Natural sesquiterpene lactones induce programmed cell death in Trypanosoma cruzi: A new therapeutic target?

Phytomedicine ◽  
2014 ◽  
Vol 21 (11) ◽  
pp. 1411-1418 ◽  
Author(s):  
V. Jimenez ◽  
U. Kemmerling ◽  
R. Paredes ◽  
J.D. Maya ◽  
M.A. Sosa ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Trypanosoma Cruzi ◽  
Therapeutic Target ◽  
Sesquiterpene Lactones

scholarly journals Programmed cell death 1 as prognostic marker and therapeutic target in upper gastrointestinal cancers

2021 ◽  
Vol 220 ◽  
pp. 153390
Author(s):  
Negar Khoshghamat ◽  
Niloufar Jafari ◽  
Mehrdad Moetamani-Ahmadi ◽  
Ghazaleh Khalili-Tanha ◽  
Mohammad-Hossein Khajavi rad ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Prognostic Marker ◽  
Therapeutic Target ◽  
Gastrointestinal Cancers ◽  
Programmed Cell Death 1 ◽  
Upper Gastrointestinal

Mitochondrial calcium overload triggers complement-dependent superoxide-mediated programmed cell death in Trypanosoma cruzi

2009 ◽  
Vol 418 (3) ◽  
pp. 595-604 ◽  
Author(s):  
Florencia Irigoín ◽  
Natalia M. Inada ◽  
Mariana P. Fernandes ◽  
Lucía Piacenza ◽  
Fernanda R. Gadelha ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Trypanosoma Cruzi ◽  
Complement Activation ◽  
Superoxide Radical ◽  
Membrane Attack Complex ◽  
Cell Respiration ◽  
Mitochondrial Uncoupling ◽  
O2 Production ◽  
Complement Deposition

The epimastigote stage of Trypanosoma cruzi undergoes PCD (programmed cell death) when exposed to FHS (fresh human serum). Although it has been known for over 30 years that complement is responsible for FHS-induced death, the link between complement activation and triggering of PCD has not been established. We have previously shown that the mitochondrion participates in the orchestration of PCD in this model. Several changes in mitochondrial function were described, and in particular it was shown that mitochondrion-derived O2•− (superoxide radical) is necessary for PCD. In the present study, we establish mitochondrial Ca2+ overload as the link between complement deposition and the observed changes in mitochondrial physiology and the triggering of PCD. We show that complement activation ends with the assembly of the MAC (membrane attack complex), which allows influx of Ca2+ and release of respiratory substrates to the medium. Direct consequences of these events are accumulation of Ca2+ in the mitochondrion and decrease in cell respiration. Mitochondrial Ca2+ causes partial dissipation of the inner membrane potential and consequent mitochondrial uncoupling. Moreover, we provide evidence that mitochondrial Ca2+ overload is responsible for the increased O2•− production, and that if cytosolic Ca2+ rise is not accompanied by the accumulation of the cation in the mitochondrion and consequent production of O2•−, epimastigotes die by necrosis instead of PCD. Thus our results suggest a model in which MAC assembly on the parasite surface allows Ca2+ entry and its accumulation in the mitochondrion, leading to O2•− production, which in turn constitutes a PCD signal.

Metacaspases of Trypanosoma cruzi: Possible candidates for programmed cell death mediators

2006 ◽  
Vol 145 (1) ◽  
pp. 18-28 ◽  
Author(s):  
Gregor Kosec ◽  
Vanina E. Alvarez ◽  
Fernán Agüero ◽  
Daniel Sánchez ◽  
Marko Dolinar ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Trypanosoma Cruzi

scholarly journals Mechanisms and Therapeutic Regulation of Pyroptosis in Inflammatory Diseases and Cancer

2020 ◽  
Vol 21 (4) ◽  
pp. 1456 ◽  
Author(s):  
Zhaodi Zheng ◽  
Guorong Li
Keyword(s):  
Cell Death ◽  
Cancer Therapy ◽  
Programmed Cell Death ◽  
Inflammatory Disease ◽  
Therapeutic Target ◽  
Mitochondrial Membrane ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Normal Cells ◽  
Caspase Cleavage

Programmed Cell Death (PCD) is considered to be a pathological form of cell death when mediated by an intracellular program and it balances cell death with survival of normal cells. Pyroptosis, a type of PCD, is induced by the inflammatory caspase cleavage of gasdermin D (GSDMD) and apoptotic caspase cleavage of gasdermin E (GSDME). This review aims to summarize the latest molecular mechanisms about pyroptosis mediated by pore-forming GSDMD and GSDME proteins that permeabilize plasma and mitochondrial membrane activating pyroptosis and apoptosis. We also discuss the potentiality of pyroptosis as a therapeutic target in human diseases. Blockade of pyroptosis by compounds can treat inflammatory disease and pyroptosis activation contributes to cancer therapy.

scholarly journals Mitochondrial superoxide radicals mediate programmed cell death in Trypanosoma cruzi: cytoprotective action of mitochondrial iron superoxide dismutase overexpression

2007 ◽  
Vol 403 (2) ◽  
pp. 323-334 ◽  
Author(s):  
Lucía Piacenza ◽  
Florencia Irigoín ◽  
María Noel Alvarez ◽  
Gonzalo Peluffo ◽  
Martin C. Taylor ◽  
...  
Keyword(s):  
Cell Death ◽  
Superoxide Dismutase ◽  
Programmed Cell Death ◽  
Trypanosoma Cruzi ◽  
Early Period ◽  
Pentose Phosphate ◽  
Iron Superoxide Dismutase ◽  
Mitochondrial Superoxide ◽  
Glucose Flux ◽  
Mitochondrial Aconitase

Trypanosoma cruzi undergo PCD (programmed cell death) under appropriate stimuli, the mechanisms of which remain to be established. In the present study, we show that stimulation of PCD in T. cruzi epimastigotes by FHS (fresh human serum) results in rapid (<1 h) externalization of phosphatidylserine and depletion of the low molecular mass thiols dihydrotrypanothione and glutathione. Concomitantly, enhanced generation of oxidants was established by EPR and immuno-spin trapping of radicals using DMPO (5,5-dimethylpyrroline-N-oxide) and augmentation of the glucose flux through the pentose phosphate pathway. In the early period (<20 min), changes in mitochondrial membrane potential and inhibition of respiration, probably due to the impairment of ADP/ATP exchange with the cytosol, were observed, conditions that favour the generation of O2•−. Accelerated rates of mitochondrial O2•− production were detected by the inactivation of the redox-sensitive mitochondrial aconitase and by oxidation of a mitochondrial-targeted probe (MitoSOX). Importantly, parasites overexpressing mitochondrial FeSOD (iron superoxide dismutase) were more resistant to the PCD stimulus, unambiguously indicating the participation of mitochondrial O2•− in the signalling process. In summary, FHS-induced PCD in T. cruzi involves mitochondrial dysfunction that causes enhanced O2•− formation, which leads to cellular oxidative stress conditions that trigger the initiation of PCD cascades; moreover, overexpression of mitochondrial FeSOD, which is also observed during metacyclogenesis, resulted in cytoprotective effects.

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