Article
Immunology
Laura Fraccaroli, Maria Daniela Ruiz, Virginia Gabriela Perdomo, Agustina Nicole Clausi, Dario Emmanuel Balcazar, Luciana Larocca, Carolina Carrillo
Summary: "Chagas disease is an endemic American parasitosis caused by Trypanosoma cruzi. Current therapies have limited efficacy and side effects, leading to the need for new trypanocidal strategies. Ivermectin shows potential as a repurposed drug for Chagas disease, with dose-dependent effects on T. cruzi and other trypanosomatids, and potential novel molecular targets identified in this study."
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)
Article
Immunology
Julian Ernesto Nicolas Gulin, Margarita Maria Catalina Bisio, Daniela Rocco, Jaime Altcheh, Maria Elisa Solana, Facundo Garcia-Bournissen
Summary: This study evaluates the efficacy of Miltefosine (MLT) as a monodrug and combined with benznidazole (BZ) for treating Trypanosoma cruzi infection. MLT showed promising results in inhibiting the parasite in both in vitro and in vivo models, with improved efficacy when combined with BZ. This study provides support for the potential use of MLT in Chagas disease treatment and the exploration of combination therapies.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)
Article
Biology
Lorraine Martins Rocha Orlando, Leonardo da Silva Lara, Guilherme Curty Lechuga, Giseli Capaci Rodrigues, Omar Ginoble Pandoli, Druval Santos de Sa, Mirian Claudia de Souza Pereira
Summary: Therapeutic alternatives for Chagas disease are urgently needed due to limitations and adverse effects of current drugs. Triazole analogues show promise in treating T. cruzi.
Article
Biochemistry & Molecular Biology
Caue Benito Scarim, Francisco Olmo, Elizabeth Igne Ferreira, Chung Man Chin, John M. Kelly, Amanda Fortes Francisco
Summary: The research indicates that NFOH has stronger anti-Trypanosoma cruzi activity, works through a inhibitory mechanism, and is more effective in treating chronic infections compared to the acute stage, sharing similar characteristics with BZN.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Pharmacology & Pharmacy
Ruben Martin-Escolano, Daniel Molina-Carreno, Javier Martin-Escolano, M. Paz Clares, Cristina Galiana-Rosello, Jorge Gonzalez-Garcia, Nuria Cirauqui, Jose M. Llinares, Maria Jose Rosales, Enrique Garcia-Espana, Clotilde Marin
Summary: Chagas disease, caused by Trypanosoma cruzi, is a potentially fatal infection that was previously limited to Latin America but has now become widespread globally. This study identified new effective agents against T. cruzi and evaluated their efficacy in vivo. Compound 15 was identified as a potential candidate for the development of new therapies for Chagas disease.
Article
Biochemistry & Molecular Biology
Lenci K. Vazquez-Jimenez, Alfredo Juarez-Saldivar, Rogelio Gomez-Escobedo, Timoteo Delgado-Maldonado, Domingo Mendez-Alvarez, Isidro Palos, Debasish Bandyopadhyay, Carlos Gaona-Lopez, Eyra Ortiz-Perez, Benjamin Nogueda-Torres, Esther Ramirez-Moreno, Gildardo Rivera
Summary: In this study, a ligand-based virtual screening was performed to identify potential TcTIM inhibitors. Molecular docking and molecular dynamics simulation analysis showed a favorable docking score of the BP5 compound on TcTIM, and a lower docking score on human TIM compared to the control ligand. Both BP2 and BP5 compounds exhibited good physicochemical and pharmacokinetic properties as new anti-T. cruzi agents.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Takatsugu Kosugi, Masahito Ohue
Summary: The study developed a quantitative estimation index QEPPI specifically for early screening of compounds targeting protein-protein interactions, which showed better performance compared to the commonly used method QED.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Immunology
Albert Ros-Lucas, Nieves Martinez-Peinado, Jaume Bastida, Joaquim Gascon, Julio Alonso-Padilla
Summary: Chagas disease, caused by Trypanosoma cruzi, is a devastating neglected disease. The discovery of safer and more effective drugs is urgently needed. The AlphaFold Protein Structure Database provides protein models that can help describe new therapeutic approaches and shed light on the molecular mechanisms of known compounds.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Leonardo S. Lara, Guilherme C. Lechuga, Caroline dos S. Moreira, Thais B. Santos, Vitor F. Ferreira, David R. da Rocha, Mirian C. S. Pereira
Summary: Chagas disease remains a serious public health problem in Latin America, with current clinical treatments considered inadequate, emphasizing the need for discovering new effective and safe drugs. Research analyzed a series of naphthoquinone derivatives for biological activity and structure-activity relationship, identifying 1g as a promising compound against Trypanosoma cruzi. However, current compounds were unable to reduce parasite load or prevent mouse mortality in infection.
