Gordana Matic
University of Belgrade, Biochemistry and Molecular Biology, Faculty Member
Background Both fructose consumption and chronic stress contribute to the development of metabolic disorders. The consequences of such combination are not fully understood. Objective We investigated whether fructose supplementation and... more
Background Both fructose consumption and chronic stress contribute to the development of metabolic disorders. The consequences of such combination are not fully understood. Objective We investigated whether fructose supplementation and chronic stress synergistically disturb hepatic lipid and glucose metabolism. The role of energy sensing, redox, and inflammatory status during development of metabolic disturbances was investigated. Methods Female Wistar rats, aged 2.5 mo, were divided into 4 experimental groups: control (C) fed a standard diet (commercial food and drinking water); fructose (F) fed the same food and 10% fructose solution; stress (S) fed the standard diet and subjected to chronic unpredictable stress and, stress + fructose (SF) combining conditions F and S as above. Stress included daily stressors: cold water forced swimming, physical restraint, cold room, wet bedding, rocking, switching, or tilting cages. After 9 wk, hepatic enzymes and transcription factors involved ...
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An increase in fructose consumption coincides with a rising incidence of metabolic disorders. Dietary fructose has been shown to affect hepatic lipid metabolism in a way that may lead to lipid deposition in the liver. In this study, we... more
An increase in fructose consumption coincides with a rising incidence of metabolic disorders. Dietary fructose has been shown to affect hepatic lipid metabolism in a way that may lead to lipid deposition in the liver. In this study, we tested the hypothesis that the effects of fructose overconsumption on hepatic lipid metabolism differ between sexes. To that end we examined the effects of a high-fructose diet on the expression of key enzymes and transcription factors involved in the regulation of fatty acid oxidation and de novo lipogenesis in the liver of 12-week-old male and female Wistar rats. Immediately after weaning, the rats were subjected to a standard diet and 10% fructose solution or drinking water for 9 weeks. The fructose-enriched diet induced hypertriglyceridemia and increased hepatic de novo lipogenesis in both sexes, without lipid deposition in the liver. At the same time, visceral adiposity was observed only in female rats, while in males the treatment stimulated hep...
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Gene expression profiles in blood are increasingly being used to identify biomarkers for different affective disorders. We have selected a set of 29 genes to generate expression profiles for healthy control subjects as well as for... more
Gene expression profiles in blood are increasingly being used to identify biomarkers for different affective disorders. We have selected a set of 29 genes to generate expression profiles for healthy control subjects as well as for patients diagnosed with acute post-traumatic stress disorder (PTSD) and with borderline personality disorder (BPD). Measurements were performed by quantitative polymerase chain reaction (qPCR). Using the actual data in an anonym-ous form we constructed a series of artificial data sets with known gene expression profiles. These sets were used to test 14 classification algorithms and feature selection methods for their ability to identify the correct expression patterns. Application of the three most effective algorithms to the actual expression data showed that control subjects can be dis-tinguished from BPD patients based on differential expression levels of the gene transcripts Gi2, GR and MAPK14, targets that may have links to stress related diseases. Co...
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OBJECTIVES/GOALS: The aim of this study was to define the transcription profiles of the molecular markers of mitochondrial biogenesis and fusion/architecture, and the markers of mtDNA copy numbers in the peripheral blood mononuclear cells... more
OBJECTIVES/GOALS: The aim of this study was to define the transcription profiles of the molecular markers of mitochondrial biogenesis and fusion/architecture, and the markers of mtDNA copy numbers in the peripheral blood mononuclear cells (PBMCs) from war veterans with/without post-traumatic stress disorder (PTSD). METHODS/STUDY POPULATION: The peripheral blood mononuclear cells (PBMCs) from war veterans with/without post-traumatic stress disorder (PTSD) were used to monitor transcription profile of the molecular markers of mitochondrial biogenesis and fusion/architecture, as well as the markers of mtDNA copy numbers. The human male immortalized monocytes were exposed in vitro to hormonal markers of PTSD in order to monitor the effects of each particular hormonal marker on the molecular markers of mitochondrial biogenesis and fusion/architecture, as well as the markers of mtDNA copy numbers. RQ-PCR analyses were used to define transcriptional profile of above mentioned markers. RESU...
