Articles publicats en revistes (Bioquímica i Fisiologia)

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Inhibition of PCSK9 with polypurine reverse hoogsteen hairpins: A novel gene therapy approach
(Elsevier B.V., 2025-08-01) López-Aguilar, Ester; Pacheco-Velázquez, Silvia Cecilia; Busquets i Viñas, Ma. Antonia; Hay, J.oshua; Mueller, P.aul A.; Fazio, Sergio; Ciudad i Gómez, Carlos Julián; Noé Mata, Verónica; Pamir, Nathalie
PCSK9 is a therapeutic target for hypercholesterolemia. Though different strategies to inhibit PCSK9, such as monoclonal antibodies, small molecules, or nucleic acid drugs are available, the need for safer and inexpensive interventions remains. We developed a time-, cost-, and resource- efficient silencing system using Polypurine Reverse Hoogsteen (PPRH) hairpins to target PCSK9. To achieve PCSK9 silencing, we designed two PPRHs targeting PCSK9 at exon 9 (HpE9) and exon 12 (HpE12). The binding capabilities of PPRHs were measured by EMSA: Kd values were 7.86 x 10-8 M and 7.58 x 10-7 M for HpE9 and HpE12, respectively. PPRHs were complexed with the cationic polymer jetPEI forming particles of 167 nm as characterized by Dynamic Light Scattering. PCSK9 gene and protein expression was evaluated upon transfections of HepG2 cells with HpE9 and HpE12. PPRHs effectively reduced PCSK9 mRNA levels (63 % and 74 % for HpE9 and HpE12, respectively) and protein (by 76 % and 87 %) at 24 h. Human PCSK9 overexpressing mice receiving a single injection of HpE12 decreased plasma PCSK9 levels by 50 % by day three post injection and levels returned to baseline by day fifteen. Plasma cholesterol levels were reduced by 47 % by day three. Mice receiving the PPRHs did not exhibit changes in body weight, liver enzymes or pro-inflammatory markers when compared to mice injected with jetPEI alone. Therefore, the PPRH technology emerges as an innovative nucleic acid based therapeutic approach that is effective, cost-efficient and easy to develop, for the inhibition of PCSK9.
Liver X receptors and inflammatory-induced C/EBPβ selectively cooperate to control CD38 transcription
(Karger, 2024-12-19) Glaría Percaz, Estibaliz; Rodríguez Martínez, Pol; Font Díaz, Joan; Rosa, Juan Vladimir de la; Castrillo, Antonio; Crawshaw, Dylan J.; Vidal Taboada, José Manuel; Saura Martí, Josep; Matalonga, Jonathan; Nunes Chini, Eduardo; Caelles Franch, Carme; Valledor Fernández, Annabel
Introduction: Macrophages abundantly express liver X receptors (LXRs), which are ligand-dependent transcription factors and sensors of several cholesterol metabolites. In response to agonists, LXRs promote the expression of key lipid homeostasis regulators. Cross talk between LXRs and inflammatory signals exists in a cell type- and gene-specific manner. A common feature in the macrophage response to inflammatory mediators is the induction of CCAAT/enhancer-binding protein beta (C/EBPβ), a master transcriptional regulator and lineage-determining transcription factor in monocytes/macrophages. Methods: Quantitative real-time PCR in control and C/EBPβ-deficient macrophages was used to explore the role of C/EBPβ in the cross talk between inflammatory mediators and the macrophage response to pharmacological LXR activation. The functional interaction between C/EBPβ and LXRs on selected genomic regions was further characterized by chromatin-immunoprecipitation (ChIP) and gene reporter studies. Results: Whereas inflammatory signaling repressed several LXR-regulated genes involved in lipid metabolism, these effects were conserved after deletion of C/EBPβ. In contrast, inflammatory mediators and LXRs synergistically induced the expression of the multifunctional protein CD38 in a C/EBPβ-dependent manner. C/EBPβ and LXRs bound to several regions with enhancer activity upstream and within the mouse Cd38 gene and their functional cooperation in macrophages required intact binding sites for LXR and C/EBPβ. Conclusion: This study reveals positive cross talk between C/EBPβ and LXRs during the macrophage inflammatory response, which selectively impacts CD38 expression.
Identification of Neuritin 1 as a local metabolic regulator of brown adipose tissue
(Nature Publishing Group, 2025-09-04) Sánchez Feutrie, Manuela; Romero De Pablos, Montserrat; Veiga, Sonia Rosa Pereira da; Borràs Ferré, Núria; Berrow, Nick; Ràfols, Martina; Giménez, Noemí; Rodgers Furones, Andrea; Sabaté Pérez, Alba; Rodríguez Pérez, Ángela; Cataldo, Luis Rodrigo; Burghardt, Hans; Sebastián, David; Plana, Natàlia; Hernández, Vanessa; Alcaide, Laura Isabel; Reina, Óscar; Monte, M. Jesús; García Marin, José Juan; Palacín Prieto, Manuel; Burcelin, Remy; Antonson, Per; Gustafsson, Jan-Ake; Zorzano Olarte, Antonio
Brown adipose tissue (BAT) plays a key role in metabolic homeostasis through its thermogenic effects and the secretion of regulatory molecules. Here we report that RAP250 haploinsufficiency stimulates BAT in mice, thus contributing to a decrease in fat accumulation. Local in vivo AAV-mediated RAP250 silencing in BAT reduces body weight and fat mass and enhances glucose oxidation, thereby indicating that RAP250 participates in the regulation of BAT metabolic activity. Analysis of the mechanisms led to the finding that Neuritin 1 is produced and released by brown adipocytes, it plays a key metabolic role, and it participates in the enhanced BAT metabolic activity under RAP250 deficiency. Forced overexpression of Neuritin 1 in UCP1-expressing cells markedly decreases fat mass and body weight gain in mice and induces the expression of thermogenic genes in BAT. Neuritin 1-deficient brown adipocytes also shows a reduced β-adrenergic response. We demonstrate a metabolic role of BAT-derived Neuritin 1 acting through an autocrine/paracrine mechanism. Based on our results, Neuritin-1 emerges as a potential target for the treatment of metabolic disorders.
