Augusto E. Bivona

University of Buenos Aires

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Emilio L. Malchiodi

University of Buenos Aires

Andrés Sánchez Alberti

Consejo Nacional de Investigaciones Científicas y Técnicas

Natacha Cerny

National University of Luján

Valeria P. Sülsen

University of Buenos Aires

Silvia I. Cazorla

Consejo Nacional de Investigaciones Científicas y Técnicas

Orlando G. Elso

University of Buenos Aires

César A.N. Catalán

National University of Tucumán

Celina Morales

University of Buenos Aires

Jimena Borgo

Consejo Nacional de Investigaciones Científicas y Técnicas

María Florencia Beer

Instituto de Química y Fisicoquímica Biológicas

Cooperative Institutions

Consejo Nacional de Investigaciones Científicas y Técnicas

University of Buenos Aires

Instituto de Química y Fisicoquímica Biológicas

Institute of Astronomy and Space Physics

Universidad de la República

Helmholtz Centre for Infection Research

Fundación Ciencias Exactas y Naturales

Instituto de Estudios Universitarios

Medicina

University of Palermo

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Characterization of a new type of neuronal 5-HT G- protein coupled receptor in the cestode nervous system

PLoS ONE (2021)

Federico Camicia Hugo Rolando Vaca Sang-Kyu Park Augusto E. Bivona Ariel Naidich

Cestodes are platyhelminth parasites with a wide range of hosts that cause neglected diseases. Neurotransmitter signaling is of critical importance for these parasites which lack circulatory, respiratory and digestive systems. For example, serotonin (5-HT) and serotonergic G-protein coupled receptors (5-HT GPCRs) play major roles in cestode motility, development and reproduction. In previous work, we deorphanized a group of 5-HT7 type GPCRs from cestodes. However, little is known about another type of 5-HT GPCR, the 5-HT1 clade, which has been studied in several invertebrate phyla but not in platyhelminthes. Three putative 5-HT GPCRs from Echinococcus canadensis , Mesocestoides vogae ( syn . M . corti ) and Hymenolepis microstoma were cloned, sequenced and bioinformatically analyzed. Evidence grouped these new sequences within the 5-HT1 clade of GPCRs but differences in highly conserved GPCR motifs were observed. Transcriptomic analysis, heterologous expression and immunolocalization studies were performed to characterize the E . canadensis receptor, called Eca-5-HT 1a . Functional heterologous expression studies showed that Eca-5-HT 1a is highly specific for serotonin. 5-Methoxytryptamine and α-methylserotonin, both known 5-HT GPCR agonists, give stimulatory responses whereas methysergide, a known 5-HT GPCR ligand, give an antagonist response in Eca-5-HT 1a . Mutants obtained by the substitution of key predicted residues resulted in severe impairment of receptor activity, confirming that indeed, these residues have important roles in receptor function. Immunolocalization studies on the protoscolex stage from E . canadensis , showed that Eca-5-HT 1a is localized in branched fibers which correspond to the nervous system of the parasite. The patterns of immunoreactive fibers for Eca-5-HT 1a and for serotonin were intimately intertwined but not identical, suggesting that they are two separate groups of fibers. These data provide the first functional, pharmacological and localization report of a serotonergic receptor that putatively belongs to the 5-HT1 type of GPCRs in cestodes. The serotonergic GPCR characterized here may represent a new target for antiparasitic intervention.

Serotonin Antagonists

Heterologous expression

10.1371/journal.pone.0259104

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Citations (4)

Anti-Trypanosoma cruzi Properties of Sesquiterpene Lactones Isolated from Stevia spp.: In Vitro and In Silico Studies

Pharmaceutics (2023)

