Articles publicats (Medicina Experimental)

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    Open Access
    Sprouty1 is a broad mediator of cellular senescence
    (2024) Anerillas Aljama, Carlos; Perramon Güell, Aida; Altés Bargalló, Gisela; Cuesta, Sara; Vaquero, Marta; Olomí, Anna; Rodríguez Barrueco, Ruth; Llobet Navàs, David; Egea Navarro, Joaquim; Dolcet Roca, Xavier; Yeramian Hakim, Andree; Encinas Martín, Mario
    Genes of the Sprouty family (Spry1-4) restrain signaling by certain receptor tyrosine kinases. Consequently, these genes participate in several developmental processes and function as tumor suppressors in adult life. Despite these important roles, the biology of this family of genes still remains obscure. Here we show that Sprouty proteins are general mediators of cellular senescence. Induction of cellular senescence by several triggers in vitro correlates with upregulation of Sprouty protein levels. More importantly, overexpression of Sprouty genes is sufficient to cause premature cellular senescence, via a conserved N-terminal tyrosine (Tyrosine 53 of Sprouty1). Accordingly, fibroblasts from knockin animals lacking that tyrosine escape replicative senescence. In vivo, heterozygous knockin mice display delayed induction of cellular senescence during cutaneous wound healing and upon chemotherapy-induced cellular senescence. Unlike other functions of this family of genes, induction of cellular senescence appears to be independent of activation of the ERK1/2 pathway. Instead, we show that Sprouty proteins induce cellular senescence upstream of the p38 pathway in these in vitro and in vivo paradigms.
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    Open Access
    Mutual modulation of gut microbiota and the immune system in type 1 diabetes models
    (Nature Research, 2023) Rosell Mases, Estela; Santiago, Alba; Corral Pujol, Marta; Yáñez, Francisca; Varela, Encarna; Egia-Mendikute, Leire; Arpa i Puigdemont, Berta; Cosovanu, Catalina; Panosa, Anais; Serrano-Gómez, Gerard; Mora, Conchi; Verdaguer Autonell, Joan; Manichanh, Chaysavanh
    The transgenic 116C-NOD mouse strain exhibits a prevalent Th17 phenotype, and reduced type 1 diabetes (T1D) compared to non-obese diabetic (NOD) mice. A cohousing experiment between both models revealed lower T1D incidence in NOD mice cohoused with 116C-NOD, associated with gut microbiota changes, reduced intestinal permeability, shifts in T and B cell subsets, and a transition from Th1 to Th17 responses. Distinct gut bacterial signatures were linked to T1D in each group. Using a RAG-2-/- genetic background, we found that T cell alterations promoted segmented filamentous bacteria proliferation in young NOD and 116C-NOD, as well as in immunodeficient NOD.RAG-2-/- and 116C-NOD.RAG-2-/- mice across all ages. Bifidobacterium colonization depended on lymphocytes and thrived in a non-diabetogenic environment. Additionally, 116C-NOD B cells in 116C-NOD.RAG-2-/- mice enriched the gut microbiota in Adlercreutzia and reduced intestinal permeability. Collectively, these results indicate reciprocal modulation between gut microbiota and the immune system in rodent T1D models.
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    Open Access
    Role of Advanced Glycation End Products as New Biomarkers in Systemic Lupus Erythematosus
    (MDPI, 2024) Carrión-Barberà, Irene; Triginer, Laura; Tío, Laura; Pérez-García, Carolina; Ribes, Anna; Abad, Victoria; Pros, Ana; Bermúdez López, Marcelino; Castro-Boqué, Eva; Lecube Torelló, Albert; Valdivielso Revilla, José Manuel; Monfort, Jordi; Salman-Monte, Tarek Carlos
    Advanced glycation end-products (AGEs) may play a relevant role as inducers in the chronic inflammatory pathway present in immune-mediated diseases, such as systemic lupus erythematosus (SLE). AGEs concentrations have been associated, with discrepant results to date, with some parameters such as disease activity or accrual damage, suggesting their potential usefulness as biomarkers of the disease. Our objectives are to confirm differences in AGEs levels measured by cutaneous autofluorescence between SLE patients and healthy controls (HC) and to study their correlation with various disease parameters. Cross-sectional study, where AGEs levels were measured by skin autofluorescence, and SLE patients' data were compared with those of sex- and age-matched HC in a 1:3 proportion through a multiple linear regression model. Associations of AGEs levels with demographic and clinical data were analyzed through ANOVA tests. Both analyses were adjusted for confounders. AGEs levels in SLE patients were significantly higher than in HC (p < 0.001). We found statistically significant positive associations with SLE disease activity index (SLEDAI) and damage index (SDI), physician and patient global assessment, C-reactive protein, leukocyturia, complement C4, IL-6 and oral ulcers. We also found a negative statistically significant association with current positivity of anti-nuclear and anti-Ro60 antibodies. AGEs seem to have a contribution in LES pathophysiology, being associated with activity and damage and having a role as a new management and prognosis biomarker in this disease. The association with specific antibodies and disease manifestations may indicate a specific clinical phenotype related to higher or lower AGEs levels.