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The modern lifestyle brings both excessive fructose consumption and daily exposure to stress which could lead to metabolic disturbances and type 2 diabetes. Muscles are important points of glucose and lipid metabolism, with a crucial role... more
The modern lifestyle brings both excessive fructose consumption and daily exposure to stress which could lead to metabolic disturbances and type 2 diabetes. Muscles are important points of glucose and lipid metabolism, with a crucial role in the maintenance of systemic energy homeostasis. We investigated whether 9-week fructose-enriched diet, with and without exposure to 4-week unpredictable stress, disturbs insulin signaling in the skeletal muscle of male rats and evaluated potential contributory roles of muscle lipid metabolism, glucocorticoid signaling and inflammation. The combination of fructose-enriched diet and stress increased peroxisome proliferator-activated receptors-α and -δ and stimulated lipid uptake, lipolysis and β-oxidation in the muscle of fructose-fed stressed rats. Combination of treatment also decreased systemic insulin sensitivity judged by lower R-QUICKI, and lowered muscle protein content and stimulatory phosphorylations of insulin receptor supstrate-1 and Ak...
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The effects of early-life fructose consumption on hepatic signaling pathways and their relation to the development of metabolic disorders in later life are not fully understood. To investigate whether fructose overconsumption at a young... more
The effects of early-life fructose consumption on hepatic signaling pathways and their relation to the development of metabolic disorders in later life are not fully understood. To investigate whether fructose overconsumption at a young age induces alterations in glucocorticoid signaling that might contribute to development of metabolic disturbances, we analysed glucocorticoid receptor hormone-binding parameters and expression of its target genes involved in gluconeogenesis (phosphoenolpyruvate carboxykinase and glucose-6-phosphatase) and lipid metabolism (lipin-1), as well as redox and inflammatory status in the liver of female rats subjected to a fructose-rich diet immediately after weaning. The fructose diet increased hepatic corticosterone concentration, 11β-hydroxysteroid dehydrogenase type 1 level, glucocorticoid receptor protein level and hormone-binding activity, as well as lipin-1 level. The expression of glucose-6-phosphatase was reduced in fructose-fed rats, while phospho...
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Research Interests: Psychology, Dexamethasone, Brain, Female, Animals, and 15 moreGender Relations, Male, Gender Difference, Rat Brain, Pituitary Gland, Rats, Heat Shock Proteins, Heat Shock Protein, Mineralocorticoid Receptor, Neurosciences, Imipramine, Tissue Specificity, Sex Characteristics, Adrenal cortex hormones, and Male rat
The macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine involved in inflammation, regulation of energy metabolism and glucocorticoid action. Chronic low-grade inflammation may be caused by fructose intake,... more
The macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine involved in inflammation, regulation of energy metabolism and glucocorticoid action. Chronic low-grade inflammation may be caused by fructose intake, contributing to visceral adipose tissue (VAT) dysfunction. Since MIF is a known antagonist of glucocorticoid signaling, and deregulated glucocorticoid signaling can contribute to lipid metabolism disturbances, we hypothesized that altered MIF signaling might underlie fructose-induced adiposity through glucocorticoid action. We analyzed physiological and biochemical parameters, adipose tissue histology, insulin sensitivity and lipid metabolism in wild type and MIF-/- C57Bl/6J mice consuming 20% fructose solution for 9 weeks. Glucocorticoid prereceptor metabolism and glucocorticoid receptor (GR) protein level were examined in VAT, together with the expression of glucocorticoid-target genes involved in lipid metabolism. The expression of adipogenic and lipogen...
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Research results on dehydroepiandrosterone sulfate ester (DHEAS) in post-traumatic stress disorder (PTSD) are inconsistent. We hypothesized that personality traits could be the confounders of DHEAS levels and disease symptoms, which could... more
Research results on dehydroepiandrosterone sulfate ester (DHEAS) in post-traumatic stress disorder (PTSD) are inconsistent. We hypothesized that personality traits could be the confounders of DHEAS levels and disease symptoms, which could in part explain the discrepancy in findings. This study was a part of a broader project in which simultaneous psychological and biological investigations were carried out in hospital conditions. 380 male subjects were categorized in four groups: A) current PTSD (n = 132), B) lifetime PTSD (n = 66), C) trauma controls (n = 101), and D) healthy controls (n = 81), matched by age. The level of DHEAS is significantly lower in the current PTSD group than in trauma controls. All groups significantly differ in personality traits Disintegration and Neuroticism (current PTSD group having the highest scores). DHEAS is related to both PTSD and depressive symptoms; however, Structural Equation Model (SEM) shows that the relations are indirect, realized via thei...
