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  1. Article ; Online: Genistein Activates Transcription Factor EB and Corrects Niemann–Pick C Phenotype

    Graciela Argüello / Elisa Balboa / Pablo J. Tapia / Juan Castro / María José Yañez / Pamela Mattar / Rodrigo Pulgar / Silvana Zanlungo

    International Journal of Molecular Sciences, Vol 22, Iss 4220, p

    2021  Volume 4220

    Abstract: Niemann–Pick type C disease (NPCD) is a lysosomal storage disease (LSD) characterized by abnormal cholesterol accumulation in lysosomes, impaired autophagy flux, and lysosomal dysfunction. The activation of transcription factor EB (TFEB), a master ... ...

    Abstract Niemann–Pick type C disease (NPCD) is a lysosomal storage disease (LSD) characterized by abnormal cholesterol accumulation in lysosomes, impaired autophagy flux, and lysosomal dysfunction. The activation of transcription factor EB (TFEB), a master lysosomal function regulator, reduces the accumulation of lysosomal substrates in LSDs where the degradative capacity of the cells is compromised. Genistein can pass the blood–brain barrier and activate TFEB. Hence, we investigated the effect of TFEB activation by genistein toward correcting the NPC phenotype. We show that genistein promotes TFEB translocation to the nucleus in HeLa TFEB-GFP, Huh7, and SHSY-5Y cells treated with U18666A and NPC1 patient fibroblasts. Genistein treatment improved lysosomal protein expression and autophagic flux, decreasing p62 levels and increasing those of the LC3-II in NPC1 patient fibroblasts. Genistein induced an increase in β-hexosaminidase activity in the culture media of NPC1 patient fibroblasts, suggesting an increase in lysosomal exocytosis, which correlated with a decrease in cholesterol accumulation after filipin staining, including cells treated with U18666A and NPC1 patient fibroblasts. These results support that genistein-mediated TFEB activation corrects pathological phenotypes in NPC models and substantiates the need for further studies on this isoflavonoid as a potential therapeutic agent to treat NPCD and other LSDs with neurological compromise.
    Keywords Niemann–Pick C ; TFEB ; genistein ; lysosomal storage diseases ; cholesterol ; lysosome clearance ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 572
    Language English
    Publishing date 2021-04-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Vitamin E Blocks Connexin Hemichannels and Prevents Deleterious Effects of Glucocorticoid Treatment on Skeletal Muscles

    Elisa Balboa / Fujiko Saavedra / Luis A. Cea / Valeria Ramírez / Rosalba Escamilla / Aníbal A. Vargas / Tomás Regueira / Juan C. Sáez

    International Journal of Molecular Sciences, Vol 21, Iss 4094, p

    2020  Volume 4094

    Abstract: Glucocorticoids are frequently used as anti-inflammatory and immunosuppressive agents. However, high doses and/or prolonged use induce undesired secondary effects such as muscular atrophy. Recently, de novo expression of connexin43 and connexin45 ... ...

    Abstract Glucocorticoids are frequently used as anti-inflammatory and immunosuppressive agents. However, high doses and/or prolonged use induce undesired secondary effects such as muscular atrophy. Recently, de novo expression of connexin43 and connexin45 hemichannels (Cx43 HCs and Cx45 HCs, respectively) has been proposed to play a critical role in the mechanism underlying myofiber atrophy induced by dexamethasone (Dex: a synthetic glucocorticoid), but their involvement in specific muscle changes promoted by Dex remains poorly understood. Moreover, treatments that could prevent the undesired effects of glucocorticoids on skeletal muscles remain unknown. In the present work, a 7-day Dex treatment in adult mice was found to induce weight loss and skeletal muscle changes including expression of functional Cx43/Cx45 HCs, elevated atrogin immunoreactivity, atrophy, oxidative stress and mitochondrial dysfunction. All these undesired effects were absent in muscles of mice simultaneously treated with Dex and vitamin E (VitE). Moreover, VitE was found to rapidly inhibit the activity of Cx HCs in freshly isolated myofibers of Dex treated mice. Exposure to alkaline pH induced free radical generation only in HeLa cells expressing Cx43 or Cx45 where Ca 2+ was present in the extracellular milieu, response that was prevented by VitE. Besides, VitE and two other anti-oxidant compounds, Tempol and Resveratrol, were found to inhibit Cx43 HCs in HeLa cells transfectants. Thus, we propose that in addition to their intrinsic anti-oxidant potency, some antioxidants could be used to reduce expression and/or opening of Cx HCs and consequently reduce the undesired effect of glucocorticoids on skeletal muscles.
    Keywords connexons ; mitochondrial dysfunction ; oxidative stress ; muscle atrophy ; dexamethasone ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Language English
    Publishing date 2020-06-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage

    Elisa Balboa / Tamara Marín / Juan Esteban Oyarzún / Pablo S. Contreras / Robert Hardt / Thea van den Bosch / Alejandra R. Alvarez / Boris Rebolledo-Jaramillo / Andres D. Klein / Dominic Winter / Silvana Zanlungo

    Cells, Vol 10, Iss 2159, p

    2021  Volume 2159

    Abstract: Niemann-Pick type C disease (NPCD) is a lysosomal storage disorder caused by mutations in the NPC1 gene. The most affected tissues are the central nervous system and liver, and while significant efforts have been made to understand its neurological ... ...

