Unit for Multidisciplinary Research in Biomedicine

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Peritoneal protein loss, inflammation, and nutrition: refuting myths

Publication . Malho Guedes, A.; Calças Marques, Roberto; Ribeiro, Brigitte; Fernandes, Mónica T.; Faísca, Marília; Silva, Ana Paula; Bragança, José; Rodrigues, Anabela

Peritoneal protein loss (PPL) has been correlated with mortality, malnutrition and inflammation. More recently overhydration was brought to the equation. This study aims to review classic and recent factors associated with PPL. Prevalent and incident peritoneal dialysis (PD) patients were included. Dialysate and serum IL-6 was obtained during PET. Hydration and nutritional status were assessed by bio-impedance. Linear regression and Cox regression were performed. The 78 included patients presented median values of PPL 4.8 g/24 h, serum IL-6: 5.1 pg/mL, and IL-6 appearance rate 153.5 pg/min. Mean extracellular water excess (EWexc) was 0.88 ± 0.94 L, and lean body mass index (LBMI) 17.3 ± 2.4 kg/m2 . After mean follow-up of 33.9 ± 29.3 months, 12 patients died. Linear univariable analysis showed positive associations between PPL and small solute transport, body composition (LBMI and EWexc), comorbidities and performing CAPD (vs. cycler). PPL correlated positively with dialysate appearance rate of IL-6, but not with serum IL-6. Linear multivariable analysis confirmed positive association between PPL and EWexc (p = 0.012; 95%CI: 4.162–31.854), LBMI (p = 0.008; 95%CI: 1.720–11.219) and performing CAPD (p = 0.023; 95%CI: 4.375–54.190). In survival analysis, no relationship was found between mortality and PPL. Multivariable Cox regression showed Charlson Comorbidity Index (HR: 1.896, 95%CI: 1.235–2.913), overhydration (HR: 10.034, 95%CI: 1.426–70.587) and lower PPL (HR: 0.576, 95%CI: 0.339–0.978) were predictors for mortality. Overhydration, was a strong predictor of PPL, overpowering variables previously reported as determinants of PPL, namely clinical correlates of endothelial dysfunction or local inflammation. PPL were not associated with malnutrition or higher mortality, emphasizing the importance of volume overload control in PD patients.

2022Journal article

Open Access

Exercise training decreases the load and changes the content of circulating SDS-resistant protein aggregates in patients with heart failure with reduced ejection fraction

Publication . Gouveia, Marisol; Schmidt, Cristine; Basilio, Priscilla Gois; Aveiro, Susana; Domingues, Pedro; Xia, Ke; Colón, Wilfredo; Vitorino, Rui; Ferreira, Rita; Santos, Mário; Vieira, Sandra I.; Ribeiro, Fernando

BackgroundHeart failure (HF) often disrupts the protein quality control (PQC) system leading to protein aggregate accumulation. Evidence from tissue biopsies showed that exercise restores PQC system in HF; however, little is known about its effects on plasma proteostasis.AimTo determine the effects of exercise training on the load and composition of plasma SDS-resistant protein aggregates (SRA) in patients with HF with reduced ejection fraction (HFrEF).MethodsEighteen patients with HFrEF (age: 63.4 +/- 6.5 years; LVEF: 33.4 +/- 11.6%) participated in a 12-week combined (aerobic plus resistance) exercise program (60 min/session, twice per week). The load and content of circulating SRA were assessed using D2D SDS-PAGE and mass spectrometry. Cardiorespiratory fitness, quality of life, and circulating levels of high-sensitive C-reactive protein, N-terminal pro-B-type natriuretic peptide (NT-proBNP), haptoglobin and ficolin-3, were also evaluated at baseline and after the exercise program.ResultsThe exercise program decreased the plasma SRA load (% SRA/total protein: 38.0 +/- 8.9 to 36.1 +/- 9.7%, p = 0.018; % SRA/soluble fraction: 64.3 +/- 27.1 to 59.8 +/- 27.7%, p = 0.003). Plasma SRA of HFrEF patients comprised 31 proteins, with alpha-2-macroglobulin and haptoglobin as the most abundant ones. The exercise training significantly increased haptoglobin plasma levels (1.03 +/- 0.40 to 1.11 +/- 0.46, p = 0.031), while decreasing its abundance in SRA (1.83 +/- 0.54 x 1011 to 1.51 +/- 0.59 x 1011, p = 0.049). Cardiorespiratory fitness [16.4(5.9) to 19.0(5.2) ml/kg/min, p = 0.002], quality of life, and circulating NT-proBNP [720.0(850.0) to 587.0(847.3) pg/mL, p = 0.048] levels, also improved after the exercise program.ConclusionExercise training reduced the plasma SRA load and enhanced PQC, potentially via haptoglobin-mediated action, while improving cardiorespiratory fitness and quality of life of patients with HFrEF.

