Biology subjects

Macedo, M. P.

Publications and source records attributed to Macedo, M. P..

5 recordsLinked to original sources

bioRxiv2026

EV-Net: A computational framework to model extracellular vesicles-mediated communication

SummaryExtracellular vesicles (EVs) are bilayer vesicles that carry a diverse cargo of molecules, such as nucleic acids, proteins and metabolites. These EVs can be transported throughout the organism to specific recipient tissues. For this reason, EVs have been recognized as pivotal mediators of cell-to-cell communication (CCC). Importantly, alterations in EV-mediated communication have been linked to pathological processes, further highlighting their biological relevance. However, the in silico exploration of the functional effects of EV cargo in recipient tissues remains limited due to the lack of dedicated tools that can be applied to EV omics datasets. Most current bioinformatics tools for assessing CCC rely on ligand-mediated communication and therefore cannot be used to explore EV-mediated communication. To address this gap, we developed EV-Net, a bioinformatics tool designed to explore the effects of EV cargo on recipient tissues. EV-Net was built by adapting NicheNet, a CCC bioinformatics tool that relies on ligand-receptor mediated communication, for the analysis of EVs proteomics and RNA-seq data. The EV-Net framework enables the identification and prioritization of EV cargo molecules with high regulatory potential in a recipient tissue of interest. This prioritization facilitates the systematic translation of EV cargo profiles into testable biological hypotheses. Availability and documentationThe source code of EV-Net is stored in GitHub https://github.com/torrejoNia/EV-Net alongside instructions on how to install it. Comprehensive tutorials and additional documentation are available at https://torrejonia.github.io/EV-Net/. The datasets used in the use cases were deposited in Zenodo. The corresponding Zenodo links are provided in the tutorials for each use case. This software is distributed under a GLP3 licence.

bioinformatics↗

bioRxiv2021

Messages From the Small Intestine Carried by Extracellular Vesicles in Prediabetes: a Proteomic Portrait

Extracellular vesicles (EVs) mediate communication in physiological and pathological conditions. In the pathogenesis of type 2 diabetes, inter-organ communication plays an important role in its progress and metabolic surgery leads to its remission. Moreover, gut dysbiosis is emerging as a diabetogenic factor. However, it remains unclear how gut senses metabolic alterations and whether this is transmitted to other tissues via EVs. Using a diet induced-prediabetic mouse model, we observed that protein packaging in gut derived EVs (GDE), specifically small intestine, is increased in prediabetes. Proteins related to lipid metabolism and to oxidative stress management were more abundant in prediabetic GDE compared to healthy controls. On the other hand, proteins related to glycolytic activity, as well as those responsible for the degradation of polyubiquitinated composites, were depleted in prediabetic GDE. Together, our findings show that protein packaging in GDE is markedly modified during prediabetes pathogenesis. Thus, suggesting that prediabetic alterations in small intestine are translated into modified GDE proteome, which are dispersed into the circulation where they can interact with and influence the metabolic status of other tissues. This study highlights the importance of the small intestine as a tissue that propagates prediabetic metabolic dysfunction throughout the body and the importance of GDE as the messenger.

pathology↗

bioRxiv2021

Pre-diabetes linked microRNA miR-193b-3p targets PPARGC1A and increases lipid accumulation in hepatocytes: potential biomarker of fatty liver disease

Distinct plasma microRNA profiles associate with different disease features. Elevated plasma microRNA hsa-miR-193b-3p has been reported in patients with pre-diabetes where early liver dysmetabolism plays a crucial role. MicroRNA target databases revealed that hsa-miR-193b-3p could potentially target PPARGC1A, a master switch transcriptional co-activator that orchestrates the expression of genes involved in multiple metabolic pathways. In this study we evaluated the effects of hsa-miR-193b-3p in the human HepG2 hepatocyte cell line. We show that hsa-miR-193b-3p targets PPARGC1A/PGC1 mRNA 3UTR and reduces its expression. Overexpression of hsa-miR-193b-3p under hyperglycemia resulted in increased accumulation of intracellular lipid droplets; and quantitative real-time RT-PCR of a panel of 24 genes revealed significant disruption in the expression of genes coordinating glucose uptake, glycolysis, pyruvate metabolism, fatty acid synthesis, fatty acid oxidation, triglyceride synthesis, VLDL secretion, insulin signalling, and mitochondrial biogenesis, dynamics and function. These results provide in vitro evidence that microRNA hsa-miR-193b-3p downregulates PPARGC1A/PGC1, disrupts downstream metabolic pathways and leads to the accumulation of intracellular lipids in hepatocytes. We propose that microRNA hsa-miR-193b-3p may have potential as a clinically relevant plasma biomarker for metabolic associated fatty liver disease in a pre-diabetic dysglycemic context.

