Publications by authors named "Marisa Repetto"

19 Publications

  • Page 1 of 1

Cannabidiol (CBD) Alters the Functionality of Neutrophils (PMN). Implications in the Refractory Epilepsy Treatment.

Pharmaceuticals (Basel) 2021 Mar 5;14(3). Epub 2021 Mar 5.

Departamento de Bioquímica Clínica, Facultad de Farmacia y Bioquímica, Instituto de Fisiopatología y Bioquímica Clínica (INFIBIOC), Universidad de Buenos Aires, Buenos Aires C1120AAF, Argentina.

Cannabidiol (CBD), a lipophilic cannabinoid compound without psychoactive effects, has emerged as adjuvant of anti-epileptic drugs (AEDs) in the treatment of refractory epilepsy (RE), decreasing the severity and/or frequency of seizures. CBD is considered a multitarget drug that could act throughout the canonical endocannabinoid receptors (CB1-CB2) or multiple non-canonical pathways. Despite the fact that the CBD mechanism in RE is still unknown, experiments carried out in our laboratory showed that CBD has an inhibitory role on P-glycoprotein excretory function, highly related to RE. Since CB2 is expressed mainly in the immune cells, we hypothesized that CBD treatment could alter the activity of polymorphonuclear neutrophils (PMNs) in a similar way that it does with microglia/macrophages and others circulating leukocytes. In vitro, CBD induced PMN cytoplasmatic vacuolization and proapoptotic nuclear condensation, associated with a significantly decreased viability in a concentration-dependent manner, while low CBD concentration decreased PMN viability in a time-dependent manner. At a functional level, CBD reduced the chemotaxis and oxygen consumption of PMNs related with superoxide anion production, while the singlet oxygen level was increased suggesting oxidative stress damage. These results are in line with the well-known CBD anti-inflammatory effect and support a potential immunosuppressor role on PMNs that could promote an eventual defenseless state during chronic treatment with CBD in RE.
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http://dx.doi.org/10.3390/ph14030220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001508PMC
March 2021

Hypoxia, Oxidative Stress, and Inflammation: Three Faces of Neurodegenerative Diseases.

J Alzheimers Dis 2021 ;82(s1):S109-S126

Universidad de Buenos Aires, Facultad de Farmacia y Bioqummica, Departamento de Bioquímica Clínica, Instituto de Fisiopatología y Bioquímica Clínica (INFIBIOC), Argentina.

The cerebral hypoxia-ischemia can induce a wide spectrum of biologic responses that include depolarization, excitotoxicity, oxidative stress, inflammation, and apoptosis, and result in neurodegeneration. Several adaptive and survival endogenous mechanisms can also be activated giving an opportunity for the affected cells to remain alive, waiting for helper signals that avoid apoptosis. These signals appear to help cells, depending on intensity, chronicity, and proximity to the central hypoxic area of the affected tissue. These mechanisms are present not only in a large list of brain pathologies affecting commonly older individuals, but also in other pathologies such as refractory epilepsies, encephalopathies, or brain trauma, where neurodegenerative features such as cognitive and/or motor deficits sequelae can be developed. The hypoxia inducible factor 1α (HIF-1α) is a master transcription factor driving a wide spectrum cellular response. HIF-1α may induce erythropoietin (EPO) receptor overexpression, which provides the therapeutic opportunity to administer pharmacological doses of EPO to rescue and/or repair affected brain tissue. Intranasal administration of EPO combined with other antioxidant and anti-inflammatory compounds could become an effective therapeutic alternative, to avoid and/or slow down neurodegenerative deterioration without producing adverse peripheral effects.
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http://dx.doi.org/10.3233/JAD-201074DOI Listing
September 2021

Supplementation with Resveratrol, Piperine and Alpha-Tocopherol Decreases Chronic Inflammation in a Cluster of Older Adults with Metabolic Syndrome.

Nutrients 2020 Oct 15;12(10). Epub 2020 Oct 15.

Unidad Polifenoles, Vino y Salud, Cuarta Cátedra de Medicina, Hospital de Clínicas "José de San Martín" Facultad de Medicina, Universidad de Buenos Aires, City of Buenos Aires C1120AAF, Argentina.