Ablation of LAT2 Transporter Causes Intramuscular Glutamine Accumulation and Inhibition of Fasting-Induced Proteolysis
(John Wiley & Sons, 2025-06-10) Espino-Guarch, Meritxell; Huang, Susie Shih Yin; Vilches, Clara; Prat, Esther; El Nahas, Rana; Missous, Ghalia; Bodoy i Salvans, Susanna; Sathappan, Abbirami; Al-Aghbar, Mohammad Ameen; Mayayo Vallverdú, Clara; Olivé, Montse; Busquets Rius, Sílvia; Sebastián Muñoz, David; Zorzano Olarte, Antonio; Palacín Prieto, Manuel; van Panhuys, Nicholas; Nunes Martínez, Virginia
Background: The neutral amino acid transporter SLC7A8 (LAT2) has been described as a key regulator of metabolic adaptation.LAT2 mutations in human populations have been linked to the early onset of age-related hearing loss and cataract growth. AsLAT2 was previously found to be highly expressed in skeletal muscle, here we characterised its role in the regulation of skeletalmuscle amino acid flux and metabolic adaptation to fasting.Methods: Wild-type (WT) and LAT2 knock-out (LAT2KO) mice were exposed to short- and long-periods of fasting (16 and48 h). The impact of the absence of LAT2 on amino acid content, gene expression, proteolysis activity, muscle tone, and histol-ogy was measured. To characterise the impact on muscle degradation, we tested LAT2 KO mice in cancer-associated cachexia,streptozocin-induced Type-1 diabetes, and ageing models.Results: LAT2KO mice experienced a notable reduction in body weight during fasting (WT:14% and LAT2KO:18%, p = 0.02), witha greater reduction in fat mass (0.5-fold, p = 0.013) and a higher relative retention of muscle mass (1.3-fold, p = 0.0003) comparedwith WT. The absence of LAT2 led to increased intramuscular glutamine (Gln) accumulation (6.3-fold, p < 0.0001), accompanied
Immunogenic Properties of a Novel Hepatitis A Vaccine Candidate Based on a Fast-Growing Viral Strain
(MDPI, 2025-04-23) Costafreda Salvany, M. Isabel (Maria Isabel); Massot Cladera, Malen; Chavarria Miró, Gemma; Arrebola, Alba; Franch i Masferrer, Àngels; Rodríguez Lagunas, María José; Martínez-Velázquez, Adán; Blanco Ortiz, Albert; Bosch, Albert; Guix Arnau, Susana; Castell, Margarida; Pintó Solé, Rosa María
Background/Objectives: Hepatitis A virus (HAV) yearly causes over 150 million new infections and around 40,000 deaths. Current vaccines are based on strains that grow poorly in cell culture, leading to high production costs and limited availability. This study aimed to compare the immunogenic properties of a novel HAV vaccine candidate based on the fast-growing HM175-HP strain with those of the parental slow-growing HM175-L0 strain, which derives from the cytopathic HM175 strain, like the prototype strain used in certain existing vaccines. Methods: The humoral and cellular immune response elicited by either HM175-HP or HM175-L0 vaccines was assessed in female BALB/c mice. Results: Both HM175-HP and HM175-L0 vaccines induced comparable levels of anti-HAV IgG, as well as similar numbers of antibody-secreting cells and cellular proliferation rates in immunized mice. Importantly, anti-HAV antibodies developed by HM175-HP-immunized mice were able to neutralize the HM175-L0 strain. In addition, both vaccines induced anti-HAV IgG1 antibodies, which are associated with Th2 immune response, but the HM175-HP vaccine showed a tendency to produce a greater IgG2a response, suggesting that it might elicit a higher Th1 response, which is of utmost importance for host defense against viruses. Conclusions: Our findings indicated that the fast-growing HM175-HP strain has similar immunogenic properties to the vaccine prototype-like HM175-L0, making it a promising candidate to reduce the elevated costs and time-consuming procedures of producing the current HAV vaccines. The novel HM175-HP-based vaccine would therefore facilitate mass vaccination programs and prevent vaccine shortages.
