57 results on '"Oliviero Danni"'
Search Results
2. Oxidative Stress Increases Expression and Activity of BACE in NT2 Neurons
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Elena Tamagno, Paola Bardini, Alessandra Obbili, Antonella Vitali, Roberta Borghi, Damiano Zaccheo, Maria A. Pronzato, Oliviero Danni, Mark A. Smith, George Perry, and Massimo Tabaton
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BACE ,Alzheimer's disease ,HNE ,NT2 neurons ,oxidative stress ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Recently an aspartyl protease with β-secretase activity called BACE was identified. In the present paper we showed that BACE is modulated by the oxidative stress product 4-hydroxynonenal (HNE). Exposure of NT2 neurons to the two classical pro-oxidant stimuli ascorbate/FeSO4 and H2O2/FeSO4 resulted in a significant generation of HNE, which is temporally followed by an increased production of BACE protein levels. HNE mediated BACE induction is accompanied by a proportional elevation of carboxy-terminal fragments of amyloid precursor protein. Moreover, the direct relationship between BACE induction and lipid peroxidation products was strongly confirmed by the protection exerted by a short pretreatment with α-tocopherol, the most important antioxidant known to prevent the formation of aldehydic end-products of lipid peroxidation, including HNE. Our results support the hypothesis that oxidative stress and Aβ production are strictly interrelated events and suggest that inhibition of BACE may have a therapeutic effect synergic with antioxidant compounds.
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- 2002
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3. SREBP-1c in nonalcoholic fatty liver disease induced by Western-type high-fat diet plus fructose in rats
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Roberto Fantozzi, Manuela Aragno, C. Tomasinelli, Giuseppe Boccuzzi, Ilenia Vercellinatto, Massimo Collino, Oliviero Danni, and Maria Graziella Catalano
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Male ,medicine.medical_specialty ,Dehydroepiandrosterone ,Hyperlipidemias ,Fructose ,Biology ,medicine.disease_cause ,Biochemistry ,chemistry.chemical_compound ,Insulin resistance ,Physiology (medical) ,Internal medicine ,Nonalcoholic fatty liver disease ,polycyclic compounds ,medicine ,Animals ,Rats, Wistar ,Cell Death ,Fatty liver ,medicine.disease ,Dietary Fats ,Rats ,Fatty Liver ,Oxidative Stress ,Insulin receptor ,Endocrinology ,chemistry ,Lipogenesis ,biology.protein ,Insulin Resistance ,Sterol Regulatory Element Binding Protein 1 ,Oxidative stress - Abstract
This study concentrated on the initial events triggering the development of nonalcoholic fatty liver disease induced by a high-fat plus fructose (HF-F) diet and on the possibility of delaying nonalcoholic fatty liver disease progression by adding dehydroepiandrosterone (DHEA) to the diet. Sterol regulatory element binding protein-1c (SREBP-1c) activation plays a crucial role in the progression of nonalcoholic fatty liver disease induced by an HF-F diet. This study investigated the protective effects of DHEA, a compound of physiological origin with multitargeted antioxidant properties, against the induction of SREBP-1c and on liver insulin resistance in rats fed an HF-F diet, which mimics a typical unhealthy Western diet. An HF-F diet, fortified or not with DHEA (0.01%, w/w), was administered for 15 weeks to male Wistar rats. After HF-F the liver showed unbalanced oxidative status, fatty infiltration, hepatic insulin resistance, and inflammation. The addition of DHEA to the diet reduced both activation of oxidative-stress-dependent pathways and expression of SREBP-1c and partially restored the expression of liver X-activated receptor-alpha and insulin receptor substrate-2 genes. DHEA supplementation of the HF-F diet reduced de novo lipogenesis and delayed progression of nonalcoholic fatty liver disease, demonstrating a relationship between oxidative stress and nonalcoholic fatty liver disease via SREBP-1c.
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- 2009
4. Cardiac impairment in rabbits fed a high-fat diet is counteracted by dehydroepiandrosterone supplementation
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A. Vercelli, C. Tomasinelli, Pier Giorgio Peiretti, Giorgia Meineri, G Boccuzzi, Oliviero Danni, Paola Bardini, Ilenia Vercellinatto, Manuela Aragno, Giuseppe Alloatti, and Stefania Raimondo
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Glycation End Products, Advanced ,Male ,medicine.medical_specialty ,Necrosis ,Heart Diseases ,Heart Ventricles ,Blotting, Western ,Myosin ,Dehydroepiandrosterone ,Inflammation ,Cardiac impairment ,Rabbit ,Myosins ,Biology ,medicine.disease_cause ,Mass Spectrometry ,General Biochemistry, Genetics and Molecular Biology ,Diabetes Mellitus, Experimental ,Contractility ,Cytosol ,Insulin resistance ,Internal medicine ,medicine ,Animals ,General Pharmacology, Toxicology and Pharmaceutics ,Chromatography, High Pressure Liquid ,Cell Nucleus ,Glucose tolerance test ,medicine.diagnostic_test ,Oxidative stress ,High fat diet ,Myocardium ,Body Weight ,General Medicine ,Glucose Tolerance Test ,medicine.disease ,Dietary Fats ,Diet ,Endocrinology ,Heart Function Tests ,RNA ,Rabbits ,medicine.symptom ,Diabetic Angiopathies ,Dyslipidemia - Abstract
Aims The biochemical and structural cardiac oxidative-dependent damage induced by high-fat (HF) diet was examined in a rabbit model, together with the role of dehydroepiandrosterone (DHEA) in contrasting tissue damage. Main methods New Zealand white rabbits fed a HF diet supplemented or not with DHEA (0.02%) were utilized for 12 weeks. Oxidative stress, inflammatory and necrosis parameters, fatty deposition, heavy-chain myosin isoforms (MHC) expression and papillary muscle functionality were examined in the left ventricle of rabbits. Key findings Rabbits fed a HF diet that showed hyperglycemia, insulin resistance and dyslipidemia together with increase of oxidative stress and of advanced end-glycation product levels have been observed. Concerning pro-inflammatory insults, there was increased p65-NFkB activation and increased tumor necrosis factor-alpha and C-reactive protein expressions. Cellular damage induced by the HF diet was detected through the switch of expression of MHC isoforms, indicating impairment of cardiac contractility, confirmed by altered of basal parameters of papillary muscle functionality. Rabbits fed the HF diet supplemented with DHEA showed a partial reduction of oxidative stress and the inflammatory state. Cardiac necrosis, the shift of MHC isoforms, and cardiac functionality, were also partially counteracted. Significance Rabbits fed with a HF diet showed a beneficial effect when low-dose DHEA was added to the diet. The steroid, without affecting high plasma glucose level or insulin resistance, restored oxidative balance, lowered lipid levels and inflammation insults, preventing cellular and functional alterations of cardiac tissue and thus delaying the onset of cardiac damage.
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- 2009
5. Oxidative Stress-Dependent Impairment of Cardiac-Specific Transcription Factors in Experimental Diabetes
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Claudio Medana, Manuela Aragno, Giuseppe Boccuzzi, Oliviero Danni, Ilenia Vercellinatto, Maria Graziella Catalano, and Raffaella Mastrocola
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Glycation End Products, Advanced ,Male ,medicine.medical_specialty ,endocrine system diseases ,Heart Ventricles ,Receptor for Advanced Glycation End Products ,medicine.disease_cause ,Diabetes Mellitus, Experimental ,Contractility ,Endocrinology ,Diabetic cardiomyopathy ,Internal medicine ,medicine ,Animals ,Myocyte ,Rats, Wistar ,Receptors, Immunologic ,Receptor ,Myosin Heavy Chains ,Tumor Necrosis Factor-alpha ,business.industry ,Myocardium ,Heart ,Dehydroepiandrosterone ,medicine.disease ,Streptozotocin ,Rats ,Rats, Zucker ,Oxidative Stress ,Autonomic nervous system ,Organ Specificity ,Receptors, Tumor Necrosis Factor, Type I ,Heart failure ,business ,Oxidative stress ,Transcription Factors ,medicine.drug - Abstract
Oxidative stress plays a key role in the pathogenesis of diabetic cardiomyopathy, which is characterized by myocyte loss and fibrosis, finally resulting in heart failure. The study looked at the downstream signaling whereby oxidative stress leads to reduced myocardial contractility in the left ventricle of diabetic rats and the effects of dehydroepiandrosterone (DHEA), which production is suppressed in the failing heart and prevents the oxidative damage induced by hyperglycemia in several experimental models. DHEA was given orally at a dose of 4 mg/rat per day for 21 d to rats with streptozotocin (STZ)-induced diabetes and genetic diabetic-fatty (ZDF) rats. Oxidative balance, advanced glycated end products (AGEs) and AGE receptors, cardiac myogenic factors, and myosin heavy-chain gene expression were determined in the left ventricle of treated and untreated STZ-diabetic rats and ZDF rats. Oxidative stress induced by chronic hyperglycemia increased AGE and AGE receptors and led to activation of the pleoitropic transcription factor nuclear factor-κB. Nuclear factor-κB activation triggered a cascade of signaling, which finally led to the switch in the cardiac myosin heavy-chain (MHC) gene expression from the α-MHC isoform to the β-MHC isoform. DHEA treatment, by preventing the activation of the oxidative pathways induced by hyperglycemia, counteracted the enhanced AGE receptor activation in the heart of STZ-diabetic rats and ZDF rats and normalized downstream signaling, thus avoiding impairment of the cardiac myogenic factors, heart autonomic nervous system and neural crest derivatives (HAND) and myogenic enhancer factor-2, and the switch in MHC gene expression, which are the early events in diabetic cardiomyopathy.
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- 2006
6. Oxidative stress and inflammatory response evoked by transient cerebral ischemia/reperfusion: Effects of the PPAR-α agonist WY14643
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Massimo Collino, Elisa Benetti, Margherita Gallicchio, Raffaella Mastrocola, Manuela Aragno, Chiara Dianzani, Oliviero Danni, Christoph Thiemermann, and Roberto Fantozzi
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Male ,Agonist ,MAP Kinase Signaling System ,medicine.drug_class ,Blotting, Western ,Ischemia ,Nitric Oxide Synthase Type II ,Pharmacology ,medicine.disease_cause ,Hippocampus ,Biochemistry ,Brain Ischemia ,Nitric oxide ,Lipid peroxidation ,Brain ischemia ,chemistry.chemical_compound ,Physiology (medical) ,medicine ,Animals ,PPAR alpha ,Rats, Wistar ,chemistry.chemical_classification ,Reactive oxygen species ,NF-kappa B ,Intercellular Adhesion Molecule-1 ,medicine.disease ,Rats ,Oxidative Stress ,Pyrimidines ,chemistry ,Cyclooxygenase 2 ,Reperfusion Injury ,Heme Oxygenase (Decyclizing) ,Immunology ,Lipid Peroxidation ,Reperfusion injury ,Oxidative stress - Abstract
This study investigated the effects of the selective peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist WY14643 on ischemia/reperfusion (I/R) injury in the rat hippocampus. Transient cerebral ischemia (30 min), followed by 1-24 h reperfusion, significantly increased the generation of reactive oxygen species, nitric oxide (NO), and lipid peroxidation end-products, as well as markedly reducing levels of the endogenous antioxidant glutathione. Reperfusion for 3-6 h led to increased expression of the proteins heme oxygenase-1 (HO-1), cyclooxygenase-2 (COX-2), inducible NO synthase (iNOS), and intercellular adhesion molecule-1 (ICAM-1). Pretreatment with WY14643 suppressed oxidative stress and expression of HO-1, iNOS, and ICAM-1, but had no effect on COX-2. These effects are due to suppression of the activation of p38 mitogen-activated protein kinase and nuclear factor-kappaB. The PPAR-alpha antagonist MK886 abolished the beneficial effects of WY14643. The levels of S100B protein, a marker of cerebral injury used in stroke trials to monitor injury, were high in the hippocampus of rats exposed to I/R, but markedly reduced by WY14643. We propose that WY14643 protects the brain against excessive oxidative stress and inflammation and may thus be useful in treating stroke.
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- 2006
7. Modulation of the oxidative stress and inflammatory response by PPAR-γ agonists in the hippocampus of rats exposed to cerebral ischemia/reperfusion
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Margherita Gallicchio, Chiara Dianzani, Oliviero Danni, Massimo Collino, Roberto Fantozzi, Manuela Aragno, Arianna Carolina Rosa, Raffaella Mastrocola, and C. Thiemermann
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Male ,medicine.medical_specialty ,Ischemia ,Biology ,medicine.disease_cause ,Hippocampus ,Brain Ischemia ,Nitric oxide ,Rosiglitazone ,Lipid peroxidation ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Inflammation ,Pharmacology ,chemistry.chemical_classification ,Reactive oxygen species ,Pioglitazone ,NF-kappa B ,medicine.disease ,Rats ,PPAR gamma ,Oxidative Stress ,Endocrinology ,chemistry ,Cyclooxygenase 2 ,Reperfusion Injury ,Injections, Intravenous ,Thiazolidinediones ,Lipid Peroxidation ,Mitogen-Activated Protein Kinases ,Reperfusion injury ,Oxidative stress ,Signal Transduction ,medicine.drug - Abstract
Agonists of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) exert protective effects in several models of ischemia/reperfusion injury, but their role in stroke is less clear. The study investigates the effects of two PPAR-gamma agonists, rosiglitazone and pioglitazone, on oxidative stress and inflammatory response induced by ischemia/reperfusion in the rat hippocampus. Common carotid artery occlusion for 30 min followed by 1 h reperfusion resulted in a significant increase in the generation of reactive oxygen species, nitric oxide and the end products of lipid peroxidation as well as markedly reduced endogenous antioxidant glutathione levels and up-regulated superoxide dismutase activity. Western blot analysis showed that ischemia/reperfusion lead to an increase in cyclooxygenase-2 (COX-2) expression, as well activating p38 and p42/44 mitogen-activated protein kinases (MAPKs) and nuclear factor-kappaB (NF-kappaB). Pre-treatment with either rosiglitazone or pioglitazone significantly reduced oxidative stress, COX-2 protein expression and activation of MAPKs and NF-kappaB. Taken together, the results provide convincing evidence that PPAR-gamma agonists exert protective effects in a rat model of mild forebrain ischemia/reperfusion injury by inhibiting oxidative stress and excessive inflammatory response.
