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  1. Article ; Online: Influence of Zika virus on the cytotoxicity, cell adhesion, apoptosis and inflammatory markers of glioblastoma cells.

    Marinowic, Daniel Rodrigo / Zanirati, Gabriele Goulart / Azevedo, Pamella Nunes / Zanatta, Ângela / Plentz, Ismael / Alcará, Allan Marinho / Morrone, Fernanda Bueno / Scheffel, Thamiris Becker / Cappellari, Angélica Regina / Roehe, Paulo Michel / Muterle Varela, Ana Paula / Machado, Denise Cantarelli / Spillari Viola, Fabiana / Da Costa, Jaderson Costa

    Oncology letters

    2024  Volume 27, Issue 4, Page(s) 176

    Abstract: Glioblastoma (GBM) is one of the most common types of brain tumor in adults. Despite the availability of treatments for this disease, GBM remains one of the most lethal and difficult types of tumors to treat, and thus, a majority of patients die within 2 ...

    Abstract Glioblastoma (GBM) is one of the most common types of brain tumor in adults. Despite the availability of treatments for this disease, GBM remains one of the most lethal and difficult types of tumors to treat, and thus, a majority of patients die within 2 years of diagnosis. Infection with Zika virus (ZIKV) inhibits cell proliferation and induces apoptosis, particularly in developing neuronal cells, and thus could potentially be considered an alternative for GBM treatment. In the present study, two GBM cell lines (U-138 and U-251) were infected with ZIKV at different multiplicities of infection (0.1, 0.01 and 0.001), and cell viability, migration, adhesion, induction of apoptosis, interleukin levels and CD14/CD73 cell surface marker expression were analyzed. The present study demonstrated that ZIKV infection promoted loss of cell viability and increased apoptosis in U-138 cells, as measured by MTT and triplex assay, respectively. Changes in cell migration, as determined by wound healing assay, were not observed; however, the GBM cell lines exhibited an increase in cell adhesion when compared with non-tumoral cells (Vero). The Luminex immunoassay showed a significant increase in the expression levels of IL-4 specifically in U-251 cells (MOI 0.001) following exposure to ZIKV. There was no significant change in the expression levels of IFN-γ upon ZIKV infection in the cell lines tested. Furthermore, a marked increase in the percentage of cells expressing the CD14 surface marker was observed in both GBM cell lines compared with in Vero cells; and significantly increased CD73 expression was observed particularly in U-251 cells, when compared with uninfected cells. These findings indicate that ZIKV infection could lead to reduced cell viability, elevated CD73 expression, improved cellular adherence, and higher rates of apoptosis in glioblastoma cells. Further studies are required to explore the potential use of ZIKV in the treatment of GBM.
    Language English
    Publishing date 2024-02-28
    Publishing country Greece
    Document type Journal Article
    ZDB-ID 2573196-8
    ISSN 1792-1082 ; 1792-1074
    ISSN (online) 1792-1082
    ISSN 1792-1074
    DOI 10.3892/ol.2024.14309
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Neuronal Death, Glial Reactivity, Microglia Activation, Oxidative Stress and Bioenergetics Impairment Caused by Intracerebroventricular Administration of D-2-hydroxyglutaric Acid to Neonatal Rats.

    Ribeiro, Rafael Teixeira / Seminotti, Bianca / Zanatta, Ângela / de Oliveira, Francine Hehn / Amaral, Alexandre Umpierrez / Leipnitz, Guilhian / Wajner, Moacir

    Neuroscience

    2021  Volume 471, Page(s) 115–132

    Abstract: D-2-hydroxyglutaric acid (D-2-HG) accumulates and is the biochemical hallmark of D-2-hydroxyglutaric acidurias (D-2-HGA) types I and II, which comprehend two inherited neurometabolic diseases with severe cerebral abnormalities. Since the pathogenesis of ... ...

