacology , Muscular Atrophy/prevention & control , Organometallic Compounds/pharmacology , Phenylalanine/analogs & derivatives , Animals , Forkhead Box Protein O1 , Forkhead Transcription Factors/metabolism , Glucose Tolerance Test , Hindlimb Suspension , Intracellular Signaling Peptides and Proteins/metabolism , JNK Mitogen-Activated Protein Kinases/metabolism , Male , Mice , Mice, Inbred C57BL , Muscle Proteins/metabolism , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Muscular Atrophy/pathology , Phenylalanine/pharmacology , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , SKP Cullin F-Box Protein Ligases/metabolism , TOR Serine-Threonine Kinases
12.
J Cardiovasc Pharmacol ; 52(5): 422-9, 2008 Nov.
Article in English | MEDLINE | ID: mdl-19033821

ABSTRACT

BACKGROUND/AIMS: Growth factor and oxidative stress-mediated migration and proliferation of vascular smooth muscle cells (VSMCs) play a key role in the pathogenesis of atherosclerosis. The objective of this study was to assess the ability of dehydrozingerone, a structural analog of curcumin, to inhibit PDGF-stimulated vascular functions in VSMCs. METHODS: VSMCs isolated from adult rats were treated with dehydrozingerone (0 to 50 microM) before challenge with PDGF (10 ng/mL) and migration, proliferation, and collagen synthesis were assayed by transwell-migration, thymidine-, and L-proline-incorporation assays, respectively. Phosphorylation of PDGF-receptor (PDGFR) and Akt were assessed by Western blotting. Cellular protein tyrosine phosphatase (PTP) activity was determined by the extent of p-nitro-phenyl phosphate hydrolysis. RESULTS: Dehydrozingerone elicited a concentration-dependent inhibition of PDGF-stimulated VSMC migration, proliferation, collagen synthesis, and PDGF/H2O2-stimulated phosphorylation of PDGFR-beta and downstream Akt. Dehydrozingerone also inhibited H2O2-mediated oxidation of PTP. CONCLUSIONS: Dehydrozingerone is a potent inhibitor of growth factor/ H2O2-stimulated VSMC functions and may play a critical role in regulating these events after vascular injury. Inhibition of oxidation of cellular phosphatases may represent one of the mechanisms by which dehydrozingerone inhibits these VSMC functions. Inability of the structural analog isoeugenol to inhibit PDGF-signaling suggests that the carbonyl side chain may be necessary for activity.


Subject(s)
Cell Movement/drug effects , Cell Proliferation/drug effects , Collagen/biosynthesis , Muscle, Smooth, Vascular/drug effects , Styrenes/pharmacology , Animals , Aorta, Thoracic/cytology , Aorta, Thoracic/drug effects , Aorta, Thoracic/enzymology , Aorta, Thoracic/metabolism , Cells, Cultured , Curcumin/pharmacology , Dose-Response Relationship, Drug , Electrophoresis, Polyacrylamide Gel , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/enzymology , Muscle, Smooth, Vascular/metabolism , Phosphorylation , Platelet-Derived Growth Factor/metabolism , Platelet-Derived Growth Factor/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Platelet-Derived Growth Factor beta/metabolism , Signal Transduction , Tunica Intima/drug effects , Tunica Intima/enzymology , Tunica Intima/metabolism
13.
J Nutr ; 138(10): 1846-51, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18806091