Targeting plasmid-encoded proteins that contain immunoglobulin-like domains to combat antimicrobial resistance
(eLife Sciences, 2024-07-24) Prieto Durán, Alejandro; Miró Martí, Ma. Lluïsa; Margolles, Yago; Bernabeu Lorenzo, Manuel; Salguero, David; Merino Montero, Susana; Tomàs Magaña, Juan; Corbera, Juan Alberto; Pérez Bosque, Anna; Hüttener Queiroz, Mário; Fernández, Luis Ángel; Juárez Giménez, Antonio
Antimicrobial resistance (AMR) poses a significant threat to human health. Although vaccines have been developed to combat AMR, it has proven challenging to associate specific vaccine antigens with AMR. Bacterial plasmids play a crucial role in the transmission of AMR. Our recent research has identified a group of bacterial plasmids (specifically, IncHI plasmids) that encode large molecular mass proteins containing bacterial immunoglobulin-like domains. These proteins are found on the external surface of the bacterial cells, such as in the flagella or conjugative pili. In this study, we show that these proteins are antigenic and can protect mice from infection caused by an AMR Salmonella strain harboring one of these plasmids. Furthermore, we successfully generated nanobodies targeting these proteins, that were shown to interfere with the conjugative transfer of IncHI plasmids. Considering that these proteins are also encoded in other groups of plasmids, such as IncA/C and IncP2, targeting them could be a valuable strategy in combating AMR infections caused by bacteria harboring different groups of AMR plasmids. Since the selected antigens are directly linked to AMR itself, the protective effect extends beyond specific microorganisms to include all those carrying the corresponding resistance plasmids.
Targeting plasmid-encoded proteins that contain immunoglobulin-like domains to combat antimicrobial resistance
(eLife Sciences, 2024-07-24) Prieto Durán, Alejandro; Miró Martí, Ma. Lluïsa; Margolles, Yago; Bernabeu Lorenzo, Manuel; Salguero, David; Merino Montero, Susana; Tomàs Magaña, Juan; Corbera, Juan Alberto; Pérez Bosque, Anna; Hüttener Queiroz, Mário; Fernández, Luis Ángel; Juárez Giménez, Antonio
Antimicrobial resistance (AMR) poses a significant threat to human health. Although vaccines have been developed to combat AMR, it has proven challenging to associate specific vaccine antigens with AMR. Bacterial plasmids play a crucial role in the transmission of AMR. Our recent research has identified a group of bacterial plasmids (specifically, IncHI plasmids) that encode large molecular mass proteins containing bacterial immunoglobulin-like domains. These proteins are found on the external surface of the bacterial cells, such as in the flagella or conjugative pili. In this study, we show that these proteins are antigenic and can protect mice from infection caused by an AMR Salmonella strain harboring one of these plasmids. Furthermore, we successfully generated nanobodies targeting these proteins, that were shown to interfere with the conjugative transfer of IncHI plasmids. Considering that these proteins are also encoded in other groups of plasmids, such as IncA/C and IncP2, targeting them could be a valuable strategy in combating AMR infections caused by bacteria harboring different groups of AMR plasmids. Since the selected antigens are directly linked to AMR itself, the protective effect extends beyond specific microorganisms to include all those carrying the corresponding resistance plasmids.
Assessment of Flurbiprofen Suspension and Composite GelPre- and Post Skin Perforation: Effectiveness in ManagingInflammatory Responses in Ear Tags and Periocular Piercings.
(2025-04-15) El Bejjaji, Sheimah; Ramos Yacasi, Gladys Rosario; Domínguez Villegas, Valeri; Chaves Moreira Dos Santos, Délia; Braza Reyes, Antonio J.; Sosa Díaz, Lilian Elisa; Rodríguez Lagunas, María José; Calpena Campmany, Ana Cristina; Zelaya, Mireia; Parra Coca, Alexander
Background: Controlled skin perforations, such as ear tags, piercings, and microdermal implants, induce inflammation and stress in individuals undergoing these procedures. This localized trauma requires care to optimize healing, reduce inflammation, and prevent infections. (2) Methods: Two formulations were developed: an FB-suspension and an FB-gel. Their in vivo efficacy was evaluated, along with drug retention in porcine and human skin after 30 min of administration, chemical stability at different temperatures, cytotoxicity, histological changes induced via transdermal application, and irritative potential, assessed using the HET-CAM assay. (3) Results: Both formulations reduced inflammation when applied 30 min before perforation compared to the positive control. The FB-suspension demonstrated no cytotoxicity and exhibited greater efficacy than the free flurbiprofen solution, highlighting the advantages of using nanoparticle-mediated drug delivery. Moreover, the FB-gel maintained chemical stability for up to 3 months across a temperature range of 4 to 40 °C. Histologically, no significant changes in skin composition were observed. (4) Conclusions: The FB-suspension is viable for both pre- and post-perforation application, as it is a sterile formulation. In contrast, the FB-gel is a convenient and easy application, making it a practical alternative for use in both clinical and veterinary settings. Keywords: flurbiprofen; suspension; hydrogel; polyethylene glycol 3350; human skin; porcine skin; NSAID; transdermal drug delivery; controlled skin perforation; inflammation management
