Articles publicats (IRBLleida)
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L'IRBLleida és un centre de recerca conjunt entre la Universitat i el Departament de Salut de la Generalitat de Catalunya. Té com a funció potenciar les sinergies de recerca biomèdica entre ambdós institucions i està compromès en avançar en la recerca biomèdica com a mitja per millorar la salut de la població i facilitar una activitat assistencial òptima en situacions de malaltia. [Més informació].
- ItemOpen AccessPlasma acylcarnitines and gut-derived aromatic amino acids as sex-specific hub metabolites of the human aging metabolome(Wiley, 2023) Sol, Joaquim; Obis Monné, Èlia; Mota Martorell, Natàlia; Pradas Barriga, Irene; Galo-Licona, José Daniel; Martín Garí, Meritxell; Fernández Bernal, Anna; Ortega Bravo, Marta; Mayneris Perxachs, Jordi; Borrás, Consuelo; Viña, José; Fuente, Monica de la; Mate, Ianire; Biarnés, Carles; Pedraza, Salvador; Vilanova, Joan Carles; Brugada, Ramon; Ramos, Rafel; Serena, Joaquín; Ramió Torrentà, Lluís; Pineda, Víctor; Daunis-i-Estadella, Pepus; Thió-Henestrosa, Santiago; Barretina Ginesta, Jordi; Garre Olmo, Josep; Portero Otín, Manuel; Fernández Real, José Manuel; Puig, Josep; Jové, Mariona; Pamplona Gras, ReinaldAging biology entails a cell/tissue deregulated metabolism that affects all levels of biological organization. Therefore, the application of “omic” techniques that are closer to phenotype, such as metabolomics, to the study of the aging process should be a turning point in the definition of cellular processes involved. The main objective of the present study was to describe the changes in plasma metabolome associated with biological aging and the role of sex in the metabolic regulation during aging. A high-throughput untargeted metabolomic analysis was applied in plasma samples to detect hub metabolites and biomarkers of aging incorporating a sex/gender perspective. A cohort of 1030 healthy human adults (45.9% females, and 54.1% males) from 50 to 98 years of age was used. Results were validated using two independent cohorts (1: n = 146, 53% females, 30–100 years old; 2: n = 68, 70% females, 19–107 years old). Metabolites related to lipid and aromatic amino acid (AAA) metabolisms arose as the main metabolic pathways affected by age, with a high influence of sex. Globally, we describe changes in bioenergetic pathways that point to a decrease in mitochondrial β-oxidation and an accumulation of unsaturated fatty acids and acylcarnitines that could be responsible for the increment of oxidative damage and inflammation characteristic of this physiological process. Furthermore, we describe for the first time the importance of gut-derived AAA catabolites in the aging process describing novel biomarkers that could contribute to better understand this physiological process but also age-related diseases.
- ItemOpen AccessGenetic Associations Between Modifiable Risk Factors and Alzheimer Disease(American Medical Association, 2023) Luo, Jiao; Qvist Thomassen, Jesper; Bellenguez, Céline; Grenier-Boley, Benjamin; De Rojas, Itziar; Castillo, Atahualpa; Parveen, Kayenat; Küçükali, Fahri; Nicolas, Aude; Peters, Oliver; Schneider, Anjal; Dichgans, Martin; Rujescu, Dan; Scherbaum, Norbert; Jürgen, Deckert; Riedel-Heller, Steffi; Hausner, Lucrezia; Molina Porcel, Laura; Düzel, Emrah; Grimmer, Timo; Wiltfang, Jens; Heilmann-Heimbach, Stefanie; Moebus, Susanne; Tegos, Thomas; Scarmeas, Nikolao; Clarimon, Jordi; Moreno, Fermin; Pérez-Tur, Jordi; Bullido, María J.; Pastor, Pau; Sánchez-Valle, Raquel; Álvarez, Victoria; Boada, Mercè; García-González, Pablo; Puerta, Raquel; Mir, Pablo; Real, Luis M.; Piñol-Ripoll, Gerard; García-Alberca, Jose María; Royo, Jose Luís; Rodriguez-Rodriguez, Eloy; Soininen, Hilkka; Kuulasmaa, Teemu; De Mendonça, Alexandre; Mehrabian, Shima; Hort, Jakub; Vyhnalek, Martin; Van Der Lee, Sven; Graff, Caroline; Papenberg, Goran; Giedraitis, Vilmantas; Boland, Anne; Bacq-Daian, Delphine; Deleuze, Jean-François; Nicolas, Gael; Dufouil, Carole; Pasquier, Florence; Hanon, Olivier; Debette, Stéphanie; Grünblatt, Edna; Popp, Julius; Benussi, Luisa; Galimberti, Daniela; Arosio, Beatrice; Mecocci, Patrizia; Solfrizzi, Vincenzo; Parnetti, Lucilla; Squassina, Alessio; Tremolizzo, Lucio; Borroni, Barbara; Nacmias, Benedetta; Sorbi, Sandro; Caffarra, Paolo; Seripa, Davide; Rainero, Innocenzo; Daniele, Antonio; Masullo, Carlo; Spalletta, Gianfranco; Williams, Julie; Amouyel, Philippe; Jessen, Frank; Kehoe, Patrick; Magda, Tsolaki; Rossi, Giacomina; Sánchez-Juan, Pascual; Sleegers, Kristel; Ingelsson, Martin; Andreassen, Ole A.; Hiltunen, Mikko; Van Duijn, Cornelia; Sims, Rebecca; Van Der Flier, Wiesje; Ruiz, Agustín; Ramirez, Alfredo; Lambert, Jean-Charles; Frikke-Schmidt, RuthImportance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, setting, and participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main outcomes and measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]). Conclusions and relevance: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.