Jimena Borgo Orlando G. Elso Jessica Gómez Mauro Coll César A.N. Catalán

Stevia species (Asteraceae) have been a rich source of terpenoid compounds, mainly sesquiterpene lactones, several of which show antiprotozoal activity. In the search for new trypanocidal compounds, S. satureiifolia var. satureiifolia and S. alpina were studied. Two sesquiterpene lactones, santhemoidin C and 2-oxo-8-deoxyligustrin, respectively, were isolated. These compounds were assessed in vitro against Trypanosoma cruzi stages, showing IC50 values of 11.80 and 4.98 on epimastigotes, 56.08 and 26.19 on trypomastigotes and 4.88 and 20.20 µM on amastigotes, respectively. Cytotoxicity was evaluated on Vero cells by the MTT assay. The effect of the compounds on trypanothyone reductase (TcTR), Trans-sialidase (TcTS) and the prolyl oligopeptidase of 80 kDa (Tc80) as potential molecular targets of T. cruzi was investigated. Santhemoidin C inhibited oligopeptidase activity when tested against recombinant Tc80 using a fluorometric assay, reaching an IC50 of 34.9 µM. Molecular docking was performed to study the interaction between santhemoidin C and the Tc80 protein, reaching high docking energy levels. Plasma membrane shedding and cytoplasmic vacuoles, resembling autophagosomes, were detected by transmission microscopy in parasites treated with santhemoidin C. Based on these results, santhemoidin C represents a promising candidate for further studies in the search for new molecules for the development of trypanocidal drugs.

Trypanocidal agent

Amastigote

MTT assay

Vero cell

Antiparasitic

Oligopeptidase

Antiprotozoal

IC50

10.3390/pharmaceutics15020647

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Citations (6)

Mucosal Heterologous Prime/Boost Vaccination Induces Polyfunctional Systemic Immunity, Improving Protection Against Trypanosoma cruzi

Frontiers in Immunology (2020)

Andrés Sánchez Alberti Augusto E. Bivona Marina N. Matos Natacha Cerny Kai Schulze

There are several unmet needs in modern immunology. Among them, vaccines against parasitic diseases and chronic infections are leading. Trypanosoma cruzi, the causative agent of Chagas disease is an excellent example of this issue producing a silent parasitic invasion but still affecting millions of people worldwide due to progression into the symptomatic chronic phase of infection. In search for novel vaccines candidates, we have previously introduced Traspain, an engineered trivalent immunogen that was designed to address some of the known mechanism of T. cruzi immune evasion. Here, we analyzed its performance in different DNA prime/protein boost protocols and characterized the systemic immune response associated with diverse levels of protection. Formulations that include a STING agonist like c-di-AMP in the boost doses, were able to prime a Th1/Th17 immune response. Moreover, comparison between them showed that vaccines that were able to prime polyfunctional cell-mediated immunity at the CD4 and CD8 compartment enhanced protection levels in the murine model. These findings contribute to a better knowledge of the desired vaccine-elicited immunity against T. cruzi and promote the definition of a vaccine correlate of protection against the infection.

Chagas Disease

Immunogen

10.3389/fimmu.2020.00128

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Citations (28)

Oxonitrogenated Derivatives of Eremophilans and Eudesmans: Antiproliferative and Anti-Trypanosoma cruzi Activity

Molecules (2022)

María Florencia Beer Guillermo F. Reta Adrián Puerta Augusto E. Bivona Andrés Sánchez Alberti

Cancer is one of the most important causes of death worldwide. Solid tumors represent the vast majority of cancers (>90%), and the chemotherapeutic agents used for their treatment are still characterized by variable efficacy and toxicity. Sesquiterpenes are a group of natural compounds that have shown a wide range of biological activities, including cytotoxic and antiparasitic activity, among others. The antiproliferative activity of natural sesquiterpenes, tessaric acid, ilicic acid, and ilicic alcohol and their semisynthetic derivatives against HeLa, T-47D, WiDr, A549, HBL-100, and SW1573 cell lines were evaluated. The effect of the compounds on Trypanosoma cruzi epimastigotes was also assessed. The selectivity index was calculated using murine splenocytes. Derivatives 13 and 15 were the most antiproliferative compounds, with GI50 values ranging between 5.3 (±0.32) and 14 (±0.90) μM, in all cell lines tested. The presence of 1,2,3-triazole groups in derivatives 15−19 led to improvements in activity compared to those corresponding to the starting natural product (3), with GI50 values ranging between 12 (±1.5) and 17 (±1.1) μM and 16 being the most active compound. In relation to the anti-T. cruzi activity, derivatives 7 and 16 obtained from tessaric acid and ilicic acid were among the most active and selective compounds with IC50 values of 9.3 and 8.8 µM (SI = 8.0 and 9.4), respectively.