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Both fructose overconsumption and increased glucocorticoids secondary to chronic stress may contribute to overall dyslipidemia. In this study we specifically assessed the effects and interactions of dietary fructose and chronic stress on... more
Both fructose overconsumption and increased glucocorticoids secondary to chronic stress may contribute to overall dyslipidemia. In this study we specifically assessed the effects and interactions of dietary fructose and chronic stress on lipid metabolism in the visceral adipose tissue (VAT) of male Wistar rats. We analyzed the effects of 9-week 20% high fructose diet and 4-week chronic unpredictable stress, separately and in combination, on VAT histology, glucocorticoid prereceptor metabolism, glucocorticoid receptor subcellular redistribution and expression of major metabolic genes. Blood triglycerides and fatty acid composition were also measured to assess hepatic Δ9 desaturase activity. The results showed that fructose diet increased blood triglycerides and Δ9 desaturase activity. On the other hand, stress led to corticosterone elevation, glucocorticoid receptor activation and decrease in adipocyte size, while phosphoenolpyruvate carboxykinase, adipose tissue triglyceride lipase,...
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High-fructose consumption and chronic stress are both associated with metabolic inflammation and insulin resistance. Recently, disturbed activity of energy sensor AMP-activated protein kinase (AMPK) was recognized as mediator between... more
High-fructose consumption and chronic stress are both associated with metabolic inflammation and insulin resistance. Recently, disturbed activity of energy sensor AMP-activated protein kinase (AMPK) was recognized as mediator between nutrient-induced stress and inflammation. Thus, we analyzed the effects of high-fructose diet, alone or in combination with chronic stress, on glucose homeostasis, inflammation and expression of energy sensing proteins in the rat liver. In male Wistar rats exposed to 9-week 20% fructose diet and/or 4-week chronic unpredictable stress we measured plasma and hepatic corticosterone level, indicators of glucose homeostasis and lipid metabolism, hepatic inflammation (pro- and anti-inflammatory cytokine levels, Toll-like receptor 4, NLRP3, activation of NFκB, JNK and ERK pathways) and levels of energy-sensing proteins AMPK, SIRT1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α). High-fructose diet led to glucose intolerance, a...
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Polycystic ovary syndrome is a heterogeneous endocrine and metabolic disorder associated with abdominal obesity, dyslipidemia and insulin resistance. Since abdominal obesity is characterized by low-grade inflammation, the aim of the study... more
Polycystic ovary syndrome is a heterogeneous endocrine and metabolic disorder associated with abdominal obesity, dyslipidemia and insulin resistance. Since abdominal obesity is characterized by low-grade inflammation, the aim of the study was to investigate whether visceral adipose tissue inflammation linked to abdominal obesity and dyslipidemia could lead to impaired insulin sensitivity in the animal model of polycystic ovary syndrome.Female Wistar rats were treated with nonaromatizable 5α-dihydrotestosterone pellets in order to induce reproductive and metabolic characteristics of polycystic ovary syndrome. Glucose, triglycerides, non-esterified fatty acids and insulin were determined in blood plasma. Visceral adipose tissue inflammation was evaluated by the nuclear factor kappa B intracellular distribution, macrophage migration inhibitory factor protein level, as well as TNFα, IL6 and IL1β mRNA levels. Insulin sensitivity was assessed by intraperitoneal glucose tolerance test and ...
