Article
Biochemistry & Molecular Biology
Roberto Docampo, Anibal Eugenio Vercesi
Summary: This review discusses the mechanisms of mitochondrial oxidant generation and removal, and the involvement of Ca2+ in trypanosome cell death, highlighting the need for further studies on ROS generation, defense mechanisms, and mitochondrial permeability transition pore in trypanosomatids.
ANTIOXIDANTS & REDOX SIGNALING
(2022)
Article
Microbiology
Marina Schock, Steffen Schmidt, Klaus Ersfeld
Summary: Trypanosome brucei, the causative agent of African sleeping sickness, has a highly ordered subpellicular microtubule cytoskeleton associated with various proteins regulating morphology, motility, and virulence. Identified protein CAP50 colocalises with microtubules but not with the flagellum, playing a crucial role in maintaining cellular integrity. Depletion of CAP50, along with CAP52 and CAP42, results in defects in cytokinesis, morphology, and microtubule organization.
Article
Immunology
Gabriela Venturini, Juliana M. Alvim, Kallyandra Padilha, Christopher N. Toepfer, Joshua M. Gorham, Lauren K. Wasson, Diogo Biagi, Sergio Schenkman, Valdemir M. Carvalho, Jessica S. Salgueiro, Karina H. M. Cardozo, Jose E. Krieger, Alexandre C. Pereira, Jonathan G. Seidman, Christine E. Seidman
Summary: This study reveals the molecular mechanisms and metabolic responses of Trypanosoma cruzi infection in cardiomyocytes. Infection activates the immune system and glycolysis pathway in cardiomyocytes, promoting intracellular infection and replication. These responses lead to heart dysfunction, cell death, and the development of cardiomyopathy.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Dagmar Flittner, Marcel Kaiser, Pascal Maeser, Norberto P. Lopes, Thomas J. Schmidt
Summary: Research found that Pachysandra terminalis contains amino steroids with anti-trypanosomal activity, with activity-guided fractionation and mass spectrometry analysis identifying 18 constituents responsible for this activity.
Article
Microbiology
Colm P. Roster, Danielle Lavigne, Jillian E. Milanes, Emily Knight, Heidi D. Anderson, Sabrina Pizarro, Elijah M. Harding, Meredith T. Morris, Victoria C. Yan, Cong-Dat Pham, Florian Muller, Samuel Kwain, Kerrick C. Rees, Brian Dominy, Daniel C. Whitehead, Md Nasir Uddin, Steven W. Millward, James C. Morris
Summary: Glucose metabolism is critical for the survival of Trypanosoma brucei, and inhibitors of human enolase have been found to be effective against the parasite.
Article
Immunology
Leila dos Santos Moura, Vinicius Santana Nunes, Antoniel A. S. Gomes, Ana Caroline de Castro Nascimento Sousa, Marcos R. M. Fontes, Sergio Schenkman, Nilmar Silvio Moretti
Summary: The research highlights the involvement of lysine acetylation in the oxidative stress response of T. cruzi, especially through the mitochondrial lysine deacetylase TcSir2rp3 regulating the activity of mitochondrial superoxide dismutase A (TcSODA). The study also shows that acetylation of K97 in TcSODA plays a key role in modulating enzyme activity and maintaining redox homeostasis in trypanosomatids. Additionally, the interaction between TcSir2rp3 and TcSODA contributes to the understanding of mechanisms used by T. cruzi to progress during infection.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2021)
Article
Multidisciplinary Sciences
Desi C. Alexander, Tanya Corman, Mariel Mendoza, Andrew Glass, Tal Belity, Ranran Wu, Rianne R. Campbell, Joseph Han, Ashley A. Keiser, Jeffrey Winkler, Marcelo A. Wood, Thomas Kim, Benjamin A. Garcia, Hagit Cohen, Philipp Mews, Gabor Egervari, Shelley L. Berger
Summary: Histone acetylation is crucial for the consolidation of long-term fear memories and is regulated by ACSS2 in the mouse hippocampus. The knockout of Acss2 reduces the acquisition of long-term fear memory and leads to decreased expression of learning and memory-related genes in the dorsal hippocampus. Inhibiting ACSS2 during the consolidation window also impairs fear-memory formation and reduces anxiety in mice and rats.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Cecilia Ortiz, Francesca Moraca, Marc Laverriere, Allan Jordan, Niall Hamilton, Marcelo A. Comini
Summary: G6PDH plays a crucial role in cell physiology by catalyzing the synthesis of NADPH(+) and ribose 5-phosphate. The study discovered that 16 alpha-brominated epiandrosterone is the most potent inhibitor of G6PDH in trypanosomatids. Further investigations showed that bromination at position 16 alpha of androstane derivatives yielded more potent T. cruzi G6PDH inhibitors.