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- 2006
8. Oxidative Stress Impairs Skeletal Muscle Repair in Diabetic Rats
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Enrico Brignardello, Maria Graziella Catalano, Giuseppe Boccuzzi, Oliviero Danni, Manuela Aragno, and Raffaella Mastrocola
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Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Oxidative phosphorylation ,Biology ,medicine.disease_cause ,Diabetes Mellitus, Experimental ,Gastrocnemius muscle ,Diabetes mellitus ,Internal medicine ,Myosin ,Internal Medicine ,medicine ,Animals ,Vitamin E ,Rats, Wistar ,Muscle, Skeletal ,Myogenin ,Skeletal muscle ,Dehydroepiandrosterone ,medicine.disease ,Streptozotocin ,Rats ,Oxidative Stress ,Endocrinology ,medicine.anatomical_structure ,Oxidative stress ,medicine.drug - Abstract
Alongside increased proteolysis, the inability to repair damaged skeletal muscle is a characteristic feature of uncontrolled diabetes. This study evaluates the role of oxidative stress in muscle-specific gene regulatory regions and myosin chain synthesis in streptozotocin (STZ)-induced diabetic and ZDF rats. In the gastrocnemius muscle of diabetic rats, prooxidant compounds were seen to increase while antioxidant levels fell. Myogenic regulatory factors—Myo, myogenin, and Jun D—were also reduced, and muscle enhancer factor (MEF)-1 DNA binding activity was impaired. Moreover, synthesis of muscle creatine kinase and both heavy and light chains of myosin were impaired, suggesting that oxidative stress triggers the cascade of events that leads to impaired muscle repair. Dehydroepiandrosterone has been reported to possess antioxidant properties. When it was administered to diabetic rats, in addition to an improved oxidative imbalance there was a recovery of myogenic factors, MEF-1 DNA binding activity, synthesis of muscle creatine kinase, and myosin light and heavy chains. Vitamin E administration to STZ-induced diabetic rats reverses oxidative imbalance and improves muscle gene transcription, reinforcing the suggestion that oxidative stress may play a role in diabetes-related impaired muscle repair.
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- 2004
9. Pro-oxidant effect of dehydroepiandrosterone in rats is mediated by PPAR activation
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Manuela Aragno, Maria Graziella Catalano, Giuseppe Boccuzzi, S Betteto, Enrico Brignardello, Raffaella Mastrocola, and Oliviero Danni
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Male ,medicine.medical_specialty ,Antioxidant ,medicine.medical_treatment ,Administration, Oral ,Receptors, Cytoplasmic and Nuclear ,Dehydroepiandrosterone ,medicine.disease_cause ,Thiobarbituric Acid Reactive Substances ,General Biochemistry, Genetics and Molecular Biology ,Lipid peroxidation ,chemistry.chemical_compound ,Cytosol ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,General Pharmacology, Toxicology and Pharmaceutics ,NADPH-Ferrihemoprotein Reductase ,Dose-Response Relationship, Drug ,biology ,Fatty Acids ,Cytochrome P450 ,Hydrogen Peroxide ,General Medicine ,Glutathione ,Catalase ,Oxidants ,Pro-oxidant ,Rats ,Endocrinology ,chemistry ,Microsomes, Liver ,biology.protein ,Lipid Peroxidation ,Oxidoreductases ,Oxidation-Reduction ,hormones, hormone substitutes, and hormone antagonists ,Oxidative stress ,Transcription Factors - Abstract
DHEA-treatment exerts a dual effect, prooxidant or antioxidant, depending on the dosage and, therefore, on the tissue concentration reached. In agreement with previous studies showing a prooxidant effect of DHEA, here we show that pharmacological doses of DHEA produce increased H(2)O(2) levels and a marked reduction of GSH content in rat liver. DHEA, also increases both catalase (by 30%) and cytochrome-C-reductase (by 30%) activities in the liver cytosol. The effectiveness of the state of increased oxidative stress is also documented by changes in fatty acid pattern of the microsomal membranes. Moreover, DHEA, at high doses, enhances beta-oxidation, as demonstrated by an increase of acyl-CoA-oxidase activity and of cytochrome P450 4A content, confirming that it acts as a PPARs inducer. Both PPARs induction and proxidant effects completely disappear when DHEA is administered at lower doses. Seven days treatment (4 or 10 mg) is unable to affect either levels of proxidant species and of antioxidant molecules, or cytochrome P450 4A content and beta-oxidation. Prolonged DHEA treatment (4 mg/day) for three weeks not only is unable to affect PPARs activation and beta-oxidation, but it also exerts a protective effect against ADP/Fe(2+) induced lipid peroxidation. This latter result confirms the antioxidant effects of DHEA at low doses, as already previously documented.
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- 2003
10. Oxidative stress and eicosanoids in the kidneys of hyperglycemic rats treated with dehydroepiandrosterone
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Manuela Aragno, Giuseppe Boccuzzi, Oliviero Danni, Roberta Manti, Enrico Brignardello, Elena Tamagno, S Betteto, and Silvia Parola
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Male ,medicine.medical_specialty ,Antioxidant ,medicine.medical_treatment ,Dehydroepiandrosterone ,Arachidonic Acids ,Kidney ,medicine.disease_cause ,Biochemistry ,Antioxidants ,Streptozocin ,Diabetes Mellitus, Experimental ,Membrane Lipids ,Lipoxygenase ,chemistry.chemical_compound ,Polyol pathway ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Diabetic Nephropathies ,Rats, Wistar ,Na+/K+-ATPase ,biology ,Chemistry ,Fatty Acids ,Kidney metabolism ,Glutathione ,Rats ,Oxidative Stress ,Endocrinology ,Hyperglycemia ,biology.protein ,Eicosanoids ,Sodium-Potassium-Exchanging ATPase ,hormones, hormone substitutes, and hormone antagonists ,Oxidative stress - Abstract
Oxidative stress plays a crucial role in the pathogenesis of chronic diabetic complications. Normoglycemic and streptozotocin-diabetic rats were treated with dehydroepiandrosterone (DHEA) (4 mg/d per rat) for 3 weeks. At the end of treatment, hydroxynonenal, hydroperoxyeicosatetraenoic acids and antioxidant levels, as well as Na/K-ATPase activity and membrane fatty acids composition were evaluated in kidney homogenates. Chronic hyperglycemia caused a marked increase of both hydroxynonenal and lipoxygenase pathway products and a drop in both GSH levels and membrane Na/K-ATPase activity. DHEA treatment restored the antioxidant levels to close to the control value and considerably reduced hydroxynonenal and hydroperoxyeicosatetraenoic acid levels. Moreover, DHEA counteracted the detrimental effect of hyperglycemia on membrane function: the drop of Na/K-ATPase activity in diabetic animals was significantly inhibited by DHEA treatment. These results show that DHEA reduces oxidative stress and the consequent increase of lipoxygenase pathway products induced by experimental diabetes in rat kidney; they also suggest that, by reducing the inflammatory response to oxidative stress, DHEA treatment might delay the progression of diabetic kidney disease.
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- 2001
11. Dehydroepiandrosterone prevents oxidative injury induced by transient ischemia/reperfusion in the brain of diabetic rats
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Enrico Brignardello, Elena Tamagno, Manuela Aragno, Silvia Parola, Giuseppe Boccuzzi, Oliviero Danni, Alessandro Mauro, and Roberta Manti
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Male ,medicine.medical_specialty ,Antioxidant ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Synaptic Membranes ,Ischemia ,Dehydroepiandrosterone ,Oxidative phosphorylation ,medicine.disease_cause ,Antioxidants ,Brain Ischemia ,Diabetes Mellitus, Experimental ,chemistry.chemical_compound ,Internal medicine ,Lactate dehydrogenase ,Internal Medicine ,Animals ,Medicine ,Rats, Wistar ,chemistry.chemical_classification ,Reactive oxygen species ,L-Lactate Dehydrogenase ,Hydroxyl Radical ,business.industry ,Cell Membrane ,Hydrogen Peroxide ,medicine.disease ,Streptozotocin ,Rats ,Oxidative Stress ,Endocrinology ,chemistry ,Reperfusion Injury ,Synapses ,Fatty Acids, Unsaturated ,Lipid Peroxidation ,Sodium-Potassium-Exchanging ATPase ,Reactive Oxygen Species ,business ,Oxidative stress ,medicine.drug - Abstract
Both chronic hyperglycemia and ischemia/reperfusion (IR) cause an imbalance in the oxidative state of tissues. Normoglycemic and streptozotocin (STZ)-diabetic rats were subjected to bilateral carotid artery occlusion for 30 min followed by reperfusion for 60 min. Rats had either been treated with dehydroepiandrosterone (DHEA) for 7, 14, or 21 days (2 or 4 mg/day per rat) or left untreated. Oxidative state, antioxidant balance, and membrane integrity were evaluated in isolated synaptosomes. IR increased the levels of reactive species and worsened the synaptic function, affecting membrane Na/K-ATPase activity and lactate dehydrogenase release in all rats. The oxidative imbalance was much severer when transient IR was induced in STZ-diabetic rats. DHEA treatment restored H2O2, hydroxyl radical, and reactive oxygen species to close to control levels in normoglycemic rats and significantly reduced the level of all reactive species in STZ-diabetic rats. Moreover, DHEA treatment counteracted the detrimental effect of IR on membrane integrity and function: the increase of lactate dehydrogenase release and the drop in Na/K-ATPase activity were significantly prevented in both normoglycemic and STZ-diabetic rats. The results confirm that DHEA, an adrenal steroid that is synthesized de novo by brain neurons and astrocytes, possesses a multitargeted antioxidant effect. They also show that DHEA treatment is effective in preventing both derangement of the oxidative state and neuronal damage induced by IR in experimental diabetes.
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- 2000
12. Protective effect of dehydroepiandrosterone against lipid peroxidation in a human liver cell line
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Marco Gallo, Manuela Aragno, Enrico Brignardello, Roberta Manti, V Gatto, Elena Tamagno, G Boccuzzi, and Oliviero Danni
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medicine.medical_specialty ,Antioxidant ,Thiobarbituric acid ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Dehydroepiandrosterone ,medicine.disease_cause ,Thiobarbituric Acid Reactive Substances ,Cell Line ,Lipid peroxidation ,chemistry.chemical_compound ,Endocrinology ,Internal medicine ,Lactate dehydrogenase ,Benzene Derivatives ,polycyclic compounds ,medicine ,TBARS ,Humans ,Cell Death ,L-Lactate Dehydrogenase ,Epithelial Cells ,Trypan Blue ,General Medicine ,Oxidants ,Culture Media ,medicine.anatomical_structure ,Liver ,chemistry ,Hepatocyte ,Lipid Peroxidation ,hormones, hormone substitutes, and hormone antagonists ,Oxidative stress - Abstract
OBJECTIVE: Dehydroepiandrosterone (DHEA) is a widely studied steroid hormone with multi-functional properties. Reports suggest that some of the many activities of DHEA are due to its protective effect against lipid peroxidation. Nevertheless, the antioxidant properties of DHEA are still the subject of debate. The aim was to evaluate whether its two opposed effects on lipid peroxidation reported in the literature may be dependent on schedule and doses used. METHODS: Chang liver cells, a line derived from normal human liver, were grown in media containing either no steroids (control) or DHEA at concentrations ranging from 0.1 micromol/l to 50 micromol/l. At specific times, cultures were halted and cells received a pro-oxidant stimulus (cumene (CuOOH) 0.5 mmol/l), at which time cell viability (by trypan blue staining and lactate dehydrogenase (LDH) release) and thiobarbituric acid reactive substances (TBARS) concentration (spectrophotometrical assay) were evaluated. RESULTS: At concentrations ranging from 0.1 micromol/l to 1 micromol/l, DHEA protects Chang liver cells against lipid peroxidation and/or death induced by cumene. This effect disappears if the concentration is increased to 10 micromol/l; at higher concentrations (50 micromol/l) a pro-oxidant/cytotoxic effect of DHEA appears. CONCLUSIONS: DHEA exhibits two opposed effects on lipid peroxidation; depending on its concentration it acts either to limit or to induce oxidative stress. The threshold concentration at which the pro-oxidant activity of DHEA prevails is not far in excess of that having an antioxidant effect. Either effect of DHEA on lipid peroxidation is only evident after a 'lag-phase'.