Metabolic Syndrome (MetS) is increasing worldwide regardless of culture, genetic, gender, and geographic differences. While multiple individual risk factors, such as obesity, hypertension, diabetes, and hyperlipidemia, can cause cardiovascular disease (CVD), it is the intercurrence of these risk factors that defines MetS as a cluster that creates an environment for atherosclerosis and other manifestations of CVD. Despite the advances in the knowledge and management of each of the components of MetS, there are two molecular biology processes, chronic inflammation and oxidative stress, which are still underdiagnosed and undertreated. In order to assess the effect of a dietary supplement on chronic inflammation in MetS, we conducted a clinical trial with volunteers receiving a formula composed of resveratrol, piperine and alpha tocopherol (FRAMINTROL), together with their habitual treatment, for three months. The inflammatory state was evaluated by ultrasensitive C reactive protein (US CRP) and ferritin in plasma, and oxygen consumption and chemiluminescence in neutrophils. The results showed that ferritin decreased by 10% ( < 0.05), US-CRP by 33% ( < 0.0001), oxygen consumption by 55% ( < 0.0001), and spontaneous chemiluminiscence was by 25% ( < 0.005) after treatment. As far as we know, this is the first study showing a chronic inflammation decrease in MetS patients due to the administration of a biopower Resveratrol-piperine and alpha tocopherol dietary supplement together with conventional therapy.
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http://dx.doi.org/10.3390/nu12103149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602615PMC
October 2020

Role of Oxidative Stress in Lithium-Induced Nephropathy.

Biol Trace Elem Res 2019 Oct 2;191(2):412-418. Epub 2019 Jan 2.

Laboratory of Experimental Medicine, Hospital Alemán, Buenos Aires, Argentina.

Long-term lithium treatment was associated with chronic kidney disease and renal failure although the underlying pathogenic mechanisms are not certainty known. The aim of this study was to evaluate changes in oxidative stress measures as well as renal functional and structural alterations associated with chronic use of lithium in rats. Forty Wistar male rats were randomized into four groups: control groups fed ad libitum powered standard diet for 1 and 3 months and experimental groups fed ad libitum the same diet supplemented with 60 mmol/kg diet for 1 and 3 months. Histopathological changes, laboratory parameters, and oxidative stress measurements were assessed at months 1 and 3. The experimental animals showed alteration of the cortical tubules from the first month of lithium-treatment and a decrease in the glomerular filtration rate and in the glomerular area at the third month. There was an increase in thiobarbituric acid reactive substances and carbonyls, as well as an increase in reduced glutathione, in the kidney of rats exposed to lithium. These changes were evident from the first month of treatment and remained throughout the experiment. Our results suggest that, oxidative stress could be one of the pathogenic mechanisms involved in the structural and functional alterations of the kidney associated with prolonged use of lithium. The study of the pathogenic mechanisms involved in lithium-induced nephropathy is a critical issue for the development of new strategies for prevention and/or early detection.
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http://dx.doi.org/10.1007/s12011-018-1617-2DOI Listing
October 2019

Copper-induced cell death and the protective role of glutathione: the implication of impaired protein folding rather than oxidative stress.

Metallomics 2018 12;10(12):1743-1754

Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Química Analítica y Fisicoquímica, Cátedra de Química General e Inorgánica, Junin 956, C1113AAD, Buenos Aires, Argentina.

Copper (Cu) is a bioelement essential for a myriad of enzymatic reactions, which when present in high concentration leads to cytotoxicity. Whereas Cu toxicity is usually assumed to originate from the metal's ability to enhance lipid peroxidation, the role of oxidative stress has remained uncertain since no antioxidant therapy has ever been effective. Here we show that Cu overload induces cell death independently of the metal's ability to oxidize the intracellular milieu. In fact, cells neither lose control of their thiol homeostasis until briefly before the onset of cell death, nor trigger a consistent antioxidant response. As expected, glutathione (GSH) protects the cell from Cu-mediated cytotoxicity but, surprisingly, fully independent of its reactive thiol. Moreover, the oxidation state of extracellular Cu is irrelevant as cells accumulate the metal as cuprous ions. We provide evidence that cell death is driven by the interaction of cuprous ions with proteins which impairs protein folding and promotes aggregation. Consequently, cells mostly react to Cu by mounting a heat shock response and trying to restore protein homeostasis. The protective role of GSH is based on the binding of cuprous ions, thus preventing the metal interaction with proteins. Due to the high intracellular content of GSH, it is depleted near the Cu entry site, and hence Cu can interact with proteins and cause aggregation and cytotoxicity immediately below the plasma membrane.
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http://dx.doi.org/10.1039/c8mt00182kDOI Listing
December 2018

Copper(II) and iron(III) ions inhibit respiration and increase free radical-mediated phospholipid peroxidation in rat liver mitochondria: Effect of antioxidants.