    Abstract D-2-hydroxyglutaric acid (D-2-HG) accumulates and is the biochemical hallmark of D-2-hydroxyglutaric acidurias (D-2-HGA) types I and II, which comprehend two inherited neurometabolic diseases with severe cerebral abnormalities. Since the pathogenesis of these diseases is poorly established, we tested whether D-2-HG could be neurotoxic to neonatal rats. D-2-HG intracerebroventricular administration caused marked vacuolation in cerebral cortex and striatum. In addition, glial fibrillary acidic protein (GFAP), S-100 calcium binding protein B (S100B) and ionized calcium-binding adapter molecule 1 (Iba-1) staining was increased in both brain structures, suggesting glial reactivity and microglial activation. D-2-HG also provoked a reduction of NeuN-positive cells in cerebral cortex, signaling neuronal death. Considering that disturbances in redox homeostasis and energy metabolism may be involved in neuronal damage and glial reactivity, we assessed whether D-2-HG could induce oxidative stress and bioenergetics impairment. D-2-HG treatment significantly augmented reactive oxygen and nitrogen species generation, provoked lipid peroxidation and protein oxidative damage, diminished glutathione concentrations and augmented superoxide dismutase and catalase activities in cerebral cortex. Increased reactive oxygen species generation, lipoperoxidation and protein oxidation were also found in striatum. Furthermore, the antagonist of NMDA glutamate receptor MK-801 and the antioxidant melatonin were able to prevent most of D-2-HG-induced pro-oxidant effects, implying the participation of these receptors in D-2-HG-elicited oxidative damage. Our results also demonstrated that D-2-HG markedly reduced the respiratory chain complex IV and creatine kinase activities. It is presumed that these deleterious pathomechanisms caused by D-2-HGA may be involved in the brain abnormalities characteristic of early-infantile onset D-2-HGA.
    MeSH term(s) Animals ; Animals, Newborn ; Cerebral Cortex ; Energy Metabolism ; Glutarates ; Microglia ; Oxidative Stress ; Rats
    Chemical Substances Glutarates ; alpha-hydroxyglutarate (2889-31-8)
    Language English
    Publishing date 2021-07-30
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 196739-3
    ISSN 1873-7544 ; 0306-4522
    ISSN (online) 1873-7544
    ISSN 0306-4522
    DOI 10.1016/j.neuroscience.2021.07.024
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: S-adenosylmethionine induces mitochondrial dysfunction, permeability transition pore opening and redox imbalance in subcellular preparations of rat liver.

    Seminotti, Bianca / Roginski, Ana Cristina / Zanatta, Ângela / Amaral, Alexandre Umpierrez / Fernandes, Thabata / Spannenberger, Kaleb Pinto / da Silva, Lucas Henrique Rodrigues / Ribeiro, Rafael Teixeira / Leipnitz, Guilhian / Wajner, Moacir

    Journal of bioenergetics and biomembranes

    2021  Volume 53, Issue 5, Page(s) 525–539

    Abstract: S-adenosylmethionine (AdoMet) predominantly accumulates in tissues and biological fluids of patients affected by liver dysmethylating diseases, particularly glycine N-methyltransferase, S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies, ... ...

    Abstract S-adenosylmethionine (AdoMet) predominantly accumulates in tissues and biological fluids of patients affected by liver dysmethylating diseases, particularly glycine N-methyltransferase, S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies, as well as in some hepatic mtDNA depletion syndromes, whose pathogenesis of liver dysfunction is still poorly established. Therefore, in the present work, we investigated the effects of S-adenosylmethionine (AdoMet) on mitochondrial functions and redox homeostasis in rat liver. AdoMet decreased mitochondrial membrane potential and Ca
    MeSH term(s) Animals ; Liver/pathology ; Male ; Mitochondrial Membrane Transport Proteins/drug effects ; Oxidation-Reduction/drug effects ; Permeability ; Rats ; Rats, Wistar ; S-Adenosylmethionine/adverse effects
    Chemical Substances Mitochondrial Membrane Transport Proteins ; S-Adenosylmethionine (7LP2MPO46S)
    Language English
    Publishing date 2021-08-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 198499-8
    ISSN 1573-6881 ; 0145-479X ; 0449-5705
    ISSN (online) 1573-6881
    ISSN 0145-479X ; 0449-5705
    DOI 10.1007/s10863-021-09914-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Disruption of Brain Redox Homeostasis, Microglia Activation and Neuronal Damage Induced by Intracerebroventricular Administration of S-Adenosylmethionine to Developing Rats.