    Abstract Niemann-Pick type C disease (NPCD) is a lysosomal storage disorder caused by mutations in the NPC1 gene. The most affected tissues are the central nervous system and liver, and while significant efforts have been made to understand its neurological component, the pathophysiology of the liver damage remains unclear. In this study, hepatocytes derived from wild type and Npc1 −/− mice were analyzed by mass spectrometry (MS)-based proteomics in conjunction with bioinformatic analysis. We identified 3832 proteins: 416 proteins had a p -value smaller than 0.05, of which 37% ( n = 155) were considered differentially expressed proteins (DEPs), 149 of them were considered upregulated, and 6 were considered downregulated. We focused the analysis on pathways related to NPC pathogenic mechanisms, finding that the most significant changes in expression levels occur in proteins that function in the pathways of liver damage, lipid metabolism, and inflammation. Moreover, in the group of DEPs, 30% ( n = 47) were identified as lysosomal proteins and 7% ( n = 10) were identified as mitochondrial proteins. Importantly, we found that lysosomal DEPs, including CTSB/D/Z, LIPA, DPP7 and GLMP, and mitocondrial DEPs, AKR1B10, and VAT1 had been connected with liver fibrosis, damage, and steatosis in previous studies, validiting our dataset. Our study found potential therapeutic targets for the treatment of liver damage in NPCD.
    Keywords liver damage ; Niemann Pick type C disease ; lysosomal storage disorder ; proteomic analysis ; mass spectrometry ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2021-08-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Oxidative Stress

    Mary Carmen Vázquez / Elisa Balboa / Alejandra R. Alvarez / Silvana Zanlungo

    Oxidative Medicine and Cellular Longevity, Vol

    A Pathogenic Mechanism for Niemann-Pick Type C Disease

    2012  Volume 2012

    Keywords Cytology ; QH573-671 ; Biology (General) ; QH301-705.5 ; Science ; Q
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Hindawi Publishing Corporation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder

    Pablo S. Contreras / Pablo J. Tapia / Lila González-Hódar / Ivana Peluso / Chiara Soldati / Gennaro Napolitano / Maria Matarese / Macarena Las Heras / Cristian Valls / Alexis Martinez / Elisa Balboa / Juan Castro / Nancy Leal / Frances M. Platt / Andrzej Sobota / Dominic Winter / Andrés D. Klein / Diego L. Medina / Andrea Ballabio /
    Alejandra R. Alvarez / Silvana Zanlungo

    iScience, Vol 23, Iss 11, Pp 101691- (2020)

    2020  

    Abstract: Summary: The transcription factor EB (TFEB) has emerged as a master regulator of lysosomal biogenesis, exocytosis, and autophagy, promoting the clearance of substrates stored in cells. c-Abl is a tyrosine kinase that participates in cellular signaling in ...

    Abstract Summary: The transcription factor EB (TFEB) has emerged as a master regulator of lysosomal biogenesis, exocytosis, and autophagy, promoting the clearance of substrates stored in cells. c-Abl is a tyrosine kinase that participates in cellular signaling in physiological and pathophysiological conditions. In this study, we explored the connection between c-Abl and TFEB. Here, we show that under pharmacological and genetic c-Abl inhibition, TFEB translocates into the nucleus promoting the expression of its target genes independently of its well-known regulator, mammalian target of rapamycin complex 1. Active c-Abl induces TFEB phosphorylation on tyrosine and the inhibition of this kinase promotes lysosomal biogenesis, autophagy, and exocytosis. c-Abl inhibition in Niemann-Pick type C (NPC) models, a neurodegenerative disease characterized by cholesterol accumulation in lysosomes, promotes a cholesterol-lowering effect in a TFEB-dependent manner. Thus, c-Abl is a TFEB regulator that mediates its tyrosine phosphorylation, and the inhibition of c-Abl activates TFEB promoting cholesterol clearance in NPC models.
    Keywords Biological Sciences ; Molecular Biology ; Cell Biology ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2020-11-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: MLN64 induces mitochondrial dysfunction associated with increased mitochondrial cholesterol content

    Elisa Balboa / Juan Castro / María-José Pinochet / Gonzalo I. Cancino / Nuria Matías / Pablo José Sáez / Alexis Martínez / Alejandra R. Álvarez / Carmen Garcia-Ruiz / José C. Fernandez-Checa / Silvana Zanlungo

    Redox Biology, Vol 12, Iss , Pp 274-

    2017  Volume 284

    Abstract: MLN64 is a late endosomal cholesterol-binding membrane protein that has been implicated in cholesterol transport from endosomal membranes to the plasma membrane and/or mitochondria, in toxin-induced resistance, and in mitochondrial dysfunction. Down- ... ...