J Inorg Biochem 2017 07 19;172:94-99. Epub 2017 Apr 19.

Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Química Analítica y Fisicoquímica, Cátedra de Química General e Inorgánica, C1113AAD Buenos Aires, Argentina.. Electronic address:

Rat liver mitochondria (1.5-2.1mg protein·mL) supplemented with either 25 and 100μM Cu or 100 and 500μM Fe show inhibition of active respiration (O consumption in state 3) and increased phospholipid peroxidation . Liver mitochondria were supplemented with the antioxidants reduced glutathione, N-acetylcysteine or butylated hydroxitoluene, to evaluate their effects on the above-mentioned alterations. Although the mitochondrial dysfunction is clearly associated to phospholipid peroxidation, the different responses to antioxidant supplementation indicate that the metal ions have differences in their mechanisms of toxicity. Mitochondrial phospholipid peroxidation through the formation of hydroxyl radical by a Fenton/Haber-Weiss mechanism seems to precede the respiratory inhibition and to be the main fact in Fe-induced mitochondrial dysfunction. In the case of Cu, it seems that the ion oxidizes glutathione, and low molecular weight protein thiol groups in a direct reaction, as part of its intracellular redox cycling. The processes involving phospholipid peroxidation, protein oxidation and mitochondrial respiratory inhibition characterize a redox dyshomeostatic situation that ultimately leads to cell death. However, Cu exposure involves an additional, yet unidentified, toxic event as previous reduction of the metal with N-acetylcysteine has only a minor effect in preventing the mitochondrial damage.
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http://dx.doi.org/10.1016/j.jinorgbio.2017.04.012DOI Listing
July 2017

Rat liver mitochondrial dysfunction by addition of copper(II) or iron(III) ions.

J Inorg Biochem 2017 01 14;166:5-11. Epub 2016 Oct 14.

University of Buenos Aires, School of Pharmacy and Biochemistry, Department of General and Inorganic Chemistry, C1113AAD Buenos Aires, Argentina. Electronic address:

Increased copper (Cu) and iron (Fe) levels in liver and brain are associated to oxidative stress and damage with increased phospholipid oxidation process. The aim of this work was to assess the toxic effects of Cu and Fe addition to rat liver mitochondria by determining mitochondrial respiration in states 3 (active respiration) and 4 (resting respiration), and phospholipid peroxidation. Both, Cu and Fe produced decreases in O consumption in a concentration-dependent manner in active state 3: both ions by 42% with malate-glutamate as complex I substrate (concentration for half maximal response (C) 60μM Cu and 1.25mM Fe), and with succinate as complex II substrate: 64-69% with C of 50μM Cu and with C of 1.25mM of Fe. Respiratory control decreased with Cu (C 50μM) and Fe (C 1.25-1-75mM) with both substrates. Cu produced a 2-fold increase and Fe a 5-fold increase of thiobarbituric acid-reactive substances (TBARS) content from 25μM Cu (C 40μM) and from 100μM Fe (C 1.75mM). Supplementations with Cu and Fe ions induce mitochondrial dysfunction with phospholipid peroxidation in rat liver mitochondria. Although is proved that a Fenton/Haber Weiss mechanism of oxidative damage occurs in metal-ion induced mitochondrial toxicity, slightly different responses to the metal ions suggest some differences in the mechanism of intracellular toxicity. The decreased rates of mitochondrial respiration and the alteration of mitochondrial function by phospholipid and protein oxidations lead to mitochondrial dysfunction, cellular dyshomeostasis and cell death.
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http://dx.doi.org/10.1016/j.jinorgbio.2016.10.009DOI Listing
January 2017

Brain antioxidant responses to acute iron and copper intoxications in rats.

