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Validation of crotamine as a biomarker and evaluation of its potential use in the therapy of human diseases


Venom toxins are of great scientific interest, mainly due to their possible use for therapeutic purposes, i.e., as pharmaceuticals and/or as structural models for the development of drugs that may be employed for the treatment of human and/or for biotechnological applications. Crotamine, which is one of the most abundant toxins of the rattlesnake venom, is capable of penetrating cells, as well as transporting DNA molecules into cells with special specificity for actively proliferating cells. The importance of proteoglycans in these processes and the selective cytotoxic activity of crotamine were demonstrated by the group. The evaluation of the feasibility for using the synthetic and/or modified analogues of native crotamine, as well as the expression of recombinant crotamine or the chemical synthesis of crotamine as alternative sources of this compound, suggested that the purified native crotamine from the venom of rattlesnakes kept in captivity, would still be the most viable strategy from an economic point of view. Therefore, thanks to the agreement signed with the international company Celtics Biotech (Ireland), and through a licensing contract mediated by the Butantan Institute and signed by the Secretary of Health of the State of São Paulo in 2015, we are currently working together to jointly develop a plan for the use the native crotamine obtained under GMP conditions as a diagnostic agent for human use, with the participation of Emory University (USA) and QIMR Berghofer Medical Research Institute (Australia). New routes of administration of crotamine, new formulations (nanoparticles) and also possible adverse effects will be also assessed in the present study.Therefore, the aim of this project is to evaluate the potential use of crotamine as a therapeutical agent, aiding in the detection of tumors (diagnosis), and at the same time acting as antitumor and/or carrier of therapeutic genes or other antitumor agents when immobilized on nanoparticles. In addition, we intend to evaluate the use of crotamine for renal disease therapy, since this is the organ with the greatest accumulation of this polypeptide in vivo. With this we hope to validate the real contribution of this toxin to the diagnosis and/or therapy of patients with renal or tumor bearing diseases. (AU)

Articles published in Agência FAPESP Newsletter about the research grant:
Pesquisa com vermes pode indicar alternativas para o tratamento da esquizofrenia 
Una investigación con gusanos sugiere alternativas en el tratamiento de la esquizofrenia 
Experiments with roundworms suggest alternatives for the treatment of schizophrenia 
Articles published in other media outlets (2 total):
Medical Xpress (Reino Unido): Experiments with roundworms suggest alternatives for the treatment of schizophrenia (20/Mar/2019)
Mindzilla (Reino Unido): Experiments with Roundworms Suggest Alternatives for the Treatment of Schizophrenia (20/Mar/2019)

Scientific publications (17)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CAMPEIRO, JOANA D. `ARC; NANI, V, JOAP; MONTE, GABRIELA G.; ALMEIDA, PRISCILA G. C.; MORI, MARCELO A.; HAYASHI, MIRIAN A. F. Regulation of monoamine levels by typical and atypical antipsychotics in Caenorhabditis elegans mutant for nuclear distribution element genes. NEUROCHEMISTRY INTERNATIONAL, v. 147, JUL 2021. Web of Science Citations: 0.
CORREIA, BANNY SILVA BARBOSA; NANI, JOAO VICTOR; WALADARES RICARDO, RANIERY; STANISIC, DANIJELA; COSTA, TASSIA BRENA BARROSO CARNEIRO; HAYASHI, MIRIAN A. F.; TASIC, LJUBICA. Effects of Psychostimulants and Antipsychotics on Serum Lipids in an Animal Model for Schizophrenia. BIOMEDICINES, v. 9, n. 3 MAR 2021. Web of Science Citations: 0.
TROMBETTA-LIMA, MARINA; ASSIS-RIBAS, THAIS; CINTRA, RICARDO C.; CAMPEIRO, JOANA D.; GUERREIRO, JULIANO R.; WINNISCHOFER, SHEILA M. B.; NASCIMENTO, ISIS C. C.; ULRICH, HENNING; HAYASHI, MIRIAN A. F.; SOGAYAR, MARI C. Impact of Reck expression and promoter activity in neuronal in vitro differentiation. MOLECULAR BIOLOGY REPORTS, v. 48, n. 2 FEB 2021. Web of Science Citations: 0.