    Seminotti, Bianca / Zanatta, Ângela / Ribeiro, Rafael Teixeira / da Rosa, Mateus Struecker / Wyse, Angela T S / Leipnitz, Guilhian / Wajner, Moacir

    Molecular neurobiology

    2018  Volume 56, Issue 4, Page(s) 2760–2773

    Abstract: S-Adenosylmethionine (AdoMet) concentrations are highly elevated in tissues and biological fluids of patients affected by S-adenosylhomocysteine hydrolase deficiency. This disorder is clinically characterized by severe neurological symptoms, whose ... ...

    Abstract S-Adenosylmethionine (AdoMet) concentrations are highly elevated in tissues and biological fluids of patients affected by S-adenosylhomocysteine hydrolase deficiency. This disorder is clinically characterized by severe neurological symptoms, whose pathophysiology is not yet established. Therefore, we investigated the effects of intracerebroventricular administration of AdoMet on redox homeostasis, microglia activation, synaptophysin levels, and TAU phosphorylation in cerebral cortex and striatum of young rats. AdoMet provoked significant lipid and protein oxidation, decreased glutathione concentrations, and altered the activity of important antioxidant enzymes in cerebral cortex and striatum. AdoMet also increased reactive oxygen (2',7'-dichlorofluorescein oxidation increase) and nitrogen (nitrate and nitrite levels increase) species generation in cerebral cortex. Furthermore, the antioxidants N-acetylcysteine and melatonin prevented most of AdoMet-induced pro-oxidant effects in both cerebral structures. Finally, we verified that AdoMet produced microglia activation by increasing Iba1 staining and TAU phosphorylation, as well as reduced synaptophysin levels in cerebral cortex. Taken together, it is presumed that impairment of redox homeostasis possibly associated with microglia activation and neuronal dysfunction caused by AdoMet may represent deleterious pathomechanisms involved in the pathophysiology of brain damage in S-adenosylhomocysteine hydrolase deficiency.
    MeSH term(s) Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism ; Brain/pathology ; Calcium-Binding Proteins/metabolism ; Glutathione Disulfide/metabolism ; Heme Oxygenase-1/metabolism ; Homeostasis/drug effects ; Injections, Intraventricular ; Lipids/chemistry ; Malondialdehyde/metabolism ; Melatonin/pharmacology ; Microfilament Proteins/metabolism ; Microglia/metabolism ; Microglia/pathology ; Neurons/drug effects ; Neurons/pathology ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Phosphorylation/drug effects ; Rats, Wistar ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; S-Adenosylmethionine/administration & dosage ; S-Adenosylmethionine/pharmacology ; Synaptophysin/metabolism ; tau Proteins/metabolism
    Chemical Substances Aif1 protein, rat ; Antioxidants ; Calcium-Binding Proteins ; Lipids ; Microfilament Proteins ; Reactive Nitrogen Species ; Reactive Oxygen Species ; Synaptophysin ; tau Proteins ; Malondialdehyde (4Y8F71G49Q) ; S-Adenosylmethionine (7LP2MPO46S) ; Heme Oxygenase-1 (EC 1.14.14.18) ; Melatonin (JL5DK93RCL) ; Glutathione Disulfide (ULW86O013H) ; Acetylcysteine (WYQ7N0BPYC)
    Language English
    Publishing date 2018-07-30
    Publishing country United States
    Document type Journal Article
    ZDB-ID 645020-9
    ISSN 1559-1182 ; 0893-7648
    ISSN (online) 1559-1182
    ISSN 0893-7648
    DOI 10.1007/s12035-018-1275-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Experimental Evidence that In Vivo Intracerebral Administration of L-2-Hydroxyglutaric Acid to Neonatal Rats Provokes Disruption of Redox Status and Histopathological Abnormalities in the Brain.

    Ribeiro, Rafael Teixeira / Zanatta, Ângela / Amaral, Alexandre Umpierrez / Leipnitz, Guilhian / de Oliveira, Francine Hehn / Seminotti, Bianca / Wajner, Moacir

    Neurotoxicity research

    2018  Volume 33, Issue 3, Page(s) 681–692

    Abstract: Tissue accumulation of L-2-hydroxyglutaric acid (L-2-HG) is the biochemical hallmark of L-2-hydroxyglutaric aciduria (L-2-HGA), a rare neurometabolic inherited disease characterized by neurological symptoms and brain white matter abnormalities whose ... ...