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Research Interests: Psychology, Dexamethasone, Brain, Female, Animals, and 15 moreGender Relations, Male, Gender Difference, Rat Brain, Pituitary Gland, Rats, Heat Shock Proteins, Heat Shock Protein, Mineralocorticoid Receptor, Neurosciences, Imipramine, Tissue Specificity, Sex Characteristics, Adrenal cortex hormones, and Male rat
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Research Interests: Nutrition and Dietetics, Obesity, Inflammation, Diet, Oxidative Stress, and 15 moreMitochondria, Insulin Resistance, Antioxidants, Female, Animals, NF-kappa B, Glutathione Peroxidase, Phosphorylation, Fructose, Superoxide Dismutase, Rats, Tumor necrosis factor-alpha, Wistar Rats, Type 2 Diabetes Mellitus, and Adiposity
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It has previously been documented that cadmium displays high affinity for protein thiol groups and induces an impairment of glucocorticoid receptor (GR) cellular functions. The present study examined the possibility that cadmium exerts... more
It has previously been documented that cadmium displays high affinity for protein thiol groups and induces an impairment of glucocorticoid receptor (GR) cellular functions. The present study examined the possibility that cadmium exerts these effects on GR activity by disturbing the receptor's redox equillibrium. To that end, the influence of cadmium on the rat liver GR potential to form intramolecular and intermolecular disulfide bonds under nonreducing conditions and under oxidizing conditions produced by the addition of hydrogen peroxide (H2O2) to the cytosol was examined by nonreducing SDS-PAGE and immunoblotting. The results show that cadmium inhibits formation of disulfide bonds within the GR both in the absence and in the presence of H2O2. The creation of intermolecular disulfide linkages between the apo-GR and associated heat shock proteins Hsp90 and Hsp70, which was evident in the presence of H2O2, was also significantly impaired after cadmium administration. These obser...
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The influence of cadmium on the rat liver glucocorticoid receptor (GR) binding capacity, on the cytosolic level of 90 kDa heat shock protein (Hsp90), and on the association of the two proteins was investigated. The results showed that the... more
The influence of cadmium on the rat liver glucocorticoid receptor (GR) binding capacity, on the cytosolic level of 90 kDa heat shock protein (Hsp90), and on the association of the two proteins was investigated. The results showed that the mode of metal application led to diverse alterations in hormone binding to the GR. Reduction of the GR binding capacity observed after in vitro treatment was proportional to the applied metal concentrations. In animals administered different doses of cadmium, GR binding capacity was not reduced, except in those that received the highest dose. A concomitant elevation of Hsp90 level was detected both in the cytosol and within the GR untransformed heterocomplexes. The results suggest that cadmium-induced reduction of the GR binding capacity seen in vitro was prevented in intact animals by the elevated level of Hsp90 within the GR heterocomplexes.
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The influence of 41 degrees C whole body hyperthermic stress on glucocorticoid receptor (GR) association with 90-kDa heat shock protein (Hsp90) in the rat liver cytosol was examined. Total cytosolic GR and Hsp90 concentrations, as well as... more
The influence of 41 degrees C whole body hyperthermic stress on glucocorticoid receptor (GR) association with 90-kDa heat shock protein (Hsp90) in the rat liver cytosol was examined. Total cytosolic GR and Hsp90 concentrations, as well as the amount of Hsp90 co-immunoprecipitated with the GR were determined by quantitative Western blotting using BuGR2 as anti-GR and AC88 as anti-Hsp90 monoclonal antibody. After exposure of the animals to the heat stress, the level of cytosolic Hsp90 increased, while its ratio to apo-receptor within non-activated GR heterooligomeric complexes remained unaltered. Therefore, the Hsp90 recruitment by the GR was not dependent on Hsp90 total cytosolic concentration.
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Treatment of the transformed glucocorticoid receptor with hydrogen peroxide promotes the formation of disulfide bonds and inhibits the ability of the receptor to bind to DNA (Tienrungroj, W., Meshinchi, S., Sanchez, E. R., Pratt, S. E.,... more
Treatment of the transformed glucocorticoid receptor with hydrogen peroxide promotes the formation of disulfide bonds and inhibits the ability of the receptor to bind to DNA (Tienrungroj, W., Meshinchi, S., Sanchez, E. R., Pratt, S. E., Grippo, J. F., Holmgren, A., and Pratt, W. B. (1987) J. Biol. Chem. 262, 6992-7000). It has not been determined whether the inhibition of DNA binding activity is due to disulfide bonds formed within the DNA binding domain or between the DNA binding domain and another region of the receptor. In this paper, we examined the ability of hydrogen peroxide to inactivate the DNA binding activity of the mouse glucocorticoid receptor. We show that inhibition of DNA binding activity caused by hydrogen peroxide can be accounted for entirely by the formation of disulfide bonds between cysteine residues lying within the 15-kDa tryptic fragment containing the DNA binding domain of the receptor. Reversal of the peroxide-induced inactivation of DNA binding activity r...
