Review
Oncology
Azmi Yerlikaya
Summary: HRI kinase controls protein synthesis initiation by phosphorylating eIF2 alpha subunit and responds to heme deprivation in erythroid cells. However, recent studies have shown that HRI can be activated by diverse signals in non-erythroid cells, causing dysregulations in intracellular homeostatic mechanisms. HRI-mediated eIF2 alpha phosphorylation can be cytoprotective or cytotoxic depending on the cell type and duration of the response.
Article
Environmental Sciences
Quanshu Wang, Wanqi Ma, Shuping Zhang
Summary: Cadmium is a toxic heavy metal pollutant that can cause anemia and metabolic disorders. Heme-regulated eIF2 alpha kinase (HRI) plays a crucial role in preventing anemia and toxicity in response to various stresses, including cadmium exposure. This study identified proteins associated with glycolysis that were upregulated after cadmium exposure in wild-type mice, but this induction was disrupted in Hri knockout mice, suggesting the involvement of HRI in cadmium-induced glycolysis. These findings provide insights into potential targets for metabolic disorders following acute cadmium exposure.
ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH
(2023)
Article
Microbiology
Francis M. S. Saraiva, Daniela Cosentino-Gomes, Job D. F. Inacio, Elmo E. Almeida-Amaral, Orlando Louzada-Neto, Ana Rossini, Natalia P. Nogueira, Jose R. Meyer-Fernandes, Marcia C. Paes
Summary: This study investigated the response of T. cruzi epimastigotes to hypoxia and found that under low oxygen conditions, the parasites produced more ROS and used increased glycolysis and fermentation pathways to sustain ATP production, allowing them to survive and proliferate in the insect vector.
Article
Biochemistry & Molecular Biology
Y. Ana, J. D. Rojas Marquez, L. Fozzatti, R. E. Baigorri, C. Marin, B. A. Maletto, F. M. Cerban, R. Radi, L. Piacenza, C. C. Stempin
Summary: The study revealed that Trypanosoma cruzi infection triggers an exacerbated metabolism and mitochondrial oxidative stress in CD4 T cells, leading to an increased risk of cell apoptosis that may not be prevented by antioxidants.
FREE RADICAL BIOLOGY AND MEDICINE
(2021)
Article
Biochemistry & Molecular Biology
Julia K. Meier, Matthias Schnetz, Susanne Beck, Tobias Schmid, Monica Dominguez, Sanela Kalinovic, Andreas Daiber, Bernhard Bruene, Michaela Jung
Summary: The study elucidates the signaling pathways through which iron-loaded lipocalin-2 (Lcn-2) affects renal cancer cell viability, highlighting the importance of ferroptosis-regulating genes in this process. Additionally, it reveals the role of oxidative stress and the integrated stress response (ISR) in promoting tumor characteristics induced by Lcn-2.
Article
Biochemistry & Molecular Biology
Yusuke Sekine, Ryan Houston, Eva -Maria Eckl, Evelyn Fessler, Derek P. Narendra, Lucas T. Jae, Shiori Sekine
Summary: In this study, the researchers found that the activation of heme-regulated kinase HRI under iron-deficient conditions requires the involvement of mitochondrial protein DELE1. The import and stability of DELE1 in the mitochondria is regulated by iron availability. Importantly, when iron is chelated, DELE1 import is inhibited, leading to its stabilization on the mitochondrial surface and activation of the HRI-mediated integrated stress response. This study also revealed that the DELE1-HRI-ISR pathway plays a protective role in iron-demanding cell lineages.
Review
Immunology
Manuel Fresno, Nuria Girones
Summary: MDSCs, immature myeloid cells that expand under pathological conditions, are characterized by their suppressor activity and can express iNOS and arginase 1 for immune suppression. They can originate from the medulla due to emergency myelopoiesis, but can also have extramedullary origins.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2021)
Article
Immunology
Maria Angelica Burgos-Reyes, Lidia Baylon-Pacheco, Patricia Espiritu-Gordillo, Silvia Galindo-Gomez, Victor Tsutsumi, Jose Luis Rosales-Encina
Summary: Leishmaniasis, caused by intracellular protozoan parasite Leishmania, is a challenging disease to treat. A potential vaccine candidate, the LmxMBA gene, was identified and tested in a murine model, showing reduced lesion size and parasitic load. Vaccination with pVAX1::LmxMBA induced a T helper 1 response characterized by increased IgG2a/IgG1 ratio and lymphoproliferative response, supporting it as a preventive strategy against L. mexicana infection.
JOURNAL OF IMMUNOLOGY RESEARCH
(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
Leonardo Augusto, Ronald C. Wek, William J. Sullivan
Summary: Toxoplasma gondii is an intracellular parasite that infects a wide range of warm-blooded vertebrates and can transition between different life cycle stages in various hosts, impacting different tissues and hosts. Understanding the mechanisms behind these stage transitions is crucial for therapeutic interventions aimed at preventing parasite transmission and pathogenesis.
MOLECULAR MICROBIOLOGY
(2021)
Article
Microbiology
Leonardo Augusto, Jennifer Martynowicz, Parth H. Amin, Kenneth R. Carlson, Ronald C. Wek, William J. Sullivan
Summary: Toxoplasma gondii must balance disseminating throughout its host without killing it, requiring the ability to counter host cell defenses. The parasite mitigates oxidative stress through activation of TgIF2K-B, essential for establishing persistent infection in the host.
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
Tatiana M. Clemente, Rochelle Ratnayake, Dhritiman Samanta, Leonardo Augusto, Paul A. Beare, Robert A. Heinzen, Stacey D. Gilk
Summary: Coxiella burnetii regulates host cholesterol metabolism to establish a mature Coxiella-containing vacuole (CCV) that supports bacterial growth.
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
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.
Article
Microbiology
Tatiana M. Clemente, Rochelle Ratnayake, Dhritiman Samanta, Leonardo Augusto, Paul A. Beare, Robert A. Heinzen, Stacey D. Gilk
Summary: Coxiella burnetii regulates its intracellular growth by controlling cholesterol levels within the Coxiella-containing vacuole (CCV), with the sterol modifying protein Stmp1 playing a crucial role in this process. Loss of Stmp1 results in abnormal CCV formation, affecting bacterial infection and growth within host cells.