ABSTRACT

Chromium has gained popularity as a nutritional supplement for diabetic and insulin-resistant subjects. This study was designed to evaluate the effect of chronic administration of a novel chromium complex of d-phenylalanine [Cr(D-phe)(3)] in insulin-resistant, sucrose-fed mice. Whole-body insulin resistance was generated in FVB mice by 9 wk of sucrose feeding, following which they were randomly assigned to be unsupplemented (S group) or to receive oral Cr(D-phe)(3) in drinking water (SCr group) at a dose of 45 mug.kg(-1).d(-1) ( approximately 3.8 mug of elemental chromium.kg(-1).d(-1)). A control group (C) did not consume sucrose and was not supplemented. Sucrose-fed mice had an elevated serum insulin concentration compared with controls and this was significantly lower in sucrose-fed mice that received Cr(D-phe)(3), which did not differ from controls. Impaired glucose tolerance in sucrose-fed mice, evidenced by the poor glucose disposal rate following an intraperitoneal glucose tolerance test, was significantly improved in mice receiving Cr(D-phe)(3). Chromium supplementation significantly enhanced insulin-stimulated Akt phosphorylation and membrane-associated glucose transporter-4 in skeletal muscles of sucrose-fed mice. In cultured adipocytes rendered insulin resistant by chronic exposure to high concentrations of glucose and insulin, Cr(D-phe)(3) augmented Akt phosphorylation and glucose uptake. These results indicate that dietary supplementation with Cr(D-phe)(3) may have potential beneficial effects in insulin-resistant, prediabetic conditions.


Subject(s)
Blood Glucose/drug effects , Glucose Transporter Type 4/metabolism , Insulin Resistance , Insulin/physiology , Organometallic Compounds/pharmacology , Phenylalanine/analogs & derivatives , Protein Transport/drug effects , Signal Transduction/drug effects , Animal Feed , Animals , Biological Transport/drug effects , Blood Glucose/metabolism , Deoxyglucose/metabolism , Dietary Supplements , Glucose Tolerance Test , Glucose Transporter Type 4/drug effects , Insulin/pharmacology , Mice , Muscle Proteins/drug effects , Muscle Proteins/metabolism , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Phenylalanine/pharmacology
14.
Eur J Pharmacol ; 593(1-3): 30-5, 2008 Sep 28.
Article in English | MEDLINE | ID: mdl-18692042

ABSTRACT

Argpyrimidine, the product of non-enzymatic protein glycation by methylglyoxal, has been implicated in the pathophysiology of diabetes mellitus and neurodegenerative diseases. Chemically, argpyrimidine is a substituted pyrimidinol with structural features common to known antioxidants. The objective of this study was to investigate the antioxidant properties of argpyrimidine. Argpyrimidine was synthesized by mixing L-arginine with 3-acetoxypentane-2,4-dione under acidic conditions and purified by chromatography. Argpyrimidine inhibited lipid peroxidation of rat brain homogenates catalyzed by hydroxyl radicals, metal ions, and autooxidation in a concentration- and time-dependent manner. In addition, argpyrimidine scavenged superoxide anion, 1,1-diphenyl 2-picryl-hydrazyl-stable free radical, intracellular-hydrogen peroxide, and inhibited free-radical-mediated nicking of plasmid-DNA. Taken together, our data suggest that argpyrimidine has antioxidant properties and may therefore have biological relevance in pathophysiologies associated with diabetes mellitus and neurodegenerative diseases.


Subject(s)
Antioxidants , Free Radical Scavengers , Ornithine/analogs & derivatives , Pyrimidines/pharmacology , Ascorbic Acid/antagonists & inhibitors , Ascorbic Acid/pharmacology , Biphenyl Compounds , Cell Line, Tumor , DNA/drug effects , Ferric Compounds/chemistry , Ferrous Compounds/chemistry , Humans , Hydrogen Peroxide/antagonists & inhibitors , Hydrogen Peroxide/pharmacology , In Situ Nick-End Labeling , Lipid Peroxidation/drug effects , Ornithine/chemical synthesis , Ornithine/pharmacology , Oxidants/pharmacology , Oxidation-Reduction , Oxidative Stress/drug effects , Picrates/chemistry , Plasmids/genetics , Pyrimidines/chemical synthesis , Superoxides/metabolism
15.
Obesity (Silver Spring) ; 16(6): 1331-7, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18388893

