Articles publicats en revistes (Bioquímica i Fisiologia)

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Is There a Future Without Gluten Restrictions for Celiac Patients? Update on Current Treatments.
(MDPI, 2025-09-15) Girbal-González, Marina; Pérez-Cano, Francisco J.
Celiac disease (CeD) is a chronic autoimmune enteropathy triggered by dietary gluten in genetically predisposed individuals. Along with other disorders such as non-celiac gluten/wheat sensitivity and gluten allergy, adherence to a strict gluten-free diet (GFD) is required as the only effective treatment for CeD. To this end, and partially due to the burdensome nature and limited efficacy in some patients of a GFD, significant research into alternative therapies has been catalyzed. This review gives a perspective on current and emerging treatment strategies targeting different aspects of CeD pathogenesis. These include gluten-degrading enzymes (e.g., AN-PEP, Latiglutenase, Zamaglutenase), gluten-sequestering agents (e.g., AGY-010, BL-7010), modulators of intestinal permeability (e.g., Larazotide acetate, IMU-856), immune-modulating agents (e.g., ZED1227, AMG 714, EQ102), and strategies for immune tolerization (e.g., TAK-101, KAN-101, Nexvax2). Newer approaches are also targeting probiotics to modulate the gut microbiota (e.g., VSL#3, Lactobacillus plantarum HEAL9), nutraceuticals (e.g., polyphenols, vitamins), or food modifications to remove the gluten from naturally gluten-containing foodstuffs (e.g., gluten transamidation, Gluten Friendly™ technology). Despite encouraging results in preclinical and clinical trials, no treatment has yet been conclusively proven to serve as an effective alternative to the GFD. Continued research is essential to validate efficacy, optimize dosing, and ensure safety in broader patient populations. Here, we provide a comprehensive overview of the therapeutic landscape for CeD, analyze the main strengths and limitations of each treatment and highlight promising directions for future management of CeD, altogether evidencing the urgent need to develop effective alternatives for these patients.
Cocoa Supplementation Alleviates Gliadin-Induced Intestinal Dysbiosis in a Mouse Model of Celiac Disease
(MDPI, 2026-01-20) Girbal, Marina; Rodríguez Lagunas, María José; Rodríguez-Banqueri, Arturo; Eckhard, Ulrich; Gomis Rüth, F. Xavier; Franch, Aina; Pérez-Cano, Francisco J.
Celiac disease (CeD) is a chronic immune-mediated enteropathy triggered by dietary gluten in genetically predisposed individuals which also entails intestinal dysbiosis. This hallmark microbial imbalance provides a rationale for exploring interventions that could modulate the gut ecosystem. Cocoa is a bioactive food rich in polyphenols, theobromine, and fiber, compounds known to have an influence on both immune function and gut microbiota composition. Here, we investigated the effects of cocoa supplementation on the gut microbial profile and predicted functionality in DQ8-Dd-villin-IL-15tg mice, genetically predisposed to CeD. Animals were assigned to a reference group receiving a gluten-free diet (GFD), a gluten-containing diet group (GLI), or the latter supplemented with defatted cocoa (GLI + COCOA) for 25 days. The cecal microbiota was analyzed via 16S rRNA sequencing, and functional pathways were inferred using PICRUSt2. Goblet cell counts and CeD-relevant autoantibodies were measured and correlated with microbial taxa. Cocoa supplementation partially attenuated gluten-induced dysbiosis, preserving beneficial taxa such as Akkermansia muciniphila and Lactobacillus species while reducing opportunistic and pro-inflammatory bacteria. Functional predictions suggested differences in the predicted microbial metabolic potential related to amino acid, vitamin, and phenolic compound metabolism. Cocoa also mitigated goblet cell loss and was inversely associated with anti-gliadin IgA levels. These findings suggest that cocoa, as an adjuvant to a GFD, could be of help in maintaining microbial homeostasis and intestinal health in CeD, supporting further studies to assess its translational potential.
Evaluation of Ultra-High Pressure Homogenization Treatments to Ensure the Microbiological Safety and Immunoglobulin Preservation in Donor Human Milk.J
(MDPI, 2025-04-09) Hernández-Herrero, M. Manuela; Jalali, Kimia; Pastor-Villaescusa, Belén; Flores-Rojas, Katherine; Pleguezuelos, Vanessa; Pérez-Cano, Francisco J.; Franch i Masferrer, Àngels; Trujillo-Mesa, Antonio J.; Roig-Sagués, Artur X.