HeLa

Antiparasitic

Natural product

10.3390/molecules27103067

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Citations (2)

Engineered trivalent immunogen adjuvanted with a STING agonist confers protection against Trypanosoma cruzi infection

npj Vaccines (2017)

Andrés Sánchez Alberti Augusto E. Bivona Natacha Cerny Kai Schulze Sebastian Weißmann

The parasite Trypanosoma cruzi is the causative agent of Chagas disease, a potentially life-threatening infection that represents a major health problem in Latin America. Several characteristics of this protozoan contribute to the lack of an effective vaccine, among them: its silent invasion mechanism, T. cruzi antigen redundancy and immunodominance without protection. Taking into account these issues, we engineered Traspain, a chimeric antigen tailored to present a multivalent display of domains from key parasitic molecules, combined with stimulation of the STING pathway by c-di-AMP as a novel prophylactic strategy. This formulation proved to be effective for the priming of functional humoral responses and pathogen-specific CD8+ and CD4+ T cells, compatible with a Th1/Th17 bias. Interestingly, vaccine effectiveness assessed across the course of infection, showed a reduction in parasite load and chronic inflammation in different proof of concept assays. In conclusion, this approach represents a promising tool against parasitic chronic infections.

Immunogen

Sting

10.1038/s41541-017-0010-z

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Citations (55)

[Plasma variations in prolactin half-way through treatment with H2-antagonists].

PubMed (1985)

Cataldo Mg A Salvia Domenico Campisi Augusto E. Bivona Alessandra Militello

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Activity of Estafietin and Analogues on Trypanosoma cruzi and Leishmania braziliensis

Molecules (2019)

Valeria P. Sülsen Emilio Lizárraga Orlando G. Elso Natacha Cerny Andrés Sánchez Alberti

Sesquiterpene lactones are naturally occurring compounds mainly found in the Asteraceae family. These types of plant metabolites display a wide range of biological activities, including antiprotozoal activity and are considered interesting structures for drug discovery. Four derivatives were synthesized from estafietin (1), isolated from Stevia alpina (Asteraceae): 11βH,13-dihydroestafietin (2), epoxyestafietin (3a and 3b), 11βH,13-methoxyestafietin, (4) and 11βH,13-cianoestafietin. The antiprotozoal activity against Trypanosoma cruzi and Leishmania braziliensis of these compounds was evaluated. Epoxyestafietin was the most active compound against T. cruzi trypomastigotes and amastigotes (IC50 values of 18.7 and 2.0 µg/mL, respectively). Estafietin (1) and 11βH,13-dihydroestafietin (2) were the most active and selective compounds on L. braziliensis promastigotes (IC50 values of 1.0 and 1.3 μg/mL, respectively). The antiparasitic activity demonstrated by estafietin and some of its derivatives make them promising candidates for the development of effective compounds for the treatment of Chagas disease and leihsmaniasis.

Antiprotozoal

Leishmania braziliensis

Amastigote

Antiparasitic

Chagas Disease

Benznidazole

IC50

Antiparasitic agent

10.3390/molecules24071209

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Citations (21)

Trypanocidal and Anti-Inflammatory Effects of Three ent-Kaurane Diterpenoids from Gymnocoronis spilanthoides var. subcordata (Asteraceae)

Pharmaceutics (2024)

Mariana G. Selener Jimena Borgo María B. Sarratea Maria Alicia Delfino Laura C. Laurella

Chagas disease, caused by the protozoan Trypanosoma cruzi, affects 6–7 million people worldwide. The dichloromethane extract obtained from the aerial parts of Gymnocoronis spilanthoides var subcordata showed trypanocidal activity in vitro. The fractionation of the dewaxed organic extract via column chromatography led to the isolation of three diterpenoids: ent-9α,11α-dihydroxy-15-oxo-kaur-16-en-19-oic acid or adenostemmoic acid B, (16R)-ent-11α-hydroxy-15-oxokauran-19-oic acid and ent-11α-hydroxy-15-oxo-kaur-16-en-19-oic acid. These compounds showed IC50 values of 10.6, 15.9 and 4.8 µM against T. cruzi epimastigotes, respectively. When tested against amastigotes, the diterpenoids afforded IC50 values of 6.1, 19.5 and 60.6 µM, respectively. The cytotoxicity of the compounds was tested on mammalian cells using an MTT assay, resulting in CC50s of 321.8, 23.3 and 14.8 µM, respectively. The effect of adenostemmoic acid B on T. cruzi was examined at the ultrastructural level using transmission microscopy. Treatment with 20 μM for 48 h stimulated the formation of abnormal cytosolic membranous structures in the parasite. This compound also showed an anti-inflammatory effect in murine macrophages stimulated with LPS and other TLR agonists. Treatment of macrophages with adenostemmoic acid B was able to reduce TNF secretion and nitric oxide production, while increasing IL-10 production. The combination of adenostemmoic acid B with benznidazole resulted in greater inhibition of NF-kB and a decrease in nitrite concentration. The administration of adenostemmoic acid B to mice infected with trypomastigotes of T. cruzi at the dose of 1 mg/kg/day for five days produced a significant decrease in parasitemia levels and weight loss. Treatment with the association with benznidazole increased the survival time of the animals. In view of these results, adenostemmoic acid B could be considered a promising candidate for further studies in the search for new treatments for Chagas disease.