Metallomics 2014 Nov;6(11):2083-9

Department of General and Inorganic Chemistry, University of Buenos Aires, Buenos Aires, Argentina.

Dose- and time-dependent antioxidant responses to Fe (0-60 mg kg(-1)) and Cu overloads (0-30 mg kg(-1)) in rat brains are described by the C50 and the t1/2, the brain metal concentration and the time for half maximal oxidative responses. Brain GSH and the GSH/GSSG ratio markedly decreased after Fe and Cu treatments (50-80%) with a t1/2 of 9-10 h for GSH and of 4 h for GSH/GSSG for both metals. The GSH/GSSG ratio was the most sensitive indicator of brain oxidative stress. The decrease of GSH and the increase of in vivo chemiluminescence had similar time courses. The C50 for brain chemiluminescence, GSH and hydrophilic and lipophilic antioxidants were in similar ranges (32-36 μg Fe g(-1) brain and 10-18 μg Cu g(-1) brain), which indicated a unique free-radical mediated process for each metal. The brain concentration of hydrophilic and lipophilic antioxidants decreased after Fe and Cu loads; hydrophilic antioxidants decreased by 46-68% with a t1/2 of 10-11 h and lipophilic antioxidants decreased by 75-45% with a t1/2 of 10-12 h. Cu,Zn-SOD and CAT activities and the protein expression were adaptively increased (100-90% after Fe and Cu loads), with a t1/2 of 8-12 h. GPx-4 activity decreased after both metal loads by 73-27% with a t1/2 of 8-4 h with decreased protein expression.
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http://dx.doi.org/10.1039/c4mt00159aDOI Listing
November 2014

Rat liver antioxidant response to iron and copper overloads.

J Inorg Biochem 2014 Aug 30;137:94-100. Epub 2014 Apr 30.

Department of General and Inorganic Chemistry, School of Pharmacy and Biochemistry, University of Buenos Aires, C1113AAD Buenos Aires, Argentina. Electronic address:

The rat liver antioxidant response to Fe and Cu overloads (0-60mg/kg) was studied. Dose- and time-responses were determined and summarized by t1/2 and C50, the time and the liver metal content for half maximal oxidative responses. Liver GSH (reduced glutathione) and GSSG (glutathione disulfide) were determined. The GSH content and the GSH/GSSG ratio markedly decreased after Fe (58-66%) and Cu (79-81%) loads, with t1/2 of 4.0 and 2.0h. The C50 were in a similar range for all the indicators (110-124μgFe/g and 40-50μgCu/g) and suggest a unique free-radical mediated process. Hydrophilic antioxidants markedly decreased after Fe and Cu (60-75%; t1/2: 4.5 and 4.0h). Lipophilic antioxidants were also decreased (30-92%; t1/2: 7.0 and 5.5h) after Fe and Cu. Superoxide dismutase (SOD) activities (Cu,Zn-SOD and Mn-SOD) and protein expression were adaptively increased after metal overloads (Cu,Zn-SOD: t1/2: 8-8.5h and Mn-SOD: t1/2: 8.5-8.0h). Catalase activity was increased after Fe (65%; t1/2: 8.5h) and decreased after Cu (26%; t1/2: 8.0h), whereas catalase expression was increased after Fe and decreased after Cu overloads. Glutathione peroxidase activity decreased after metal loads by 22-39% with a t1/2 of 4.5h and with unchanged protein expression. GSH is the main and fastest responder antioxidant in Fe and Cu overloads. The results indicate that thiol (SH) content and antioxidant enzyme activities are central to the antioxidant defense in the oxidative stress and damage after Fe and Cu overloads.
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http://dx.doi.org/10.1016/j.jinorgbio.2014.04.014DOI Listing
August 2014

Oxidative damage to rat brain in iron and copper overloads.

Metallomics 2014 Aug;6(8):1410-6

Department of General and Inorganic Chemistry, University of Buenos Aires, Buenos Aires, Argentina.