Article
Biochemistry & Molecular Biology
Kyung-Hwa Baek, Trong-Nhat Phan, Satish R. Malwal, Hyeryon Lee, Zhu-Hong Li, Silvia N. J. Moreno, Eric Oldfield, Joo Hwan No
Summary: SQ109 is an anti-tubercular drug candidate that has shown potent activity against protozoan parasites including Leishmania, Trypanosoma cruzi, and Toxoplasma gondii in vitro. It has demonstrated efficacy in mouse models of T. cruzi and T. gondii infections, but moderate efficacy in models of Trypanosoma brucei and Leishmania donovani infections. Metabolites of SQ109 also exhibit activity against protozoan parasites in vitro.
Article
Biochemistry & Molecular Biology
Kevin P. Gillespie, Ross Pirnie, Clementina Mesaros, Ian A. Blair
Summary: It has been found that cisplatin treatment can induce secretion of HMGB1 from human non-small cell lung cancer cells, while carboplatin cannot. This secretion is dose-dependent and regulated by nuclear exportin 1. Additionally, the secreted HMGB1 after cisplatin treatment is mainly in the fully reduced form.
Review
Pharmacology & Pharmacy
Aline A. Zuma, Emile dos Santos Barrias, Wanderley de Souza
Summary: This review discusses the basic biology of the pathogenic protozoa Trypanosoma cruzi and Trypanosoma brucei, highlighting their developmental stages and unique structural characteristics, which can potentially serve as chemotherapeutic targets. Understanding these aspects contributes to drug development for chemotherapy.
CURRENT PHARMACEUTICAL DESIGN
(2021)
Article
Biochemistry & Molecular Biology
George E. Magoulas, Pantelis Afroudakis, Kalliopi Georgikopoulou, Marina Roussaki, Chiara Borsari, Theano Fotopoulou, Nuno Santarem, Emile Barrias, Paloma Tejera Nevado, Julia Hachenberg, Eugenia Bifeld, Bernhard Ellinger, Maria Kuzikov, Irini Fragiadaki, Effie Scoulica, Joachim Clos, Sheraz Gul, Maria Paola Costi, Wanderley de Souza, Kyriakos C. Prousis, Anabela Cordeiro da Silva, Theodora Calogeropoulou
Summary: A library of novel ether phospholipid analogues was designed and synthesized, with compounds showing potent antiparasitic activity against different parasitic species. The structure-activity relationships of these compounds were studied, and a potential lead compound with broad spectrum antiparasitic activity was identified, laying a foundation for the development of improved derivatives to control neglected tropical diseases.
Article
Chemistry, Medicinal
David Cisneros, Eduardo J. Cueto-Diaz, Tania Medina-Gil, Rebecca Chevillard, Teresa Bernal-Fraile, Ramon Lopez-Sastre, Mustafa M. Aldfer, Marzuq A. Ungogo, Hamza A. A. Elati, Natsumi Arai, Momoka Otani, Shun Matsushiro, Chiaki Kojima, Godwin U. Ebiloma, Tomoo Shiba, Harry P. de Koning, Christophe Dardonville
Summary: Research showed that modifying the mitochondrion-targeting cations and scaffold of TAO inhibitors affected their in vitro activity, with the addition of polar substituents in the tail region generally having a detrimental impact on enzyme and cellular activity.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Biochemistry & Molecular Biology
Shreya Bandopadhyay, Izaz M. Kamal, E. Padmanaban, Damayanti D. Ghosh, Saikat Chakrabarti, Sib S. Roy
Summary: Homeobox genes, including PITX2, play important roles in embryonic development and organogenesis. This study demonstrates that PITX2 is also involved in regulating tumorigenesis and enhancing glycolysis in ovarian cancer cells through AKT phosphorylation. It further shows that PITX2-induced epigenetic changes contribute to increased cancer cell proliferation and tumor growth.
JOURNAL OF CELLULAR BIOCHEMISTRY
(2023)
Article
Cell Biology
Yu Zhang, Ping Wen, Jing Luo, Hao Ding, Hongdi Cao, Weichun He, Ke Zen, Yang Zhou, Junwei Yang, Lei Jiang
Summary: Proximal tubular epithelial cells (TECs) require high energy and rely on mitochondrial oxidative phosphorylation as their main energy source. However, in renal fibrosis, this process is disrupted. Sirtuin 3 (SIRT3), a mitochondrial protein, regulates mitochondrial metabolic function through deacetylation. Decreased SIRT3 expression in TECs during early renal fibrosis leads to increased acetylation in mitochondria, contributing to the development of severe renal fibrosis.Activation of SIRT3 can prevent renal fibrosis by reducing acetylation levels in mitochondrial proteins.
