Browsing by Subject "Extracellular matrix remodeling"

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    A comparative study of extracellular matrix remodeling in two murine models of emphysema
    (F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2013) Lopes, F.D.T.Q.S.; Toledo, A.C.; Olivo, C.R.; Prado, C.M.; Leick, E.A.; Medeiros, M.C.; Santos, A.B.G.; Garippo, A.; Martins, M.A.; Mauad, T.
    A single instillation of porcine pancreatic elastase (PPE) results in significant airspace enlargement on the 28th day after instillation, whereas cigarette smoke (CS) exposure requires 6 months to produce mild emphysema in rodents. Considering that there are differences in the pathogenesis of parenchymal destruction in these different experimental models, it is likely that there may be different patterns of extracellular matrix (ECM) remodeling. To evaluate ECM remodeling, C57BL/6 mice were submitted to either a nasal drop of PPE (PPE 28 Days) or exposed for 6 months to cigarette smoke (CS 6 months). Control groups received either an intranasal instillation of saline solution (Saline 28 Days) or remained without any smoke inhalation for six months (Control 6 months). We measured the mean linear intercept and the volume proportion of collagen type I, collagen type III, elastin and fibrillin. We used emission-scanning confocal microscopy to verify the fiber distribution. Both models induced increased mean linear intercept in relation to the respective controls, being larger in the elastase model in relation to the CS model. In the CS model, emphysema was associated with an increase in the volume proportion of fibrillin, whereas in the PPE model there was an increase in the parenchymal elastin content. In both models, there was an increase in collagen type III, which was higher in the CS-exposed mice. We concluded that ECM remodeling is different in the two most used experimental models of emphysema.
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    Molecular insights into the interaction of cathepsin D and iron in chronic wound healing: exploring therapeutic potential and mechanisms
    (MDPI, 2025-02-21) Rodríguez-Moreno, María; Legaz Pérez, Isabel; Ciencias Sociosanitarias; Facultad de Química
    Background: Chronic wounds, such as diabetic ulcers, often fail to progress through healing due to persistent inflammation, infections, and extracellular matrix (ECM) imbalances. Cathepsin D, an aspartate protease active in acidic environments, plays a pivotal role in wound healing by mediating inflammatory responses, ECM remodeling, and macrophage phenotype transitions. Its dysregulation, however, can impair healing, highlighting the need for targeted modulation of its activity. The aim of this study was to investigate the molecular interaction between Fe2+ and cathepsin D’s catalytic core and ionic zipper under physiological and acidic conditions to identify strategies to enhance tissue repair and accelerate the healing of chronic wounds. Methods: The molecular structure of active cathepsin D was obtained from the Protein Data Bank (PDB) and analyzed using UCSF Chimera. Molecular interactions between cathepsin D and ferrous ions (Fe2+) were studied, focusing on key residues (D33 and D231) and ionic zipper residues (E5, E180, and D187). Results: Our results showed that the active form of cathepsin D, a 96 kDa dimer, consisted of heterodimers with distinct amino acid chains, where residues D33 and D231 formed the active site, and E5, E180, and D187 constituted the ionic zipper. A functional pocket containing the conserved residues D33 and D231, essential for proteolytic activity, was identified. At physiological pH (~7.5), D33 exhibited the most potent interactions with Fe2+, with interaction energies of −7 × 1017 J at oxygen atoms of the carboxylate group (OD1) and α-carbon (CA) atoms, whereas D231 showed slightly lower energies of −6 × 1017 J at γ-carbon atom (CG) and CA atoms. At acidic pH (~4), E5 was the primary interacting residue, with the shortest distance to Fe2+ (2.69 Å), and showed stable interactions across several atoms, emphasizing its role in metal binding. Conclusions: pH conditions strongly influence the interaction of cathepsin D with Fe2. At physiological pH, residues D33 and D231 demonstrate robust and energetically efficient binding with Fe2+. At the same time, under acidic conditions, E5 emerges as the primary residue involved, potentially affecting the ionic zipper of cathepsin D. These insights provide a molecular foundation for targeting specific residues to modulate cathepsin D activity, presenting promising opportunities for therapeutic strategies aimed at improving chronic wound healing.