This study reports on the acute brain toxicity of Fe and Cu in male Sprague-Dawley rats (200 g) that received 0 to 60 mg kg(-1) (ip) FeCl2 or CuSO4. Brain metal contents and time-responses were determined for rat survival, in situ brain chemiluminescence and phospholipid and protein oxidation products. Metal doses hyperbolically defined brain metal content. Rat survival was 91% and 60% after Fe and Cu overloads. Brain metal content increased from 35 to 114 μg of Fe per g and from 3.6 to 34 μg of Cu per g. Brain chemiluminescence (10 cps cm(-2)) increased 3 and 2 times after Fe and Cu overloads, with half maximal responses (C50) of 38 μg of Fe per g of brain and 15 μg of Cu per g of brain, and with half time responses (t1/2) of 12 h for Fe and 20 h for Cu. Phospholipid peroxidation increased by 56% and 31% with C50 of 40 μg of Fe per g and 20 μg of Cu per g and with t1/2 of 9 h and 14 h. Protein oxidation increased by 45% for Fe with a C50 of 40 μg of Fe per g and 18% for Cu with a C50 of 10 μg of Cu per g and a t1/2 of 12 h for both metals. Fe and Cu brain toxicities are likely mediated by Haber-Weiss type HO˙ formation with subsequent oxidative damage.
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http://dx.doi.org/10.1039/c3mt00378gDOI Listing
August 2014

The protective effect of menhaden oil in the oxidative damage and renal necrosis due to dietary choline deficiency.

Food Funct 2013 Feb 12;4(3):448-52. Epub 2012 Dec 12.

Centre of Experimental Pathology, Faculty of Medicine, University of Buenos Aires, JE Uriburu 950, Buenos Aires, Argentina.

Weanling rats fed a choline-deficient diet develop kidney oxidative damage, tubular and cortical kidney necrosis, renal failure and animal death. The effect of dietary menhaden oil was assayed on the mentioned sequence correlating oxidative stress with renal structure and function. Rats were fed ad libitum 4 different diets: (a) a choline-deficient diet with corn oil and sunflower hydrogenated oil as a source of fatty acids; (b) the same diet supplemented with choline; (c) a choline-deficient diet with menhaden oil as a source of fatty acids; and (d) the previous diet supplemented with choline. Animals were sacrificed at days 0, 2, 4 and 7. The histopathological study of the kidneys showed that renal necrosis was only observed at day 7 in choline-deficient rats receiving the vegetable oil diet, simultaneously with increased creatinine plasma levels. Homogenate chemiluminescence (BOOH-initiated chemiluminescence) and phospholipid oxidation indicate the development of oxidative stress and damage in choline-deficient rats fed vegetable oils as well as the protective effect of menhaden oil. Rats fed with the fish oil diet showed that oxidative stress and damage develop later, as compared with vegetable oil, with no morphological damage during the experimental period.
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http://dx.doi.org/10.1039/c2fo30229bDOI Listing
February 2013

The acute toxicity of iron and copper: biomolecule oxidation and oxidative damage in rat liver.

J Inorg Biochem 2012 Nov 11;116:63-9. Epub 2012 Jul 11.

Institute of Biochemistry and Molecular Medicine (IBIMOL, UBA-CONICET), School of Pharmacy and Biochemistry, University of Buenos Aires, C1113AAD Buenos Aires, Argentina.

The transition metals iron (Fe) and copper (Cu) are needed at low levels for normal health and at higher levels they become toxic for humans and animals. The acute liver toxicity of Fe and Cu was studied in Sprague Dawley male rats (200 g) that received ip 0-60 mg/kg FeCl(2) or 0-30 mg/kg CuSO(4). Dose and time-responses were determined for spontaneous in situ liver chemiluminescence, phospholipid lipoperoxidation, protein oxidation and lipid soluble antioxidants. The doses linearly defined the tissue content of both metals. Liver chemiluminescence increased 4 times and 2 times after Fe and Cu overloads, with half maximal responses at contents (C(50%)) of 110 μgFe/g and 42 μgCu/g liver, and with half maximal time responses (t(1/2)) of 4h for both metals. Phospholipid peroxidation increased 4 and 1.8 times with C(50%) of 118 μg Fe/g and 45 μg Cu/g and with t(1/2) of 7h and 8h. Protein oxidation increased 1.6 times for Fe with C(50%) at 113 μg Fe/g and 1.2 times for Cu with 50 μg Cu/g and t(1/2) of 4h and 5h respectively. The accumulation of Fe and Cu in liver enhanced the rate of free radical reactions and produced oxidative damage. A similar free radical-mediated process, through the formation HO(•) and RO(•) by a Fenton-like homolytic scission of H(2)O(2) and ROOH, seems to operate as the chemical mechanism for the liver toxicity of both metals.
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http://dx.doi.org/10.1016/j.jinorgbio.2012.07.004DOI Listing
November 2012

Type 2 diabetes and/or its treatment leads to less cognitive impairment in Alzheimer's disease patients.