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    Open Access
    Gender-specific risk factors and outcomes of hyperkalemia in CKD patients: smoking as a driver of hyperkalemia in men
    (Oxford University Press, 2024) Valdivielso Revilla, José Manuel; Carriazo, Sol; Martin, Marisa; Fernández-Fernández, Beatriz; Bermúdez López, Marcelino; Ortiz, Alberto
    Background: Hyperkalemia is common among patients with chronic kidney disease (CKD) but there is scarce information on differential risk factors and outcomes for men and women. For instance, smoking has been suggested to be a risk factor for hyperkalemia, but specific analysis of the sex-specific impact of smoking on hyperkalemia in CKD is lacking. Methods: We studied serum potassium levels in 2891 participants from the NEFRONA cohort: 483 controls (47% women) and 2408 CKD patients (38% women) without prior cardiovascular disease (CVD), assessing whether smoking is a risk factor for hyperkalemia, and if hyperkalemia is associated with outcomes separately for men and women. Results: Median potassium levels and prevalence of hypo and hyperkalemia were higher in CKD participants than in controls. Serum potassium levels were higher and hyperkalemia and severe hyperkalemia more prevalent in men than in women with non-dialysis CKD (G3-G5). The highest prevalence of hyperkalemia for each gender was found in CKD G4-G5 and hemodialysis patients for men (46%) and in hemodialysis (54%) for women. Gender-specific etiological multivariate analysis identified current smoking as a risk factor for hyperkalemia only in men. Hyperkalemia was independently associated with stopping RAASi, an outcome which was more common in women. Hyperkalemia was also associated to higher risk of cardiovascular events within 4 years in men. In conclusion, hyperkalemia is common among men and women with CKD, but the prevalence, risk factors and outcomes may differ by gender. Specifically, current smoking is a driver of hyperkalemia in men.
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    Open Access
    Understanding the Episodic Memory and Executive Functioning Axis Impairment in MCI Patients: A Multicenter Study in Comparison with CSF Biomarkers
    (MDPI, 2023) Chino, Brenda; Torres-Simón, Lucía; Żelwetro, Agnieszka; Rodríguez-Rojo, Inmaculada Concepción; Carnes Vendrell, Anna; Piñol Ripoll, Gerard; Yubero, Raquel; Paúl, Nuria; Maestú, Fernando
    Background: This study aimed to explore the association between a verbal learning task that evaluates the potential mutual dependency between memory and executive functions (i.e., the Test of Memory Strategies, TMS) and cerebrospinal fluid (CSF) Alzheimer’s Disease (AD) biomarkers. Methods: A sample of 47 mild cognitive impairment (MCI) participants from Poland and Spain were classified according to the Erlangen Score Diagnostic Algorithm (ESA) into CSF- (n = 16) and CSF+ (n = 31) groups. Correlation analyses between TMS word-list conditions and CSF biomarkers were conducted. Additionally, an analysis of covariance was performed to define the effect on ESA classification in the sample, using as a covariable the country of origin of the participants. Results: Significant associations between the TMS-3 condition and Aβ42, t-tau, and p-tau were observed for the whole sample. In addition, the CSF- participants obtained higher cognitive performance in TMS-3 compared to the CSF+ group. This outcome persisted if the groups were based on Aβ42 scores, but not t-tau or p-tau values. Conclusions: These findings could indicate that poor performance on verbal learning tests may be affected by executive dysfunctions. Therefore, future intervention plans focused on training executive functions would be of interest to improve the ability of MCI patients to encode and organize information.