2023-10Journal article

Open Access

Characterization of plasma SDS-protein aggregation profile of patients with heart failure with preserved ejection fraction

Publication . Gouveia, Marisol; Schmidt, Cristine; Teixeira, Manuel; Lopes, Mário; Aveiro, Susana; Domingues, Pedro; Xia, Ke; Colón, Wilfredo; Vitorino, Rui; Ferreira, Rita; Santos, Mário; Vieira, Sandra; Ribeiro, Fernando

This study characterizes the plasma levels and composition of SDS-resistant aggregates (SRAs) in patients with heart failure with preserved ejection fraction (HFpEF) to infer molecular pathways associated with disease and/or proteostasis disruption. Twenty adults (ten with HFpEF and ten age-matched individuals) were included. Circulating SRAs were resolved by diagonal two-dimensional SDS-PAGE, and their protein content was identified by mass spectrometry. Protein carbonylation, ubiquitination and ficolin-3 were evaluated. Patients with HFpEF showed higher SRA/total (36.6 +/- 4.9% vs 29.6 +/- 2.2%, p = 0.009) and SRA/soluble levels (58.6 +/- 12.7% vs 40.6 +/- 5.8%, p = 0.008). SRAs were carbonylated and ubiquitinated, suggesting they are composed of dysfunctional proteins resistant to degradation. SRAs were enriched in proteins associated with cardiovascular function/disease and with proteostasis machinery. Total ficolin-3 levels were decreased (0.77 +/- 0.22, p = 0.041) in HFpEF, suggesting a reduced proteostasis capacity to clear circulating SRA. Thus, the higher accumulation of SRA in HFpEF may result from a failure or overload of the protein clearance machinery.

2022Journal article

Restricted

A systematic review of bleomycin-induced gonadotoxicity: Mechanistic implications for male reproductive health and fertility

Publication . Almeida, Ana Lobo de; Fortuna, Ana; Sousa, Mário; Sá, Rosália

Long-term cancer treatment complications in men include testicular dysfunction and infertility. Although various chemotherapies have been studied, there is limited evidence on their effects, especially for bleomycin. Despite its known lung toxicity, bleomycin's impact on male reproductive health is not well-researched. This systematic review aimed to evaluate bleomycin's effects on testicular function and fertility. A search of PubMed and Web of Science identified seven relevant animal studies on bleomycin's gonadotoxicity. The research, limited to animal models, shows that bleomycin significantly disrupts male reproductive health, including DNA damage in sperm, analogous to its effects on cancer cells, and notable histopathological changes in rodent testes. It reduces sperm quality and testosterone levels, correlating with Leydig cell degeneration and inflammatory responses, which further aligns with the drug's known capacity to induce lung inflammation. Due to the inherent limitations in extrapolating results from rodents to humans, further research, particularly in humans, is needed to confirm these findings, assess hormonal impacts, temporal patterns of effects (whether transient or permanent), and their impacts implications for offspring, as well explore potential mitigation strategies. These findings are a first step in raising awareness among clinicians about bleomycin's fertility risks and developing strategies for fertility preservation.

2024-12Journal article

Open Access