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- Application of curcuminoids in inflammatory, neurodegenerative and aging conditions - Pharmacological potential and bioengineering approaches to improve efficiencyPublication . Lagoa, Ricardo; Rajan, Logesh; Violante, Cristiana; Babiaka, Smith B.; Marques da Silva, Dorinda; Kapoor, Bhupinder; Reis, Flávio; Atanasov, Atanas G.Curcumin, a natural compound found in turmeric, has shown promise in treating brain-related diseases and conditions associated with aging. Curcumin has shown multiple anti-inflammatory and brain-protective effects, but its clinical use is limited by challenges like poor absorption, specificity and delivery to the right tissues. A range of contemporary approaches at the intersection with bioengineering and systems biology are being explored to address these challenges. Data from preclinical and human studies highlight various neuroprotective actions of curcumin, including the inhibition of neuroinflammation, modulation of critical cellular signaling pathways, promotion of neurogenesis, and regulation of dopamine levels. However, curcumin’s multifaceted effects - such as its impact on microRNAs and senescence markers - suggest novel therapeutic targets in neurodegeneration. Tetrahydrocurcumin, a primary metabolite of curcumin, also shows potential due to its presence in circulation and its anti-inflammatory properties, although further research is needed to elucidate its neuroprotective mechanisms. Recent advancements in delivery systems, particularly brain-targeting nanocarriers like polymersomes, micelles, and liposomes, have shown promise in enhancing curcumin’s bioavailability and therapeutic efficacy in animal models. Furthermore, the exploration of drug-laden scaffolds and dermal delivery may extend the pharmacological applications of curcumin. Studies reviewed here indicate that engineered dermal formulations and devices could serve as viable alternatives for neuroprotective treatments and to manage skin or musculoskeletal inflammation. This work highlights the need for carefully designed, long-term studies to better understand how curcumin and its bioactive metabolites work, their safety, and their effectiveness.
- New Insights into Immunological Involvement in Congenital Disorders of Glycosylation (CDG) from a People-Centric ApproachPublication . Francisco, Rita; Pascoal, Carlota; Marques da Silva, Dorinda; Brasil, Sandra; Pimentel-Santos, Fernando M.; Altassan, Ruqaiah; Jaeken, Jaak; Grosso, Ana Rita; Ferreira, Vanessa dos Reis; Videira, Paula A.Congenital disorders of glycosylation (CDG) are rare diseases with variable phenotypes and severity. Immunological involvement remains a largely uncharted topic in CDG, mainly due to lack of robust data. To better characterize immune-related manifestations’ prevalence, relevance, and quality-of-life (QoL) impact, we developed electronic questionnaires targeting (1) CDG patients and (2) the general “healthy” population. Two-hundred and nine CDG patients/caregivers and 349 healthy participants were included in this study. PMM2-CDG was the most represented CDG (n = 122/209). About half of these participants (n = 65/122) described relevant infections with a noteworthy prevalence of those affecting the gastrointestinal tract (GI) (63.1%, n = 41/65). Infection burden and QoL impact were shown as infections correlated with more severe clinical phenotypes and with a set of relevant non-immune PMM2-CDG signs. Autoimmune diseases had only a marginal presence in PMM2-CDG (2.5%, n = 3/122), all being GI-related. Allergy prevalence was also low in PMM2-CDG (33%, n = 41/122) except for food allergies (26.8%, n = 11/41, of PMM2-CDG and 10.8%, n = 17/158, of controls). High vaccination compliance with greater perceived ineffectiveness (28.3%, n = 17/60) and more severe adverse reactions were described in PMM2-CDG. This people-centric approach not only confirmed literature findings, but created new insights into immunological involvement in CDG, namely by highlighting the possible link between the immune and GI systems in PMM2-CDG. Finally, our results emphasized the importance of patient/caregiver knowledge and raised several red flags about immunological management.