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- 1999
13. Inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase activity and gene expression by dehydrocpiandrosterone in preneoplastic liver nodules
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Maria Maddalena Simile, Maria Antonietta Seddaiu, Rosa Maria Pascale, Oliviero Danni, Francesco Feo, Maria Rosaria Muroni, A. Nufris, Kalipatnapu N. Rao, and Maria Rosaria De Miglio
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Male ,Cancer Research ,medicine.medical_specialty ,Gene Expression ,Mevalonic Acid ,Dehydroepiandrosterone ,Reductase ,Biology ,chemistry.chemical_compound ,Liver Neoplasms, Experimental ,Internal medicine ,medicine ,Animals ,Cholesterol ,Liver cell ,Body Weight ,General Medicine ,Hydroxymethylglutaryl-CoA reductase ,Rats, Inbred F344 ,17-Ketosteroids ,Rats ,Lipoproteins, LDL ,Endocrinology ,medicine.anatomical_structure ,Liver ,Receptors, LDL ,chemistry ,Hepatocyte ,LDL receptor ,Hydroxymethylglutaryl CoA Reductases ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Growth inhibition ,Precancerous Conditions - Abstract
Previous work has demonstrated that dehydroepiandrosterone (DHEA) strongly inhibits growth and de novo cholesterol (CH) biosynthesis in preneoplastic rat liver. Administration of a mixture of 4 ribo- or deoxyribonucleosides of adenine, guanine, cytosine and uracil/thymine, prevents growth inhibition but not inhibition of CH synthesis. The purpose of this paper was to identify the site of inhibition of CH synthesis by DHEA. Persistent nodules (PNs) were induced, in diethylnitrosamine-initiated male F344 rats, by ‘resistant hepatocyte’ protocol. Fifteen weeks after initiation, nodule bearing rats and normal controls received a diet containing 0.6% DHEA for 3 weeks. They were then killed. 3-Hydroxy-3-methylglutaryl-CoA reductase (HMGR) activity and mRNA levels were 18- and 14-fold higher, respectively in nodules than in normal liver. DHEA strongly inhibited HMGR activity in both tissues in vivo , but had a slight effect on HMGR activity, when added in vitro ,to the reaction mixture for determination of this activity. In vivo , DHEA treatment caused a 65% decrease in the level of HMGR mRNA in PNs, which, however, does not seem to completely account for the decrease in HMGR activity (83%). Low density lipoprotein receptor (LDL-R) mRNA level underwent a slight decrease in PNs, with respect to control liver, which did not lead to a significant decrease in 125 I-LDL binding to LDL-R. DHEA treatment caused 30% and 24% increases in LDL-R expression and 125 I-LDL binding, respectively, in nodules. These observations indicate that in addition to HMGR gene expression, increased influx of LDL into preneoplastic cells may contribute to the deregulation of mevalonate synthesis by DHEA. The observation that HMGR activity and gene expression were still 3- to 5-fold higher in PNs of DHEA-treated rats than in control liver, and previous findings of preneoplastic liver cell growth in the presence of relatively low CH synthesis, suggest that even relatively low levels of mevalonate are sufficient for the growth of preneoplastic liver cells.
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- 1995
14. Prevention of Carbon Tetrachloride-Induced Lipid Peroxidation in Liver Microsomes from Dehydroepiandrosterone-Pretreated Rats
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Giuseppe Poli, Oliviero Danni, Enrico Brignardello, Manuela Aragno, Giuseppe Boccuzzi, and Elena Tamagno
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Male ,medicine.medical_specialty ,Antioxidant ,medicine.medical_treatment ,Intraperitoneal injection ,Dehydroepiandrosterone ,CCL4 ,7-Alkoxycoumarin O-Dealkylase ,Biochemistry ,Steroid ,Lipid peroxidation ,chemistry.chemical_compound ,Cytochrome P-450 Enzyme System ,Malondialdehyde ,Internal medicine ,medicine ,Animals ,Cytochrome P-450 Enzyme Inhibitors ,Rats, Wistar ,Carbon Tetrachloride ,NADPH-Ferrihemoprotein Reductase ,Carbon Tetrachloride Poisoning ,Chemistry ,Cytochrome P-450 CYP2E1 ,Oxidoreductases, N-Demethylating ,gamma-Glutamyltransferase ,General Medicine ,Rats ,Kinetics ,Endocrinology ,Glucose-6-Phosphatase ,Microsomes, Liver ,Microsome ,Carbon tetrachloride ,Lipid Peroxidation ,Biomarkers ,Aminopyrine N-Demethylase - Abstract
Dehydroepiandrosterone (DHEA), a lipid soluble steroid, administered to rats (100 mg/kg b.wt) by a single intraperitoneal injection, increases to twice its normal level in the liver microsomes. Microsomes so enriched become resistant to lipid peroxidation induced by incubation with carbon tetrachloride in the presence of a NADPH-regenerating system: also the lipid peroxidation-dependent inactivation of glucose-6-phosphatase and gamma-glutamyl transpetidase due to the haloalkane are prevented. Noteworthy, the liver microsomal drug-metabolizing enzymes and in particular the catalytic activity of cytochrome P450IIE1, responsible for the CCl4-activation, are not impaired by the supplementation with the steroid. Consistently, in DHEA-pretreated microsomes the protein covalent binding of the trichloromethyl radical (CCl3 degrees), is similar to that of not supplemented microsomes treated with CCl4. It thus seems likely that DHEA protects liver microsomes from oxidative damage induced by carbon tetrachloride through its own antioxidant properties rather than inhibiting the metabolism of the toxin.
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- 1994
15. Dehydroepiandrosterone pretreatment protects rats against the pro-oxidant and necrogenic effects of carbon tetrachloride
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Elena Chiarpotto, Andrea Pizzini, Manuela Aragno, Enrico Brignardello, Elena Tamagno, G Boccuzzi, and Oliviero Danni
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medicine.medical_specialty ,Antioxidant ,medicine.medical_treatment ,Intraperitoneal injection ,Biochemistry ,Antioxidants ,Lipid peroxidation ,chemistry.chemical_compound ,Malondialdehyde ,Internal medicine ,medicine ,Animals ,Carbon Tetrachloride ,Pharmacology ,Liver injury ,Carbon Tetrachloride Poisoning ,Chemistry ,Dehydroepiandrosterone ,Glutathione ,medicine.disease ,Rats ,medicine.anatomical_structure ,Endocrinology ,Hepatocyte ,Microsomes, Liver ,Carbon tetrachloride ,Lipid Peroxidation - Abstract
A single intraperitoneal injection of dehydroepiandrosterone (3β-hydroxy-5-androsten-17-one, DHEA) 17 hr before carbon tetrachloride (CCl 4 ) poisoning protects rats against liver injury induced by the haloalkane. In liver homogenates, both the increase in malondialdehyde production and the formation of fluorescent lipid peroxidation products are significantly reduced. Also, liver microsomes obtained from DHEA-pretreated rats incubated in vitro with CCl 4 are less susceptible to lipid peroxidation than microsomes from normal animals. The release of liver enzymes into the blood is much reduced in DHEA-pretreated rats, confirming a cause-effect relationship between lipid peroxidation and hepatocyte death. Treatment with DHEA inhibits neither glucose-6-phosphate dehydrogenase activity in the cytosol, nor the microsomal mixed function oxidase system (cytochrome P450 content, aminopyrine demethylase and ethoxycoumarine de-ethylase activities). In animals treated with DHEA, the liver content of total glutathione and vitamin E is not modified. These results support the hypothesis that DHEA protects against CCL 4 -induced liver injury through its own antioxidant activity, rather than by interfering with the metabolism of the toxin or with the tissue level of primary antioxidants.
- Published
- 1993
16. AGEs/RAGE complex upregulates BACE1 via NF-κB pathway activation
- Author
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Manuela Aragno, Sonia Visentin, Elena Tamagno, George Perry, Giuseppe Boccuzzi, Michela Guglielmotto, Claudio Medana, Ilenia Vercellinatto, Maria Graziella Catalano, Mark A. Smith, Massimo Tabaton, and Oliviero Danni
- Subjects
Glycation End Products, Advanced ,Male ,Aging ,Advanced glycation end products ,Alzheimer disease ,BACE1 ,Diabetes ,NF-κB pathway ,RAGE ,Advanced Glycosylation End Product-Specific Receptor ,Alzheimer Disease ,Amyloid Precursor Protein Secretases ,Amyloid beta-Peptides ,Animals ,Aspartic Acid Endopeptidases ,Diabetes Mellitus, Experimental ,Glycosylation End Products, Advanced ,NF-kappa B ,Rats ,Rats, Wistar ,Reactive Oxygen Species ,Receptors, Immunologic ,Risk Factors ,Signal Transduction ,Up-Regulation ,Neurology (clinical) ,Neuroscience (all) ,Developmental Biology ,Geriatrics and Gerontology ,Receptor for Advanced Glycation End Products ,Wistar ,RAGE (receptor) ,Pathogenesis ,chemistry.chemical_compound ,Immunologic ,Glycation ,Receptors ,Receptor ,General Neuroscience ,medicine.drug ,medicine.medical_specialty ,Experimental ,Downregulation and upregulation ,Internal medicine ,Diabetes Mellitus ,Glycosylation End Products ,medicine ,Pentosidine ,business.industry ,NF-κB ,Streptozotocin ,Endocrinology ,chemistry ,Advanced ,business - Abstract
Although the pathogenesis of sporadic Alzheimer disease (AD) is not clearly understood, it is likely dependent on several age-related factors. Diabetes is a risk factor for AD, and multiple mechanisms connecting the 2 diseases have been proposed. Hyperglycemia enhances the formation of advanced glycation end products (AGEs) that result from the auto-oxidation of glucose and fructose. The interaction of AGEs with their receptor, named RAGE, elicits the formation of reactive oxygen species that are also believed to be an early event in AD pathology. To investigate a functional link between the disorders diabetes and AD, the effect of 2 AGEs, pentosidine and glyceraldehydes-derived pyridinium (GLAP), was studied on BACE1 expression both in vivo, in streptozotocin treated rats, and in vitro in differentiated neuroblastoma cells. We showed that pentosidine and GLAP were able to upregulate BACE1 expression through their binding with RAGE and the consequent activation of NF-κB. In addition, both pentosidine and GLAP were found to be increased in the brain in sporadic AD patients. Our findings demonstrate that activation of the AGEs/RAGE axis, by upregulating the key enzyme for amyloid-β production, provides a pathologic link between diabetes mellitus and AD.
- Published
- 2010
17. Oxidative stress and hypoxia contribute to Alzheimer's disease pathogenesis: two sides of the same coin
- Author
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Oliviero Danni, Elena Tamagno, and Michela Guglielmotto
- Subjects
Pathology ,medicine.medical_specialty ,Ischemia ,lcsh:Medicine ,Disease ,Biology ,Disease pathogenesis ,medicine.disease_cause ,lcsh:Technology ,General Biochemistry, Genetics and Molecular Biology ,Electron Transport ,Alzheimer Disease ,medicine ,Amyloid precursor protein ,Aspartic Acid Endopeptidases ,Humans ,lcsh:Science ,General Environmental Science ,Mini-Review Article ,chemistry.chemical_classification ,Reactive oxygen species ,Cerebral hypoperfusion ,lcsh:T ,hypoxia ,lcsh:R ,BACE1 ,General Medicine ,Hypoxia (medical) ,medicine.disease ,Cell biology ,Oxidative Stress ,chemistry ,Enzyme Induction ,biology.protein ,lcsh:Q ,medicine.symptom ,Amyloid Precursor Protein Secretases ,Reactive Oxygen Species ,Alzheimer’s disease ,Oxidative stress - Abstract
While it is well established that stroke and cerebral hypoperfusion are risk factors for Alzheimer's disease (AD), the molecular link between ischemia/hypoxia and amyloid precursor protein (APP) processing has only been recently established. Here we review the role of the release of reactive oxygen species (ROS) by the mitochondrial electron chain in response to hypoxia, providing evidence that hypoxia fosters the amyloidogenic APP processing through a biphasic mechanism that up-regulates β-secretase activity, which involves an early release of ROS and an activation of HIF-1α.
- Published
- 2009
18. The up-regulation of BACE1 mediated by hypoxia and ischemic injury: role of oxidative stress and HIF1alpha
- Author
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Mark A. Smith, George Perry, Michela Guglielmotto, Elena Tamagno, Oliviero Danni, Riccardo Autelli, Luca Giliberto, Erica Novo, Maurizio Parola, Sebastiano Colombatto, Massimo Tabaton, and Manuela Aragno
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Oxidative phosphorylation ,Mitochondrion ,medicine.disease_cause ,Biochemistry ,Brain ischemia ,Cellular and Molecular Neuroscience ,Alzheimer Disease ,Cell Line, Tumor ,mental disorders ,Amyloid precursor protein ,Medicine ,Animals ,Aspartic Acid Endopeptidases ,Humans ,Rats, Wistar ,chemistry.chemical_classification ,Reactive oxygen species ,Amyloid beta-Peptides ,Electron Transport Complex I ,biology ,business.industry ,Uncoupling Agents ,JNK Mitogen-Activated Protein Kinases ,Brain ,Hypoxia (medical) ,medicine.disease ,Hypoxia-Inducible Factor 1, alpha Subunit ,Cell biology ,Rats ,Up-Regulation ,Isoenzymes ,Disease Models, Animal ,Oxidative Stress ,chemistry ,Hypoxia-Ischemia, Brain ,biology.protein ,medicine.symptom ,Amyloid Precursor Protein Secretases ,business ,Reactive Oxygen Species ,Amyloid precursor protein secretase ,Oxidative stress - Abstract
While it is well established that stroke and cerebral hypoperfusion are both significant risk factors for Alzheimer's disease, the molecular link between ischemia and amyloid precursor protein processing has only been recently established. Specifically, hypoxia significantly increases beta-site APP cleaving enzyme (BACE1) gene transcription through the over-expression of hypoxia inducible factor 1alpha, resulting in increased BACE1 secretase activity and amyloid-beta production. In this study, we significantly extend these findings both in vitro, in differentiated SK-N-BE neuroblastoma cells, and in vivo, in rats subjected to cerebral ischemia, showing that hypoxia up-regulates BACE1 expression through a biphasic mechanism. The early post-hypoxic up-regulation of BACE1 depends on the production of reactive oxygen species mediated by the sudden interruption of the mitochondrial electron transport chain, while the later expression of BACE1 is caused by hypoxia inducible factor 1alpha activation. The involvement of reactive oxygen species released by mitochondria in the BACE1 up-regulation was confirmed by the complete protection exerted by complex I inhibitors such as rotenone and diphenyl-phenylen iodonium. Moreover, the oxidative stress-mediated up-regulation of BACE1 is mediated by c-jun N terminal kinase pathway as demonstrated by the protection exerted by the silencing of c-jun N-terminal kinase isoforms 1 and 2. Our study strengthens the hypothesis that oxidative stress is a basic common mechanism of amyloid-beta accumulation.