    Abstract Tissue accumulation of L-2-hydroxyglutaric acid (L-2-HG) is the biochemical hallmark of L-2-hydroxyglutaric aciduria (L-2-HGA), a rare neurometabolic inherited disease characterized by neurological symptoms and brain white matter abnormalities whose pathogenesis is not yet well established. L-2-HG was intracerebrally administered to rat pups at postnatal day 1 (P1) to induce a rise of L-2-HG levels in the central nervous system (CNS). Thereafter, we investigated whether L-2-HG in vivo administration could disturb redox homeostasis and induce brain histopathological alterations in the cerebral cortex and striatum of neonatal rats. L-2-HG markedly induced the generation of reactive oxygen species (increase of 2',7'-dichloroflurescein-DCFH-oxidation), lipid peroxidation (increase of malondialdehyde concentrations), and protein oxidation (increase of carbonyl formation and decrease of sulfhydryl content), besides decreasing the antioxidant defenses (reduced glutathione-GSH) and sulfhydryl content in the cerebral cortex. Alterations of the activities of various antioxidant enzymes were also observed in the cerebral cortex and striatum following L-2-HG administration. Furthermore, L-2-HG-induced lipid peroxidation and GSH decrease in the cerebral cortex were prevented by the antioxidant melatonin and by the classical antagonist of NMDA glutamate receptor MK-801, suggesting the involvement of reactive species and of overstimulation of NMDA receptor in these effects. Finally, L-2-HG provoked significant vacuolation and edema particularly in the cerebral cortex with less intense alterations in the striatum that were possibly associated with the unbalanced redox homeostasis caused by this metabolite. Taken together, it is presumed that these pathomechanisms may underlie the neurological symptoms and brain abnormalities observed in the affected patients.
    MeSH term(s) Animals ; Animals, Newborn ; Brain/drug effects ; Brain/growth & development ; Catalase/metabolism ; Glucosephosphate Dehydrogenase/metabolism ; Glutarates/administration & dosage ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/metabolism ; Glutathione Transferase/metabolism ; Malondialdehyde/metabolism ; Nitrates/metabolism ; Nitrites/metabolism ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Protein Carbonylation/drug effects ; Rats ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; Time Factors
    Chemical Substances Glutarates ; Nitrates ; Nitrites ; Reactive Oxygen Species ; alpha-hydroxyglutarate (2889-31-8) ; Malondialdehyde (4Y8F71G49Q) ; Glucosephosphate Dehydrogenase (EC 1.1.1.49) ; Catalase (EC 1.11.1.6) ; Glutathione Peroxidase (EC 1.11.1.9) ; Superoxide Dismutase (EC 1.15.1.1) ; Glutathione Reductase (EC 1.8.1.7) ; Glutathione Transferase (EC 2.5.1.18) ; Glutathione (GAN16C9B8O)
    Language English
    Publishing date 2018-02-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2036826-4
    ISSN 1476-3524 ; 1029-8428
    ISSN (online) 1476-3524
    ISSN 1029-8428
    DOI 10.1007/s12640-018-9874-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: S-Adenosylmethionine Promotes Oxidative Stress and Decreases Na

    Zanatta, Ângela / Cecatto, Cristiane / Ribeiro, Rafael Teixeira / Amaral, Alexandre Umpierrez / Wyse, Angela Ts / Leipnitz, Guilhian / Wajner, Moacir

    Molecular neurobiology

    2017  Volume 55, Issue 7, Page(s) 5868–5878

    Abstract: S-Adenosylmethionine (AdoMet) concentrations are highly elevated in tissues and biological fluids of patients affected by S-adenosylhomocysteine hydrolase deficiency, who are clinically characterized by cerebral symptoms whose pathogenesis is still ... ...

