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Gla-Rich protein, magnesium and phosphate associate with mitral and aortic valves calcification in Didabetic patients with moderate CKD
Publication . Silva, Ana P.; Viegas, Carla; Guilherme, Patrícia; Tavares, Nelson; Dias, Carolina; Rato, Fátima; Santos, Nélio; Faísca, Marília; de Almeida, Edgar; Neves, Pedro L.; Simes, Dina C.
Accelerated and premature cardiovascular calcification is a hallmark of chronic kidney disease (CKD) patients. Valvular calcification (VC) is a critical indicator of cardiovascular disease and all-cause mortality in this population, lacking validated biomarkers for early diagnosis. Gla-rich protein (GRP) is a cardiovascular calcification inhibitor recently associated with vascular calcification, pulse pressure, mineral metabolism markers and kidney function. Here, we examined the association between GRP serum levels and mitral and aortic valves calcification in a cohort of 80 diabetic patients with CKD stages 2–4. Mitral and aortic valves calcification were detected in 36.2% and 34.4% of the patients and associated with lower GRP levels, even after adjustments for age and gender. In this pilot study, univariate, multivariate and Poisson regression analysis, show that low levels of GRP and magnesium (Mg), and high levels of phosphate (P) are associated with mitral and aortic valves calcification. Receiver operating characteristic (ROC) curves showed that the area under the curve (AUC) values of GRP for mitral (0.762) and aortic (0.802) valves calcification were higher than those of Mg and P. These results suggest that low levels of GRP and Mg, and high levels of P, are independent and cumulative risk factors for VC in this population; the GRP diagnostic value might be potentially useful in cardiovascular risk assessment.
Targeting a silent disease: vascular calcification in chronic Kidney disease
Publication . Marreiros, Catarina; Viegas, Carla; Simes, Dina
Chronic kidney disease (CKD) patients have a higher risk of developing early cardiovascular disease (CVD). Although vascular calcification (VC) is one of the strongest predictors of CVD risk, its diagnosis among the CKD population remains a serious clinical challenge. This is mainly due to the complexity of VC, which results from various interconnected pathological mechanisms occurring at early stages and at multiples sites, affecting the medial and intimal layers of the vascular tree. Here, we review the most used and recently developed imaging techniques, here referred to as imaging biomarkers, for VC detection and monitoring, while discussing their strengths and limitations considering the specificities of VC in a CKD context. Although imaging biomarkers have a crucial role in the diagnosis of VC, with important insights into CVD risk, circulating biomarkers represent an added value by reflecting the molecular dynamics and mechanisms involved in VC pathophysiological pathways, opening new avenues into the early detection and targeted interventions. We propose that a combined strategy using imaging and circulating biomarkers with a role in multiple VC molecular mechanisms, such as Fetuin-A, Matrix Gla protein, Gla-rich protein and calciprotein particles, should represent high prognostic value for management of CVD risk in the CKD population.
Nanoencapsulation of Gla-Rich Protein (GRP) as a novel approach to target inflammation
Publication . Viegas, Carla; Araújo, Nuna; Carreira, Joana; Pontes, Jorge Filipe; Macedo, Anjos L.; Vinhas, Maurícia; Moreira, Ana S.; Faria, Tiago Q.; Grenha, Ana; de Matos, António A.; Schurgers, Leon; Vermeer, Cees; Simes, Dina
Chronic inflammation is a major driver of chronic inflammatory diseases (CIDs), with a tremendous impact worldwide. Besides its function as a pathological calcification inhibitor, vitamin K-dependent protein Gla-rich protein (GRP) was shown to act as an anti-inflammatory agent independently of its gamma-carboxylation status. Although GRP’s therapeutic potential has been highlighted, its low solubility at physiological pH still constitutes a major challenge for its biomedical application. In this work, we produced fluorescein-labeled chitosan-tripolyphosphate nanoparticles containing non-carboxylated GRP (ucGRP) (FCNG) via ionotropic gelation, increasing its bioavailability, stability, and anti-inflammatory potential. The results indicate the nanosized nature of FCNG with PDI and a zeta potential suitable for biomedical applications. FCNG’s anti-inflammatory activity was studied in macrophage-differentiated THP1 cells, and in primary vascular smooth muscle cells and chondrocytes, inflamed with LPS, TNFα and IL-1β, respectively. In all these in vitro human cell systems, FCNG treatments resulted in increased intra and extracellular GRP levels, and decreased pro-inflammatory responses of target cells, by decreasing pro-inflammatory cytokines and inflammation mediators. These results suggest the retained anti-inflammatory bioactivity of ucGRP in FCNG, strengthening the potential use of ucGRP as an anti-inflammatory agent with a wide spectrum of application, and opening up perspectives for its therapeutic application in CIDs.
New food frequency questionnaire to estimate vitamin K intake in a Mediterranean population
Publication . Pinto, Ezequiel; Viegas, Carla; Martins, Paula Ventura; Nascimento, Tânia; Schurgers, Leon; Simes, Dina
Vitamin K is a multifunctional micronutrient essential for human health, and deficiency has been linked to multiple pathological conditions. In this study, we aimed to develop and validate a new food frequency questionnaire (FFQ) to estimate total vitamin K intake, over the course of a 30-day interval, in a Portuguese, Mediterranean-based, population. We conducted a prospective study in a non-random sample of 38 healthy adult volunteers. The FFQ was designed based on a validated Portuguese FFQ used in nationally representative studies and on literature reviews, to include foods containing ≥5 μg of vitamin K/100 g and foods with a lower vitamin K content, yet commonly included in a Mediterranean diet. Vitamin K intake was estimated from 24 h recalls and six days of food records. The final FFQ included 54 food items which, according to regression analyses, explains 90% of vitamin K intake. Mean differences in vitamin K intake based on food records (80 ± 47.7 μg/day) and on FFQ (96.5 ± 64.3 μg/day) were statistically non-significant. Further, we found a strong correlation between both methods (r = 0.7; p = 0.003). Our results suggest that our new FFQ is a valid instrument to assess the last 30 days of vitamin K intake in the Portuguese Mediterranean population.
Mediterranean Diet favors Vitamin K intake: A descriptive study in a Mediterranean population
Publication . Pinto, Ezequiel; Viegas, Carla; Ventura Martins, Paula; Marreiros, Catarina; Nascimento, Tânia; Schurgers, Leon; Simes, Dina
The Mediterranean diet (MD) is associated with improved longevity and the prevention
and management of chronic inflammatory diseases (CIDs). Vitamin K, which is present in MD core
components such as leafy green vegetables, is also known as a protective factor for CIDs. Estimates
of vitamin K intake in Mediterranean settings are still scarce, and the association between MD and
vitamin K intake is yet to be established. This study analyzed vitamin K intake and MD adherence
in the Algarve region, in Portugal. We conducted a cross-sectional study in a nonrandom sample
of adults using an online questionnaire which included a validated food-frequency questionnaire
and a screener for MD adherence. A total of 238 participants were recruited (68% women and
32% men). Adherence to the MD was low (11%). Only 10% of the participants had vitamin K
intake below the adequate intake. Adherence to the MD was positively correlated with vitamin K
intake (r = 0.463; p < 0.001) and age (r = 0.223; p < 0.001). Our findings underscore the importance
of promoting adherence to the MD for optimal vitamin K intake, and future research should focus
on developing effective interventions to promote this dietary pattern, particularly among younger
individuals and men.
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Funding agency
Fundação para a Ciência e a Tecnologia
Funding programme
3599-PPCDT
Funding Award Number
EXPL/BTM-TEC/0990/2021