Browsing by Author "Ferreira, Jorge"
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- ItemAllergens of the urushiol family promote mitochondrial dysfunction by inhibiting the electron transport at the level of cytochromes b and chemically modify cytochrome c1(2021) Pacheco, Rodrigo; Quezada, Sergio A.; Kalergis Parra, Alexis Mikes; Becker C., María Inés; Ferreira, Jorge; Ioannes, Alfredo E. deBackground: Urushiols are pro-electrophilic haptens that cause severe contact dermatitis mediated by CD8+ effector T-cells and downregulated by CD4+ T-cells. However, the molecular mechanism by which urushiols stimulate innate immunity in the initial stages of this allergic reaction is poorly understood. Here we explore the sub-cellular mechanisms by which urushiols initiate the allergic response. Results: Electron microscopy observations of mouse ears exposed to litreol (3-n-pentadecyl-10-enyl-catechol]) showed keratinocytes containing swollen mitochondria with round electron-dense inclusion bodies in the matrix. Biochemical analyses of sub-mitochondrial fractions revealed an inhibitory effect of urushiols on electron flow through the mitochondrial respiratory chain, which requires both the aliphatic and catecholic moieties of these allergens. Moreover, urushiols extracted from poison ivy/oak (mixtures of 3-n-pentadecyl-8,11,13 enyl/3-n-heptadecyl-8,11 enyl catechol) exerted a higher inhibitory effect on mitochondrial respiration than did pentadecyl catechol or litreol, indicating that the higher number of unsaturations in the aliphatic chain, stronger the allergenicity of urushiols. Furthermore, the analysis of radioactive proteins isolated from mitochondria incubated with 3H-litreol, indicated that this urushiol was bound to cytochrome c1. According to the proximity of cytochromes c1 and b, functional evidence indicated the site of electron flow inhibition was within complex III, in between cytochromes bL (cyt b566) and bH (cyt b562). Conclusion: Our data provide functional and molecular evidence indicating that the interruption of the mitochondrial electron transport chain constitutes an important mechanism by which urushiols initiates the allergic response. Thus, mitochondria may constitute a source of cellular targets for generating neoantigens involved in the T-cell mediated allergy induced by urushiols.
- ItemButhionine sulfoximine has anti-Trypanosoma cruzi activity in a murine model of acute Chagas' disease and enhances the efficacy of nifurtimox(2008) Faúndez Cáceres, Mario; Lopez-Munoz, Rodrigo; Torres, Gloria; Morello, Antonio; Ferreira, Jorge; Kemmerling, Ulrike; Orellana, Myriam; Maya, Juan D.
- ItemChemosensitizing Effect Of Nordihydroguaiaretic Acid (Ndga) And Its Tetra Acetylated Derivative (Ndgata) On Parental And Multiresistant Ta3 Mouse Mammary Adenocarcinoma Cell Lines(2008) Ferreira, Jorge; Pavani, Mario; Jana, Fabian; Burgos, Paula I.; Morello, Antonio; Maya, Juan Diego; Faúndez Cáceres, Mario; Lopez, Americo; De Ioannes I., Alfredo E.; Becker C., María Inés
- ItemIncreased ER-mitochondrial coupling promotes mitochondrial respiration and bioenergetics during early phases of ER stress(COMPANY BIOLOGISTS LTD, 2011) Bravo, Roberto; Miguel Vicencio, Jose; Parra, Valentina; Troncoso, Rodrigo; Pablo Munoz, Juan; Bui, Michael; Quiroga, Clara; Rodriguez, Andrea E.; Verdejo, Hugo E.; Ferreira, Jorge; Iglewski, Myriam; Chiong, Mario; Simmen, Thomas; Zorzano, Antonio; Hill, Joseph A.; Rothermel, Beverly A.; Szabadkai, Gyorgy; Lavandero, SergioIncreasing evidence indicates that endoplasmic reticulum (ER) stress activates the adaptive unfolded protein response (UPR), but that beyond a certain degree of ER damage, this response triggers apoptotic pathways. The general mechanisms of the UPR and its apoptotic pathways are well characterized. However, the metabolic events that occur during the adaptive phase of ER stress, before the cell death response, remain unknown. Here, we show that, during the onset of ER stress, the reticular and mitochondrial networks are redistributed towards the perinuclear area and their points of connection are increased in a microtubule-dependent fashion. A localized increase in mitochondrial transmembrane potential is observed only in redistributed mitochondria, whereas mitochondria that remain in other subcellular zones display no significant changes. Spatial re-organization of these organelles correlates with an increase in ATP levels, oxygen consumption, reductive power and increased mitochondrial Ca2+ uptake. Accordingly, uncoupling of the organelles or blocking Ca2+ transfer impaired the metabolic response, rendering cells more vulnerable to ER stress. Overall, these data indicate that ER stress induces an early increase in mitochondrial metabolism that depends crucially upon organelle coupling and Ca2+ transfer, which, by enhancing cellular bioenergetics, establishes the metabolic basis for the adaptation to this response.