    Abstract S-Adenosylmethionine (AdoMet) concentrations are highly elevated in tissues and biological fluids of patients affected by S-adenosylhomocysteine hydrolase deficiency, who are clinically characterized by cerebral symptoms whose pathogenesis is still unknown. In the present work, we investigated the effects of AdoMet on redox homeostasis and on the activity of Na
    MeSH term(s) Adenosylhomocysteinase/deficiency ; Adenosylhomocysteinase/metabolism ; Aging/pathology ; Animals ; Antioxidants/metabolism ; Cerebral Cortex/enzymology ; Cerebral Cortex/pathology ; Homeostasis ; Lipid Peroxidation/drug effects ; Malondialdehyde/metabolism ; Membrane Fluidity ; Oxidation-Reduction ; Oxidative Stress ; Protein Carbonylation ; Rats, Wistar ; S-Adenosylmethionine ; Sodium-Potassium-Exchanging ATPase/metabolism ; Synaptic Membranes/enzymology
    Chemical Substances Antioxidants ; Malondialdehyde (4Y8F71G49Q) ; S-Adenosylmethionine (7LP2MPO46S) ; Adenosylhomocysteinase (EC 3.3.1.1) ; Sodium-Potassium-Exchanging ATPase (EC 3.6.3.9)
    Language English
    Publishing date 2017-11-03
    Publishing country United States
    Document type Journal Article
    ZDB-ID 645020-9
    ISSN 1559-1182 ; 0893-7648
    ISSN (online) 1559-1182
    ISSN 0893-7648
    DOI 10.1007/s12035-017-0804-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Ornithine and Homocitrulline Impair Mitochondrial Function, Decrease Antioxidant Defenses and Induce Cell Death in Menadione-Stressed Rat Cortical Astrocytes: Potential Mechanisms of Neurological Dysfunction in HHH Syndrome.

    Zanatta, Ângela / Rodrigues, Marília Danyelle Nunes / Amaral, Alexandre Umpierrez / Souza, Débora Guerini / Quincozes-Santos, André / Wajner, Moacir

    Neurochemical research

    2016  Volume 41, Issue 9, Page(s) 2190–2198

    Abstract: Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is caused by deficiency of ornithine translocase leading to predominant tissue accumulation and high urinary excretion of ornithine (Orn), homocitrulline (Hcit) and ammonia. Although ... ...

    Abstract Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is caused by deficiency of ornithine translocase leading to predominant tissue accumulation and high urinary excretion of ornithine (Orn), homocitrulline (Hcit) and ammonia. Although affected patients commonly present neurological dysfunction manifested by cognitive deficit, spastic paraplegia, pyramidal and extrapyramidal signs, stroke-like episodes, hypotonia and ataxia, its pathogenesis is still poorly known. Although astrocytes are necessary for neuronal protection. Therefore, in the present study we investigated the effects of Orn and Hcit on cell viability (propidium iodide incorporation), mitochondrial function (thiazolyl blue tetrazolium bromide-MTT-reduction and mitochondrial membrane potential-ΔΨm), antioxidant defenses (GSH) and pro-inflammatory response (NFkB, IL-1β, IL-6 and TNF-α) in unstimulated and menadione-stressed cortical astrocytes that were previously shown to be susceptible to damage by neurotoxins. We first observed that Orn decreased MTT reduction, whereas both amino acids decreased GSH levels, without altering cell viability and the pro-inflammatory factors in unstimulated astrocytes. Furthermore, Orn and Hcit decreased cell viability and ΔΨm in menadione-treated astrocytes. The present data indicate that the major compounds accumulating in HHH syndrome impair mitochondrial function and reduce cell viability and the antioxidant defenses in cultured astrocytes especially when stressed by menadione. It is presumed that these mechanisms may be involved in the neuropathology of this disease.
    MeSH term(s) Amino Acid Transport Systems, Basic/drug effects ; Animals ; Antioxidants/metabolism ; Antioxidants/pharmacology ; Astrocytes/drug effects ; Astrocytes/metabolism ; Cell Death/drug effects ; Citrulline/analogs & derivatives ; Citrulline/pharmacology ; Hyperammonemia/drug therapy ; Hyperammonemia/metabolism ; Male ; Mitochondria/drug effects ; Mitochondria/metabolism ; Ornithine/deficiency ; Ornithine/metabolism ; Ornithine/pharmacology ; Rats, Wistar ; Tumor Necrosis Factor-alpha/metabolism ; Urea Cycle Disorders, Inborn/drug therapy ; Urea Cycle Disorders, Inborn/metabolism
    Chemical Substances Amino Acid Transport Systems, Basic ; Antioxidants ; Tumor Necrosis Factor-alpha ; ornithine transporter ; homocitrulline (1190-49-4) ; Citrulline (29VT07BGDA) ; Ornithine (E524N2IXA3)
    Language English
    Publishing date 2016-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 199335-5
    ISSN 1573-6903 ; 0364-3190
    ISSN (online) 1573-6903
    ISSN 0364-3190
    DOI 10.1007/s11064-016-1933-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Metabolite accumulation in VLCAD deficiency markedly disrupts mitochondrial bioenergetics and Ca