Diabetes Res Clin Pract 2012 Oct 2;98(1):68-74. Epub 2012 Jun 2.

Sirio-Libanés Hospital, Department of Neurology, School of Medicine, University of Buenos Aires (UBA), Buenos Aires, Argentina.

Aim: To evaluate the cognitive performance of a homogeneous population of Alzheimer's disease (AD), non-demented Type 2 Diabetes Mellitus (DIAB), demented with concomitant diseases (AD+DIAB) and healthy control subjects. AD is a progressive dementia disorder characterized clinically by impairment of memory, cognition and behavior. Recently, a major research interest in AD has been placed on early evaluation. Diabetes is one of the clinical conditions that represent the greatest risk of developing oxidative stress and dementia. Glucose overload, leading to the development of impaired-induced insulin secretion in DIAB and has been suggested to slow or deter AD pathogenesis.

Methods: The degree of cognitive impairment was determined on the Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog) and the Folstein's Mini Mental State Examination (MMSE); the severity of dementia was quantified applying the Clinical Dementia Rating (CDR) test; the Hamilton test was employed to evaluate depressive conditions; the final population studied was 101 subjects.

Results: The cognitive deterioration is statistically significantly lower (p<0.05) in AD+DIAB patients as compared with AD patients.

Conclusions: In this longitudinal study the superimposed diabetic condition was associated with a lower rate of cognitive decline, while diabetic non-demented patients and controls present normal scores.
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http://dx.doi.org/10.1016/j.diabres.2012.05.013DOI Listing
October 2012

Effects of rotenone and pyridaben on complex I electron transfer and on mitochondrial nitric oxide synthase functional activity.

J Bioenerg Biomembr 2010 Oct 1;42(5):405-12. Epub 2010 Oct 1.

Department of Biochemistry and Molecular Biology, School of Medicine, University of Cádiz, Plaza Fragela 9, 11003 Cádiz, Spain.

Rotenone and pyridaben were tested on activities and properties of rat brain mitochondria determining Ki (inhibitor concentration at half maximal inhibition) and Imax (% of inhibition at maximal inhibitor concentration). The assayed activities were complexes I, II and IV, respiration in states 3, 3u (uncoupled) and 4, biochemical and functional activities of mitochondrial nitric oxide synthase (mtNOS), and inner membrane potential. Selective inhibitions of complex I activity, mitochondrial respiration and membrane potential with malate-glutamate as substrate were observed, with a Ki of 0.28-0.36 nmol inhibitor/mg of mitochondrial protein. Functional mtNOS activity was half-inhibited at 0.70-0.74 nmol inhibitor/mg protein in state 3 mitochondria and at 2.52-2.98 nmol inhibitor/mg protein in state 3u mitochondria. This fact is interpreted as an indication of mtNOS being structurally adjacent to complex I with an intermolecular mtNOS-complex I hydrophobic bonding that is stronger at high Δψ and weaker at low Δψ.
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http://dx.doi.org/10.1007/s10863-010-9309-4DOI Listing
October 2010

The involvement of transition metal ions on iron-dependent lipid peroxidation.

Arch Toxicol 2010 Apr 20;84(4):255-62. Epub 2009 Nov 20.

Laboratory of Free Radical Biology, Department of Physical Chemistry, School of Pharmacy and Biochemistry, University of Buenos Aires, C1113AAD Buenos Aires, Argentina.