ABSTRACT

OBJECTIVE: Chromium has gained popularity as a nutritional supplement for diabetic patients. This study evaluated the effect of chronic administration of a chromium complex of D-phenylalanine (Cr(D-phe)(3)) on glucose and insulin tolerance in obese mice. The study tested the hypothesis that Cr(D-phe)(3) suppresses endoplasmic reticulum (ER) stress and insulin resistance in these animals. METHODS AND PROCEDURES: C57BL lean and ob/ob obese mice were randomly divided to orally receive vehicle or Cr(D-phe)(3) (3.8 mug of elemental chromium/kg/day) for 6 months. Insulin sensitivity was evaluated by glucose and insulin tolerance tests. Protein levels of phosphorylated pancreatic ER kinase (PERK), alpha subunit of translation initiation factor 2 (eIF2alpha) and inositol-requiring enzyme-1 (IRE-1), p-c-Jun, and insulin receptor substrate-1 (IRS-1) phosphoserine-307 were assessed by western blotting. In vitro ER stress was induced by treating cultured muscle cells with thapsigargin in the presence or absence of Cr(D-phe)(3). RESULTS: ob/ob mice showed poor glucose and insulin tolerance compared to the lean controls, which was attenuated by Cr(D-phe)(3). Markers of insulin resistance (phospho-c-Jun and IRS-1 phosphoserine) and ER stress (p-PERK, p-IRE-1, p-eIF2alpha), which were elevated in ob/ob mice, were attenuated following Cr(D-phe)(3) treatment. Chromium treatment was also associated with a reduction in liver triglyceride levels and lipid accumulation. In cultured myotubes, Cr(D-phe)(3) attenuated ER stress induced by thapsigargin. DISCUSSION: Oral Cr(D-phe)(3) treatment reduces glucose intolerance, insulin resistance, and hepatic ER stress in obese, insulin-resistant mice.


Subject(s)
Chromium/pharmacology , Endoplasmic Reticulum/physiology , Glucose Intolerance/physiopathology , Insulin Resistance/physiology , Liver/metabolism , Obesity/physiopathology , Trace Elements/pharmacology , Animals , Blood Glucose/metabolism , Chromium/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/physiopathology , Disease Models, Animal , Endoplasmic Reticulum/drug effects , Glucose Intolerance/drug therapy , Insulin/blood , Leptin/blood , Lipids/blood , Liver/drug effects , Male , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Obese , Obesity/drug therapy , Obesity/metabolism , Protein Serine-Threonine Kinases/metabolism , Thapsigargin/pharmacology , Trace Elements/therapeutic use , eIF-2 Kinase/metabolism
16.
Am J Physiol Regul Integr Comp Physiol ; 294(3): R793-802, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18199585

ABSTRACT

IGF-I rescues diabetic heart defects and oxidative stress, although the underlying mechanism of action remains poorly understood. This study was designed to delineate the beneficial effects of IGF-I with a focus on RhoA, Akt, and eNOS coupling. Echocardiography was performed in normal or diabetic Friend Virus-B type (FVB) and IGF-I transgenic mice. Cardiomyocyte contractile properties were evaluated using peak shortening (PS), time-to-90% relengthening (TR90), and intracellular Ca2+ rise and decay. Diabetes reduced fraction shortening, PS, and intracellular Ca2+; it increased chamber size, prolonged TR90, and intracellular Ca2+ decay. Levels of RhoA mRNA, active RhoA, and O2(-) were elevated, whereas nitric oxide (NO) levels were reduced in diabetes. Diabetes-induced O2(-) accumulation was ablated by the NO synthase (NOS) inhibitor nitro-L-arginine methyl ester (L-NAME), indicating endothelial NOS (eNOS) uncoupling, all of which except heart size were negated by IGF-I. The IGF-I-elicited beneficial effects were mimicked by the Rho kinase inhibitor Y27632 and BH4. Diabetes depressed expression of Kv1.2 and dihydrofolate reductase (DHFR), increased beta-myosin heavy-chain expression, stimulated p38 MAPK, and reduced levels of total Akt and phosphorylated Akt/eNOS, all of which with the exception of myosin heavy chain were attenuated by IGF-I. In addition, Y27632 and the eNOS coupler folate abrogated glucose toxicity-induced PS decline, TR90 prolongation, while it increased O2(-) and decreased NO and Kv1.2 levels. The DHFR inhibitor methotrexate impaired myocyte function, NO/O2(-) balance, and rescued Y27632-induced cardiac protection. These results revealed that IGF-I benefits diabetic hearts via Rho inhibition and antagonism of diabetes-induced decrease in pAkt, eNOS uncoupling, and K+ channel expression.