- Published
- 2009
19. JNK and ERK1/2 pathways have a dual opposite effect on the expression of BACE1
- Author
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Oliviero Danni, Roberta Borghi, Michela Guglielmotto, Elena Tamagno, Riccardo Autelli, Luca Giliberto, Antonella Vitali, and Massimo Tabaton
- Subjects
Aging ,Cell Survival ,MAP Kinase Signaling System ,Mitogen-activated protein kinase kinase ,Biology ,medicine.disease_cause ,Neuroprotection ,Cell Line, Tumor ,mental disorders ,medicine ,Aspartic Acid Endopeptidases ,Humans ,ASK1 ,RNA, Messenger ,Phosphorylation ,Protein kinase B ,Mitogen-Activated Protein Kinase 1 ,Neurons ,Mitogen-Activated Protein Kinase 3 ,Kinase ,General Neuroscience ,JNK Mitogen-Activated Protein Kinases ,Presenilins ,Oxidative Stress ,AP-1 transcription factor ,Mitogen-activated protein kinase ,Cancer research ,biology.protein ,Neurology (clinical) ,Amyloid Precursor Protein Secretases ,Geriatrics and Gerontology ,Proto-Oncogene Proteins c-akt ,Oxidative stress ,Developmental Biology - Abstract
The activity of beta-secretase (BACE1), the endo-protease essential for the production of amyloid beta (Abeta) peptides, is increased in brain of late-onset sporadic Alzheimer's disease (AD), and oxidative stress is the potential cause of this event. Oxidative stress up-regulates the expression and the activity of BACE1 in cellular and animal models, through a mechanism that involves the increase of gamma-secretase cleavage on APP and the activation of c-jun N-terminal kinase/activator protein 1 (JNK/AP1) pathway. We further characterized the cellular pathways that control BACE1 expression under oxidative stress. We investigated the involvement of extracellular signal regulated MAP kinase (ERK1/2) pathway in the regulation of BACE1 expression, since it has been recently shown that ERK1/2 is an endogenous regulator of the gamma-secretase activity. We found that ERK1/2 pathway negatively modulates BACE1 expression and activity. Moreover, we observed that conditions that abrogate the gamma-secretase activity favor the activation of signalling pathways that promote cell survival, such as ERK1/2 and the serine/threonine kinase Akt/protein kinase B (Akt). These data suggest that the positive or negative cellular responses to oxidative stress parallel the activities of the beta- and the gamma-secretase. ERK1/2 and JNK pathways are involved in this bipartite response, which can lead to neurodegeneration or neuroprotection depending on the cellular and environmental conditions or cooperation with other signalling pathways such as Akt cascade.
- Published
- 2009
20. Treatment with the glycogen synthase kinase-3beta inhibitor, TDZD-8, affects transient cerebral ischemia/reperfusion injury in the rat hippocampus
- Author
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Elisa Benetti, Margherita Gallicchio, Raffaella Mastrocola, Gianluca Miglio, Manuela Aragno, Sara Castiglia, Christoph Thiemermann, Roberto Fantozzi, Oliver Murch, Chiara Dianzani, Massimo Collino, and Oliviero Danni
- Subjects
Male ,p38 mitogen-activated protein kinases ,Ischemia ,S100 Calcium Binding Protein beta Subunit ,Pharmacology ,Critical Care and Intensive Care Medicine ,medicine.disease_cause ,Hippocampus ,Models, Biological ,Antioxidants ,Brain Ischemia ,Glycogen Synthase Kinase 3 ,GSK-3 ,Thiadiazoles ,medicine ,Animals ,Nerve Growth Factors ,Phosphorylation ,Rats, Wistar ,chemistry.chemical_classification ,Reactive oxygen species ,Glycogen Synthase Kinase 3 beta ,biology ,Kinase ,Chemistry ,S100 Proteins ,Brain ,medicine.disease ,Mitochondria ,Rats ,Nitric oxide synthase ,Reperfusion Injury ,Emergency Medicine ,biology.protein ,Reperfusion injury ,Oxidative stress - Abstract
The serine/threonine glycogen synthase kinase 3beta (GSK-3beta) is abundant in the central nervous system, particularly in the hippocampus, and plays a pivotal role in the pathophysiology of a number of diseases, including neurodegeneration. This study was designed to investigate the effects of GSK-3beta inhibition against I/R injury in the rat hippocampus. Transient cerebral ischemia (30 min) followed by 1 h of reperfusion significantly increased generation of reactive oxygen species and modulated superoxide dismutase activity; 24 h of reperfusion evoked apoptosis (determined as mitochondrial cytochrome c release and Bcl-2 and caspase-9 expression), resulted in high plasma levels of TNF-alpha and increased expression of cyclooxygenase-2, inducible nitric oxide synthase, and intercellular adhesion molecule-1. The selective GSK-3beta inhibitor, 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), was administered before and after ischemia or during reperfusion alone to assess its potential as prophylactic or therapeutic strategy. Prophylactic or therapeutic administration of TDZD-8 caused the phosphorylation (Ser(9)) and hence inactivation of GSK-3beta. Infarct volume and levels of S100B protein, a marker of cerebral injury, were reduced by TDZD-8. This was associated with a significant reduction in markers of oxidative stress, apoptosis, and the inflammatory response resulting from cerebral I/R. These beneficial effects were associated with a reduction of I/R-induced activation of the mitogen-activated protein kinases JNK1/2 and p38 and nuclear factor-kappaB. The present study demonstrates that TDZD-8 protects the brain against I/R injury by inhibiting GSK-3beta activity. Collectively, our data may contribute to focus the role of GSK-3beta in cerebral I/R.
- Published
- 2008
21. Oxidative Stress Triggers Cardiac Fibrosis in the Heart of Diabetic Rats
- Author
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Maria Graziella Catalano, Oliviero Danni, Raffaella Mastrocola, Giuseppe Alloatti, Stefano Geuna, Paola Bardini, Giuseppe Boccuzzi, Ilenia Vercellinatto, and Manuela Aragno
- Subjects
0301 basic medicine ,Glycation End Products, Advanced ,Male ,medicine.medical_specialty ,Heart Diseases ,Cardiac fibrosis ,Heart Ventricles ,Receptor for Advanced Glycation End Products ,Drug Evaluation, Preclinical ,030209 endocrinology & metabolism ,medicine.disease_cause ,Streptozocin ,Diabetes Mellitus, Experimental ,Immediate-Early Proteins ,Contractility ,Transforming Growth Factor beta1 ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Fibrosis ,Diabetes mellitus ,Internal medicine ,Diabetic cardiomyopathy ,Medicine ,Myocyte ,Animals ,Rats, Wistar ,Receptors, Immunologic ,business.industry ,Myocardium ,Connective Tissue Growth Factor ,Dehydroepiandrosterone ,medicine.disease ,Rats ,Transcription Factor AP-1 ,Oxidative Stress ,030104 developmental biology ,Gene Expression Regulation ,Intercellular Signaling Peptides and Proteins ,Myocardial fibrosis ,Receptors, Adrenergic, beta-1 ,business ,Oxidative stress - Abstract
Diabetic cardiomyopathy is characterized by myocyte loss and myocardial fibrosis, leading to decreased elasticity and impaired contractile function. The study examines the downstream signaling whereby oxidative stress, induced by hyperglycemia, leads to myocardial fibrosis and impaired contractile function in the left ventricle of diabetic rats. It also examines the effects of dehydroepiandrosterone (DHEA), which prevents the oxidative damage induced by hyperglycemia in experimental models. DHEA was administered for 6 wk in the diet [0.02%, wt/wt)] to rats with streptozotocin-induced diabetes. Oxidative balance, advanced glycated end products (AGEs) and AGE receptors, transcription factors nuclear factor-kappaB and activator protein-1, and profibrogenic growth factors (connective tissue growth factor and TGFbeta1) were determined in the left ventricle of treated and untreated streptozotocin-diabetic rats. Structural and ultrastructural changes, and the contractile force developed by electrically driven papillary muscles, under basal conditions and after stimulation with isoproterenol, were also evaluated. Oxidative stress induced by hyperglycemia increased AGEs and AGE receptors and triggered a cascade of signaling, eventually leading to interstitial fibrosis. DHEA treatment, by improving oxidative balance, counteracted the enhanced AGE receptor activation and increase of profibrogenic factors and restored tissue levels of collagen I, collagen IV, and fibronectin to those of control animals. Moreover, DHEA completely restored the contractility of isolated papillary muscle. Oxidative stress led to cardiac fibrosis, the most important pathogenetic factor of the heart's impaired functional integrity in diabetes. Structural and ultrastructural changes and impairment of muscle function induced by experimental diabetes were minimized by DHEA treatment.
- Published
- 2008
22. Oxidative stress activates a positive feedback between the γ- and β-secretase cleavages of the β-amyloid precursor protein
- Author
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Riccardo Autelli, Xiongwei Zhu, Giuseppe Muraca, Oliviero Danni, Roberta Borghi, Mark A. Smith, Manuela Aragno, Mark P. Mattson, George Perry, Michela Guglielmotto, Dong-Gyu Jo, Elena Tamagno, Luca Giliberto, and Massimo Tabaton
- Subjects
medicine.medical_specialty ,Time Factors ,Amyloid beta ,MAP Kinase Kinase 4 ,medicine.disease_cause ,Transfection ,Biochemistry ,Presenilin ,Article ,Feedback ,Cellular and Molecular Neuroscience ,Amyloid beta-Protein Precursor ,Mice ,Internal medicine ,mental disorders ,medicine ,Amyloid precursor protein ,Animals ,Aspartic Acid Endopeptidases ,Enzyme Inhibitors ,Cells, Cultured ,Mice, Knockout ,Mice, Inbred BALB C ,biology ,Presenilins ,Infarction, Middle Cerebral Artery ,Hydrogen Peroxide ,medicine.disease ,Embryo, Mammalian ,Cell biology ,Oxidative Stress ,Endocrinology ,Gene Expression Regulation ,Mitogen-activated protein kinase ,biology.protein ,Alzheimer's disease ,Signal transduction ,Amyloid Precursor Protein Secretases ,Reactive Oxygen Species ,Amyloid precursor protein secretase ,Oxidative stress ,Signal Transduction - Abstract
Sequential cleavages of the beta-amyloid precursor protein cleaving enzyme 1 (BACE1) by beta-secretase and gamma-secretase generate the amyloid beta-peptides, believed to be responsible of synaptic dysfunction and neuronal cell death in Alzheimer's disease (AD). Levels of BACE1 are increased in vulnerable regions of the AD brain, but the underlying mechanism is unknown. Here we show that oxidative stress (OS) stimulates BACE1 expression by a mechanism requiring gamma-secretase activity involving the c-jun N-terminal kinase (JNK)/c-jun pathway. BACE1 levels are increased in response to OS in normal cells, but not in cells lacking presenilins or amyloid precursor protein. Moreover, BACE1 is induced in association with OS in the brains of mice subjected to cerebral ischaemia/reperfusion. The OS-induced BACE1 expression correlates with an activation of JNK and c-jun, but is absent in cultured cells or mice lacking JNK. Our findings suggest a mechanism by which OS induces BACE1 transcription, thereby promoting production of pathological levels of amyloid beta in AD.
- Published
- 2007
23. Clusterin up-regulation following sub-lethal oxidative stress and lipid peroxidation in human neuroblastoma cells
- Author
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George Perry, Elena Tamagno, Mark A. Smith, Oliviero Danni, Annalisa Pession, Barbara Dozza, Alessia Gaiba, Paola Strocchi, Strocchi P., Smith M.A., Perry G., Tamagno E., Danni O., Pession A., Gaiba A., and Dozza B.
- Subjects
Aging ,Cell Survival ,Blotting, Western ,Lipid peroxidation ,Clusterin ,Human neuroblastoma cells ,Reactive oxygen species ,Ascorbic Acid ,medicine.disease_cause ,4-Hydroxynonenal ,chemistry.chemical_compound ,Alzheimer Disease ,Cell Line, Tumor ,medicine ,Humans ,Ferrous Compounds ,Viability assay ,HSF1 ,Cell damage ,Neurons ,chemistry.chemical_classification ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,General Neuroscience ,Hydrogen Peroxide ,Oxidants ,medicine.disease ,Molecular biology ,eye diseases ,Up-Regulation ,Cell biology ,Oxidative Stress ,chemistry ,biology.protein ,sense organs ,Neurology (clinical) ,Geriatrics and Gerontology ,Oxidative stress ,Developmental Biology - Abstract
Clusterin/apolipoprotein J is a multifunctional protein up-regulated during various pathophysiological states. Since oxidative stress plays an important role in brain aging, and in many neurodegenerative disorders, to further understand the mechanistic underpinnings of clusterin expression, in this study, we examined clusterin expression in human neuroblastoma cells under conditions of increased production of reactive oxygen species and lipid peroxidation. Specifically, we analyzed clusterin mRNA and protein levels in human neuroblastoma IMR-32 and SH-SY5Y cells following exposure to sub-lethal amounts of iron–ascorbate to induce an increase in reactive oxygen species generation and lipid peroxidation. Under such conditions, we observed a time-dependent up-regulation of clusterin protein and mRNA levels, detected by immunoblot analysis and RT-PCR, respectively. Given the known roles of clusterin, the results of the present study support the notion that an increase in clusterin expression may be a physiological defence mounted to reduce cell damage and maintain cell viability during periods of increased oxidative stress.