The metals iron (Fe) and copper (Cu) are considered trace elements, and the metals cobalt (Co) and nickel (Ni) are known as ultra-trace elements, considering their presence in low to very low quantity in humans. The biologic activity of these transition metals is associated with the presence of unpaired electrons that favor their participation in redox reactions. They are part of important enzymes involved in vital biologic processes. However, these transition metals become toxic to cells when they reach elevated tissue concentrations and produce cellular oxidative damage. Phospholipid liposomes (0.5 mg/ml, phosphatidylcholine (PC)/phosphatidylserine (PS), 60/40) were incubated for 60 min at 37 degrees C with 25 microM of Fe2+ in the absence and in the presence of Cu2+, Co2+, and Ni2+ (0-100 microM) with and without the addition of hydrogen peroxide (H2O2, 5-50 microM). Iron-dependent lipid peroxidation in PC/PS liposomes was assessed by thiobarbituric acid-reactive substances (TBARS) production. Metal transition ions promoted lipid peroxidation by H2O2 decomposition and direct homolysis of endogenous hydroperoxides. The Fe2+-H2O2-mediated lipid peroxidation takes place by a pseudo-second order process, and the Cu2+-mediated process by a pseudo-first order reaction. Co2+ and Ni2+ alone do not induce lipid peroxidation. Nevertheless, when they are combined with Fe2+, Fe2+-H2O2-mediated lipid peroxidation was stimulated in the presence of Ni2+ and was inhibited in the presence of Co2+. The understanding of the effects of transition metal ions on phospholipids is relevant to the prevention of oxidative damage in biologic systems.
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http://dx.doi.org/10.1007/s00204-009-0487-yDOI Listing
April 2010

Oxidative damage: the biochemical mechanism of cellular injury and necrosis in choline deficiency.

Exp Mol Pathol 2010 Feb 12;88(1):143-9. Epub 2009 Nov 12.

Laboratory of Free Radical Biology, School of Pharmacy and Biochemistry, Universidad de Buenos Aires, Buenos Aires, Argentina.

Oxidative stress and damage are characterized by decreased tissue antioxidant levels, consumption of tissue alpha-tocopherol, and increased lipid peroxidation. These processes occur earlier than necrosis in the liver, heart, kidney, and brain of weanling rats fed a choline deficient (CD) diet. In tissues, water-soluble antioxidants were analyzed as total reactive antioxidant potential (TRAP), alpha-tocopherol content was estimated from homogenate chemiluminescence (homogenate-CL), and lipid peroxidation was evaluated by thiobarbituric acid reactive substances (TBARS). Histopathology showed hepatic steatosis at days 1-7, tubular and glomerular necrosis in kidney at days 6 and 7, and inflammation and necrosis in heart at days 6 and 7. TRAP levels decreased by 18%, 48%, 56%, and 66% at day 7, with t(1/2) (times for half maximal change) of 2.0, 1.8, 2.5, and 3.0 days in liver, kidney, heart, and brain, respectively. Homogenate-CL increased by 97%, 113%, 18%, and 297% at day 7, with t(1/2) of 2.5, 2.6, 2.8, and 3.2 days in the four organs, respectively. TBARS contents increased by 98%, 157%, 104%, and 347% at day 7, with t(1/2) of 2.6, 2.8, 3.0, and 5.0 days in the four organs, respectively. Plasma showed a 33% decrease in TRAP and a 5-fold increase in TBARS at day 5. Oxidative stress and damage are processes occurring earlier than necrosis in the kidney and heart. In case of steatosis prior to antioxidant consumption and increased lipid peroxidation, no necrosis is observed in the liver.
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http://dx.doi.org/10.1016/j.yexmp.2009.11.002DOI Listing
February 2010

Oxidative damage lipid peroxidation in the kidney of choline-deficient rats.

Front Biosci 2007 Jan 1;12:1174-83. Epub 2007 Jan 1.

Centro de Patología Experimental, Departamento de Patología, Facultad de Medicina, Universidad de Buenos Aires, Argentina.