Pemafibrate abrogates SLD in a rat experimental dietary model inducing a shift in fecal bile acids and microbiota composition
(Elsevier Masson SAS, 2024-06-29) Bentanachs Raset, Roger; Miró Martí, Ma. Lluïsa; Sánchez Peñarroya, Rosa M.; Ramírez-Carrasco, Patricia; Amat, Concepció; Alegret i Jordà, Marta; Pérez, Anna; Roglans i Ribas, Núria; Laguna Egea, Juan Carlos
Background and aims: Drugs resolving steatotic liver disease (SLD) could prevent the evolution of metabolic dysfunction associated SLD (MASLD) to more aggressive forms but must show not only efficacy, but also a high safety profile. Repurposing of drugs in clinical use, such as pemafibrate and mirabegron, could facilitate the finding of an effective and safe drug-treatment for SLD. Approach and results: The SLD High Fat High Fructose (HFHFr) rat model develops steatosis without the influence of other metabolic disturbances, such as obesity, inflammation, or type 2 diabetes. Further, liver fatty acids are provided, as in human pathology, both from dietary origin and de novo lipid synthesis. We used the HFHFr model to evaluate the efficacy of pemafibrate and mirabegron, alone or in combination, in the resolution of SLD, analyzing zoometric, biochemical, histological, transcriptomic, fecal metabolomic and microbiome data. We provide evidence showing that pemafibrate, but not mirabegron, completely reverted liver steatosis, due to a direct effect on liver PPARα-driven fatty acid catabolism, without changes in total energy consumption, subcutaneous, perigonadal and brown fat, blood lipids and body weight. Moreover, pemafibrate treatment showed a neutral effect on whole-body glucose metabolism, but deeply modified fecal bile acid composition and microbiota. Conclusions: Pemafibrate administration reverts liver steatosis in the HFHFr dietary rat SLD model without altering parameters related to metabolic or organ toxicity. Our results strongly support further clinical research to reposition pemafibrate for the treatment of SLD/MASLD. Keywords: ANGPTL3; MASLD; Mirabegron; PNPLA3; SPPARMα.
Insight into the Antioxidant Activity of Ascorbic Acid-Containing Gelatin Nanoparticles in Simulated Chronic Wound Conditions
(MDPI, 2024-02-28) Morán Badenas, María del Carmen; Porredon, Cristina; Gibert, Coloma
Chronic wounds differ from acute wounds by remaining in the inflammatory phase for a long time. This chronic inflammation confers a high concentration of inflammatory cytokines, proteases, and ROS. Likewise, the pH environment of chronic wounds has been recorded within the range of 7.2-8.9 due to the alkaline by-products of bacterial proliferation. In this work, differences in pH between healthy skin and chronic cutaneous wounds have been used for the design and development of pH-responsive gelatin-based nanoparticles (NPs). Ascorbic acid (AA), as an antioxidant compound that can neutralize reactive oxygen species (ROS), has been the therapeutic model compound included in these NPs. The goal of the present work has been the preparation and characterization (physicochemical and biological properties) of NPs for the effective release of AA under simulated chronic wound conditions. In vitro experiments demonstrated total AA release at pH corresponding to the chronic wounds. The biocompatible character of these gelatin-based NPs based on their hemolytic and cytotoxicity responses has been highlighted under in vitro conditions. The reversible and protective antioxidant properties of the AA-including NPs in erythrocytes and skin cell lines, respectively, have been confirmed to be modulated by the gelatin A gel strength. Keywords: antioxidant; ascorbic acid; chronic wound; gelatin; hydrogen peroxide; pH.
Polypurine reverse hoogsteen hairpins as a therapeutic tool for SARS-CoV-2 infection
(Elsevier, 2024-10-11) Chillón, Miguel; Ciudad i Gómez, Carlos Julián; Valiuska, Simonas; Rojas, Manuel (Rojas Castellanos); Nogales-Altozano, Pablo; Aviñó Andrés, Anna; Eritja i Casadellà, Ramon; Sevilla, Noemí; Noé Mata, Verónica
Although the COVID-19 pandemic was declared no longer a global emergency by the World Health Organization in May 2023, SARS-CoV-2 is still infecting people across the world. Many therapeutic oligonucleotides such as ASOs, siRNAs, or CRISPR-based systems emerged as promising antiviral strategies for the treatment of SARS-CoV-2. In this work, we explored the inhibitory potential on SARS-CoV-2 replication of Polypurine Reverse Hoogsteen Hairpins (PPRHs), CC1-PPRH, and CC3-PPRH, targeting specific polypyrimidine sequences within the replicase and Spike regions, respectively, and previously validated for COVID-19 diagnosis. Both PPRHs are bound to their target sequences in the viral genome with high affinity in the order of nM. In vitro, both PPRHs reduced viral replication by more than 92% when transfected into VERO-E6 cells 24 h prior to infection with SARS-CoV-2. In vivo intranasal administration of CC1-PPRH in K18-hACE2 mice expressing the human ACE receptor protected all the animals from SARS-CoV-2 infection. The properties of PPRHs position them as promising candidates for the development of novel therapeutics against SARS-CoV-2 and other viral infections.