- Published
- 2006
24. The various aggregation states of beta-amyloid 1-42 mediate different effects on oxidative stress, neurodegeneration, and BACE-1 expression
- Author
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Michela Guglielmotto, Elena Tamagno, Paola Bardini, Massimo Tabaton, and Oliviero Danni
- Subjects
Fibrillar Aβ1–42 ,Programmed cell death ,Amyloid ,Free radicals ,medicine.disease_cause ,Biochemistry ,Cell Line ,Physiology (medical) ,Prefibrillar Aβ1–42 ,medicine ,Aspartic Acid Endopeptidases ,Humans ,DNA Primers ,Amyloid beta-Peptides ,Base Sequence ,Cell Death ,Reverse Transcriptase Polymerase Chain Reaction ,Chemistry ,BACE-1 ,Neurodegeneration ,Neurotoxicity ,medicine.disease ,Peptide Fragments ,Cell biology ,Oligomeric Aβ1–42 ,Apoptosis ,Oxidative stress ,Toxicity ,Amyloid Precursor Protein Secretases ,Alzheimer's disease ,Alzheimer disease ,Protein Binding - Abstract
The amyloid cascade hypothesis suggests that the insoluble and fibrillar form of beta-amyloid (A beta) may play a primary pathogenic role in Alzheimer disease at the molecular level. However, neither the rate of dementia nor the extent of neuronal change seems to correlate with the levels of amyloidotic plaques (i.e., aggregated/fibrillar A beta). Recent evidence suggests, however, that neurotoxicity may be exerted also by rather small soluble aggregates of A beta, including oligomers. To characterize the mechanisms underlying toxicity mediated by the various aggregation states of A beta peptides is then a major goal of research. In this work we investigated the effects of fibrillar, prefibrillar, and oligomeric A beta(1-42) on the induction of oxidative stress, cell death, and BACE-1 expression in NT2 neuronal cells. We found that prefibrillar and oligomeric A beta(1-42) resulted in a more dramatic increase in the oxidative stress markers 4-hydroxynonenal and hydrogen peroxide compared to fibrillar A beta(1-42). Moreover, increased oxidative stress levels also resulted in a more rapid and significant induction of both apoptotic and necrotic neuronal cell death. Accordingly, fibrillar A beta(1-42), but not the soluble nonfibrillar forms, was the only condition able to up-regulate BACE-1 expression and activity.
- Published
- 2006
25. Overexpression of kidney neutral endopeptidase (EC 3.4.24.11) and renal function in experimental cirrhosis
- Author
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Giovanni Sansoè, Mario Rizzetto, Oliviero Danni, Antonina Smedile, Manuela Aragno, Juan Carlos Cutrin, Giulio Mengozzi, S. Silvano, Raffaella Mastrocola, and Floriano Rosina
- Subjects
Liver Cirrhosis ,Male ,medicine.medical_specialty ,Cyclohexanecarboxylic Acids ,Physiology ,Blotting, Western ,Natriuresis ,Renal function ,Bradykinin ,Kidney ,chemistry.chemical_compound ,Atrial natriuretic peptide ,Internal medicine ,Ascites ,medicine ,Animals ,Enzyme Inhibitors ,Rats, Wistar ,Carbon Tetrachloride ,Neprilysin ,Experimental cirrhosis ,Chemistry ,Advanced cirrhosis ,Osmolar Concentration ,Diuresis ,Rats ,medicine.anatomical_structure ,Endocrinology ,medicine.symptom - Abstract
Neutral endopeptidase degrades atrial natriuretic peptide (ANP) and bradykinin and may generate endothelin-1 from big-endothelin. In advanced cirrhosis, sodium retention is accompanied by elevated plasma ANP levels, and infusion of ANP causes hypotension, but in normal humans increasing the concentration of ANP through the inhibition of neutral endopeptidase, localized in renal proximal tubule cells, causes natriuresis without any arterial pressure drop. The purpose of this study was the assessment of kidney neutral endopeptidase expression and responses to candoxatrilat (a specific inhibitor of this enzyme) in rats with CCl4-induced cirrhosis. Two groups of control rats ( n = 5) were injected with vehicle or 3 mg/kg candoxatrilat. Three groups of cirrhotic rats with ascites ( n = 10) received vehicle alone or 3 or 10 mg/kg candoxatrilat. In cirrhotic rats, Western blot analysis revealed a 170% increase in renal neutral endopeptidase protein content ( P < 0.03), mainly in the proximal nephron and macula densa, and both candoxatrilat dosages increased plasma ANP levels, urinary volume, and urinary excretion of sodium, ANP, and cGMP compared with vehicle alone (all P < 0.03). Candoxatrilat (10 mg/kg) also reduced tubular solute-free water reabsorption ( P < 0.03) in cirrhotic rats, but renal blood flow, arterial pressure, and plasma renin activity were unaffected. Neutral endopeptidase inhibition has natriuretic and aquaretic actions in cirrhosis without any effect on blood pressure and kidney perfusion due to a significant overexpression of this enzyme in renal cortex.
- Published
- 2006
26. Neutral endopeptidase (EC 3.4.24.11) in cirrhotic liver: a new target to treat portal hypertension?
- Author
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Raffaella Mastrocola, Maurizio Parola, Floriano Rosina, Manuela Aragno, Mario Rizzetto, Antonina Smedile, F Restivo, Giulio Mengozzi, Giovanni Sansoè, and Oliviero Danni
- Subjects
Male ,medicine.medical_specialty ,Cirrhosis ,Cyclohexanecarboxylic Acids ,Portal venous pressure ,Blood Pressure ,Liver Cirrhosis, Experimental ,Plasma renin activity ,Atrial natriuretic peptide ,Internal medicine ,Hypertension, Portal ,medicine ,Animals ,Humans ,Protease Inhibitors ,Rats, Wistar ,Carbon Tetrachloride ,Cyclic GMP ,Hepatology ,Endothelin-1 ,business.industry ,Portal Vein ,medicine.disease ,Brain natriuretic peptide ,Rats ,Arginine Vasopressin ,medicine.anatomical_structure ,Endocrinology ,Liver ,Vascular resistance ,Portal hypertension ,Cytokines ,Neprilysin ,Vascular Resistance ,Liver function ,business ,Atrial Natriuretic Factor - Abstract
In liver cirrhosis atrial natriuretic peptide (ANP) decreases portal vascular resistance and tributary flow. The enzyme neutral endopeptidase (NEP) degrades ANP and bradykinin and generates endothelin-1 from big-endothelin. We determined the effects of NEP inhibition by candoxatrilat on hormonal status, liver function and arterial and portal pressures in rats with CCl4-induced cirrhosis.Two groups of seven control rats received 1 ml 5% glucose solution alone or containing 10 mg/kg candoxatrilat; three groups of 10 ascitic cirrhotic rats received placebo, 5 or 10 mg/kg candoxatrilat. NEP protein concentration and immunostaining were analyzed in normal and cirrhotic livers.In cirrhotic rats 10 mg/kg candoxatrilat significantly increased steady-state indocyanine green clearance (a parameter reflecting liver plasma flow) (P0.01), decreased portal pressure (P0.01), had no effect on arterial pressure and plasma renin activity but increased ANP plasma levels (P0.05) and urinary excretions (P0.01) of ANP and cGMP. In the cytosol fraction of rat cirrhotic livers a 280% increase in NEP content was found (P0.01), chiefly localized in desmin-positive myofibroblast-like cells of fibrous septa.Candoxatrilat has few effects on systemic hemodynamics and hormonal status; its portal hypotensive action depends on effects exerted on intrahepatic vascular resistance.
- Published
- 2005
27. Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways
- Author
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Roberta Borghi, Oliviero Danni, Mark A. Smith, Elena Tamagno, Alessandra Piccini, Michela Guglielmotto, Paola Bardini, Annalisa Davit, George Perry, Gianni Santoro, Maurizio Parola, and Massimo Tabaton
- Subjects
Cell signaling ,Alzheimer’s disease ,beta-site APP cleaving enzyme ,cell signaling ,4-hydroxynonenal ,oxidative stress ,stress-activated protein kinase ,Enzyme Activators ,Apoptosis ,Protein Serine-Threonine Kinases ,p38 Mitogen-Activated Protein Kinases ,Biochemistry ,Cell Line ,4-Hydroxynonenal ,Phosphatidylinositol 3-Kinases ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Proto-Oncogene Proteins ,Endopeptidases ,Amyloid precursor protein ,Aspartic Acid Endopeptidases ,Humans ,Phosphatidylinositol ,Protein kinase B ,Neurons ,Aldehydes ,biology ,Kinase ,JNK Mitogen-Activated Protein Kinases ,Up-Regulation ,DNA-Binding Proteins ,STAT1 Transcription Factor ,Beta-secretase 1 ,chemistry ,Mitogen-activated protein kinase ,Trans-Activators ,biology.protein ,Amyloid Precursor Protein Secretases ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
4-Hydroxynonenal (HNE), an aldehydic product of lipid peroxidation, up-regulates expression of the beta-site APP cleaving enzyme (BACE-1), an aspartyl protease responsible for the beta-secretase cleavage of amyloid precursor protein (AbetaPP), and results in increased levels of amyloid beta (Abeta) peptide. The mechanisms underlying this remain unclear but are of fundamental importance because prevention of BACE-1 up-regulation is viewed as an important therapeutic strategy. In this study, we exposed NT(2) neurons to a range of HNE concentrations (0.5-5 microm) that elicited an up-regulation of BACE-1 expression, a significant increase in intracellular and secreted levels of Abeta peptides as well as apoptosis involving poly-ADP ribose polymerase cleavage and activation of caspase 3. To delineate the molecular events involved in HNE-mediated BACE-1 activation, we investigated the involvement of stress-activated protein kinases (SAPK), signal transducers and activators of transcription (STAT) and serine-threonine kinase B/phosphatidylinositol phosphate 3 kinase (Akt/PtdIns3K). Using specific pharmacological inhibitors, our results show that activation of c-Jun N-terminal kinases and p38(MAPK.), but not STAT or Akt/PtdIns3K, pathways mediate the HNE-dependent up-regulation of BACE-1 expression. Therefore, HNE, an oxidative stress mediator detected in vivo in the brains of Alzheimer's disease patients, may play a pathogenetic role in Alzheimer's disease by selectively activating SAPK pathways and BACE-1 that regulate the proteolytic processing of AbetaPP.
- Published
- 2005
28. 4-Hydroxynonenal modulation of p53 family gene expression in the SK-N-BE neuroblastoma cell line
- Author
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Giuseppina Barrera, Cristina Toaldo, Paola Costelli, Stefano Laurora, Mario U. Dianzani, Federica Briatore, Paola Bardini, Stefania Pizzimenti, P. Reffo, Elena Tamagno, and Oliviero Danni
- Subjects
p53 ,Time Factors ,Cellular differentiation ,Apoptosis ,Cell Cycle Proteins ,Biochemistry ,Retinoblastoma Protein ,chemistry.chemical_compound ,Neuroblastoma ,cell growth ,Tumor Protein p73 ,Genes, Tumor Suppressor ,Phosphorylation ,Chromatography, High Pressure Liquid ,Cyclin ,bcl-2-Associated X Protein ,p63 ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Cell Cycle ,Nuclear Proteins ,Cell Differentiation ,Cell cycle ,Flow Cytometry ,Cell biology ,Peroxides ,DNA-Binding Proteins ,Proto-Oncogene Proteins c-bcl-2 ,4-hydroxynonenal ,p73 ,apoptosis ,SK-N-BE human neuroblastoma cell line ,free radicals ,Cyclin-Dependent Kinase Inhibitor p21 ,Blotting, Western ,HL-60 Cells ,Tretinoin ,Cysteine Proteinase Inhibitors ,4-Hydroxynonenal ,Bcl-2-associated X protein ,Cyclin D2 ,Physiology (medical) ,Cell Line, Tumor ,Humans ,Cell Proliferation ,Aldehydes ,Cell growth ,Tumor Suppressor Proteins ,Lipid Metabolism ,Phosphoproteins ,chemistry ,Microscopy, Fluorescence ,biology.protein ,Cancer research ,Trans-Activators ,Tumor Suppressor Protein p53 ,Transcription Factors - Abstract
4-Hydroxynonenal (HNE), a product of lipid peroxidation, inhibits proliferation of several tumor cells. The p53 tumor suppressor protein plays a critical role in cell cycle control, by inducing p21 expression, and in apoptosis, by inducing bax expression. Recently, two other proteins with many p53-like properties, TAp73 (p73) and TAp63 (p63), have been discovered. SK-N-BE human neuroblastoma cells express the three p53 family proteins and can be used for the study of their induction. We investigated HNE action in the control of proliferation, differentiation, and apoptosis in SK-N-BE cells and the HNE effect on the expression of p53, p63, p73, p21, bax, and G1 cyclins. Retinoic acid (RA) was used as a positive control. HNE inhibited cell proliferation without inducing differentiation; it decreased S-phase cells and increased the number of apoptotic cells. RA reduced the proportion of S-phase cells and did not induce apoptosis. HNE increased p53, p73, p63, p21, and bax expression at different time points. HNE reduced cyclin D2 expression and the phosphorylation of pRb protein. Our results demonstrated that HNE inhibits SK-N-BE cell proliferation by increasing the expression of p53 family proteins and p53 target proteins which modulate cell cycle progression and apoptosis.