Article
Microbiology
Suzana Marques de Jesus, Leonardo Pinto, Fernanda de Lima Moreira, Glauco Henrique Balthazar Nardotto, Rodrigo Cristofoletti, Luisa Perin, Katia da Silva Fonseca, Pauliana Barbedo, Lorena Cera Bandeira, Paula Melo de Abreu Vieira, Claudia Martins Carneiro
Summary: Chronic infection with Trypanosoma cruzi alters the pharmacokinetics and tissue distribution of benznidazole in mice, potentially impacting the therapeutic dosing regimen. This study suggests that chronic Chagas disease patients may require adjustments in benznidazole pharmacokinetics and dosing due to changes in drug exposure and tissue distribution.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Article
Microbiology
A. J. Berenstein, N. Falk, G. Moscatelli, S. Moroni, N. Gonzalez, F. Garcia-Bournissen, G. Ballering, H. Freilij, J. Altcheh
Summary: The study found that adverse drug reactions (ADRs) associated with Nifurtimox treatment for Chagas disease were relatively rare and mainly mild to moderate. ADRs primarily affected the nutritional, central nervous, and digestive systems, with no significant differences between adults and children. The proportion of treatment discontinuations due to ADRs was higher in adults compared to children.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Article
Immunology
Marianne Rocha-Hasler, Gabriel Melo de Oliveira, Aline Nefertiti da Gama, Ludmila Ferreira de Almeida Fiuza, Anna Frieda Fesser, Monica Cal, Romina Rocchetti, Raiza Brandao Peres, Xue Li Guan, Marcel Kaiser, Maria de Nazare Correia Soeiro, Pascal Maser
Summary: The study found that treatment with posaconazole alone in chronic Chagas disease patients resulted in a high relapse rate, prompting the search for suitable combination partners such as inhibitors of sterol and sphingolipid biosynthetic enzymes. In vitro and in vivo experiments revealed that the combination of tomatidine (TH) with posaconazole showed synergistic effects against Trypanosoma cruzi, indicating a potential for improved treatment outcomes.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2021)
Review
Immunology
Maria Gabriela Libisch, Natalia Rego, Carlos Robello
Summary: Chagas Disease is caused by the complex taxon T. cruzi, affecting nearly eight million people worldwide. T. cruzi has the ability to infect and interact with almost any nucleated cell, triggering molecular signaling cascades that depend on cell type, strain, and experimental variables. Host cell responses to infection, particularly in the respiratory chain and oxidative phosphorylation, vary depending on the T. cruzi strain and experimental model, while some responses remain consistent across strains, cell types, and conditions.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Everton Dias D'Andrea, Joren Sebastian Retel, Anne Diehl, Peter Schmieder, Hartmut Oschkinat, Jose Ricardo Pires
Summary: The protein Q4DY78 from Trypanosoma cruzi is highly conserved in related kinetoplastid pathogens, with a structure consisting of a -helices and a beta-sheet. While overall rigid, flexibility is observed at specific residues. The protein may interact with the host cytoskeleton through a short motif, and despite lacking calcium-binding motifs, its fold resembles eukaryotic calcium-binding proteins.
JOURNAL OF STRUCTURAL BIOLOGY
(2021)
Article
Cell Biology
Mariana De Niz, Daniela Bras, Marie Ouarne, Mafalda Pedro, Ana M. Nascimento, Lenka Henao Misikova, Claudio A. Franco, Luisa M. Figueiredo
Summary: Trypanosoma brucei is a cause of lethal diseases in humans and cattle in Sub-Saharan Africa, extravasating from blood circulation into various tissues before compromising vascular permeability. Blocking certain endothelial adhesion molecules or CD36 significantly reduces parasite density in tissues, delaying host lethality. This research highlights the importance of vasculature and organ-specific adhesion molecules in tissue tropism during T. brucei infection.
Article
Chemistry, Multidisciplinary
Michal Antoszczak, Sebastian Muller, Tatiana Caneque, Ludovic Colombeau, Nelson Dusetti, Patricia Santofimia-Castano, Christine Gaillet, Alain Puisieux, Juan Lucio Iovanna, Raphael Rodriguez
Summary: Persisting cancer cells are resistant to therapy and can adopt a drug-tolerant state through epithelial-mesenchymal plasticity. This study synthesized complex small molecule chimeras that accumulate in lysosomes and induce ferroptosis in drug-tolerant pancreatic cancer cells. The findings pave the way for the development of new cancer medicines targeting active ferroptosis.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Multidisciplinary
Yunfang Xiong, Ran Ke, Qingyu Zhang, Wenjun Lan, Wanjun Yuan, Karol Nga Ieng Chan, Tom Roussel, Yifan Jiang, Jing Wu, Shuai Liu, Alice Sze Tsai Wong, Joong Sup Shim, Xuanjun Zhang, Ruiyu Xie, Nelson Dusetti, Juan Iovanna, Nagy Habib, Ling Peng, Leo Tsz On Lee
Summary: This study reports the effective modulation of a GPCR for cancer treatment using small activating RNAs (saRNAs) for the first time. The saRNAs promote the expression of MAS1, a GPCR that counteracts cancer cell proliferation and migration. By enhancing MAS1 expression, these saRNAs suppress tumorigenesis and inhibit tumor progression in multiple cancer models. This research not only provides a new strategy for cancer therapy by targeting the renin-angiotensin system, but also offers a new avenue to modulate GPCR signaling through RNA activation.