- ItemInhibitory effect of nordihydroguaiaretic acid and its tetra-acetylated derivative on respiration and growth of adenocarcinoma TA3 and its multiresistant variant TA3MTX-R(2008) Plaza, Claudio; Pavani, Mario; Faúndez Cáceres, Mario; Maya, Juan Diego; Morello, Antonio; Becker C., María Inés; De Ioannes I., Alfredo E.; Cumsille, Miguel Angel; Ferreira, Jorge
- ItemInsulin Stimulates Mitochondrial Fusion and Function in Cardiomyocytes via the Akt-mTOR-NF kappa B-Opa-1 Signaling Pathway(AMER DIABETES ASSOC, 2014) Parra, Valentina; Verdejo, Hugo E.; Iglewski, Myriam; del Campo, Andrea; Troncoso, Rodrigo; Jones, Deborah; Zhu, Yi; Kuzmicic, Jovan; Pennanen, Christian; Lopez Crisosto, Camila; Jana, Fabian; Ferreira, Jorge; Noguera, Eduard; Chiong, Mario; Bernlohr, David A.; Klip, Amira; Hill, Joseph A.; Rothermel, Beverly A.; Abel, Evan Dale; Zorzano, Antonio; Lavandero, SergioInsulin regulates heart metabolism through the regulation of insulin-stimulated glucose uptake. Studies have indicated that insulin can also regulate mitochondrial function. Relevant to this idea, mitochondrial function is impaired in diabetic individuals. Furthermore, the expression of Opa-1 and mitofusins, proteins of the mitochondrial fusion machinery, is dramatically altered in obese and insulin-resistant patients. Given the role of insulin in the control of cardiac energetics, the goal of this study was to investigate whether insulin affects mitochondrial dynamics in cardiomyocytes. Confocal microscopy and the mitochondrial dye MitoTracker Green were used to obtain three-dimensional images of the mitochondrial network in cardiomyocytes and L6 skeletal muscle cells in culture. Three hours of insulin treatment increased Opa-1 protein levels, promoted mitochondrial fusion, increased mitochondrial membrane potential, and elevated both intracellular ATP levels and oxygen consumption in cardiomyocytes in vitro and in vivo. Consequently, the silencing of Opa-1 or Mfn2 prevented all the metabolic effects triggered by insulin. We also provide evidence indicating that insulin increases mitochondrial function in cardiomyocytes through the Akt-mTOR-NFB signaling pathway. These data demonstrate for the first time in our knowledge that insulin acutely regulates mitochondrial metabolism in cardiomyocytes through a mechanism that depends on increased mitochondrial fusion, Opa-1, and the Akt-mTOR-NFB pathway.
- ItemTrypanosoma cruzi: Activities of lapachol and alpha- and beta-lapachone derivatives against epimastigote and trypomastigote forms(PERGAMON-ELSEVIER SCIENCE LTD, 2008) Salas, Cristian; Tapia, Ricardo A.; Ciudad, Karina; Armstrong, Veronica; Orellana, Myriam; Kemmerling, Ulrike; Ferreira, Jorge; Maya, Juan Diego; Morello, AntonioDerivatives of natural quinones with biological activities, such as lapachol, alpha- and beta-lapachones, have been synthesized and their trypanocidal activity evaluated in vitro in Trypanosoma cruzi cells. All tested compounds inhibited epimastigote growth and trypomastigote viability. Several compounds showed similar or higher activity as compared with current trypanocidal drugs, nifurtimox and benznidazole. The results presented here show that the anti-T Cruzi activity of the alpha-lapachone derivatives can be increased by the replacement of the benzene ring by a pyridine moiety. Free radical production and consequently oxidative stress through redox cycling or production of electrophilic metabolites are the potential biological mechanism of action for these synthetic quinones. (c) 2007 Elsevier Ltd. All rights reserved.
- ItemTrypanosoma cruzi: In vitro effect of aspirin with nifurtimox and benznidazole(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2010) Lopez Munoz, Rodrigo; Faundez, Mario; Klein, Sebastian; Escanilla, Sebastian; Torres, Gloria; Lee Liu, Dasfne; Ferreira, Jorge; Kemmerling, Ulrike; Orellana, Myriam; Morello, Antonio; Ferreira, Arturo; Maya, Juan D.Nifurtimox and benznidazole are the only active drugs against Trypanosoma cruzi; however, they have limited efficacy and severe side effects. During primoinfection, T cruzi infected macrophages mount an antiparasitic response, which the parasite evades through an increase of tumor growth factor beta and PGE(2) activation as well as decreased iNOS activity. Thus, prostaglandin synthesis inhibition with aspirin might increase macrophage antiparasitic activity and increase nifurtimox and benznidazole effect.