Characteristics of Non-Therapeutic Pregabalin Users Detected by a Community Pharmacies Network in a Region of Southern Europe
(MDPI, 2024-10-01) Perelló, Maria; Rio-Aige, Karla; Rius, Pilar; Pérez-Cano, Francisco J.; Rabanal i Tornero, Manel
Background: Since 2008, several cases of pregabalin abuse have been reported to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Despite this evidence, gabapentinoids are increasingly being prescribed. Moreover, pregabalin is being used in a recreational setting for its dissociative effects and euphoria. Objectives: To assess the characteristics of non-therapeutic users of pregabalin and to show behavioral trends associated with requests for the medicine at community pharmacies. Methods: The Medicine Abuse Observatory (MAO), an epidemiological surveillance system, was able to analyze trends about the most diverted drugs and the behavioral patterns of the population from community pharmacies. We have conducted an observational and cross-sectional study from January 2022 to April 2023, to determinate trends in the behavior of patients who have requested pregabalin in the Catalan Sephanet. Results: Behavior with respect to sex was similar in all health problems, although one difference was raised when considering neuropathic pain, in which the females were more involved (72.7%), especially around 2.5 times more than the males (27.3%, p < 0.05). The study showed a potential recreational use related to patients aged <25 years and patients aged 25–35 years (p < 0.05). Neuropathic pain was mainly identified in patients >65 years. In 75% of the cases, there was a preceding prescription. Conclusions: This study underlines the evidence of non-therapeutic use of pregabalin among the Catalan population and the need to take control measures. Actions should be promoted, both at the level of prescription and dispensing, and focusing on education and knowledge about the risks that may appear with the use of pregabalin. Keywords: pregabalin; prescription drug abuse; misuse; community pharmacy; neuropathic pain
Interleukin-16 is increased in obesity and alters adipogenesis and inflammation in vitro
(Frontiers Media, 2024) Reyes, Majorie; Fernández-García, Pablo; Corrales, Patricia; González, Lorena; Soria-Gondek, Andrea; Martínez, Esther; Pellitero, Silvia; Tarascó, Jordi; Moreno, Pau; Sumoy, Laura; Medina-Gómez, Gema; Sánchez-Infantes, David; Herrero Rodríguez, Laura
Introduction: Obesity is a chronic condition associated with low-grade
inflammation mainly due to immune cell infiltration of white adipose tissue
(WAT). WAT is distributed into two main depots: subcutaneous WAT (sWAT)
and visceral WAT (vWAT), each with different biochemical features and metabolic
roles. Proinflammatory cytokines including interleukin (IL)-16 are secreted by
both adipocytes and infiltrated immune cells to upregulate inflammation. IL-16
has been widely studied in the peripheral proinflammatory immune response;
however, little is known about its role in adipocytes in the context of obesity.
Aim & Methods: We aimed to study the levels of IL-16 in WAT derived from sWAT
and vWAT depots of humans with obesity and the role of this cytokine in
palmitate-exposed 3T3-L1 adipocytes.
Results: The results demonstrated that IL-16 expression was higher in vWAT
compared with sWAT in individuals with obesity. In addition, IL-16 serum levels
were higher in patients with obesity compared with normal-weight individuals,
increased at 6 months after bariatric surgery, and at 12 months after surgery
decreased to levels similar to before the intervention. Our in vitro models showed
that IL-16 could modulate markers of adipogenesis (Pref1), lipid metabolism
(Plin1, Cd36, and Glut4), fibrosis (Hif1a, Col4a, Col6a, and Vegf), and inflammatory
signaling (IL6) during adipogenesis and in mature adipocytes. In addition, lipid
accumulation and glycerol release assays suggested lipolysis alteration.
Discussion: Our results suggest a potential role of IL-16 in adipogenesis, lipid and
glucose homeostasis, fibrosis, and inflammation in an obesity context.
Impact of maternal Bifidobacterium breve M-16V and scGOS/lcFOS supplementation during pregnancy and lactation on the maternal immune system and milk composition
(Frontiers Media, 2024-12-01) Sáez Fuertes, Laura; Kapravelou, Garyfallia; Grases Pintó, Blanca; Massot Cladera, Malen; Bernabeu Lorenzo, Manuel; Knipping, K.; Garssen, J.; Bourdet-Sicard, Raphaëlle; Castell, Margarida; Rodríguez Lagunas, María José; Collado, Maria Carmen; Pérez-Cano, Francisco J.
Maternal synbiotic supplementation during pregnancy and lactation can significantly influence the immune system. Prebiotics and probiotics have a positive impact on the immune system by preventing or ameliorating among others intestinal disorders. This study focused on the immunomodulatory effects of B. breve M-16V and short chain galacto-oligosaccharides (scGOS)/long chain fructo-oligosachairdes (lcFOS), including systemic and mucosal compartments and milk composition. Methods: Lewis rats were orally administered with the synbiotic or vehicle during pregnancy (21 days) and lactation (21 days). At the weaning day, small intestine (SI), mammary gland (MG), adipose tissue, milk, mesenteric lymph nodes (MLN), salivary gland (SG), feces and cecal content were collected from the mothers. Results: The immunoglobulinome profile showed increased IgG2c in plasma and milk, as well as elevated sIgA in feces at weaning. The supplementation improved lipid metabolism through enhanced brown adipose tissue activity and reinforced the intestinal barrier by increasing the expression of Muc3, Cldn4, and Ocln. The higher production of short chain fatty acids in the cecum and increased Bifidobacterium counts suggest a potential positive impact on the gastrointestinal tract. Discussion: These findings indicate that maternal synbiotic supplementation during gestation and lactation improves their immunological status and improved milk composition. Keywords: Bifidobacterium breve M-16V; breastfeeding; long chain fructo-oligosachairdes (lcFOS); pregnancy; short chain galacto-oligosaccharides (scGOS).
