Biology subjects

dos Santos, E.

Publications and source records attributed to dos Santos, E..

4 recordsLinked to original sources

bioRxiv2026

Genome-scale modelling and stable isotope tracing reveal dynamic metabolic reprogramming in a human cardiac hypertrophy model

Pathological cardiac hypertrophy is associated with metabolic remodelling; however the temporal dynamics of this remodelling remain poorly defined in human cardiomyocyte systems. Here, we combined transcriptomic profiling, genome-scale metabolic modelling and stable isotope-resolved metabolomics (SIRM) to map the metabolic consequences of endothelin-1 (ET-1) stimulation in human iPSC-derived cardiomyocytes (hiPSC-CMs). Integration of RNA sequencing data obtained after 8 and 48 hours of ET-1 treatment with the Human2.0 genome-scale metabolic model predicted time-dependent remodelling, characterised by progressive increases in glycolytic flux, enhanced glucose carbon entry into the TCA cycle, and a decrease in fatty acid {beta}-oxidation. Computational flux predictions were independently confirmed by extracellular flux analysis and 13C-substrate tracing, with concordance between modelled and measured fluxes. Extracellular flux analysis showed increased glycolytic capacity and mitochondrial respiration after 48 hours, with greater sensitivity to inhibition of mitochondrial pyruvate transport. Glucose tracing revealed increased 13C enrichment of glycolytic, pentose phosphate pathway, serine-glycine and TCA cycle metabolites, consistent with altered glucose-derived carbon allocation. Increased m+3 labelling of selected TCA-related metabolites was compatible with pyruvate anaplerosis, although pathway-specific fluxes were not resolved. In three-dimensional engineered heart tissue (EHTs) treated with ET-1 for 7 days, increased hypertrophic marker expression was accompanied by a blunted inotropic response, and metabolomics showed similar changes in metabolite abundance and glucose-derived labelling to 2D cultures. These findings support hiPSC-CMs and EHTs as complementary platforms for studying early metabolic remodelling in pathological cardiac hypertrophy and provide an integrated framework linking model predictions to functional and isotope-tracing measurements.

cell biology↗

bioRxiv2024

Genomic insights into Plasmodium vivax and Plasmodium simium host shifts in Latin America

Malaria in Latin America is largely caused by Plasmodium vivax, but its lesser-known sister species, Plasmodium simium, has recently emerged from monkeys to infect humans, thus raising new public health concerns. By analyzing 719 monkey samples and whole genome variations for 19 P. simium and 408 P. vivax isolates, we investigated the evolutionary history and population genetics of the two species. P. vivax, typically restricted to humans, was identified in three Colombian and one Brazilian monkeys, suggesting host niche expansion. Genetic analysis reveals recent genetic exchanges between both species and indicates that P. simium originated from a host jump approximately a century ago, possibly linked to P. vivax migration from Mexico to Brazil. Genome-wide scans revealed signals of positive selection in P. simium genes involved in interactions with primate hosts and mosquito vectors. These findings highlight P. simium evolutionary history and zoonotic malaria risks, and underscore the need to include monkeys in malaria prevention measures while ensuring human-wildlife coexistence.

evolutionary biology↗

bioRxiv2024

Systemic extracellular acidification is a hallmark of aging

Understanding the critical pathophysiological processes that promote age-related disease is needed to uncover effective targets for preventive medicine. Here, we investigate how extracellular pH changes with age and its impact on longevity, using fly and mouse models. We find that extracellular acidification occurs in flies during aging and correlates to mortality rate. With age, flies also become more susceptible to die from acidotic stress, which can be prevented by alkalotic treatment. Acidification is caused by insufficient acid elimination, linked to downregulation of genes in the fly excretory tract that control pH and ATP production, essential for active secretion initiation. In mice, we show that lymph-drained interstitial fluids acidify with age. Expression of genes, whose pathogenic loss-of-function variants cause tubular acidosis in humans, is decreased in the kidneys of aging mice. Overall, this study sheds light on dysregulated systemic acid-base balance as a conserved pathophysiological mechanism of aging.

physiology↗

bioRxiv2022

The central role of pyruvate metabolism on the epigenetic and molecular maturation of bovine cumulus-oocytes complexes.

Pyruvate, the end-product of glycolysis in aerobic conditions, is produced by cumulus cells, and is converted in Acetyl-CoA into the mitochondria of both cumulus cells (CCs) and oocytes as a master fuel input for the tricarboxylic acid cycle (TCA). The citrate generated in the TCA cycle can be directed to the cytoplasm and converted back to acetyl-CoA, being driven to lipid synthesis or, still, being used as the substrate for histones acetylation. This work aimed to verify the impact of pyruvate metabolism on the dynamic of lysine 9 histone 3 acetylation (H3K9ac) and RNA transcription in bovine cumulus-oocyte complexes during in vitro maturation (IVM). Bovine oocytes were IVM for 24h in three experimental groups: Control [IVM medium], sodium dichloroacetate [DCA, a stimulator of pyruvate oxidation in acetyl-CoA] or sodium iodoacetate [IA, a glycolysis inhibitor]. Our results show that both treatments change the metabolic profile of oocytes and CCs, stimulating the use of lipids for energy metabolism in the gamete. This leads to changes in the dynamics of H3K9ac during the IVM in both oocytes and CCs with impact on the synthesis of new transcripts in CCs. A total of 148 and 356 differentially expressed genes were identified in DCA and IA oocytes groups, respectively, when compared to the control group. In conclusion, disorders in pyruvate metabolism during maturation stimulate the beta-oxidation pathway, altering the mitochondrial metabolism, with consequences for the mRNA content of bovine oocytes.

molecular biology↗