Percorrer por autor "Gil, Ana M."
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- Fibrinogen scaffolds with immunomodulatory properties promote in vivo bone regenerationPublication . Vasconcelos, Daniel M.; Gonçalves, Raquel M.; Almeida, Catarina R.; Pereira, Inês O.; Oliveira, Marta I.; Neves, Nuno; Silva, Andreia M.; Ribeiro, António C.; Cunha, Carla; Almeida, Ana R.; Ribeiro, Cristina C.; Gil, Ana M.; Seebach, Elisabeth; Kynast, Katharina L.; Richter, Wiltrud; Lamghari, Meriem; Santos, Susana G.; Barbosa, Mário A.The hypothesis behind this work is that fibrinogen (Fg), classically considered a pro-inflammatory protein, can promote bone repair/regeneration. Injury and biomaterial implantation naturally lead to an inflammatory response, which should be under control, but not necessarily minimized. Herein, porous scaffolds entirely constituted of Fg (Fg-3D) were implanted in a femoral rat bone defect and investigated at two important time points, addressing the bone regenerative process and the local and systemic immune responses, both crucial to elucidate the mechanisms of tissue remodelling. Fg-3D led to early infiltration of granulation tissue (6 days post-implantation), followed by bone defect closure, including periosteum repair (8 weeks post-injury). In the acute inflammatory phase (6 days) local gene expression analysis revealed significant increases of pro-inflammatory cytokines IL-6 and IL-8, when compared with non-operated animals. This correlated with modified proportions of systemic immune cell populations, namely increased T cells and decreased B, NK and NKT lymphocytes and myeloid cell, including the Mac- 1þ (CD18þ/CD11bþ) subpopulation. At 8 weeks, Fg-3D led to decreased plasma levels of IL-1b and increased TGF-b1. Thus, our data supports the hypothesis, establishing a link between bone repair induced by Fg-3D and the immune response. In this sense, Fg-3D scaffolds may be considered immunomodulatory biomaterials.
- NMR-based urinary biomarkers in pediatric primary mitochondrial disorders and chronic kidney disease: shared mitochondrial dysfunction, diverging biosignaturesPublication . Coelho, Margarida Paiva; Rodrigues, João E.; Costa, Teresa; Dias, Aureliano; Graça, Inês C. R.; Rocha, Hugo; Vilarinho, Laura; Martins, Esmeralda; Gil, Ana M.; Carvalho de Azevedo Rocha, Hugo DanielRenal involvement is a recognized feature of primary mitochondrial disorders (PMD), either at presentation or during the disease course. Simultaneously, the metabolomic fingerprint of chronic kidney disease (CKD) is often associated with underlying mitochondrial dysfunction. This study aimed to characterize urinary metabolic signatures in genetically confirmed paediatric PMD without chronic kidney disease, comparing them to healthy controls, suspected (unconfirmed) mitochondrial disease (SMD), and non-mitochondrial CKD. We performed untargeted 1 H NMR metabolomic profiling of 76 urine samples from 51 paediatric patients and 10 healthy controls. PMD patients in acute decompensation or known CKD and statistical outlier samples were excluded. Final comparisons included genetically confirmed PMD without CKD (n=13), SMD (n=10), non-mitochondrial CKD (n=28; 17 at stages 1–2 and 9 at stages 3–5), and healthy controls (n=10). Spectral data were analyzed using multivariate statistical approaches—including principal component analysis (PCA) and partial least squares–discriminant analysis (PLS-DA)—as well as univariate methods with Mann-Whitney U for pairwise group metabolite comparison. Urinary metabolic profiles of PMD patients differed from healthy controls and CKD patients. Multivariate analysis revealed a strong discriminative ability between PMD and controls (Q² = 0.53) and advanced CKD (Q2=0.78). Compared to controls, PMD patients had increased levels of Krebs cycle intermediates (cis-aconitate, fumarate and succinate), creatine, tryptophan, homovanillate (HVA) and hypoxanthine, as well as decreased histidine. All, except fumarate and histidine, remained discriminative when comparing PMD to CKD. CKD patients showed a diverging metabolomic fingerprint with 1-methylnicotinamide (MNA) and 2-hydroxyisobutyrate emerging as potential CKD-specific biomarkers, effectively discriminating between CKD stage 3–5 from earlier stages and controls. A five-metabolite panel comprising cis-aconitate, fumarate, HVA, tryptophan and histidine achieved high diagnostic performance for identifying PMD, with an area under the curve (AUC) of 0.836 (PMD vs. controls) and AUC=0.783 across all groups. This biosignature integrates metabolites involved in distinct functional domains including energy metabolism, neurotransmitter turnover and amino acid metabolism and renal handling. Urinary metabolomic profiling by NMR revealed a distinct biosignature in pediatric PMD patients without renal involvement, characterized by elevated levels of tryptophan, HVA, and Krebs cycle intermediates, and diminished histidine. The divergent changes in tryptophan, histidine and HVA, suggest a mitochondria-specific metabolic phenotype in PMD. These findings support the use of urinary NMR metabolomics as a non-invasive tool for biomarker discovery in PMD and highlight the potential of integrated, multiparametric metabolic fingerprints for diagnostic refinement and patient stratification.