- Metal alginates for polyphenol delivery systems: Studies on crosslinking ions and easy-to-use patches for release of protective flavonoids in skinPublication . Silva, João; Vanat, Pavlo; Marques da Silva, Dorinda; Rodrigues, Joaquim Rui; Lagoa, RicardoIncorporation of bioactive natural compounds like polyphenols is an attractive approach for enhanced functionalities of biomaterials. In particular flavonoids have important pharmacological activities, and controlled release systems may be instrumental to realize the full potential of these phytochemicals. Alginate presents interesting attributes for dermal and other biomaterial applications, and studies were carried here to support the development of polyphenol-loaded alginate systems. Studies of capillary viscosity indicated that ionic medium is an effective strategy to modulate the polyelectrolyte effect and viscosity properties of alginates. On gelation, considerable differences were observed between alginate gels produced with Ca2+, Ba2+, Cu2+, Fe2+, Fe3+ and Zn2+ as crosslinkers, especially concerning shrinkage and morphological regularity. Stability assays with different polyphenols in the presence of alginate-gelling cations pointed to the choice of calcium, barium and zinc as safer crosslinkers. Alginate-based films loaded with epicatechin were prepared and the kinetics of release of the flavonoid investigated. The results with calcium, barium and zinc alginate matrices indicated that the release dynamics is dependent on film thicknesses, but also on the crosslinking metal used. On these grounds, an alginate-based system of convenient use was devised, so that flavonoids can be easily loaded at simple point-of-care conditions before dermal application. This epicatechin-loaded patch was tested on an ex-vivo skin model and demonstrated capacity to deliver therapeutically relevant concentrations on skin surface. Moreover, the flavonoid released was not modified and retained full antioxidant bioactivity. The alginate-based system proposed offers a multifunctional approach for flavonoid controllable delivery and protection of skin injured or under risk.
- Humic acid aggregates with laccase and decreases the performance of the enzyme catalytic systems through various mechanismsPublication . Lopes, João; Marques-da-Silva, Dorinda; Peralta, Cláudia; Rodrigues, Joaquim Rui; Vaz, Daniela; Lagoa, RicardoLaccases are among the best-rated enzymes for industrial and environmental applications, yet their use in bioremediation is limited by interference from environmental components like humic acid (HA). This study evaluated HA impact on the oxidation of 2,2 ′-azino-bis-(3-ethylbenzothiazoline-6-sulphonate (ABTS) and two model pollutants — anthracene and methyl orange — by laccase( mediator) systems. HA consistently diminished conversion rates, with EC50 values between 5 and 51 mg/L suggesting diverse inhibitory mechanisms. We investigated potential mechanisms including substrate sequestration, radical quenching, and chelation of laccase coppers by HA. Incubations with free and immobilized HA showed that adsorption can impede anthracene degradation, at least at high concentrations, but not methyl orange. Using chemically generated ABTS radical and azide-blocked enzyme, it was demonstrated that HA scavenges free radicals produced by laccase, though this alone did not fully explain the observed interference with catalysis. Further assays with metal chelator and added copper or calcium ruled out HA binding to the laccase metal centers. Instead, data from molecular docking, f luorescence, light scattering, and microscopy revealed that HA forms micrometer-scale aggregates with laccase that encapsulate the enzyme. This newly identified mechanism likely applies broadly to laccase-based systems and must be considered in applications involving aqueous media containing humic substances.
- Permeation studies of chlorpyrifos through skin and synthetic membranes to improve the in vitro dermal absorption assay of lipophilic compounds with ethanolic receptorsPublication . Marques da Silva, Dorinda; Franco, Margarida; Lagoa, Ricardo; Violante, CristianaThe in vitro percutaneous absorption assay is standardized, but the common use of 50 % ethanol in the receptor compartment for lipophilic compounds is questioned. In parallel, the demand for animal-free methodologies is driving the application of synthetic membranes without standardization guidelines. To address these issues, this study investigated the permeation of the lipophilic compound chlorpyrifos using different ethanol-containing receptor fluids with human and pig skin ex vivo, and silicone and STRAT-M® membranes. The results considered several factors, particularly chlorpyrifos solubility and the contact angles between skin models and receptor fluids. Original experimental approaches demonstrated that ethanol from the receptor rapidly crosses to the donor compartment increasing chlorpyrifos diffusivity. Compared to the described in vivo dermal absorption, human skin and STRAT-M® yielded the best predictive permeation parameters. However, high percentage of ethanol in the receptor fluid can lead to an overestimation of percutaneous absorption. Summing up, it is important to carefully determine the concentration of ethanol to be used in the receptor fluid of lipophilic compounds’ assays while further research with synthetic membranes is needed prior to their wider adoption.