- Published
- 2004
29. 4-Hydroxynonenal as a selective pro-fibrogenic stimulus for activated human hepatic stellate cells
- Author
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E. Zamara, Erica Novo, Fabio Marra, A. Gentilini, Manuela Aragno, Maurizio Parola, Sebastiano Colombatto, Mario U. Dianzani, Massimo Pinzani, Alessandra Caligiuri, Roberto Giulio Romanelli, Elena Tamagno, Riccardo Autelli, Gaia Robino, and Oliviero Danni
- Subjects
Liver Cirrhosis ,Male ,Programmed cell death ,Pathology ,medicine.medical_specialty ,Gene Expression ,Apoptosis ,Matrix metalloproteinase ,Biology ,4-Hydroxynonenal ,chemistry.chemical_compound ,medicine ,Animals ,Humans ,Rats, Wistar ,Carbon Tetrachloride ,Cells, Cultured ,Cytoskeleton ,Aldehydes ,Cell Death ,Dose-Response Relationship, Drug ,Hepatology ,DNA synthesis ,Liver Diseases ,Osmolar Concentration ,Molecular biology ,Actins ,Extracellular Matrix ,Rats ,Phenotype ,Liver ,chemistry ,Acute Disease ,Hepatic stellate cell ,Chemical and Drug Induced Liver Injury ,Signal transduction ,Wound healing ,Signal Transduction - Abstract
Background/Aims : 4-Hydroxynonenal (HNE) is a putative pro-fibrogenic product of oxidative stress able to elicit apoptosis and cytotoxicity in several cell types. This study has been performed to evaluate its ‘in vivo' levels in injured liver and whether HNE may induce apoptosis and/or affect selected phenotypic responses in activated human hepatic stellate cells (HSC/MF). Methods/Results : During the development of acute liver injury induced by CCl 4 , liver tissue HNE levels were in the range 0.5–10 μM, as shown by high performance liquid chromatography analysis. Cultured human HSC/MF, developed cytotoxicity only if exposed to very high HNE concentrations (25–50 μM) without any sign of induction of classic, caspase-dependent apoptosis, as assessed by evaluating morphology and biochemical parameters of cell death. HNE, at non-cytotoxic doses, up-regulated procollagen type I and tissue inhibitor of metalloproteinases-1 gene expression and/or protein synthesis without significantly affecting chemotaxis (wound healing and haptotaxis assay), matrix metalloproteinases 1 and 2 mRNA expression and activity as well as basal DNA synthesis. Conclusions : HNE, at concentrations compatible with those detected in vivo, does not elicit HSC/MF classic apoptosis but, rather, may act as a potent pro-fibrogenic stimulus for the expression of genes involved in excess extracellular matrix deposition and proposed as survival signals for HSC/MF.
- Published
- 2004
30. Oxidative stress and kidney dysfunction due to ischemia/reperfusion in rat: attenuation by dehydroepiandrosterone
- Author
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Raffaella Mastrocola, Maria-Giulia Perrelli, Juan Carlos Cutrin, F Restivo, Oliviero Danni, Giuseppe Poli, Manuela Aragno, and Giuseppe Boccuzzi
- Subjects
Male ,medicine.medical_specialty ,ischemia ,medicine.disease_cause ,Kidney ,Antioxidants ,Hydropic degeneration ,Nitric oxide ,Renal Circulation ,Lipid peroxidation ,Superoxide dismutase ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Reactive nitrogen species ,biology ,Dehydroepiandrosterone ,medicine.disease ,Immunohistochemistry ,Rats ,iNOS ,Oxidative Stress ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Catalase ,Nephrology ,TNF-α ,Reperfusion Injury ,biology.protein ,Oxidative stress - Abstract
Oxidative stress and kidney dysfunction due to ischemia/reperfusion in rat: Attenuation by dehydroepiandrosterone. Background The pathogenesis of ischemia/reperfusion (I/R) involves generation of reactive oxygen and nitrogen species. This in vivo study investigates the effect of dehydroepiandrosterone (DHEA), a physiologic steroid with antioxidant properties, on oxidative balance and renal dysfunctions induced by monolateral I/R. Methods Normal and DHEA-treated rats (4mg/day × 21 days, orally) were subjected to monolateral renal I/R (30 minutes/6 hours). The oxidative state was determined by measuring hydrogen peroxide level and activities of glutathione-peroxidase, catalase, and superoxide dismutase. Tumor necrosis factor-α (TNF-α) and nitric oxide production and inducible nitric oxide synthase (iNOS) levels were also measured. Hydroxynonenal content was used to probe lipid peroxidation. Functional parameters determined were creatinine levels and Na/K-ATPase activity. Immunohistochemical and morphologic studies were also performed. Results A markedly pro-oxidant state was evident in the kidney of rats subjected to I/R. Both hydrogen peroxide and reactive nitrogen species (nitric oxide and iNOS) increased, whereas antioxidants decreased. Oxidant species induce TNF-α increase, which, in turn, produces lipoperoxidative processes, as documented by the increased hydroxynonenal (HNE) level. As final result, impaired renal functionality, hydropic degeneration, and vacuolization of proximal convolute tubules were observed in kidneys of I/R rats. DHEA pretreatment improved the parameters considered. Conclusion I/R induces oxidative stress and consequently damages the proximal convolute renal tubules. Rats supplemented with DHEA and subjected to I/R had reduced pro-oxidant state, oxidative damage, and improved renal functionality, indicating an attenuation of oxidative injury and dysfunctions mediated by I/R.
- Published
- 2003
31. H2O2 and 4-hydroxynonenal mediate amyloid beta-induced neuronal apoptosis by activating JNKs and p38MAPK
- Author
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A Obbili, Oliviero Danni, Paola Bardini, Gaia Robino, Elena Tamagno, Maurizio Parola, and Manuela Aragno
- Subjects
MAPK/ERK pathway ,Programmed cell death ,Amyloid beta ,p38 mitogen-activated protein kinases ,Apoptosis ,medicine.disease_cause ,p38 Mitogen-Activated Protein Kinases ,Antioxidants ,4-Hydroxynonenal ,Cell Line ,chemistry.chemical_compound ,Developmental Neuroscience ,Alzheimer Disease ,mental disorders ,medicine ,Humans ,Enzyme Inhibitors ,Neurons ,Aldehydes ,Amyloid beta-Peptides ,biology ,Chemistry ,Kinase ,JNK Mitogen-Activated Protein Kinases ,Hydrogen Peroxide ,Molecular biology ,Peptide Fragments ,Enzyme Activation ,Oxidative Stress ,Neuroprotective Agents ,Neurology ,Biochemistry ,biology.protein ,Mitogen-Activated Protein Kinases ,Oxidative stress - Abstract
Amyloid beta peptides (Abeta) may be neurotoxic during the progression of Alzheimer's disease by eliciting oxidative stress. Exposure of neuronally differentiated SK-N-BE cells to Abeta(25-35) fragment as well as to full-length Abeta(1-40) and Abeta(1-42) induces early and time-dependent generation of oxidative stress that has been evaluated by carefully monitoring generation of hydrogen peroxide (H(2)O(2)), 4-hydroxynonenal (HNE), thiobarbituric acid reactive substances (TBARS), and fluorescent chromolipids. Abeta treatment also results in the activation of c-Jun aminoterminal kinases (JNKs) and p38(MAPK) and is followed by characteristic nuclear changes of apoptosis as evaluated by DAPI staining and TUNEL technique. To reproduce the relationships between oxidative stress and Abeta apoptosis we found that only the simultaneous administration of HNE and H(2)O(2), at concentrations similar to those generated within the first 3 h of Abeta exposure, can fully mimic Abeta-dependent activation of JNKs and p38(MAPK) and occurrence of apoptosis. Antioxidants such as alpha-tocopherol and N-acetylcysteine prevent completely either neuronal apoptosis or activation of JNKs and p38(MAPK) elicited by Abeta or by simultaneous HNE and H(2)O(2) addition. Finally, direct evidence that activation of these kinases is required for cell death induced by Abeta has been obtained by pretreating cell with specific inhibitors of JNKs and p38(MAPK). These results suggest the existence of a sequence of events in Abeta-induced apoptosis involving simultaneous generation of HNE and H(2)O(2) and oxidative stress-dependent activation of JNKs and p38(MAPK).
- Published
- 2003
32. Effects of Candoxatrilat a neutral endopeptidase inhibitor on sodium and free water urinary excretion in the rat model of CCl4-induced cirrhosis with ascites
- Author
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Manuela Aragno, Antonina Smedile, Giovanni Antonio Touscoz, Giovanni Sansoè, Oliviero Danni, Raffaella Mastrocola, Mario Rizzetto, Giulio Mengozzi, and S. Silvano
- Subjects
medicine.medical_specialty ,Candoxatrilat ,Cirrhosis ,Hepatology ,Chemistry ,Sodium ,Rat model ,Gastroenterology ,chemistry.chemical_element ,medicine.disease ,Urinary excretion ,Endocrinology ,Internal medicine ,Ascites ,medicine ,Free water ,medicine.symptom ,Neprilysin - Published
- 2003
33. Multiple signaling events in amyloid beta-induced, oxidative stress-dependent neuronal apoptosis
- Author
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Oliviero Danni, Elena Tamagno, Gianni Santoro, Michela Guglielmotto, Massimo Tabaton, Maurizio Parola, Laura Marra, and Paola Bardini
- Subjects
Programmed cell death ,MAP Kinase Kinase 4 ,p38 mitogen-activated protein kinases ,alpha-Tocopherol ,Apoptosis ,Caspase 3 ,Biology ,medicine.disease_cause ,p38 Mitogen-Activated Protein Kinases ,Biochemistry ,Neuroblastoma ,Proto-Oncogene Proteins ,Physiology (medical) ,Tumor Cells, Cultured ,medicine ,Humans ,Benzothiazoles ,Enzyme Inhibitors ,bcl-2-Associated X Protein ,Mitogen-Activated Protein Kinase Kinases ,Amyloid beta-Peptides ,Kinase ,Cytochrome c ,JNK Mitogen-Activated Protein Kinases ,Cytochromes c ,Cell Differentiation ,Hydrogen Peroxide ,Peptide Fragments ,Acetylcysteine ,Mitochondria ,Cell biology ,Enzyme Activation ,Oxidative Stress ,Thiazoles ,Cytosol ,Proto-Oncogene Proteins c-bcl-2 ,Caspases ,biology.protein ,Mitogen-Activated Protein Kinases ,Poly(ADP-ribose) Polymerases ,Tumor Suppressor Protein p53 ,Oxidative stress ,Toluene - Abstract
Current evidence suggests that amyloid beta peptides (Abeta) may play a major role in the pathogenesis of Alzheimer's disease by eliciting oxidative stress and neuronal apoptosis. In this study we have used differentiated SK-N-BE neurons to investigate molecular mechanisms and regulatory pathways underlying apoptotic neuronal cell death elicited by Abeta(1-40) and Abeta(1-42) peptides as well as the relationships between apoptosis and oxidative stress. Abeta peptides, used at concentrations able to induce oxidative stress, elicit a classic type of neuronal apoptosis involving mitochondrial regulatory proteins and pathways (i.e. affecting Bax and Bcl-2 protein levels as well as release of cytochrome c in the cytosol), poly-ADP rybose polymerase cleavage and activation of caspase 3. This pattern of neuronal apoptosis, that is significantly prevented by alpha-tocopherol and N-acetylcysteine and completely abolished by specific inhibitors of stress-activated protein kinases (SAPK) such as JNKs and p38(MAPK), involved early elevation of p53 protein levels. Pretreatment of neurons with alpha-pifithrin, a specific p53 inhibitor, resulted in a 50-60% prevention of Abeta induced apoptosis. These results suggest that oxidative stress - mediated neuronal apoptosis induced by amyloid beta operates by eliciting a SAPK-dependent multiple regulation of pro-apoptotic mitochondrial pathways involving both p53 and bcl-2.
- Published
- 2003
34. Dehydroepiandrosterone modulates nuclear factor-kappaB activation in hippocampus of diabetic rats
- Author
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Oliviero Danni, Giuseppe Boccuzzi, Maria Graziella Catalano, Gaia Robino, Maurizio Parola, Manuela Aragno, Raffaella Mastrocola, Enrico Brignardello, and Roberta Manti
- Subjects
Male ,medicine.medical_specialty ,Antioxidant ,medicine.medical_treatment ,Blotting, Western ,Dehydroepiandrosterone ,Oxidative phosphorylation ,medicine.disease_cause ,Hippocampus ,Antioxidants ,Diabetes Mellitus, Experimental ,Endocrinology ,NF-KappaB Inhibitor alpha ,Diabetes mellitus ,Internal medicine ,medicine ,Hippocampus (mythology) ,Animals ,Rats, Wistar ,Transcription factor ,chemistry.chemical_classification ,Cell Nucleus ,Reactive oxygen species ,Aldehydes ,Binding Sites ,NF-kappa B ,DNA ,Hydrogen Peroxide ,medicine.disease ,Rats ,DNA-Binding Proteins ,Oxidative Stress ,chemistry ,I-kappa B Proteins ,Lipid Peroxidation ,Reactive Oxygen Species ,Oxidation-Reduction ,Oxidative stress ,Biomarkers - Abstract
Oxidative stress induced by chronic hyperglycemia contributes to cerebrovascular complications in diabetes. Reactive oxygen species activate the transcription factor nuclear factor-kappaB (NF-kappaB), which in turn activates a variety of target genes linked to the development of diabetic complications. Dehydroepiandrosterone, an adrenal steroid, which possesses a multitargeted antioxidant effects, is also synthesized de novo by the brain. Normoglycemic and streptozotocin-diabetic rats were either treated with dehydroepiandrosterone (DHEA) for 7, 14, or 21 d (4 mg/d per rat) or left untreated. Oxidative state, antioxidant balance and activation of nuclear transcriptional redox-sensitive factor NF-kappaB were evaluated in the hippocampus area. In streptozotocin-treated rats, besides the strong increase in oxygen reactive species, there is also a persistent activation of NF-kappaB. The derangement of the oxidative balance in the brain induced by diabetes improves with DHEA. Moreover, DHEA completely counteracts NF-kappaB activation, measured as DNA binding activity, and hinders the increase of IkappaB-alpha inhibitory subunit induced by oxidative stress. The time-lag of DHEA's effects on NF-kappaB activation parallels its effects on oxidative balance. Results indicate that DHEA might protect hippocampus from chronic activation of NF-kappaB-dependent genes by reducing NF-kappaB nuclear translocation. This could result in protection from diabetes-dependent brain damage.