Association of circulating biomarkers with illness severity measures differentiates myalgic encephalomyelitis/chronic fatigue syndrome and post-COVID-19 condition: a prospective pilot cohort study
(BioMed Central, 2024) Domingo i Pedrol, Joan Carles; Battistini, Federica; Cordobilla, Begoña; Zaragoza, Maria; Sanmartín-Sentañes, Ramon; Alegre-Martín, José; Cambras Riu, Trinitat; Castro-Marrero, Jesús
Background: Accumulating evidence suggests that autonomic dysfunction and persistent systemic inflammation are common clinical features in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID. However, there is limited knowledge regarding their potential association with circulating biomarkers and illness severity in these conditions. Methods: This single-site, prospective, cross-sectional, pilot cohort study aimed to distinguish between the two patient populations by using self-reported outcome measures and circulating biomarkers of endothelial function and systemic inflammation status. Thirty-one individuals with ME/CFS, 23 individuals with long COVID, and 31 matched sedentary healthy controls were included. All study participants underwent non-invasive cardiovascular hemodynamic challenge testing (10 min NASA lean test) for assessment of orthostatic intolerance. Regression analysis was used to examine associations between outcome measures and circulating biomarkers in the study participants. Classification across groups was based on principal component and discriminant analyses. Results: Four ME/CFS patients (13%), 1 with long COVID (4%), and 1 healthy control (3%) presented postural orthostatic tachycardia syndrome (POTS) using the 10-min NASA lean test. Compared with matched healthy controls, ME/CFS and long COVID subjects showed higher levels of ET-1 (p < 0.05) and VCAM-1 (p < 0.001), and lower levels of nitrites (NOx assessed as NO2- + NO3-) (p < 0.01). ME/CFS patients also showed higher levels of serpin E1 (PAI-1) and E-selectin than did both long COVID and matched control subjects (p < 0.01 in all cases). Long COVID patients had lower TSP-1 levels than did ME/CFS patients and matched sedentary healthy controls (p < 0.001). As for inflammation biomarkers, both long COVID and ME/CFS subjects had higher levels of TNF-α than did matched healthy controls (p < 0.01 in both comparisons). Compared with controls, ME/CFS patients had higher levels of IL-1β (p < 0.001), IL-4 (p < 0.001), IL-6 (p < 0.01), IL-10 (p < 0.001), IP-10 (p < 0.05), and leptin (p < 0.001). Principal component analysis supported differentiation between groups based on self-reported outcome measures and biomarkers of endothelial function and inflammatory status in the study population. Conclusions: Our findings revealed that combining biomarkers of endothelial dysfunction and inflammation with outcome measures differentiate ME/CFS and Long COVID using robust discriminant analysis of principal components. Further research is needed to provide a more comprehensive characterization of these underlying pathomechanisms, which could be promising targets for therapeutic and preventive strategies in these conditions. Keywords: Biomarkers; Chronic fatigue syndrome; Endothelial dysfunction; Inflammation; Long COVID; Myalgic encephalomyelitis; Post-acute sequelae of COVID-19; Post-exertional malaise.
Mechanical power is not associated with mortality in COVID-19 mechanically ventilated patients
(SpringerOpen, 2025-02-25) Barbeta, Enric; Barreiros, Claudia; Forin, Edoardo; Guzzardella, Amedeo; Motos, Ana; Fernández Barat, Laia; Gabarrús, Albert; Ceccato, Adrian; Ferrer i Roig, Ruth; Riera, Jordi; Peñuelas, Oscar; Lorente, José Angel; Gonzalo-Calvo, David de; González, Jessica; Amaya Villar, Rosario; Añón, José M.; Balan, Ana; Barberà, Carme; Barberán, José; Blandino Ortiz, Aaron; Boado Varela, Maria Victoria; Bustamante Munguira, Elena; Caballero, Jesús; Canton-Bulnes, María L.; Carbajales Pérez, Cristina; Carbonell, Nieves; Catalán González, Mercedes; Franco, Nieves; Galbán, Cristóbal; Gumucio Sanguino, Víctor D.; De La Torre, Maria Del Carmen; Diaz, Emili; Estella, Ángel; Gallego, Elena; Gomez, José Manuel; Huerta, Arturo; Jorge García, Ruth Noemí; Loza Vázquez, Ana; Marin Corral, Judith; Martín Delgado, María Cruz; Martínez, Amalia; Martínez, Ignacio; López, Juan; Albaiceta, Guillermo M.; Nieto, María Teresa; Novo, Mariana Andrea; Peñasco, Yhivian; Pérez-García, Felipe; Ricart, Pilar; Rodríguez, Alejandro; Sagredo, Víctor; Sánchez Miralles, Ángel; Sancho, Susana; Roche Campo, Ferran; Socias, Lorenzo; Solé Violán, Jordi; Tamayo Lomas, Luis; Trenado, Josep; Úbeda, Alejandro; Valdivia, Luis Jorge; Vidal, Pablo; Barbe, Ferran; Vallverdú, Jordi; Torres Martí, Antoni