    Abstract MLN64 is a late endosomal cholesterol-binding membrane protein that has been implicated in cholesterol transport from endosomal membranes to the plasma membrane and/or mitochondria, in toxin-induced resistance, and in mitochondrial dysfunction. Down-regulation of MLN64 in Niemann-Pick C1 deficient cells decreased mitochondrial cholesterol content, suggesting that MLN64 functions independently of NPC1. However, the role of MLN64 in the maintenance of endosomal cholesterol flow and intracellular cholesterol homeostasis remains unclear. We have previously described that hepatic MLN64 overexpression increases liver cholesterol content and induces liver damage. Here, we studied the function of MLN64 in normal and NPC1-deficient cells and we evaluated whether MLN64 overexpressing cells exhibit alterations in mitochondrial function. We used recombinant-adenovirus-mediated MLN64 gene transfer to overexpress MLN64 in mouse liver and hepatic cells; and RNA interference to down-regulate MLN64 in NPC1-deficient cells. In MLN64-overexpressing cells, we found increased mitochondrial cholesterol content and decreased glutathione (GSH) levels and ATPase activity. Furthermore, we found decreased mitochondrial membrane potential and mitochondrial fragmentation and increased mitochondrial superoxide levels in MLN64-overexpressing cells and in NPC1-deficient cells. Consequently, MLN64 expression was increased in NPC1-deficient cells and reduction of its expression restore mitochondrial membrane potential and mitochondrial superoxide levels. Our findings suggest that MLN64 overexpression induces an increase in mitochondrial cholesterol content and consequently a decrease in mitochondrial GSH content leading to mitochondrial dysfunction. In addition, we demonstrate that MLN64 expression is increased in NPC cells and plays a key role in cholesterol transport into the mitochondria.
    Keywords Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2017-08-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Mitochondrial GSH replenishment as a potential therapeutic approach for Niemann Pick type C disease

    Sandra Torres / Nuria Matías / Anna Baulies / Susana Nuñez / Cristina Alarcon-Vila / Laura Martinez / Natalia Nuño / Anna Fernandez / Joan Caballeria / Thierry Levade / Alba Gonzalez-Franquesa / Pablo Garcia-Rovés / Elisa Balboa / Silvana Zanlungo / Gemma Fabrías / Josefina Casas / Carlos Enrich / Carmen Garcia-Ruiz / José C. Fernández-Checa

    Redox Biology, Vol 11, Iss , Pp 60-

    2017  Volume 72

    Abstract: Niemann Pick type C (NPC) disease is a progressive lysosomal storage disorder caused by mutations in genes encoding NPC1/NPC2 proteins, characterized by neurological defects, hepatosplenomegaly and premature death. While the primary biochemical feature ... ...

    Abstract Niemann Pick type C (NPC) disease is a progressive lysosomal storage disorder caused by mutations in genes encoding NPC1/NPC2 proteins, characterized by neurological defects, hepatosplenomegaly and premature death. While the primary biochemical feature of NPC disease is the intracellular accumulation of cholesterol and gangliosides, predominantly in endolysosomes, mitochondrial cholesterol accumulation has also been reported. As accumulation of cholesterol in mitochondria is known to impair the transport of GSH into mitochondria, resulting in mitochondrial GSH (mGSH) depletion, we investigated the impact of mGSH recovery in NPC disease. We show that GSH ethyl ester (GSH-EE), but not N-acetylcysteine (NAC), restored the mGSH pool in liver and brain of Npc1-/- mice and in fibroblasts from NPC patients, while both GSH-EE and NAC increased total GSH levels. GSH-EE but not NAC increased the median survival and maximal life span of Npc1-/- mice. Moreover, intraperitoneal therapy with GSH-EE protected against oxidative stress and oxidant-induced cell death, restored calbindin levels in cerebellar Purkinje cells and reversed locomotor impairment in Npc1-/- mice. High-resolution respirometry analyses revealed that GSH-EE improved oxidative phosphorylation, coupled respiration and maximal electron transfer in cerebellum of Npc1-/- mice. Lipidomic analyses showed that GSH-EE treatment had not effect in the profile of most sphingolipids in liver and brain, except for some particular species in brain of Npc1-/- mice. These findings indicate that the specific replenishment of mGSH may be a potential promising therapy for NPC disease, worth exploring alone or in combination with other options. Keywords: Ceramide, Sphingolipids, Mitochondrial GSH, Cerebellum, Hepatosplenomegaly, Lysosomal disorders
    Keywords Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
    Subject code 616
    Language English
    Publishing date 2017-04-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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