- ItemOpen AccessSphingolipid desaturase DEGS1 is essential for mitochondria-associated membrane integrity(American Society for Clinical Investigation, 2023) Planas Serra, Laura; Launay, Nathalie; Goicoechea, Leire; Heron, Bénédicte; Jou, Cristina; Juliá Palacios, Natalia; Ruiz, Montserrat; Fourcade, Stéphane; Casasnovas, Carlos; de la Torre Gómez, Carolina; Gelot, Antoinette; Marsal, Maria; Loza-Alvarez, Pablo; García-Cazorla, Àngels; Fatemi, Ali; Ferrer, Isidre; Portero Otín, Manuel; Area-Gómez, Estela; Pujol, AuroraSphingolipids function as membrane constituents and signaling molecules, with crucial roles in human diseases, from neurodevelopmental disorders to cancer, best exemplified in the inborn errors of sphingolipid metabolism in lysosomes. The dihydroceramide desaturase Δ4-dihydroceramide desaturase 1 (DEGS1) acts in the last step of a sector of the sphingolipid pathway, de novo ceramide biosynthesis. Defects in DEGS1 cause the recently described hypomyelinating leukodystrophy-18 (HLD18) (OMIM #618404). Here, we reveal that DEGS1 is a mitochondria-associated endoplasmic reticulum membrane-resident (MAM-resident) enzyme, refining previous reports locating DEGS1 at the endoplasmic reticulum only. Using patient fibroblasts, multiomics, and enzymatic assays, we show that DEGS1 deficiency disrupts the main core functions of the MAM: (a) mitochondrial dynamics, with a hyperfused mitochondrial network associated with decreased activation of dynamin-related protein 1; (b) cholesterol metabolism, with impaired sterol O-acyltransferase activity and decreased cholesteryl esters; (c) phospholipid metabolism, with increased phosphatidic acid and phosphatidylserine and decreased phosphatidylethanolamine; and (d) biogenesis of lipid droplets, with increased size and numbers. Moreover, we detected increased mitochondrial superoxide species production in fibroblasts and mitochondrial respiration impairment in patient muscle biopsy tissues. Our findings shed light on the pathophysiology of HLD18 and broaden our understanding of the role of sphingolipid metabolism in MAM function.
- ItemOpen AccessAMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration(Nature Research, 2023) Crosas-Molist, Eva; Graziani, Vittoria; Maiques Carlos, Oscar; Pandya, Pahini; Monger, Joanne; Samain, Remi; George, Samantha L.; Malik, Saba; Salise, Jerrine; Morales, Valle; Le Guennec, Adrien; Atkinson, R. Andrew; Martí Laborda, Rosa Ma.; Matias-Guiu, Xavier; Charras, Guillaume; Conte, Maria R.; Elosegui-Artola, Alberto; Holt, Mark; Sanz Moreno, VictoriaCell migration is crucial for cancer dissemination. We find that AMP-activated protein kinase (AMPK) controls cell migration by acting as an adhesion sensing molecular hub. In 3-dimensional matrices, fast-migrating amoeboid cancer cells exert low adhesion/low traction linked to low ATP/AMP, leading to AMPK activation. In turn, AMPK plays a dual role controlling mitochondrial dynamics and cytoskeletal remodelling. High AMPK activity in low adhering migratory cells, induces mitochondrial fission, resulting in lower oxidative phosphorylation and lower mitochondrial ATP. Concurrently, AMPK inactivates Myosin Phosphatase, increasing Myosin II-dependent amoeboid migration. Reducing adhesion or mitochondrial fusion or activating AMPK induces efficient rounded-amoeboid migration. AMPK inhibition suppresses metastatic potential of amoeboid cancer cells in vivo, while a mitochondrial/AMPK-driven switch is observed in regions of human tumours where amoeboid cells are disseminating. We unveil how mitochondrial dynamics control cell migration and suggest that AMPK is a mechano-metabolic sensor linking energetics and the cytoskeleton.
- ItemOpen AccessPhysiotherapists' experiences on assisting physiotherapy users during the COVID-19 pandemic with lockdown measures in Spain.(Wiley, 2023-05-19) Fernández-Lago, Helena; Climent Sanz, Carolina; Bravo Navarro, Cristina; Bosch Barceló, Pere; Masbernat Almenara, Maria; Sanjuan Sánchez, Daniel; Briones Vozmediano, EricaBackground Physiotherapists had faced a new healthcare scenario characterised by the restrictions caused by the COVID-19 pandemic. Purpose To explore the impact of the COVID-19 pandemic on the physiotherapy profession from the perspective of physiotherapists working in the public and private sectors. Methods Qualitative study based on semi-structured personal interviews with 16 physiotherapists working in public, private, or public-private partnership sectors in Spain. The data were collected between March and June 2020. Inductive qualitative content analysis was performed. Results The participants (13 women, 3 men; aged 24–44 years) had professional experience in diverse healthcare settings (primary, hospital, home, consultations, insurance companies, associations). Five categories were identified: (1) the impact of lockdown on the health of physiotherapy users; (2) managing the demand for physiotherapy services during lockdown; (3) introducing protocols and protective measures in physiotherapy consultations; (4) changes in therapeutic approaches; and (5) future expectations in the physiotherapy care model. Physiotherapists perceived that lockdown caused a decline in the functionality of people with chronic conditions, together with a reduction in the physiotherapy services. Difficulties in prioritising users considered urgent became evident, and the inclusion of prophylactic measures affected treatment duration differently depending on the care setting and the pandemic prompted the use of telerehabilitation. Discussion The pandemic affected the functional status of chronic physiotherapy users and made treatment time, quality of care and triage protocols visible. In physiotherapy, technological barriers need to be solved, such as digital literacy, families without resources, situations of dependency and cultural barriers.