CELL DEATH & DISEASE
(2021)
Review
Chemistry, Medicinal
Fernando Altamura, Rishi Rajesh, Carolina M. C. Catta-Preta, Nilmar S. Moretti, Igor Cestari
Summary: Human trypanosomiasis and leishmaniasis, caused by protozoan parasites, have become globally distributed tropical diseases due to human migration, climate change, and anthropogenic disturbance. The current chemotherapy for these diseases has limited efficacy and drug resistance is a growing concern. This review discusses the limitations of available drugs and highlights promising leads from current drug-based clinical trials. It also examines the challenges in target-based drug discovery and the advantages and limitations of modern research tools.
DRUG DEVELOPMENT RESEARCH
(2022)
Article
Cell Biology
Gregory Pedroso dos Santos, Fernanda Midori Abukawa, Normanda Souza-Melo, Laura Maria Alcantara, Paula Bittencourt-Cunha, Carolina Borsoi Moraes, Bijay Kumar Jha, Bradford S. McGwire, Nilmar Silvio Moretti, Sergio Schenkman
Summary: Infection by Trypanosoma cruzi essentially relies on the release of a 19 kDa cyclophilin protein, TcCyp19, which triggers an increase in reactive oxygen species (ROS) levels in host cells, leading to enhanced parasite proliferation in mammalian hosts.
CELLULAR MICROBIOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Suellen Rodrigues Maran, Joao Luiz de Lemos Padilha Pitta, Crhisllane Rafaele dos Santos Vasconcelos, Suzanne M. McDermott, Antonio Mauro Rezende, Nilmar Silvio Moretti
Summary: Trypanosoma and Leishmania parasites cause devastating tropical diseases with complex life cycles involving mammalian hosts and insect vectors. RNA modifications like m6A, m1A, m5C, ac4C, and psi regulate RNA stability and translation, but little is known about their role in Trypanosomatids.
MOLECULAR MICROBIOLOGY
(2021)
Review
Parasitology
Suellen Rodrigues Maran, Krista Fleck, Natalia Melquie Monteiro-Teles, Tony Isebe, Pegine Walrad, Victoria Jeffers, Igor Cestari, Elton J. R. Vasconcelos, Nilmar Moretti
Summary: Protein lysine acetylation is a major regulatory post-translational modification across different organisms, affecting chromatin structure, gene expression, and various cellular processes. The discovery of acetylomes in protozoan parasites suggests that acetylation may regulate crucial biological processes in these parasites. Furthermore, the regulation of glycolytic enzymes by acetylation in protozoans indicates the potential role of this modification in regulating other processes essential for parasite survival and adaptation during their life cycle.
TRENDS IN PARASITOLOGY
(2021)
Editorial Material
Parasitology
Tiago R. Ferreira, Rafael M. Counago, Nilmar S. Moretti
Summary: By utilizing CRISPR/Cas9 technology, researchers successfully dissected the function of 204 kinases in the life cycle of Leishmania mexicana.
TRENDS IN PARASITOLOGY
(2021)
Review
Parasitology
Samuel Cota Teixeira, Marcelo Santos da Silva, Antoniel Augusto Severo Gomes, Nilmar Silvio Moretti, Daiana Silva Lopes, Eloisa Amalia Vieira Ferro, Veridiana de Melo Rodrigues
Summary: The study highlights the potential of snake venom phospholipases A(2) (PLA(2)s) as effective agents against various parasites. Their mechanisms of action and interactions with parasite membrane components provide insights for drug design targeting parasites and improving treatment effectiveness.
TRENDS IN PARASITOLOGY
(2022)
Editorial Material
Chemistry, Medicinal
Rubens L. Monte-Neto, Christopher Fernandez-Prada, Nilmar S. Moretti
DRUG DEVELOPMENT RESEARCH
(2022)
Editorial Material
Parasitology
Rubens L. Monte-Neto, Christopher Fernandez-Prada, Nilmar S. Moretti
Summary: Recently, it has been discovered that induced DNA damage in axenic culture facilitates genetic exchange in Leishmania hybrids, leading to the formation of full genome tetraploid progenies in vitro. Meiosis-related gene homologues HAP2, GEX1, and RAD51 play a crucial role in this process, opening up new avenues for functional genomic studies.