Amastigote

Benznidazole

IC50

Chagas Disease

10.3390/pharmaceutics16030415

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Citations (0)

Preparation of Sesquiterpene Lactone Derivatives: Cytotoxic Activity and Selectivity of Action

Molecules (2019)

María Florencia Beer Augusto E. Bivona Andrés Sánchez Alberti Natacha Cerny Guillermo F. Reta

Cancer is one of the most important causes of death worldwide. Solid tumors represent the great majority of cancers (>90%) and the chemotherapeutic agents used for their treatment are still characterized by variable efficacy and toxicity. Sesquiterpene lactones are a group of naturally occurring compounds that have displayed a diverse range of biological activities including cytotoxic activity. A series of oxygenated and oxy-nitrogenated derivatives (4⁻15) from the sesquiterpene lactones cumanin (1), helenalin (2), and hymenin (3) were synthesized. The silylated derivatives of helenalin, compounds 13 and 14, were found to be the most active against tumor cell lines, with GI50 values ranging from 0.15 to 0.59 μM. The ditriazolyl cumanin derivative (11) proved to be more active and selective than cumanin in the tested breast, cervix, lung, and colon tumor cell lines. This compound was the least toxic against splenocytes (CC50 = 524.1 µM) and exhibited the greatest selectivity on tumor cell lines. This compound showed a GI50 of 2.3 µM and a SI of 227.9 on WiDr human colon tumor cell lines. Thus, compound 11 can be considered for further studies and is a candidate for the development of new antitumor agents.

Sesquiterpene lactone

Splenocyte

10.3390/molecules24061113

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Citations (12)

Recombinant Cysteine Proteinase B from Leishmania braziliensis and Its Domains: Promising Antigens for Serodiagnosis of Cutaneous and Visceral Leishmaniasis in Dogs

Journal of Clinical Microbiology (2019)

Augusto E. Bivona Lucas Czentner Andrés Sánchez Alberti Natacha Cerny Alejandro Cardoso Landaburu

Leishmaniasis represents a group of parasitic diseases caused by a protozoan of the genus Leishmania and is widely distributed in tropical and subtropical regions. Leishmaniasis is one of the major tropical neglected diseases, with 1.5 to 2 million new cases occurring annually. Diagnosis remains a challenge despite advances in parasitological, serological, and molecular methods. Dogs are an important host for the parasite and develop both visceral and cutaneous lesions. Our goal was to contribute to the diagnosis of canine cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL) using the recombinant cysteine proteinase B (F-CPB) from Leishmania braziliensis and its N- and C-terminal domains (N-CPB and C-CPB) as antigens in an enzyme-linked immunosorbent assay (ELISA). Sera from dogs from Northwest Argentina diagnosed with CL were tested by ELISA against a supernatant of L. braziliensis lysate, the F-CPB protein, and its domains. We found values of sensitivity (Se) of 90.7%, 94.4%, and 94.3% and specificity (Sp) of 95.5%, 90.9%, and 91.3% for F-CPB and its N- and C-terminal domains, respectively. In sera from dogs diagnosed with VL from Northeast Argentina, we found Se of 93.3%, 73.3%, and 66.7% and Sp of 92.3%, 76.9%, and 88.5% for F-CPB and its N- and C-terminal domains, respectively. These results support CPB as a relevant antigen for canine leishmaniasis diagnosis in its different clinical presentations. More interestingly, the amino acid sequence of CPB showed high percentages of identity in several Leishmania species, suggesting that the CPB from L. braziliensis qualifies as a good antigen for the diagnosis of leishmaniasis caused by different species.

Leishmania braziliensis

Kinetoplastida

10.1128/jcm.00819-19

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Citations (5)