NANI, V, JOAO; DAL MAS, CAROLINE; YONAMINE, CAMILA M.; OTA, VANESSA K.; NOTO, CRISTIANO; BELANGERO, I, SINTIA; MARI, JAIR J.; BRESSAN, RODRIGO; CORDEIRO, QUIRINO; GADELHA, ARY; HAYASHI, MIRIAN A. F. A Study in First-Episode Psychosis Patients: Does Angiotensin I-Converting Enzyme Activity Associated With Genotype Predict Symptom Severity Reductions After Treatment With Atypical Antipsychotic Risperidone?. INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, v. 23, n. 11, p. 721-730, NOV 2020. Web of Science Citations: 0.
NANI, JOAO V.; LEE, RICHARD S.; YONAMINE, CAMILA M.; SANT'ANNA, OSVALDO A.; JULIANO, MARIA A.; GADELHA, ARY; MARI, JAIR J.; HAYASHI, MIRIAN A. F. Evaluation of NDEL1 oligopeptidase activity in blood and brain in an animal model of schizophrenia: effects of psychostimulants and antipsychotics. SCIENTIFIC REPORTS, v. 10, n. 1 OCT 28 2020. Web of Science Citations: 0.
PORTA, LUCAS C.; CAMPEIRO, JOANA D.; PAPA, GIOVANNA B.; OLIVEIRA, EDUARDO B.; GODINHO, ROSELY O.; RODRIGUES, TIAGO; HAYASHI, MIRIAN A. F. In vivo effects of the association of the psychoactive phenotiazine thioridazine on antitumor activity and hind limb paralysis induced by the native polypeptide crotamine. Toxicon, v. 185, p. 64-71, OCT 15 2020. Web of Science Citations: 0.
DE CARVALHO PORTA, LUCAS; FADEL, VALMIR; D'ARC CAMPEIRO, JOANA; OLIVEIRA, EDUARDO BRANDT; GODINHO, ROSELY OLIVEIRA; HAYASHI, MIRIAN AKEMI FURUIE. Biophysical and pharmacological characterization of a full-length synthetic analog of the antitumor polypeptide crotamine. JOURNAL OF MOLECULAR MEDICINE-JMM, v. 98, n. 11 SEP 2020. Web of Science Citations: 0.
NANI, V, JOAO; FONSECA, MATHEUS C.; ENGI, SHEILA A.; PERILLO, MAYARA G.; DIAS, CARLOS S. B.; GAZARINI, MARCOS L.; KORTH, CARSTEN; CRUZ, FABIO C.; HAYASHI, MIRIAN A. F. Decreased nuclear distribution nudE-like 1 enzyme activity in an animal model with dysfunctional disrupted-in-schizophrenia 1 signaling featuring aberrant neurodevelopment and amphetamine-supersensitivity. JOURNAL OF PSYCHOPHARMACOLOGY, v. 34, n. 4 JAN 2020. Web of Science Citations: 0.
RODRIGUEZ, BENJAMIN; NANI, JOAO VICTOR; ALMEIDA, PRISCILA G. C.; BRIETZKE, ELISA; LEE, RICHARD S.; HAYASHI, MIRIAN A. F. Neuropeptides and oligopeptidases in schizophrenia. NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS, v. 108, p. 679-693, JAN 2020. Web of Science Citations: 0.
MONTE, GABRIELA GUILHERME; NANI, V, JOAO; DE ALMEIDA CAMPOS, MARINA ROSSETO; DAL MAS, CAROLINE; NEGRI MARINS, LUCAS AUGUSTO; MARTINS, LUCAS GELAIN; TASIC, LJUBICA; MORI, MARCELO A.; HAYASHI, MIRIAN A. F. Impact of nuclear distribution element genes in the typical and atypical antipsychotics effects on nematode Caenorhabditis elegans: Putative animal model for studying the pathways correlated to schizophrenia. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 92, p. 19-30, JUN 8 2019. Web of Science Citations: 0.
