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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 Nível Superior (CAPES, Brazil), Conselho Nacional de Desenvolvimento Científico 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)
Socioeconomic inequalities in the use of outpatient services in Brazil according to health care need: evidence from the World Health Survey
<p>Abstract</p> <p>Background</p> <p>The Brazilian health system is founded on the principle of equity, meaning provision of equal care for equal needs. However, little is known about the impact of health policies in narrowing socioeconomic health inequalities. Using data from the Brazilian World Health Survey, this paper addresses socioeconomic inequalities in the use of outpatient services according to intensity of need.</p> <p>Methods</p> <p>A three-stage cluster sampling was used to select 5000 adults (18 years and over). The non-response rate was 24.7% and calibration of the natural expansion factors was necessary to obtain the demographic structure of the Brazilian population. Utilization was established by use of outpatient services in the 12 months prior to the interview. Socioeconomic inequalities were analyzed by logistic regression models using years of schooling and private health insurance as independent variables, and controlling by age and sex. Effects of the socioeconomic variables on health services utilization were further analyzed according to self-rated health (good, fair and poor), considered as an indicator of intensity of health care need.</p> <p>Results</p> <p>Among the 5000 respondents, 63.4% used an outpatient service in the year preceding the survey. The association of health services utilization and self-rated health was significant (p < 0.001). Regarding socioeconomic inequalities, the less educated used health services less frequently, despite presenting worse health conditions. Highly significant effects were found for both socioeconomic variables, years of schooling (p < 0.001) and private health insurance (p < 0.00), after controlling for age and sex. Stratifying by self-rated health, the effects of both socioeconomic variables were significant among those with good health status, but not statistically significant among those with poor self-rated health.</p> <p>Conclusions</p> <p>The analysis showed that the social gradient in outpatient services utilization decreases as the need is more intense. Among individuals with good self-rated health, possible explanations for the inequality are the lower use of preventive services and unequal supply of health services among the socially disadvantaged groups, or excessive use of health services by the wealthy. On the other hand, our results indicate an adequate performance of the Brazilian health system in narrowing socioeconomic inequalities in health in the most serious situations of need.</p
Evolutionary diversity is associated with wood productivity in Amazonian forests
Higher levels of taxonomic and evolutionary diversity are expected to maximize ecosystem function, yet their relative importance in driving variation in ecosystem function at large scales in diverse forests is unknown. Using 90 inventory plots across intact, lowland, terra firme, Amazonian forests and a new phylogeny including 526 angiosperm genera, we investigated the association between taxonomic and evolutionary metrics of diversity and two key measures of ecosystem function: aboveground wood productivity and biomass storage. While taxonomic and phylogenetic diversity were not important predictors of variation in biomass, both emerged as independent predictors of wood productivity. Amazon forests that contain greater evolutionary diversity and a higher proportion of rare species have higher productivity. While climatic and edaphic variables are together the strongest predictors of productivity, our results show that the evolutionary diversity of tree species in diverse forest stands also influences productivity. As our models accounted for wood density and tree size, they also suggest that additional, unstudied, evolutionarily correlated traits have significant effects on ecosystem function in tropical forests. Overall, our pan-Amazonian analysis shows that greater phylogenetic diversity translates into higher levels of ecosystem function: tropical forest communities with more distantly related taxa have greater wood productivity
Carbon uptake by mature Amazon forests has mitigated Amazon nations' carbon emissions
BACKGROUND: Several independent lines of evidence suggest that Amazon forests have provided a significant carbon sink service, and also that the Amazon carbon sink in intact, mature forests may now be threatened as a result of different processes. There has however been no work done to quantify non-land-use-change forest carbon fluxes on a national basis within Amazonia, or to place these national fluxes and their possible changes in the context of the major anthropogenic carbon fluxes in the region. Here we present a first attempt to interpret results from ground-based monitoring of mature forest carbon fluxes in a biogeographically, politically, and temporally differentiated way. Specifically, using results from a large long-term network of forest plots, we estimate the Amazon biomass carbon balance over the last three decades for the different regions and nine nations of Amazonia, and evaluate the magnitude and trajectory of these differentiated balances in relation to major national anthropogenic carbon emissions. RESULTS: The sink of carbon into mature forests has been remarkably geographically ubiquitous across Amazonia, being substantial and persistent in each of the five biogeographic regions within Amazonia. Between 1980 and 2010, it has more than mitigated the fossil fuel emissions of every single national economy, except that of Venezuela. For most nations (Bolivia, Colombia, Ecuador, French Guiana, Guyana, Peru, Suriname) the sink has probably additionally mitigated all anthropogenic carbon emissions due to Amazon deforestation and other land use change. While the sink has weakened in some regions since 2000, our analysis suggests that Amazon nations which are able to conserve large areas of natural and semi-natural landscape still contribute globally-significant carbon sequestration. CONCLUSIONS: Mature forests across all of Amazonia have contributed significantly to mitigating climate change for decades. Yet Amazon nations have not directly benefited from providing this global scale ecosystem service. We suggest that better monitoring and reporting of the carbon fluxes within mature forests, and understanding the drivers of changes in their balance, must become national, as well as international, priorities