- Published
- 2002
35. NT2 neurons, a classical model for Alzheimer's disease, are highly susceptible to oxidative stress
- Author
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Enrico Brignardello, Manuela Aragno, Silvia Parola, G Boccuzzi, Oliviero Danni, Maurizio Parola, and Elena Tamagno
- Subjects
Lipid Peroxides ,Antioxidant ,medicine.medical_treatment ,Oxidative phosphorylation ,Ascorbic Acid ,medicine.disease_cause ,Thiobarbituric Acid Reactive Substances ,Lipid peroxidation ,chemistry.chemical_compound ,Alzheimer Disease ,medicine ,Tumor Cells, Cultured ,Humans ,Vitamin E ,Ferrous Compounds ,Cell damage ,chemistry.chemical_classification ,Neurons ,biology ,Cell Death ,L-Lactate Dehydrogenase ,General Neuroscience ,Fatty Acids ,Cell Differentiation ,Glutathione ,Hydrogen Peroxide ,medicine.disease ,Oxidants ,Drug Combinations ,Oxidative Stress ,chemistry ,Biochemistry ,Catalase ,biology.protein ,Oxidative stress ,Polyunsaturated fatty acid - Abstract
We have tested undifferentiated NT 2 cells as well as differentiated NT 2 neurons (NT 2 N) for vulnerability to oxidative stress, lipid composition and antioxidant pattern. NT 2 N, but not NT 2 cells, are highly susceptible to oxidative stress elicited by different classic pro-oxidant stimuli. In particular, NT 2 N cells undergo a high level of oxidative decomposition of ω-3 and ω-6 polyunsaturated fatty acids (PUFA) of membrane phospholipids, as evaluated by monitoring generation of thiobarbituric reactive substances, 4-hydroxynonenal (HNE) and chromolipid fluorescent adducts. NT 2 N cells exhibit low levels of natural antioxidants such as glutathione (GSH) and α-tocopherol and of antioxidant enzymatic activities such as Se-dependent GSH peroxidase and catalase. Accordingly, a direct correlation between lipid peroxidation and irreversible cell damage is suggested by prevention of NT 2 N cell death by α-tocopherol.
- Published
- 2000
36. Oxidative derangement in rat synaptosomes induced by hyperglycaemia: restorative effect of dehydroepiandrosterone treatment
- Author
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Giuseppe Boccuzzi, Oliviero Danni, Manuela Aragno, Enrico Brignardello, Silvia Parola, Elena Tamagno, and Roberta Manti
- Subjects
Male ,medicine.medical_specialty ,Antioxidant ,Free Radicals ,medicine.medical_treatment ,Dehydroepiandrosterone ,medicine.disease_cause ,Biochemistry ,Antioxidants ,Streptozocin ,Diabetes Mellitus, Experimental ,Lipid peroxidation ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Unsaturated fatty acid ,Pharmacology ,chemistry.chemical_classification ,Synaptosome ,Reactive oxygen species ,Cell Membrane ,Glutathione ,Axons ,Rats ,Endocrinology ,chemistry ,Hyperglycemia ,Lipid Peroxidation ,Oxidation-Reduction ,Oxidative stress ,Synaptosomes - Abstract
Central nervous system damage in diabetes is caused by both cerebral atherosclerosis and the detrimental effect of chronic hyperglycaemia on nervous tissue. Hyperglycaemia is the primer of a series of cascade reactions causing overproduction of free radicals. There is increasing evidence that these reactive molecules contribute to neuronal tissue damage. Dehydroepiandrosterone (DHEA) has been reported to possess antioxidant properties. This study evaluates the oxidative status in the synaptosomal fraction isolated from the brain of streptozotocin-treated rats and the antioxidant effect of DHEA treatment on diabetic rats. Hydroxyl radical generation, hydrogen peroxide content, and the level of the reactive oxygen species was increased (P < 0.05) in synaptosomes isolated from streptozotocin-treated rats. The derangement of the oxidative status was confirmed by a low level of reduced glutathione and alpha-tocopherol. DHEA treatment (4 mg per day for 3 weeks, per os) protected the synaptosomes against oxidative damage: synaptosomes from diabetic DHEA-treated rats showed a significant decrease in reactive species (P < 0.05) and in the formation of end products of lipid peroxidation, evaluated in terms of fluorescent chromolipid (P < 0.01). Moreover, DHEA treatment restored the unsaturated fatty acid content of the membrane and the reduced glutathione and alpha-tocopherol levels to normal levels and restored membrane NaK-ATPase activity close to control levels. The results demonstrate that DHEA supplementation greatly reduces oxidative damage in synaptosomes isolated from diabetic rats and suggest that this neurosteroid may participate in protecting the integrity of synaptic membranes against hyperglycaemia-induced damage.
- Published
- 2000
37. Dehydroepiandrosterone protects tissues of streptozotocin-treated rats against oxidative stress
- Author
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Giuseppe Boccuzzi, Manuela Aragno, Elena Tamagno, Oliviero Danni, Valentina Gatto, Enrico Brignardello, and Silvia Parola
- Subjects
Male ,medicine.medical_specialty ,Antioxidant ,Free Radicals ,Thiobarbituric acid ,medicine.medical_treatment ,Drug Evaluation, Preclinical ,Dehydroepiandrosterone ,medicine.disease_cause ,Kidney ,Biochemistry ,Antioxidants ,Diabetes Mellitus, Experimental ,Superoxide dismutase ,Lipid peroxidation ,chemistry.chemical_compound ,Physiology (medical) ,Internal medicine ,medicine ,TBARS ,Animals ,Rats, Wistar ,biology ,Chemistry ,Brain ,Glutathione ,Rats ,Oxidative Stress ,Endocrinology ,Liver ,Hyperglycemia ,biology.protein ,Lipid Peroxidation ,Oxidative stress - Abstract
Chronic hyperglycemia in diabetes determines the overproduction of free radicals, and evidence is increasing that these contribute to the development of diabetic complications. It has recently been reported that dehydroepiandrosterone possesses antioxidant properties; this study evaluates whether, administered daily for three weeks per os, it may provide antioxidant protection in tissues of rats with streptozotocin-induced diabetes. Lipid peroxidation was evaluated on liver, brain and kidney homogenates from diabetic animals, measuring both steady-state concentrations of thiobarbituric acid reactive substances and fluorescent chromolipids. Hyperglycemic rats had higher thiobarbituric acid reactive substances formation and fluorescent chromolipids levels than controls. Dehydroepiandrosterone-treatment (4 mg/day for 3 weeks) protected tissues against lipid peroxidation: liver, kidney and brain homogenates from dehydroepiandrosterone-treated animals showed a significant decrease of both thiobarbituric acid reactive substances and fluorescent chromolipids formation. The effect of dehydroepiandrosterone on the cellular antioxidant defenses was also investigated, as impaired antioxidant enzyme activities were considered proof of oxygen-dependent toxicity. In kidney and liver homogenates, dehydroepiandrosterone treatment restored to near-control values the cytosolic level of reduced glutathione, as well as the enzymatic activities of superoxide-dismutase, glutathione-peroxidase, catalase. In the brain, only an increase of catalase activity was evident (p < .05), which reverted with dehydroepiandrosterone treatment. The results demonstrate that DHEA treatment clearly reduces oxidative stress products in the tissues of streptozotocin-treated rats.
- Published
- 1999
38. Liver AP-1 activation due to carbon tetrachloride is potentiated by 1,2-dibromoethane but is inhibited by alpha-tocopherol or gadolinium chloride
- Author
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Fiorella Biasi, Maurizio Parola, Manuela Aragno, Simonetta Camandola, Giuseppe Poli, Oliviero Danni, Elena Chiarpotto, Gabriella Leonarduzzi, Juan Carlos Cutrin, and Elena Tamagno
- Subjects
Male ,Antioxidant ,Kupffer Cells ,medicine.medical_treatment ,Gadolinium ,Pharmacology ,In Vitro Techniques ,Biochemistry ,Antioxidants ,Lipid peroxidation ,chemistry.chemical_compound ,Lipid oxidation ,Physiology (medical) ,medicine ,TBARS ,Animals ,Vitamin E ,Electrophoretic mobility shift assay ,Drug Interactions ,Rats, Wistar ,Carbon Tetrachloride ,Hepatotoxin ,Rats ,Up-Regulation ,Ethylene Dibromide ,Transcription Factor AP-1 ,chemistry ,Liver ,Carbon tetrachloride ,Lipid Peroxidation ,alpha-Tocopherol ,Oxidation-Reduction - Abstract
Experimental acute intoxication by prooxidant haloalkanes produces marked stimulation of hepatic lipid peroxidation and cytolysis, which is followed by tissue regeneration. Our aim was to clarify the role of oxidative imbalance in the activation of the redox-sensitive transcription factor, activator protein-1 (AP-1), which is involved in tissue repair. Rats were poisoned with a very low concentration of carbon tetrachloride, given alone or in combination with another hepatotoxin, 1,2-dibromoethane, to provide varying extents of oxidative damage. The level of AP-1-DNA binding was analyzed by electrophoretic mobility shift assay on liver extracts, obtained from rats killed 6 h after poisoning. Stimulation of lipid peroxidation and AP-1 upregulation were already established when the hepatic damage due to carbon tetrachloride +/-1,2-dibromoethane was beginning to appear. Rat supplementation with the antioxidant vitamin E completely inhibited AP-1 upregulation, thus supporting a causative role of membrane lipid oxidation in the observed modulation of the transcription factor. Moreover, activation of Kupffer cells appears to be a crucial step in the increased AP-1 binding to DNA, the latter being largely prevented by gadolinium chloride, a macrophage-specific inhibitor.
- Published
- 1999
39. Oxygen free radical scavenger properties of dehydroepiandrosterone
- Author
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Bice Fubini, Manuela Aragno, Giuseppe Poli, Giuseppe Boccuzzi, Silvia Parola, Elena Tamagno, Marco Gallo, and Oliviero Danni
- Subjects
endocrine system ,Antioxidant ,Radical ,medicine.medical_treatment ,Iron ,Clinical Biochemistry ,Dehydroepiandrosterone ,Biochemistry ,Lipid peroxidation ,chemistry.chemical_compound ,polycyclic compounds ,medicine ,Animals ,Rats, Wistar ,skin and connective tissue diseases ,Oxidase test ,Chemistry ,Cell Biology ,General Medicine ,Free Radical Scavengers ,Rats ,Deoxyribose ,Microsome ,Microsomes, Liver ,Hydroxyl radical ,human activities ,hormones, hormone substitutes, and hormone antagonists - Abstract
The microsomes from dehydroepiandrosterone (DHEA)-supplemented animals are good hydroxyl radical scavengers, as demonstrated through electron spin resonance and deoxyribose degradation. The ability of DHEA-supplemented microsomes to react with superoxide radical was also demonstrated through the inhibition of nitroblue-tetrazolium reduction determined by superoxide radicals produced in a hypoxanthine-xanthine oxidase system. DHEA-enriched microsomes, obtained from acutely DHEA-treated rats, become resistant to iron-dependent lipid peroxidation triggered by H2O2/FeSO4 and ascorbate/FeSO4. The direct addition of DHEA to microsomes from untreated rats failed to prevent iron-dependent lipid peroxidation, even if the microsomes were preincubated with DHEA for up to 15 min, indicating that in vivo transformation is required before antioxidant action can be exerted.
- Published
- 1998
40. Oxidative Damage Induced by Acute Hyperglycemia Is Reduced by Dehydroepiandrosterone Supplementation in the Rat
- Author
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G Boccuzzi, Oliviero Danni, Manuela Aragno, V Gatto, Elena Tamagno, C. Fantino, and E. Brignardello
- Subjects
Oxidative damage ,medicine.medical_specialty ,Acute hyperglycemia ,Endocrinology ,business.industry ,Internal medicine ,Medicine ,Dehydroepiandrosterone ,business - Published
- 1998
41. Protective effect of dehydroepiandrosterone against copper-induced lipid peroxidation in the rat
- Author
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Emanuele Albano, Giuseppe Boccuzzi, Enrico Brignardello, Giorgio Bellomo, Elena Tamagno, Manuela Aragno, M. Seccia, and Oliviero Danni
- Subjects
Male ,medicine.medical_specialty ,Antioxidant ,Thiobarbituric acid ,medicine.medical_treatment ,Dehydroepiandrosterone ,Biochemistry ,Antioxidants ,Lipid peroxidation ,chemistry.chemical_compound ,Physiology (medical) ,Internal medicine ,Microsomes ,medicine ,TBARS ,Animals ,Rats, Wistar ,Brain ,Rats ,Lipoproteins, LDL ,Endocrinology ,chemistry ,Low-density lipoprotein ,Microsome ,Microsomes, Liver ,lipids (amino acids, peptides, and proteins) ,Lipid Peroxidation ,hormones, hormone substitutes, and hormone antagonists ,Copper ,Lipoprotein - Abstract
This study investigates the effectiveness and multitargeted activity of dehydroepiandrosterone (DHEA) as antioxidant in vivo. A single dose of DHEA was given IP to male rats. Liver and brain microsomes, and plasma low density lipoprotein (LDL), were isolated from rats sacrified 17 h later. Liver and brain microsomes were challenged with CuSO4 and, as index of lipid peroxidation, the production of thiobarbituric acid reactive substances (TBARS) was measaured. Also, plasma low-density lipoprotein (LDL) were challenged with copper and the time course of lipid peroxidation was evaluated following the formation of conjugated dienes. The onset of TBARS generation induced by copper was marked delayed in both liver and brain microsomes from DHEA-treated animals. Also, the resistance of LDL to oxidation, expressed by the duration of the lag-phase of the kinetic curve, was significantly enhanced in DHEA-treated rats. Results indicate that in vivo DHEA supplementation makes subcellular fractions isolated from different tissues and plasma constituents (LDL) more resistant to lipid peroxidation triggered by copper. The antioxidant effect on plasma LDL might be of special relevance to the proposed antiatherogenic activity of DHEA. Moreover, multitargeted antioxidant activity of DHEA might protect tissues from oxygen radicals damage. © 1997 Elsevier Science Inc.