Letter
Oncology
Nicolas A. Fraunhoffer, Analia Meilerman Abuelafia, Nelson Dusetti, Juan Iovanna
CANCER COMMUNICATIONS
(2022)
Article
Oncology
Nicolas A. Fraunhoffer, Analia Meilerman Abuelafia, Martin Bigonnet, Odile Gayet, Julie Roques, Remy Nicolle, Gwen Lomberk, Raul Urrutia, Nelson Dusetti, Juan Iovanna
Summary: This study developed a Master Regulators (MR)-Gradient model based on transcriptomic profiles derived from both PDAC epithelial and microenvironment cells to reveal the transcriptional networks, epigenomic states, and metabolic pathways underlying PDAC heterogeneity. Integration of methylome and metabolome datasets, along with experimental measurements, showed a close association between PDAC prognosis, tumor epithelial cell phenotype, and immunological component. Metabolic analysis indicated a positive correlation between favorable PDAC phenotype and enzymes involved in complex lipid biosynthesis, while an unfavorable phenotype exhibited an OXPHOS independent metabolism centered on the Warburg effect and glutaminolysis. The study also identified key deregulated pathways in PDAC related to epigenetics.
NPJ PRECISION ONCOLOGY
(2022)
Article
Gastroenterology & Hepatology
Raphael Rapetti-Mauss, Jeremy Nigri, Camille Berenguier, Pascal Finetti, Sarah Simha Tubiana, Bonnie Labrum, Benoit Allegrini, Bernard Pellissier, Georgios Efthymiou, Zainab Hussain, Corinne Bousquet, Nelson Dusetti, Francois Bertucci, Helene Guizouarn, Patricia Melnyk, Franck Borgese, Richard Tomasini, Olivier Soriani
Summary: This study reveals that ion channel SK2 plays a role in intercellular communication in pancreatic ductal adenocarcinoma (PDAC). Stimulation of SK2 by cues from cancer-associated fibroblasts (CAFs) leads to the activation of the integrin-epidermal growth factor receptor (EGFR)-AKT signaling pathway, promoting cancer cell invasiveness and metastasis formation. The formation of the signaling hub involving SK2 and AKT requires the sigma-1 receptor chaperone. Targeting the sigma-1 receptor with pharmacological approaches inhibits tumor progression and prolongs overall survival in mice.
Article
Medicine, Research & Experimental
Tara L. Hogenson, Hao Xie, William J. Phillips, Merih D. Toruner, Jenny J. Li, Isaac P. Horn, Devin J. Kennedy, Luciana L. Almada, David L. Marks, Ryan M. Carr, Murat Toruner, Ashley N. Sigafoos, Amanda N. Koenig-Kappes, Rachel L. O. Olson, Ezequiel J. Tolosa, Cheng Zhang, Hu Li, Jason D. Doles, Jonathan Bleeker, Michael T. Barrett, James H. Boyum, Benjamin R. Kipp, Amit Mahipal, Joleen M. Hubbard, Temperance J. Scheffler Hanson, Gloria M. Petersen, Surendra Dasari, Ann L. Oberg, Mark J. Truty, Rondell P. Graham, Michael J. Levy, Mojun Zhu, Daniel D. Billadeau, Alex A. Adjei, Nelson Dusetti, Juan L. Iovanna, Tanios S. Bekaii-Saab, Wen Wee Ma, Martin E. Fernandez-Zapico
Summary: The study evaluated the ability of patient-derived organoids (PDO) in predicting clinical response to gastrointestinal cancers, showing an approximately 80% concordance rate between PDO and donor tumor response. The significant influence of culture media on PDO phenotype was also demonstrated, with different media leading to distinct responses to chemotherapies, morphologies, and transcriptomes within the same PDO cultures.