Phosphatidylcholine is the most abundant phospholipid constituent of cell membranes and choline is a quaternary amine required for phosphatidylcholine synthesis. The impairment of membrane functions is considered as an indication of oxidative damage. In order to kinetically analyze the time course of the pathogenesis of renal necrosis following to choline deficiency in weanling rats, we determined markers of membrane lipid peroxidation (thiobarbituric acid reactive substances; TBARS and hydroperoxide-induced chemiluminescence (BOOH-CL) ) and studied the histopathological damage. Plasma TBARS (t(1/2) = 2.5 days) was an early indicator of systemic oxidative stress, likely involving liver and kidney. The levels of TBARS an BOOH-CL increased by 80% and by 183%, respectively, in kidney homogenates with t(1/2) = 1.5 days and 4 days, respectively. The levels of BOOH-CL were statistically higher in rats fed a choline-deficient diet at day 6, in a mixture of membranes (from plasmatic, smooth and rough endoplasmic reticulum and Golgi), in mitochondrial membranes and in lysosomal membranes. The results indicate that choline deficiency produces oxidative damage in kidney subcellular membranes. Necrosis involved mainly convoluted tubules and appeared with a t(1/2) = 5.5 days. An increase in the production of reactive oxygen species, triggered by NADH overproduction in the mitochondrial dysfunction associated with choline deficiency appears as one of the pathogenic mechanism of mitochondrial and cellular oxidative damage in choline-deficiency.
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http://dx.doi.org/10.2741/2135DOI Listing
January 2007

Protective effect of Artemisia douglasiana Besser extracts in gastric mucosal injury.

J Pharm Pharmacol 2003 Apr;55(4):551-7

Cátedra de Química General e Inorgánica, Departamento de Química Analítica y Fisicoquímica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 (1113), Buenos Aires, Argentina.

The aim of this work was to evaluate markers of oxidative stress in ethanol-induced gastric ulcers and the protective antioxidant activity in-vivo of Artemisia douglasiana Besser extracts in ethanol-treated rats. Ethanol-induced oxidative damage is believed to be associated with generation of reactive oxygen molecules, which leads to oxidative stress. A. douglasiana is used in folk medicine as a cytoprotective agent against peptic ulcer. Different bioassays were performed: in-vivo stomach chemiluminescence, tert-butyl hydroperoxide initiated chemiluminescence (in-vitro chemiluminescence), total antioxidant capacity (TRAP) and catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity in stomach homogenates. When ethanol (3 g kg(-1)) was administered, the in-vivo chemiluminescence increased by 107%, in-vitro chemiluminescence by 108%, SOD by 130% (P < 0.001), and catalase and TRAP decreased by 43 and 59% (P < 0.05 and 0.001, respectively). A. douglasiana (400 mg kg(-1)) pretreatment decreased in-vivo chemiluminescence by 41% (P < 0.05), in-vitro chemiluminescence by 66% (P < 0.001) and SOD by 56% (P < 0.001) and increased catalase by 14% and TRAP by 168% (P < 0.001, respectively) but GPx activity was not significantly different from the ethanol group. These results illustrate the significant antioxidant activity of A. douglasiana extract in-vivo and in-vitro.
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http://dx.doi.org/10.1211/002235702919DOI Listing
April 2003

Evidence of oxidative stress in familial amyloidotic polyneuropathy type 1.

Arch Neurol 2003 Apr;60(4):593-7

Instituto de Investigaciones Farmacológicas-CONICET.

Objective: To evaluate the oxidative state in patients with familial amyloidotic polyneuropathy type 1 (FAP1).

Design: From 3 unrelated families, patients with FAP1 carrying a transthyretin Met-30 mutation were studied. The diagnosis was confirmed by genetic analysis. Eleven of 21 patients carried the mutation; all were symptomatic and were clinically assessed using a clinical score. All of the patients were evaluated for copper-zinc superoxide dismutase type 1 activity in red blood cells using spectrophotometry. Plasma total reactive antioxidant potential was studied using a chemiluminescent method. The results were compared with those obtained from an age-matched control group.

Setting: A public and academic multidisciplinary research clinic.

Results: Six of the 11 FAP1-positive patients disclosed superoxide dismutase type 1 activity values greater than 55 U/mg of protein (upper control limit), whereas 9 of 10 patients in whom total reactive antioxidant potential was measured had values below the lower limit of the control group. No relationship was found between the levels of superoxide dismutase type 1 activity and the severity of the clinical involvement.

Conclusions: Oxidative stress may be part of the mechanisms leading to tissue damage in patients with FAP1. The lack of correlation between the laboratory findings and the severity of clinical involvement may signal that oxidative processes are at work throughout the natural history of the disease.
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http://dx.doi.org/10.1001/archneur.60.4.593DOI Listing
April 2003
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