Subject(s)
Cardiomyopathies/physiopathology , Diabetes Mellitus, Experimental/metabolism , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/physiology , Nitric Oxide Synthase Type III/metabolism , rho GTP-Binding Proteins/metabolism , Animals , Biopterins/analogs & derivatives , Biopterins/metabolism , Cardiomyopathies/diagnostic imaging , Cell Separation , Folic Acid Antagonists/pharmacology , Kv1.2 Potassium Channel/metabolism , Mice , Mice, Transgenic , Mitogen-Activated Protein Kinases/metabolism , Myocardial Contraction/drug effects , Myocardial Contraction/physiology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Myosin Heavy Chains/metabolism , Oncogene Protein v-akt/metabolism , Oxidation-Reduction , Phosphorylation , Tetrahydrofolate Dehydrogenase/metabolism , Ultrasonography , p38 Mitogen-Activated Protein Kinases/metabolism , rho GTP-Binding Proteins/biosynthesis , rho GTP-Binding Proteins/genetics , rho-Associated Kinases/biosynthesis , rho-Associated Kinases/genetics , rhoA GTP-Binding Protein
17.
Obesity (Silver Spring) ; 15(11): 2699-711, 2007 Nov.
Article in English | MEDLINE | ID: mdl-18070761

ABSTRACT

OBJECTIVE: Low-molecular weight chromium compounds, such as chromium picolinate [Cr(pic)(3)], improve insulin sensitivity, although toxicity is a concern. We synthesized a novel chromium complex, chromium (d-phenylalanine)(3) [Cr(d-phe)(3)], in an attempt to improve insulin sensitivity with reduced toxicity. The aim of this study was to compare the two chromium compounds on cardiac contractile function in ob/ob obese mice. RESEARCH METHODS AND PROCEDURES: C57BL lean and ob/ob obese mice were randomly divided into three groups: H(2)O, Cr(d-phe)(3), or Cr(pic)(3) (45 mug/kg per day orally for 6 months). RESULTS: The glucose tolerance test displayed improved glucose clearance by Cr(d-phe)(3) but not Cr(pic)(3). Myocytes from ob/ob mice exhibited depressed peak shortening (PS) and maximal velocity of shortening/relengthening (+/-dL/dt), prolonged time-to-PS and time-to-90% relengthening (TR90), reduced electrically stimulated rise in intracellular Ca(2+) (Deltafura-2 fluorescence intensity), and slowed intracellular Ca(2+) decay. Although a 3-month Cr(d-phe)(3) treatment for a separate group of ob/ob and lean 2-month-old mice only rectified reduced +/-dL/dt in ob/ob mice, all mechanical and intracellular Ca(2+) abnormalities were significantly attenuated or ablated by 6 months of Cr(d-phe)(3) but not Cr(pic)(3) treatment (except TR90). Sarco(endo)plasmic reticulum Ca(2+) ATPase activity and Na(+)-Ca(2+) exchanger expression were depressed in ob/ob mice, which were reversed by both Cr(d-phe)(3) and Cr(pic)(3), with a more pronounced effect from Cr(d-phe)(3). Cr(d-phe)(3) corrected reduced insulin-stimulated glucose uptake and improved basal phosphorylation of Akt and insulin receptor, as well as insulin-stimulated phosphorylation of Akt and insulin receptor in ob/ob myocytes. Heart homogenates from ob/ob mice had enhanced oxidative stress and protein carbonyl formation compared with the lean group, which were attenuated by both Cr(d-phe)(3) and Cr(pic)(3). DISCUSSION: Our data suggest that the new Cr(d-phe)(3) compound possesses better cardio-protective and insulin-sensitizing properties against obesity.