TRENDS IN PARASITOLOGY
(2022)
Article
Microbiology
Gabriela de A. Burle-Caldas, Nailma S. A. dos Santos, Julia T. de Castro, Fernanda L. B. Mugge, Viviane Grazielle-Silva, Antonio Edson R. Oliveira, Milton C. A. Pereira, Joo Luis Reis-Cunha, Anderson Coqueiro dos Santos, Dawidson Assis Gomes, Daniella C. Bartholomeu, Nilmar S. Moretti, Sergio Schenkman, Ricardo T. Gazzinelli, Santuza M. R. Teixeira
Summary: Trans-sialidases (TS) are enzymes present on the surface of Trypanosoma cruzi, the causative agent of Chagas disease, and play a crucial role in the late stages of intracellular development and parasite egress. In this study, TS knockout parasites were generated using CRISPR-Cas9 technology, resulting in impaired parasite egress from infected cells. These TS mutants lost their ability to cause infection in vivo but provided full protection against a challenge infection with a virulent strain, indicating their potential as a live attenuated vaccine against Chagas disease.
Article
Immunology
Leila dos Santos Moura, Vinicius Santana Nunes, Antoniel A. S. Gomes, Ana Caroline de Castro Nascimento Sousa, Marcos R. M. Fontes, Sergio Schenkman, Nilmar Silvio Moretti
Summary: The research highlights the involvement of lysine acetylation in the oxidative stress response of T. cruzi, especially through the mitochondrial lysine deacetylase TcSir2rp3 regulating the activity of mitochondrial superoxide dismutase A (TcSODA). The study also shows that acetylation of K97 in TcSODA plays a key role in modulating enzyme activity and maintaining redox homeostasis in trypanosomatids. Additionally, the interaction between TcSir2rp3 and TcSODA contributes to the understanding of mechanisms used by T. cruzi to progress during infection.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2021)
Article
Immunology
Jose L. Saenz-Garcia, Beatriz S. Borges, Normanda Souza-Melo, Luiz V. Machado, Juliana S. Miranda, Lisandro Alfonso Pacheco-Lugo, Nilmar S. Moretti, Richard Wheleer, Lia C. Soares Medeiros, Wanderson D. DaRocha
Summary: The flagellum of Trypanosomatids contributes to multiple functions, and this study explores the role of Trypanin in T. cruzi. The deletion of Trypanin affects the growth and motility of T. cruzi epimastigotes, as well as their infection capacity.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)
Article
Immunology
Camilla Ioshida Vasconcelos, A. Cronemberger-Andrade, Normanda Souza-Melo, Juliana Terzi Maricato, Patricia Xander, Wagner Luiz Batista, Rodrigo Pedro Soares, Sergio Schenkman, Ana Claudia Torrecilhas
Summary: This study evaluated the release and internalization of EVs from Trypanosoma cruzi under different stress conditions. It was found that EV release is dependent on membrane structure and parasite integrity, and stress conditions do not affect the functional properties of EVs during interaction with host cells. EVs released under stress conditions maintained their proinflammatory activity and stimulated the expression of certain genes in preactivated macrophages. Variations in EV release under stress conditions may be a physiological response against environmental changes.
JOURNAL OF IMMUNOLOGY RESEARCH
(2021)
Article
Parasitology
Rubens Lima do Monte Neto, Paulo Otavio Lourenco Moreira, Alessandra Mara de Sousa, Miguel Antonio do Nascimento Garcia, Suellen Rodrigues Maran, Nilmar Silvio Moretti
Summary: Despite the increasing number of studies on potential antileishmanial compounds, there are still challenges in translating this knowledge into new treatments for leishmaniasis. The lack of standardization in pre-clinical drug discovery and the need for alignment among universities/research centers, government, and pharmaceutical industry are contributing factors. Metal-based drugs and the exploration of post-translational modifications as drug targets have shown promising progress, but there are still limitations in the drug discovery/development process.
MEMORIAS DO INSTITUTO OSWALDO CRUZ
(2022)
Article
Microbiology
Gabriela de A. Burle-Caldas, Nailma S. A. dos Santos, Julia T. de Castro, Fernanda L. B. Mugge, Viviane Grazielle-Silva, Antonio Edson R. Oliveira, Milton C. A. Pereira, Joao Luis Reis-Cunha, Anderson Coqueiro dos Santos, Dawidson Assis Gomes, Daniella C. Bartholomeu, Nilmar S. Moretti, Sergio Schenkman, Ricardo T. Gazzinelli, Santuza M. R. Teixeira
Summary: Trans-sialidases play a crucial role in the virulence of Trypanosoma cruzi, and using CRISPR-Cas9, aTS mutant parasites were generated which lost infectivity in vivo but provided full protection against a challenge infection with a virulent strain.