Background: The relative contribution of the different components of mechanical power to mortality is a subject of debate and has not been studied in COVID-19. The aim of this study is to evaluate both the total and the relative impact of each of the components of mechanical power on mortality in a well-characterized cohort of patients with COVID-19-induced acute respiratory failure undergoing invasive mechanical ventilation. This is a secondary analysis of the CIBERESUCICOVID project, a multicenter observational cohort study including fifty Spanish intensive care units that included COVID-19 mechanically ventilated patients between February 2020 and December 2021. We examined the association between mechanical power and its components (elastic static, elastic dynamic, total elastic and resistive power) with 90-day mortality after adjusting for confounders in seven hundred ninety-nine patients with COVID-19-induced respiratory failure undergoing invasive mechanical ventilation. Results: At the initiation of mechanical ventilation, the PaO2/FiO2 ratio was 106 (78; 150), ventilatory ratio was 1.69 (1.40; 2.05), and respiratory system compliance was 35.7 (29.2; 44.5) ml/cmH2O. Mechanical power at the initiation of mechanical ventilation was 24.3 (18.9; 29.6) J/min, showing no significant changes after three days. In multivariable regression analyses, mechanical power and its components were not associated with 90-day mortality at the start of mechanical ventilation. After three days, total elastic and elastic static power were associated with higher 90-day mortality, but this relationship was also found for positive end-expiratory pressure. Conclusions: Neither mechanical power nor its components were independently associated with mortality in COVID-19-induced acute respiratory failure at the start of MV. Nevertheless, after three days, static elastic power and total elastic power were associated with lower odds of survival. Positive end-expiratory pressure and plateau pressure, however, captured this risk in a similar manner. Keywords: COVID-19; Mechanical power; Mechanical ventilation; Respiratory failure.
Developing a global education hub for animal-free innovation
(Springer Verlag, 2025-12-01) Janssens, Monique R. E.; Salvatori, Daniela; Hogervorst, Janneke; Nonis, Cristheena; Bailey, Jarrod; Bajramovic, Jeffrey; Burgers, Anne; Caloni, Francesca; van Deel, Elza D.; van den Eijnden-van Raaij, Janny; Amirabadi, Hossein E.; Filipova, Dilyana; Gastaldello, Annalisa; Gibbs, Susan; Goversen, Birgit; Green, Nicole; van Hengel, Jolanda; Kienhuis, Anne; van de Kolk, Sjoukje; Paggi, Carlo A.; Penning, Louis C.; Pistollato, Francesca; Riegger, Silke; Ritskes-Hoitinga, Merel; Vinardell Martínez-Hidalgo, Ma. Pilar
In recent decades, the life sciences have witnessed remarkable advancements, leading to breakthroughs in medicine, agriculture, and environmental science. Although experiments on animals have been used on the way to making these advancements, the scientific community and society are increasingly questioning the scientific validity and ethics of using animals in research, testing, teaching, and training. Systematic reviews have shown that the translatability of results from animal studies to humans is often poor (Leenaars et al., 2019), and the use of animals in experiments is often termed “a black box” because the mechanisms at work are unclear. In addition, experiments using genetically homog-enous strains of animals do not reflect the interindividual differ-ences among patients. Diseases are often induced in experimental animals in an artificial way, for example by genetic modification or chemical insult, which means that the human etiology of the diseases is not accurately represented, hindering opportunities to identify avenues for prevention and treatment.
The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ cross-talk
(Nature Publishing Group, 2024) Valdecantos, M. Pilar; Ruiz, Laura; Folgueira, Cintia; Rada, Patricia; Gómez-Santos, Beatriz; Solas, Maite; Hitos, Ana B.; Field, Joss; Francisco, Vera; Escalona-Garrido, Carmen; Zagmutt Caroxa, Sebastián; Calderón Domínguez, María; Mera Nanín, Paula; García Martínez, Irma; Maymó Masip, Elsa; Grajales, Diana; Alen, Rosa; Mora, Alfonso; Sainz, Neira; Vides-Urrestarazu, Irene; Vilarrasa, Nuria; Arbones-Mainar, Jose M.; Zaragoza, Carlos; Moreno-Aliaga, María J.; Aspichueta, Patricia; Fernández Veledo, Sonia; Vendrell, Joan; Serra i Cucurull, Dolors; Herrero Rodríguez, Laura; Schreiber, Renate; Zechner, Rudolf; Sabio, Guadalupe; Hornigold, David; Rondinone, Cristina M.; Jermutus, Lutz; Grimsby, Joseph; Valverde, Ángela M.
Bariatric surgery is effective for the treatment and remission of obesity and type 2 diabetes, but pharmacological approaches which exert similar metabolic adaptations are needed to avoid post-surgical complications. Here we show how G49, an oxyntomodulin (OXM) analog and dual glucagon/glucagon-like peptide-1 receptor (GCGR/GLP-1R) agonist, triggers an inter-organ crosstalk between adipose tissue, pancreas, and liver which is initiated by a rapid release of free fatty acids (FFAs) by white adipose tissue (WAT) in a GCGR-dependent manner. This interactome leads to elevations in adiponectin and fibroblast growth factor 21 (FGF21), causing WAT beiging, brown adipose tissue (BAT) activation, increased energy expenditure (EE) and weight loss. Elevation of OXM, under basal and postprandial conditions, and similar metabolic adaptations after G49 treatment were found in plasma from patients with obesity early after metabolic bariatric surgery. These results identify G49 as a potential pharmacological alternative sharing with bariatric surgery hormonal and metabolic pathways.
