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Piplartine eliminates CD34+ AML stem/progenitor cells by inducing oxidative stress and suppressing NF-κB signalling
Data availability: Data will be made available on request.Supplementary information is available online at: https://www.nature.com/articles/s41420-024-01909-4#Sec20 .Author notes: These authors contributed equally: Cristina Pina, Daniel P. Bezerra.Acute myeloid leukaemia (AML) is a haematological malignancy characterised by the accumulation of transformed myeloid progenitors in the bone marrow. Piplartine (PL), also known as piperlongumine, is a pro-oxidant small molecule extracted from peppers that has demonstrated antineoplastic potential in solid tumours and other haematological malignancies. In this work, we explored the potential of PL to treat AML through the use of a combination of cellular and molecular analyses of primary and cultured leukaemia cells in vitro and in vivo. We showed that PL exhibits in vitro cytotoxicity against AML cells, including CD34+ leukaemia-propagating cells, but not healthy haematopoietic progenitors, suggesting anti-leukaemia selectivity. Mechanistically, PL treatment increased reactive oxygen species (ROS) levels and induced ROS-mediated apoptosis in AML cells, which could be prevented by treatment with the antioxidant scavenger N-acetyl-cysteine and the pancaspase inhibitor Z-VAD(OMe)-FMK. PL treatment reduced NFKB1 gene transcription and the level of NF-κB p65 (pS536), which was depleted from the nucleus of AML cells, indicating suppression of NF-κB p65 signalling. Significantly, PL suppressed AML development in a mouse xenograft model, and its combination with current AML treatments (cytarabine, daunorubicin and azacytidine) had synergistic effects, indicating translational therapeutic potential. Taken together, these data position PL as a novel anti-AML candidate drug that can target leukaemia stem/progenitors and is amenable to combinatorial therapeutic strategies.This work received financial support and fellowships from the Brazilian agencies Coordenação de Aperfeiçoamento de Pessoal de NÃvel Superior (CAPES, Brazil), Conselho Nacional de Desenvolvimento CientÃfico e Tecnológico (CNPq, Brazil) and Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB, Brazil). Work in the Pina lab was funded by a British Society for Haematology Early-stage Research Grant (33932) and a BRIEF award by Brunel University London (2020–2022)
Genetic parameters of racing performance traits of Quarter horses in Brazil
The data used in the present study were recorded at the Jockey Club of Sorocaba for 5094 racing performance of 1350 Quarter Horses at the Paulista Race Track of Sorocaba, state of São Paulo, Brazil, from 1991 to 1997. The considered traits were time and final rank. The model used in analysis included random animal and permanent environmental effects, and race, sex, age and origin as fixed effects. The variance and covariance components were estimated by the restricted maximum likelihood for an animal model, using the derivative-free process method and the MTDFREML software. For the time, heritability was 0.17 (0.05), while estimate of repeatability 0.55 (0.05). The lower heritability for the final rank, 0.13 (0.04), indicate that this trait is not the most appropriate one for inclusion in programs of Quarter horse selection in Sorocaba racetrack. The repeatability estimate for rank was 0.44 (0.04) and the genetic correlation between this trait and time was 0.99
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