Subject(s)
Myocardial Contraction/drug effects , Myocytes, Cardiac/drug effects , Obesity/physiopathology , Organometallic Compounds/pharmacology , Phenylalanine/analogs & derivatives , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Glucose/metabolism , Homeodomain Proteins/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Myocardial Contraction/physiology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Obesity/metabolism , Oxidative Stress/drug effects , Phenylalanine/pharmacology , Picolinic Acids/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Receptor, Insulin/metabolism , Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism , Sodium-Calcium Exchanger/metabolism , Thinness/metabolism , Thinness/physiopathology
18.
Rejuvenation Res ; 10(4): 501-12, 2007 Dec.
Article in English | MEDLINE | ID: mdl-17979500

ABSTRACT

Interruption of insulin-like growth factor I (IGF-1) signaling has been demonstrated to prolong life span although the underlying mechanism has not been elucidated. The aim of this study was to examine the influence of severe IGF-1 deficiency on survival rate, cardiomyocyte viability, contractile function, and intracellular Ca(2+) property in response to challenge with the pro-oxidant paraquat. C57 negative and liver IGF-1 deficient (LID) transgenic mice were administrated paraquat (75 mg/kg) and survival was monitored. LID mice displayed a significantly improved survival than did C57 mice evaluated by the Kaplan-Meier curve. MTT assay revealed that in vitro IGF-1 treatment significantly sensitized paraquat-induced cell death in both C57 and LID groups, with significantly better cell viability in LID cardiomyocytes. Compared to C57 mouse cardiomyocytes, LID myocytes displayed reduced peak shortening (PS), decreased maximal velocity of shortening/relengthening (+/- dL/dt), prolonged time-to-90% relengthening (TR(90)), and comparable tolerance to high stimulus frequency and intracellular Ca(2+) homeostasis. Paraquat treatment for 48 hours reduced PS, +/- dL/dt, tolerance to high stimulus frequency, resting and rise in intracellular Ca(2+), and prolonged TR(90), all of which were nullified or masked by IGF-1 deficiency. Paraquat increased reactive oxygen species and carbonyl production upregulated the Ca(2+) regulating protein SERCA2a, and downregulated Na(+) -Ca(2+) exchanger, the effects of which were nullified or masked by IGF-1 deficiency. Although LID mice displayed reduced whole body glucose clearance, cardiomyocytes from LID mice exhibited dramatically enhanced insulin-stimulated phosphorylation of insulin receptor and Akt. These data demonstrated that IGF-1 deficiency may antagonize or mask the paraquat-induced decrease in survival, cardiomyocyte dysfunction, oxidative stress, and change in Ca(2+) regulating proteins.


Subject(s)
Insulin-Like Growth Factor I/deficiency , Myocytes, Cardiac/drug effects , Oxidative Stress , Paraquat/toxicity , Animals , Calcium/metabolism , Cell Survival/drug effects , Female , Glucose Tolerance Test , Insulin-Like Growth Factor I/physiology , Mice , Mice, Inbred C57BL , Myocardial Contraction/drug effects , Myocytes, Cardiac/physiology , Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism
19.
Cardiovasc Toxicol ; 7(4): 273-81, 2007.
Article in English | MEDLINE | ID: mdl-17960499