    Cecatto, Cristiane / Amaral, Alexandre Umpierrez / da Silva, Janaína Camacho / Wajner, Alessandro / Schimit, Mariana de Oliveira Vargas / da Silva, Lucas Henrique Rodrigues / Wajner, Simone Magagnin / Zanatta, Ângela / Castilho, Roger Frigério / Wajner, Moacir

    The FEBS journal

    2018  Volume 285, Issue 8, Page(s) 1437–1455

    Abstract: We studied the effects of the major long-chain fatty acids accumulating in very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, namely cis-5-tetradecenoic acid (Cis-5) and myristic acid (Myr), on important mitochondrial functions in isolated ... ...

    Abstract We studied the effects of the major long-chain fatty acids accumulating in very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, namely cis-5-tetradecenoic acid (Cis-5) and myristic acid (Myr), on important mitochondrial functions in isolated mitochondria from cardiac fibers and cardiomyocytes of juvenile rats. Cis-5 and Myr at pathological concentrations markedly reduced mitochondrial membrane potential (ΔΨ
    MeSH term(s) Acyl-CoA Dehydrogenase, Long-Chain/deficiency ; Acyl-CoA Dehydrogenase, Long-Chain/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Calcium/metabolism ; Cell Line ; Energy Metabolism ; Fatty Acids/metabolism ; Homeostasis ; Lipid Metabolism, Inborn Errors/metabolism ; Membrane Potential, Mitochondrial ; Mitochondria, Heart/metabolism ; Mitochondrial Diseases/metabolism ; Muscular Diseases/metabolism ; Myocardium/cytology ; Myocardium/metabolism ; Oxidative Phosphorylation ; Oxygen Consumption ; Rats, Wistar
    Chemical Substances Fatty Acids ; Adenosine Triphosphate (8L70Q75FXE) ; Acyl-CoA Dehydrogenase, Long-Chain (EC 1.3.8.8) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2018-03-25
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2173655-8
    ISSN 1742-4658 ; 1742-464X
    ISSN (online) 1742-4658
    ISSN 1742-464X
    DOI 10.1111/febs.14419
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: 2-Methylbutyrylglycine induces lipid oxidative damage and decreases the antioxidant defenses in rat brain

    Knebel, Lisiane Aurélio / Zanatta, Ângela / Tonin, Anelise Miotti / Grings, Mateus / Alvorcem, Leonardo de Moura / Wajner, Moacir / Leipnitz, Guilhian

    Brain research. 2012 Oct. 10, v. 1478

    2012  

    Abstract: Short/branched chain acyl-CoA dehydrogenase (SBCAD) deficiency is an autosomal recessive disorder of isoleucine metabolism biochemically characterized by accumulation of 2-methylbutyrylglycine (2MBG) and 2-methylbutyric acid (2MB). Affected patients ... ...

    Abstract Short/branched chain acyl-CoA dehydrogenase (SBCAD) deficiency is an autosomal recessive disorder of isoleucine metabolism biochemically characterized by accumulation of 2-methylbutyrylglycine (2MBG) and 2-methylbutyric acid (2MB). Affected patients present predominantly neurological symptoms, whose pathophysiology is not yet established. In the present study, we investigated the in vitro effects of 2MBG and 2MB on important parameters of oxidative stress in cerebral cortex of young rats and C6 glioma cells. 2MBG increased thiobarbituric acid-reactive species (TBA-RS), indicating an increase of lipid oxidation. 2MBG induced sulfhydryl oxidation in cortical supernatants and decreased glutathione (GSH) in these brain preparations, as well as in C6 cells, indicating a reduction of nonenzymatic brain antioxidant defenses. In contrast, 2MB did not alter any of these parameters and 2MBG and 2MB did not affect carbonyl formation (protein damage). In addition, 2MBG-induced increase of TBA-RS levels and decrease of GSH were prevented by free radical scavengers, implying that reactive species were involved in these effects. Furthermore, the decrease of GSH levels caused by 2MBG was not due to a direct oxidative action since this metabolite did not alter sulfhydryl content from a commercial solution of GSH. Nitric oxide production was not altered by 2MBG and 2MB, suggesting that reactive oxygen species possibly underlie 2MBG effects. Finally, we verified that 2MBG did not induce cell death in C6 cells. The present data show that 2MBG induces lipid oxidative damage and reduces the antioxidant defenses in rat brain. Therefore, it may be postulated that oxidative stress induced by 2MBG is involved, at least in part, in the pathophysiology of the brain damage found in SBCAD deficiency.
    Keywords acyl-CoA dehydrogenase ; brain damage ; cell death ; cerebral cortex ; free radical scavengers ; glutathione ; isoleucine ; lipid peroxidation ; metabolism ; metabolites ; nitric oxide ; oxidation ; oxidative stress ; pathophysiology ; patients ; rats ; reactive oxygen species
    Language English
    Dates of publication 2012-1010
    Size p. 74-82.
    Publishing place Elsevier B.V.
    Document type Article
    ZDB-ID 1200-2
    ISSN 1872-6240 ; 0006-8993
    ISSN (online) 1872-6240
    ISSN 0006-8993
    DOI 10.1016/j.brainres.2012.08.039
    Database NAL-Catalogue (AGRICOLA)