DAL MAS, CAROLINE; ROSSATO, LUANA; SHIMIZU, THAIS; OLIVEIRA, EDUARDO B.; DA SILVA JUNIOR, I, PEDRO; MEIS, JACQUES F.; COLOMBO, ARNALDO LOPES; HAYASHI, MIRIAN A. F. Effects of the Natural Peptide Crotamine from a South American Rattlesnake on Candida auris, an Emergent Multidrug Antifungal Resistant Human Pathogen. BIOMOLECULES, v. 9, n. 6 JUN 2019. Web of Science Citations: 1.
CAMPEIRO, JOANA DARC; DAM, WENDY; MONTE, GABRIELA GUILHERME; PORTAL, LUCAS CARVALHO; GONCALVES DE OLIVEIRA, LILIAN CAROLINE; NERING, MARCELA BEGO; VIANA, GUSTAVO MONTEIRO; CARAPETOS, FERNANDO CINTRA; OLIVEIRA, EDUARDO BRANDT; VAN DEN BORN, JACOB; HAYASHI, MIRIAN A. F. Long term safety of targeted internalization of cell penetrating peptide crotamine into renal proximal tubular epithelial cells in vivo. SCIENTIFIC REPORTS, v. 9, MAR 1 2019. Web of Science Citations: 0.
LIMA, SUNAMITA DE CARVALHO; PORTA, LUCAS DE CARVALHO; LIMA, ALVARO DA COSTA; CAMPEIRO, JOANA D'ARC; MEURER, YWLLIANE; TEIXEIRA, NATHALIA BERNARDES; DUARTE, THIAGO; OLIVEIRA, EDUARDO BRANDT; PICOLO, GISELE; GODINHO, ROSELY OLIVEIRA; SILVA, REGINA HELENA; FURUIE HAYASHI, MIRIAN AKEMI. Pharmacological characterization of crotamine effects on mice hind limb paralysis employing both ex vivo and in vivo assays: Insights into the involvement of voltage-gated ion channels in the crotamine action on skeletal muscles. PLoS Neglected Tropical Diseases, v. 12, n. 8 AUG 2018. Web of Science Citations: 2.
MARINOVIC, MARCELO P.; CAMPEIRO, JOANA D.; LIMA, SUNAMITA C.; ROCHA, ANDREA L.; NERING, MARCELA B.; OLIVEIRA, EDUARDO B.; MORI, MARCELO A.; HAYASHI, MIRIAN A. F. Crotamine induces browning of adipose tissue and increases energy expenditure in mice. SCIENTIFIC REPORTS, v. 8, MAR 22 2018. Web of Science Citations: 1.
CAMPEIRO, JOANA D.; MARINOVIC, MARCELO P.; CARAPETO, FERNANDO CINTRA; DAL MAS, CAROLINE; MONTE, GABRIELA GUILHERME; PORTA, LUCAS CARVALHO; NERING, MARCELA B.; OLIVEIRA, EDUARDO B.; HAYASHI, MIRIAN A. F. Oral treatment with a rattlesnake native polypeptide crotamine efficiently inhibits the tumor growth with no potential toxicity for the host animal and with suggestive positive effects on animal metabolic profile. Amino Acids, v. 50, n. 2, p. 267-278, FEB 2018. Web of Science Citations: 3.
DAL MAS, C.; PINHEIRO, D. A.; CAMPEIRO, J. D.; MATTEI, B.; OLIVEIRA, V.; OLIVEIRA, E. B.; MIRANDA, A.; PEREZ, K. R.; HAYASHI, M. A. F. Biophysical and biological properties of small linear peptides derived from crotamine, a cationic antimicrobial/antitumoral toxin with cell penetrating and cargo delivery abilities. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, v. 1859, n. 12, p. 2340-2349, DEC 2017. Web of Science Citations: 4.

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