biochemistry↗

bioRxiv2019

Trem-2 modulation of gut microbiota is blunted during hepatotoxic injury and uncoupled from liver repair responses

The involvement of gut microbiota in liver disease has been addressed in the context of the "leaky gut hypothesis" postulating that dysbiosis allow microbial components to elicit liver inflammatory responses and hepatic tissue damage. Conversely, commensal gut microbiota acting on innate immune receptors protect against hepatotoxic insults. Given that mice deficient for the triggering receptor expressed on myeloid cells-2 (Trem-2) show increased vulnerability to experimental drug-induced hepatic damage we explored the possibility that Trem-2 is a modulator of gut microbiota composition. We found that microbiota composition in untreated Trem-2 KO mice differs from the wild-type showing overall decrease in microbiota diversity and increased representation of Verrucomicrobia. Interestingly, induction of liver damage with hepatotoxic drugs blunted this microbiota diversity difference and altered phyla composition with increased representation of Verrucomicrobia during acute hepatic injury and Proteobacteria during chronic challenge. Furthermore, co-housing experiments that homogenized microbiota diversity showed that the increased liver tissue vulnerability to hepatotoxic insults in Trem-2 KO mice was not dependent on microbiota composition. This work uncouples Trem-2 dependent alterations in gut commensal microbiota from Trem-2 pro-recovery effects in the damaged liver tissue. These findings support the possibility that unlinked actions of innate immune receptors contribute to disease association with microbiota alterations, particularly with the Verrucomicrobia phylum. ImportanceTrem-2 is a mammalian innate immunity receptor involved in development and resolution of tissue damage, namely in the brain and in the liver. Nevertheless, it is not known whether gut microbiota is contributing to these Trem-2 mediated phenotypes. We found that Trem-2 KO mice spontaneously display different gut microbiota composition as compared to wild-type mice, namely with increased abundance of the phylum Verrucomicrobia. Notably these differences do not impact the control of Trem-2 on liver tissue vulnerability to hepatotoxic insults. This work uncouples Trem-2 modulation of gut microbiota and the role of Trem-2 on responses to liver damage. This work brings new insights on role of innate immune receptors on the association of organic and systemic diseases with gut microbiota.

microbiology↗

bioRxiv2019

Trem-2 promotes emergence of restorative macrophages and endothelial cells during recovery from hepatic tissue damage.

Macrophages are pivotal in mounting liver inflammatory and tissue repair reactions upon hepatic injury showing remarkable functional plasticity. Nevertheless, the molecular mechanisms determining macrophage transition from inflammatory to restorative phenotypes in the damaged liver remain unclear. Using mouse models of acute (APAP) or chronic (CCl4) drug-induced hepatotoxic injury we show that the immune receptor Trem-2 controls phenotypic shifts in liver macrophages and impacts endothelial cell differentiation during tissue recovery.\n\nTrem-2 gene ablation led to delayed re-population of Kupffer cells correlating with deterred resolution of hepatic damage following acute and chronic injury. We found that during tissue recovery macrophages in transition to the Kupffer cell compartment expressed high levels of Trem-2. Acquisition of the transition phenotype was associated with an unique transcriptomic profile denoting strong responsiveness to oxidative stress and downmodulation of the pro-inflammatory phenotype, which was not observed in absence of Trem-2.\n\nDuring tissue recovery lack of Trem-2 favored accumulation of a liver-damage associated endothelial cell population (LDECs) engaged in a transcriptional program compatible with endothelial de-differentiation. Accordingly, LDECs precursor potential is supported by the downregulation of surface endothelial cell markers and striking in vitro morphological changes towards typical endothelial cells.\n\nIn conclusion, we found that the dynamics of liver macrophages in response to liver injury is critically controlled by Trem-2 and is interlinked with the de-differentiation of endothelial cells and heightened liver pathology. We propose that Trem-2 promotes the transition from the pro-inflammatory to the tissue repair phase by driving the acquisition of restorative properties of phagocytic macrophages.

immunology↗