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  10. Article ; Online: Disruption of oxidative phosphorylation and synaptic Na(+), K(+)-ATPase activity by pristanic acid in cerebellum of young rats.

    Busanello, Estela Natacha Brandt / Lobato, Vannessa Gonçalves Araujo / Zanatta, Angela / Viegas, Carolina Maso / Ribeiro, César Augusto João / Wajner, Moacir

    Life sciences

    2014  Volume 94, Issue 1, Page(s) 67–73

    Abstract: Aims: Peroxisomal biogenesis disorders (PBD) are inherited disorders clinically manifested by neurological symptoms and brain abnormalities, in which the cerebellum is usually involved. Biochemically, patients affected by these neurodegenerative ... ...

    Abstract Aims: Peroxisomal biogenesis disorders (PBD) are inherited disorders clinically manifested by neurological symptoms and brain abnormalities, in which the cerebellum is usually involved. Biochemically, patients affected by these neurodegenerative diseases accumulate branched-chain fatty acids, including pristanic acid (Prist) in the brain and other tissues.
    Main methods: In the present investigation we studied the in vitro influence of Prist, at doses found in PBD, on oxidative phosphorylation, by measuring the activities of the respiratory chain complexes I-IV and ATP production, as well as on creatine kinase and synaptic Na(+), K(+)-ATPase activities in rat cerebellum.
    Key findings: Prist significantly decreased complexes I-III (65%), II (40%) and especially II-III (90%) activities, without altering the activities of complex IV of the respiratory chain and creatine kinase. Furthermore, ATP formation and synaptic Na(+), K(+)-ATPase activity were markedly inhibited (80-90%) by Prist. We also observed that this fatty acid altered mitochondrial and synaptic membrane fluidity that may have contributed to its inhibitory effects on the activities of the respiratory chain complexes and Na(+), K(+)-ATPase.
    Significance: Considering the importance of oxidative phosphorylation for mitochondrial homeostasis and of Na(+), K(+)-ATPase for the maintenance of cell membrane potential, the present data indicate that Prist compromises brain bioenergetics and neurotransmission in cerebellum. We postulate that these pathomechanisms may contribute to the cerebellar alterations observed in patients affected by PBD in which Prist is accumulated.
    MeSH term(s) Animals ; Cerebellum/physiopathology ; Disease Models, Animal ; Fatty Acids/administration & dosage ; Homeostasis ; Membrane Potentials ; Mitochondria/drug effects ; Mitochondria/metabolism ; Multienzyme Complexes/metabolism ; Oxidative Phosphorylation/drug effects ; Peroxisomal Disorders/physiopathology ; Rats ; Rats, Wistar ; Sodium-Potassium-Exchanging ATPase/metabolism ; Synapses/metabolism
    Chemical Substances Fatty Acids ; Multienzyme Complexes ; pristanic acid (5FMQ2908AP) ; Sodium-Potassium-Exchanging ATPase (EC 3.6.3.9)
    Language English
    Publishing date 2014-01-14
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3378-9
    ISSN 1879-0631 ; 0024-3205
    ISSN (online) 1879-0631
    ISSN 0024-3205
    DOI 10.1016/j.lfs.2013.10.032
    Database MEDical Literature Analysis and Retrieval System OnLINE

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