ABSTRACT

Migration and proliferation of vascular smooth muscle cells (VSMCs) are important events in the progression of atherosclerosis. Insulin-like growth factor I (IGF-1) possesses both antiapoptotic and mitogenic/motogenic effects in VSMCs although the influence of life cycle on IGF-1-induced effects is unclear. This study was designed to evaluate the effect of IGF-1 on migration, proliferation, and signaling mechanisms in VSMCs from early (3-5) to late (20-22) passages. Migration, proliferation, and cell survival were measured using monolayer wounding, 3[H]-thymidine incorporation and MTT assay, respectively. Akt and ERK, which are critical to proliferation, differentiation and migration, were examined using Western blot analysis. DCF-DA fluorescence was used to quantify Reactive Oxygen Species (ROS) production. Late-passage VSMCs exhibited significantly higher basal cell proliferation and enhanced sensitivity to IGF-1-stimulated migration compared to cells from early-passages. Phosphorylated Akt and ERK levels were significantly higher in late-passage cells compared to early-passage, which was further enhanced by IGF-1 treatment. Late-passage cells exhibited higher levels of ROS production compared to early-passage, cells. IGF-1 did not significantly alter ROS levels in either passage. Expression of the cell cycle regulator p53, p21, and p16 was not affected by repeated passaging of cells. These results indicated that repeated passaging of VSMCs exhibits a phenotype which has higher proliferative capacity. Activation of trophic signaling molecules such as ERK1/2 and Akt and generation of ROS may represent the mechanisms by which repeated passages of VSMCs acquire a motogenic and mitogenic phenotype.


Subject(s)
Cell Movement/drug effects , Insulin-Like Growth Factor I/pharmacology , Mitogen-Activated Protein Kinases/physiology , Muscle, Smooth, Vascular/cytology , Oncogene Protein v-akt/physiology , Animals , Animals, Newborn , Blotting, Western , Cell Cycle Proteins/biosynthesis , Cell Cycle Proteins/genetics , Cell Proliferation/drug effects , Cells, Cultured , DNA/biosynthesis , Electrophoresis, Polyacrylamide Gel , Phosphorylation , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Tetrazolium Salts , Thiazoles , Thymidine/metabolism
20.
Diabetes ; 56(9): 2201-12, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17575086

ABSTRACT

Obesity is associated with oxidative stress and mitochondrial and myocardial dysfunction, although interaction among which remains elusive. This study was designed to evaluate the impact of the free radical scavenger metallothionein on high-fat diet-induced myocardial, intracellular Ca(2+), and mitochondrial dysfunction. FVB and metallothionein transgenic mice were fed a high- or low-fat diet for 5 months to induce obesity. Echocardiography revealed decreased fractional shortening, increased end-systolic diameter, and cardiac hypertrophy in high-fat-fed FVB mice. Cardiomyocytes from high-fat-fed FVB mice displayed enhanced reactive oxygen species (ROS) production, contractile and intracellular Ca(2+) defects including depressed peak shortening and maximal velocity of shortening/relengthening, prolonged duration of relengthening, and reduced intracellular Ca(2+) rise and clearance. Transmission microscopy noted overt mitochondrial damage with reduced mitochondrial density. Western blot analysis revealed enhanced phosphorylation of nuclear factor Foxo3a without changes in Foxo3a, Foxo1a, pFoxo1a, silent information regulator (Sirt), and Akt and pAkt in hearts of high-fat diet-fed FVB mice. The peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), a key regulator of mitochondrial biogenesis, was significantly depressed by high-fat diet feeding and in vitro palmitic acid treatment. RT-PCR further depicted reduced levels of the PGC-1alpha downstream nuclear respiratory factors 1 and 2, mitochondrial transcription factor A, and mitochondrial DNA copy number in hearts of high-fat-fed FVB mice. Intriguingly, the high-fat diet-induced alterations in ROS, myocardial contractile, and mitochondrial and cell signaling were negated by metallothionein, with the exception of pFoxo3a. These data suggest that metallothionein may protect against high-fat diet-induced cardiac dysfunction possibly associated with upregulation of PGC-1alpha and preservation of mitochondrial biogenesis.


Subject(s)
Dietary Fats/pharmacology , Metallothionein/physiology , Mitochondria, Heart/physiology , Myocardial Contraction/drug effects , Myocytes, Cardiac/physiology , Trans-Activators/physiology , Animals , Calcium/physiology , Echocardiography , Glucose/pharmacology , Heart Ventricles/ultrastructure , Male , Mice , Mice, Inbred Strains , Microscopy, Electron , Myocytes, Cardiac/drug effects , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Reactive Oxygen Species/metabolism , Transcription Factors
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