- Published
- 1997
42. In vivo potentiation of 1,2-dibromoethane hepatotoxicity by ethanol through inactivation of glutathione-s-transferase
- Author
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Oliviero Danni, Giuseppe Poli, Elena Chiarpotto, Emanuele Albano, Mario U. Dianzani, Manuela Aragno, Elena Tamagno, Antonella Scavazza, and Fiorella Biasi
- Subjects
Male ,L-Iditol 2-Dehydrogenase ,Metabolite ,Aldehyde dehydrogenase ,Pharmacology ,Toxicology ,chemistry.chemical_compound ,Cytochrome P-450 Enzyme System ,Malondialdehyde ,mental disorders ,Demethylase activity ,Disulfiram ,medicine ,Animals ,Rats, Wistar ,Glutathione Transferase ,Fomepizole ,Ethanol ,biology ,Acetaldehyde ,Alcohol Dehydrogenase ,Cytochrome P-450 CYP2E1 ,Oxidoreductases, N-Demethylating ,General Medicine ,Glutathione ,Rats ,Ethylene Dibromide ,chemistry ,Biochemistry ,Liver ,Toxicity ,biology.protein ,Pyrazoles ,medicine.drug - Abstract
In the rat, a single ethanol (EtOH) pretreatment (2.5 g/kg b.w., per os) was able to strongly enhance the cytotoxicity of 1,2-dibromoethane (DBE) (87 mg/kg b.w., per os). The principal metabolic routes of DBE involve both oxidative and conjugative transformations. Microsomal cytochrome P450 content and dimethyl nitrosamine demethylase activity were not changed, while a significant loss of cytosolic total GSH-transferase was observed in rats killed 6 h after EtOH pretreatment. Pretreatment with methylpyrazole, an inhibitor of alcoholdehydrogenase prevented the effects provoked by ethanol. The major EtOH metabolite, acetaldehyde, seemed thus to play a fundamental role in the mechanism responsible for the potentiation of DBE toxicity mediated by EtOH. To further support this hypothesis, disulfiram (75 mg/kg b.w.), an inhibitor of aldehyde dehydrogenase, was given i.p. to rats. When DBE was administered to disulfiram- and EtOH-pretreated rats, a marked increase of liver cytolysis was shown and cytosolic GSH-transferase activity was further inhibited if compared to that induced by EtOH treatment alone. The results are consistent with the hypothesis that EtOH given to rats increases DBE liver toxicity because its major metabolite, acetaldehyde, reduces the DBE conjugation to GSH transferase, with consequent shift of DBE metabolism to the oxidative route and accumulation of reactive oxidative intermediates no longer effectively conjugated with GSH.
- Published
- 1996
43. ACETALDEHYDE INVOLVEMENT IN ETHANOL-INDUCED POTENTIATION OF RAT HEPATOCYTE DAMAGE DUE TO THE CARCINOGEN 1,2-DIBROMOETHANE
- Author
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Simonetta Camandola, Mario U. Dianzani, Giuseppe Poli, Manuela Aragno, Antonella Scavazza, Elena Tamagno, Elena Chiarpotto, Oliviero Danni, and Fiorella Biasi
- Subjects
Male ,Time Factors ,Acetaldehyde ,In Vitro Techniques ,Lipid peroxidation ,chemistry.chemical_compound ,medicine ,Animals ,Rats, Wistar ,Ethanol metabolism ,Carcinogen ,Glutathione Transferase ,Fomepizole ,Analysis of Variance ,Ethanol ,Drug Synergism ,General Medicine ,Rats ,Ethylene Dibromide ,medicine.anatomical_structure ,Liver ,chemistry ,Mechanism of action ,Biochemistry ,Hepatocyte ,Toxicity ,Carcinogens ,Pyrazoles ,Lipid Peroxidation ,medicine.symptom - Abstract
Previous experiments with hepatocytes isolated from ethanol-treated rats showed that alcohol potentiates the toxic action of 1,2-dibromoethane (DBE) by inhibiting its metabolism via glutathione-S-transferase. The aim of this study was to investigate whether acetaldehyde, the main product of ethanol metabolism, may be responsible for such inactivation. By pretreatment with 4-methylpyrazole, an inhibitor of acetaldehyde formation, the ethanol inactivation of glutathione transferase was actually prevented. As a consequence of this protective action, 4-methylpyrazole also prevented the high basal lipid peroxidation and the potentiated DBE toxicity observed in hepatocytes from ethanol-dosed animals. Finally, the inactivation of glutathione-S-transferase by concentrations of acetaldehyde likely to occur in the ethanol-intoxicated animal was confirmed in an in vitro model by direct aldehyde addition to hepatocyte suspensions.
- Published
- 1995
44. Ethanol-induced potentiation of rat hepatocyte damage due to 1,2-dibromoethane
- Author
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Mario U. Dianzani, Manuela Aragno, Antonella Scavazza, Fiorella Biasi, Oliviero Danni, Giuseppe Poli, and Elena Chiarpotto
- Subjects
Male ,Pharmacology ,Lipid peroxidation ,chemistry.chemical_compound ,Lactate dehydrogenase ,Malondialdehyde ,medicine ,Animals ,Rats, Wistar ,biology ,Ethanol ,Liver cell ,Liver Diseases ,Cell Membrane ,Drug Synergism ,General Medicine ,Glutathione ,Rats ,Ethylene Dibromide ,medicine.anatomical_structure ,Glutathione S-transferase ,chemistry ,Biochemistry ,Liver ,Hepatocyte ,Toxicity ,Carbon tetrachloride ,biology.protein ,Lipid Peroxidation - Abstract
Low amounts of 1,2-dibromoethane (DBE), not able per se to exert pro-oxidant and cytotoxic activity on rat hepatocyte suspensions, become effective when administered with carbon tetrachloride (CCl4), due to impairment of the glutathione transferase detoxication pathway by CCl4. Treatment of rats with a single dose of ethanol (2.5 g/kg body wt) 2 h before liver cell isolation potentiates the effect of DBE alone on both malonaldehyde formation and lactate dehydrogenase release by the hepatocyte. The potentiation of the DBE effects by ethanol may be through a series of mechanisms, such as a strong inactivation of hepatocyte glutathione transferase similar to that caused by CCl4, an increased basal level of lipid peroxidation and a significant loss of total glutathione.
- Published
- 1995
45. Lipid peroxidation and irreversible cell damage: synergism between carbon tetrachloride and 1,2-dibromoethane in isolated rat hepatocytes
- Author
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Flavio Belliardo, Fiorella Biasi, Adriana Comoglio, Manuela Aragno, Mario U. Dianzani, Giuseppe Poli, Elena Chiarpotto, and Oliviero Danni
- Subjects
Male ,Antioxidant ,Cell Survival ,medicine.medical_treatment ,Pharmacology ,Toxicology ,digestive system ,Lipid peroxidation ,chemistry.chemical_compound ,Malondialdehyde ,parasitic diseases ,medicine ,Animals ,Vitamin E ,Glutathione transferase activity ,Cell damage ,Carbon Tetrachloride ,Cells, Cultured ,Glutathione Transferase ,Glutathione Peroxidase ,L-Lactate Dehydrogenase ,Drug Synergism ,Rats, Inbred Strains ,Glutathione ,medicine.disease ,digestive system diseases ,Rats ,Ethylene Dibromide ,medicine.anatomical_structure ,Glutathione Reductase ,chemistry ,Biochemistry ,Liver ,Hepatocyte ,Lipid Peroxidation - Abstract
The combination of 1,2-dibromoethane (DBE) with carbon tetrachloride (CCl4) in the isolated rat hepatocyte model produces a significant potentiation of both lipid peroxidation and plasma membrane damage induced by the latter compound. The increase in malondialdehyde production precedes the hepatocyte damage, evaluated in terms both of lactate dehydrogenase leakage and trypan blue exclusion. When hepatocytes are isolated from vitamin E pretreated rats, both the prooxidant and the cytotoxic effects of CCl4 are prevented. Also the synergism between CCl4 and DBE on lipid peroxidation disappears completely while that on cell damage is strongly reduced. The increased lipid peroxidation appears to be one of the mechanisms of the observed synergism between CCl4 and DBE on hepatocyte damage. Regarding the antioxidant status of the hepatocyte challenged with CCl4 and DBE, an early and significant consumption of vitamin E is observed only in the presence of the mixture of these xenobiotics. Total nonprotein thiol content is not significantly modified by CCl4 poisoning while DBE, alone and in association with CCl4, markedly decreases it. Vitamin E supplementation does not prevent but moderately delays total nonprotein thiol depletion due to DBE or to the mixture. Finally, glutathione transferase activity is significantly reduced by CCl4 treatment and not by DBE, and vitamin E supplementation totally prevents such inhibition. The increased prooxidant effect of CCl4 plus DBE compared to CCl4 alone seems related to the shift in DBE metabolism consequent to the CCl4-dependent inactivation of glutathione transferase.
- Published
- 1991
46. Corrigendum to 'Oxidative stress and inflammatory response evoked by transient cerebral ischemia/reperfusion: Effects of the PPAR-α agonist WY14643' [Free Radic. Biol. Med. 41: 579–589; 2006]
- Author
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Elisa Benetti, Manuela Aragno, Christoph Thiemermann, Chiara Dianzani, Raffaella Mastrocola, Oliviero Danni, Massimo Collino, Margherita Gallicchio, and Roberto Fantozzi
- Subjects
Agonist ,medicine.drug_class ,business.industry ,Physiology (medical) ,Inflammatory response ,Anesthesia ,Ischemia ,medicine ,medicine.disease ,business ,medicine.disease_cause ,Biochemistry ,Oxidative stress - Abstract
a Department of Anatomy, Pharmacology, and Forensic Medicine, University of Turin, 10125 Turin, Italy b Department of Experimental Medicine and Oncology, University of Turin, 10125 Turin, Italy c Centre for Experimental Medicine, Nephrology and Critical Care, William Harvey Research Institute, St. Bartholomew’s and The Royal London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Published
- 2006
47. P4-230 HNE-dependent BACE 1 upregulation in NT2 neurons: role of SAPK and STAT pathways
- Author
-
Maurizio Parola, Oliviero Danni, Massimo Tabaton, Elena Tamagno, and Paola Bardini
- Subjects
Aging ,Downregulation and upregulation ,Chemistry ,General Neuroscience ,Neurology (clinical) ,Geriatrics and Gerontology ,stat ,Developmental Biology ,Cell biology - Published
- 2004
48. 32 Increased expression of renal neutral endopeptidase (EC 3.4.24.11) in rats with CCL4-induced ascitic cirrhosis: Acute effects of its pharmacological inhibition with IV. Candoxatrilat
- Author
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A. Smedile, F Restivo, Giovanni Sansoè, S. Silvano, Oliviero Danni, M. Rizzetto, Giulio Mengozzi, Raffaella Mastrocola, Manuela Aragno, and Floriano Rosina
- Subjects
Acute effects ,Candoxatrilat ,Cirrhosis ,Hepatology ,Chemistry ,medicine ,CCL4 ,Pharmacology ,medicine.disease ,Neprilysin - Published
- 2004
49. 14 Hormonal and renal effects of candoxatrilat, a neutral endopeptidase inhibitor, in the rat model of CCL4-induced cirrhosis with ascites
- Author
-
Giulio Mengozzi, Giovanni Antonio Touscoz, S. Silvano, M. Rizzetto, A. Smedile, Raffaella Mastrocola, Manuela Aragno, Oliviero Danni, and Giovanni Sansoè
- Subjects
medicine.medical_specialty ,Cirrhosis ,Candoxatrilat ,Hepatology ,business.industry ,Rat model ,Gastroenterology ,CCL4 ,medicine.disease ,Endocrinology ,Internal medicine ,Ascites ,medicine ,medicine.symptom ,business ,Neprilysin ,Hormone - Published
- 2003
50. 538 Effects of candoxatrilat, a neutral endopeptidase inhibitor, on sodium and free water urinary excretion in the rat model of CCL4-induced cirrhosis with ascites
- Author
-
Manuela Aragno, Mario Rizzetto, Giovanni Antonio Touscoz, Oliviero Danni, S. Silvano, Giulio Mengozzi, Floriano Rosina, Giovanni Sansoè, Antonina Smedile, and Raffaella Mastrocola
- Subjects
medicine.medical_specialty ,Cirrhosis ,Hepatology ,Chemistry ,Sodium ,Rat model ,chemistry.chemical_element ,CCL4 ,medicine.disease ,Endocrinology ,Urinary excretion ,Internal medicine ,Ascites ,medicine ,Free water ,medicine.symptom ,Neprilysin - Published
- 2003
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