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Positive allosteric modulation of indoleamine 2,3-dioxygenase 1 restrains neuroinflammation
( 2020 ) Mondanelli, Giada; Coletti, Alice; Greco, Francesco Antonio; Pallotta, Maria Teresa; Orabona, Ciriana; Iacono, Alberta; Belladonna, Maria Laura; Albini, Elisa; Panfili, Eleonora; Fallarino, Francesca; Gargaro, Marco; Manni, Giorgia; Matino, Davide; Carvalho, Agostinho; Cunha, Cristina; Maciel, P.; Filippo, Massimiliano Di; Gaetani, Lorenzo; Bianchi, Roberta; Vacca, Carmine; Iamandii, Ioana Maria; Proietti, Elisa; Boscia, Francesca; Annunziato, Lucio; Peppelenbosch, Maikel; Puccetti, Paolo; Calabresi, Paolo; Macchiarulo, Antonio; Santambrogio, Laura; Volpi, Claudia; Grohmann, Ursula
L-tryptophan (Trp), an essential amino acid for mammals, is the precursor of a wide array of immunomodulatory metabolites produced by the kynurenine and serotonin pathways. The kynurenine pathway is a paramount source of several immunoregulatory metabolites, including L-kynurenine (Kyn), the main product of indoleamine 2,3-dioxygenase 1 (IDO1) that catalyzes the rate-limiting step of the pathway. In the serotonin pathway, the metabolite N-acetylserotonin (NAS) has been shown to possess antioxidant, antiinflammatory, and neuroprotective properties in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, little is known about the exact mode of action of the serotonin metabolite and the possible interplay between the 2 Trp metabolic pathways. Prompted by the discovery that NAS neuroprotective effects in EAE are abrogated in mice lacking IDO1 expression, we investigated the NAS mode of action in neuroinflammation. We found that NAS directly binds IDO1 and acts as a positive allosteric modulator (PAM) of the IDO1 enzyme in vitro and in vivo. As a result, increased Kyn will activate the ligand-activated transcription factor aryl hydrocarbon receptor and, consequently, antiinflammatory and immunoregulatory effects. Because NAS also increased IDO1 activity in peripheral blood mononuclear cells of a significant proportion of MS patients, our data may set the basis for the development of IDO1 PAMs as first-in-class drugs in autoimmune/neuroinflammatory diseases.
Self-efficacy and dropout rates among university engineering students: vocational training as an alternative to dropping out of education
( 2026 ) García-Gutiérrez, Vanesa; Bernardo, Ana B.; Diego-Rodriguez, Iván; Casanova, Joana R.
University dropout is a multicausal phenomenon influenced by many academic, personal and contextual factors that can, in turn, predict whether students remain in the higher education system. In this regard, self-efficacy is a key factor in academic success, associated with better academic performance and lower intention to drop out. However, leaving the university system does not necessarily mean dropping out of education altogether, as students may consider Vocational Training Programs (VTP) as an alternative for completing their education. This chapter will address the problem of university dropout considering levels of student self-efficacy and will present some findings from the Spanish National Project "Study of the risk and protection factors of university dropout. Creation of a guide to good practice" (PID2022-141290NB-I00). The research results indicate differences in levels of self-efficacy between students who express the intention to drop out of university and those who consider the option of studying Vocational Training. This demonstrates the importance of self-efficacy in the formation of the intention to drop out in new engineering students. Given the importance of self-efficacy in the academic context, some measures are presented for improving university guidance services and tutoring programs that strengthen self-efficacy as a strategy for improving students academic success and reducing the intention to drop out. Finally, the chapter highlights the need to prevent students from dropping out of higher education altogether by supporting their academic journey through other alternatives, such as Vocational Training courses.
Nisin Z and cinnamaldehyde co-delivery via fiber-reinforced alginate hydrogels: a synergistic in vitro strategy against infected pressure ulcers
( 2027 ) Fernandes, Joana; Gomes, Micaela; Bastos, Ana Rita C.; Pinho, Sonia L.; Felgueiras, Helena Prado
Infected pressure ulcers remain difficult to manage because conventional dressings cannot simultaneously provide mechanical robustness, sustained antimicrobial delivery, and a favorable healing environment. Here, sodium alginate (SA) hydrogels were engineered with a dual-reinforcement strategy, electrospun polycaprolactone (PCL) fibrous films versus their hydrolysis-derived fragments, to independently tune mechanical behavior while compartmentalizing two bioactive agents, Nisin Z (NZ) and cinnamaldehyde (CN), for combined antimicrobial and antioxidant function. This architecture-driven approach distinguishes the system from previous single- reinforcement or single-agent SA-based dressings. NZ was highly active against Gram-positive bacteria (S. aureus, S. epidermidis; MBC = 8 against Gram-negative strains (E. coli, 128 μ g/mL; P. aeruginosa, 32 μ μ g/mL) and less so g/mL), with CN requiring 20–320 g/mL. Combined, NZ and CN acted synergistically against S. aureus (FICI = 0.019). Film-reinforced hydrogels preserved compressive strength, while fragment-reinforced systems favored flexibility and recovery after 50% deformation, giving the platform tunable mechanics for different wound geometries. NZ and CN were released over 48 h through diffusion- and retention-dominated mechanisms, respectively, sustaining >90% bacterial reduction against Gram-positive strains, strong antibiofilm activity, and > 80% DPPH antioxidant scavenging, without compromising HaCaT keratinocyte viability (> 85%). μ By showing that reinforcement architecture and bioactive compartmentalization can be engineered jointly rather than independently, this work introduces a versatile SA-based platform for infected chronic wound management, with direct translational potential for pressure ulcer care.