Research Interests: Biological Chemistry, Western blotting, Biological Sciences, DNA, Mice, and 12 moreAnimals, Biological, Zinc, Trypsin, Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis, CHEMICAL SCIENCES, Hydrogen Peroxide, Epitopes, Glucocorticoid Receptors, Oxidation-Reduction, Chymotrypsin, and Medical and Health Sciences
Hypoxanthine Guanine Phosphoribosyl Transferase is the Most Stable Reference Gene for Gene Expression Analysis by Quantitative PCR in Peripheral Blood Mononuclear Cells from Women with the Polycystic Ovary Syndrome/Hipoksantin Guanin Fosforibozil Transferaza Je Najstabilniji Referentni Gen Za Ana...more
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Research Interests: Molecular Medicine, Western blotting, Molecular chaperones, Humans, Haplotypes, and 15 moreFemale, Male, Risk factors, Aged, Middle Aged, Adult, Adrenal cortex, Heat Shock Proteins, Risk Factors, Subcellular Fractions, Glucocorticoid Receptors, Glucocorticoids, Intracellular Space, Biochemistry and cell biology, and Case Control Studies
Research Interests: Dexamethasone, Humans, Affective Disorders, Serbia, Male, and 11 moreMiddle Aged, Adult, Genetic Polymorphism, Glucocorticoid Receptors, Mineralocorticoid Receptor, Glucocorticoids, Case Control Studies, Psychology and Cognitive Sciences, Gene frequency, hydrocortisone, and Medical and Health Sciences
Plastic response and successful adaptation to stress are of particular importance in the hippocampus, where chronic stress may cause cell death instead of neural remodeling. Structural modifications that occur both in the brain of... more
Plastic response and successful adaptation to stress are of particular importance in the hippocampus, where chronic stress may cause cell death instead of neural remodeling. Structural modifications that occur both in the brain of depressed patients and animal stress models may be reversed by antidepressants. Since morphological changes induced by stress and/or antidepressants could be mediated by presynaptically located proteins, determining the levels of these proteins may be a useful way to identify molecular changes associated with synaptic plasticity. In this study we analyzed the effects of chronic (six-week) social isolation and long-term (three-week) fluoxetine treatment on molecular markers of plasticity and apoptosis in the hippocampus of Wistar rats. Compartmental redistribution of NFκB transcription factor involved in the regulation of plasticity and apoptosis was also examined. To establish whether social isolation is able to evoke behavioral-like effects, which might b...
Research Interests: Plasticity, Depression, Stress, Apoptosis, Hippocampus, and 15 moreAnimals, Male, Cell Death, Neuronal Plasticity, Behavior change, Social Isolation, Rats, Molecular Marker, Forced Swim Test, FLUOXETINE, Protein Expression, Chronic Stress, Psychology and Cognitive Sciences, Medical and Health Sciences, and Forced swimming test
Alterations in the antioxidative defense parameters upon chronic stress are considered critical for pathophysiology of stress related psychiatric disorders, and their status in blood serves as biomarker for effects of pharmacological... more
Alterations in the antioxidative defense parameters upon chronic stress are considered critical for pathophysiology of stress related psychiatric disorders, and their status in blood serves as biomarker for effects of pharmacological treatments. The present study was designed to investigate the modulation of erythrocyte antioxidant enzymes (AOEs): CuZn superoxide dismutase (CuZnSOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GLR) activities and their protein expression in Wistar male rats subjected to chronic psychosocial isolation and/or to pharmacological treatment with fluoxetine. Chronically isolated animals exhibited decreased levels of serum corticosterone, as opposed to other chronic stress paradigms. In addition to that, SOD, CAT and GPx status was not altered either by chronic psychosocial isolation or by fluoxetine treatment. In contrast, GLR activity and its protein level were both markedly reduced by fluoxetine. Since, GLR is crucial for ove...