Letter
Oncology
Nicolas Alejandro Fraunhoffer, Analia Meilerman Abuelafia, Brice Chanez, Martin Bigonnet, Odile Gayet, Julie Roques, Eduardo Chuluyan, Nelson Dusetti, Juan Iovanna
CANCER COMMUNICATIONS
(2022)
Letter
Gastroenterology & Hepatology
Nicolas Fraunhoffer, Brice Chanez, Carlos Teyssedou, Juan L. Iovanna, Emmanuel Mitry, Nelson J. Dusetti
Article
Multidisciplinary Sciences
Charlie Saillard, Flore Delecourt, Benoit Schmauch, Olivier Moindrot, Magali Svrcek, Armelle Bardier-Dupas, Jean Francois Emile, Mira Ayadi, Vinciane Rebours, Louis de Mestier, Pascal Hammel, Cindy Neuzillet, Jean Baptiste Bachet, Juan Iovanna, Nelson Dusetti, Yuna Blum, Magali Richard, Yasmina Kermezli, Valerie Paradis, Mikhail Zaslavskiy, Pierre Courtiol, Aurelie Kamoun, Remy Nicolle, Jerome Cros
Summary: This study developed a deep learning model called PACpAInt to predict the tumor tissue and subtypes of pancreatic adenocarcinoma (PDAC) using transcriptomic data. The model identified PDAC heterogeneity and revealed the presence of different tumor subtypes and transitional states during PDAC evolution.
NATURE COMMUNICATIONS
(2023)
Article
Infectious Diseases
Gabriel Ferri, Daniel Musikant, Martin Edreira
Summary: As an intracellular parasite, T. cruzi invades host cells by activating various signaling pathways, including cAMP signaling. We have shown that the activation of Epac, not PKA, mediates the effect of cAMP on parasite internalization. In this study, we investigated the downstream effectors of the cAMP/Epac pathway during host cell infection and found that Rap1b and MEK/ERK are involved in the pathway. We also observed a PKA-dependent inhibition of infection, potentially through phosphorylation of Rap1b and Epac. These findings provide insights into the detailed mechanism of cAMP-mediated invasion by T. cruzi.
PLOS NEGLECTED TROPICAL DISEASES
(2023)
Article
Medicine, General & Internal
Nicolas A. Fraunhoffer, Aura I. Moreno Vega, Anala Meilerman Abuelafia, Marie Morvan, Emilie Lebarbier, Tristan Mary-Huard, Michael Zimmermann, Gwen Lomberk, Raul Urrutia, Nelson Dusetti, Yuna Blum, Remy Nicolle, Juan Iovanna
Summary: Using epigenomic inhibitors to reset gene expression patterns in pancreatic tumors shows promise in developing new therapies for pancreatic cancer.
Article
Medicine, General & Internal
Abdessamad El Kaoutari, Nicolas A. Fraunhoffer, Luc Camoin, Yolande Berthois, Odile Gayet, Julie Roques, Martin Bigonnet, Claire Bongrain, Joseph Ciccolini, Juan L. Iovanna, Nelson J. Dusetti, Philippe Soubeyran
Summary: Through specific proteomic tools and bioinformatics analysis, we established the ubiquitin dependent proteome of 60 PDAC, identifying 38 ubiquitination site profiles correlated with tumor phenotype and having prognostic capabilities. These findings have potential application in predicting chemotherapy response and personalized treatment in clinical settings.
Article
Multidisciplinary Sciences
Gabriela Reyes-Castellanos, Nadine Abdel Hadi, Scarlett Gallardo-Arriaga, Rawand Masoud, Julie Garcia, Sophie Lac, Abdessamad El Kaoutari, Tristan Gicquel, Melanie Planque, Sarah-Maria Fendt, Laetitia Karine Linares, Odile Gayet, Fabienne Guillaumond, Nelson Dusetti, Juan Iovanna, Alice Carrier
Summary: Pancreatic ductal adenocarcinoma is a highly fatal cancer. A study found that mitochondrial respiration in primary human PDAC cells relies on fatty acid oxidation for energy production. The use of perhexiline, an inhibitor of fatty acid oxidation, in combination with chemotherapy showed promising results in inhibiting PDAC cell growth in vitro and in vivo. Molecular analysis revealed the importance of the CPT1C isoform in the response to perhexiline and its association with better prognosis in PDAC patients.
Article
Oncology
Ellis Michiels, Hediel Madhloum, Silke Van Lint, Nouredin Messaoudi, Rastislav Kunda, Sandrina Martens, Philippe Giron, Catharina Olsen, Pierre Lefesvre, Nelson Dusetti, Leila EL Mohajer, Richard Tomasini, Lukas J. A. C. Hawinkels, Farah Ahsayni, Remy Nicolle, Tatjana Arsenijevic, Christelle Bouchart, Jean-Luc Van Laethem, Ilse Rooman
Summary: This study identifies two subtypes of pancreatic cancer and reveals spatial phenotypes within tumors through analysis of mRNA panels. These findings are important for understanding tumor heterogeneity and guiding therapeutic approaches.
JOURNAL OF PATHOLOGY
(2023)