Defective Slc7a7 transport reduces erythropoietin compromising erythropoiesis
(BioMed Central, 2025-01-29) Giroud-Gernetant Deus, Judith; Sotillo, Fernando; Hernández, Gonzalo; Ruano, Irene; Sebastián, David; Fort, Joana; Sánchez, Mayka; Weiss, Günter; Prats, Neus; Zorzano Olarte, Antonio; Palacín Prieto, Manuel; Bodoy i Salvans, Susanna
Background: Lysinuric protein intolerance is a rare autosomal disorder caused by mutations in the Slc7a7 gene that lead to impaired transport of neutral and basic amino acids. The gold standard treatment for lysinuric protein intolerance involves a low-protein diet and citrulline supplementation. While this approach partially improves cationic amino acid plasma levels and alleviates some symptoms, long-term treatment is suggested to be detrimental and may lead to life-threatening complications characterized by a wide range of hematological and immunological abnormalities. The specific cause of these hematopoietic defects-whether intrinsic to hematopoietic cells or driven by external factors-remains unclear. Given the limitations of current citrulline-based treatments and the unknown role of SLC7A7 in red blood cell production, there is an urgent need to investigate the pathways affected by SLC7A7 deficiency. Methods: We employed total inducible and cell type-specific Slc7a7 knockout mouse models to determine whether the hematological abnormalities observed in LPI are due to the loss of Slc7a7 function in hematopoietic cells. We analyzed erythropoiesis in these mice and performed bone marrow transplantation experiments to assess the role of Slc7a7 in erythroblasts and myeloid cells. The statistical significance of differences between groups was evaluated via standard statistical tests, including Student's t test and ANOVA. Results: Whole-body Slc7a7 knockout mice presented impaired erythropoiesis. However, this defect was not replicated in mice with Slc7a7 deficiency restricted to erythroblasts or myeloid cells, suggesting that the observed hematopoietic abnormalities are not due to intrinsic Slc7a7 loss in these cell types. Additionally, bone marrow transplants from control mice did not rescue the hematopoietic defects in Slc7a7-deficient mice, nor did the transplantation of Slc7a7-deficient cells induce defects in control recipients. Further investigation indicated that defective erythropoiesis is linked to impaired erythropoietin production in the kidney and subsequent iron overload. Conclusions: The hematopoietic defects in the Lysinuric protein intolerance mouse model are not caused by intrinsic Slc7a7 loss in hematopoietic cells but rather by impaired erythropoietin production in the kidney. This finding opens potential avenues for therapeutic strategies targeting erythropoietin production to address hematological abnormalities in humans with lysinuric protein intolerance. Keywords: Amino acids; Erythropoiesis; Kidney disease; Rare disease.
BNIP3 Downregulation Ameliorates Muscle Atrophy in Cancer Cachexia
(MDPI, 2024-12-01) Fornelli, Claudia; Beltrà, Marc; Zorzano Olarte, Antonio; Costelli, Paola; Sebastián Muñoz, David; Penna, Fabio
Background and aims: Cancer cachexia is a complex syndrome affecting most cancer patients and is directly responsible for about 20% of cancer-related deaths. Previous studies showed muscle proteolysis hyper-activation and mitophagy induction in tumor-bearing animals. While basal mitophagy is required for maintaining muscle mass and quality, excessive mitophagy promotes uncontrolled protein degradation, muscle loss and impaired function. BNIP3, a key mitophagy-related protein, is significantly increased in the muscles of both mice and human cancer hosts. This study aimed to define the potential of mitigating mitophagy via BNIP3 downregulation in preserving mitochondrial integrity, counteracting skeletal muscle loss in experimental cancer cachexia. Methods: Two in vivo gene delivery methods were performed to knock down muscle BNIP3: electroporation of a BNIP3-specific shRNA expression vector or adenovirus injection. Results: The electroporation effectively reduced muscle BNIP3 in healthy mice but was ineffective in C26 tumor-bearing mice. In contrast, adenovirus-mediated BNIP3 knockdown successfully decreased BNIP3 levels also in tumor hosts. Although BNIP3 knockdown did not impact overall on body or muscle mass, it improved muscle fiber size in C26-bearing miceh2, suggesting partial prevention of muscle atrophy. Mitochondrial respiratory chain complexes (OxPhos) and TOM20 protein levels were consistently rescued, indicating improvements in mitochondrial mass, while H2O2 levels were unchanged among the groups, suggesting that BNIP3 downregulation does not impair the endogenous control of oxidative balance. Conclusions: These findings suggest that a fine balance between mitochondrial disposal and biogenesis is fundamental for preserving muscle homeostasis and highlight a potential role for BNIP3 modulation against cancer-induced muscle wasting. Keywords: BNIP3; cancer cachexia; mitochondria; mitophagy; muscle wasting.

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