Most donor human milk (HM) banks use Holder pasteurization (HoP) to ensure microbiological safety, although it can degrade essential bioactive factors for newborns. This study evaluates the innovative ultra-high-pressure homogenization (UHPH) technology as a potential alternative. Listeria innocua, Staphylococcus carnosus, Franconibacter helveticus (formerly named Cronobacter helveticus) and Escherichia coli strains were used as surrogates for common HM pathogens according to European Milk Bank Association (EMBA) guidelines, to evaluate the efficacy of new technologies. A reconstituted powder milk formula inoculated with these strains was used to determine the most efficient conditions (those to achieve a lethality of ≥5 Log), applying treatments from 150 to 300 MPa. These treatments were later validated using inoculated HM with the same strains. Immunoglobulin (sIgA, IgG, IgM) retention was also evaluated and compared with HoP. Results showed that UHPH treatments at 200 MPa achieved a lethality > 5 Log for all strains, except for St. carnosus, which required 250 MPa for complete inactivation in HM. Unlike HoP, UHPH at 200 and 250 MPa did not significantly reduce the basal concentration of sIgA, IgG, or IgM compared with raw HM. These findings suggest UHPH as a promising alternative to HoP, maintaining both microbiological safety and immunological quality.
Editorial: Immunonutrition: bridging precision nutrition and modern medicine.
(Frontiers Media, 2025-08-29) Almeida, Jani; Sá, Helena; Pérez-Cano, Francisco J.; Viana, Sofia
Inflammation imposes substantial metabolic demands and depletes critical nutrient reserves, often impairing immune function. While adequate nutrition is foundational to immune homeostasis, the targeted use of supraphysiological doses of immunomodulatory nutrients to redirect immune responses toward tolerance or resolution of inflammation remains an evolving frontier. Immunonutrition, a key domain within precision nutrition, encompasses bioactive compounds—nutrients and non-nutrients—such as amino acids, fatty acids, nucleotides, vitamins, minerals, polyphenols, glucans, and an expanding repertoire of pre-, pro-, sym-, and post-biotics. Its clinical applications span early-life immune development, cancer and infection management, modulation of autoimmunity and allergies, and attenuation of immunosenescence and inflamm-aging in chronic diseases. Despite the advances propelled by multi-omics research, critical gaps remain in mechanistic understanding, immune–nutrient interactions, synergy of bioactives within the food, biomarker identification, and the safety profile of immunonutrients, including nutrient–drug interactions.
Novel nanostructured lipid carriers loading Apigenin for anterior segment ocular pathologies
(Elsevier B.V., 2024-06-10) Bonilla-Vidal, L; Espina García, Marta; García López, María Luisa; Baldomà Llavinés, Laura; Badía Palacín, Josefa; González Sánchez, Jose Antonio; Delgado, Luís María; Gliszczyńska, Anna; Souto, Eliana B.; Sánchez-López, E. (Elena)
Dry eye disease (DED) is a chronic multifactorial disorder of the ocular surface caused by tear film dysfunction and constitutes one of the most common ocular conditions worldwide. However, its treatment remains unsatisfactory. While artificial tears are commonly used to moisturize the ocular surface, they do not address the underlying causes of DED. Apigenin (APG) is a natural product with anti-inflammatory properties, but its low solubility and bioavailability limit its efficacy. Therefore, a novel formulation of APG loaded into biodegradable and biocompatible nanoparticles (APG-NLC) was developed to overcome the restricted APG stability, improve its therapeutic efficacy, and prolong its retention time on the ocular surface by extending its release. APG-NLC optimization, characterization, biopharmaceutical properties and therapeutic efficacy were evaluated. The optimized APG-NLC exhibited an average particle size below 200 nm, a positive surface charge, and an encapsulation efficiency over 99 %. APG-NLC exhibited sustained release of APG, and stability studies demonstrated that the formulation retained its integrity for over 25 months. In vitro and in vivo ocular tolerance studies indicated that APG-NLC did not cause any irritation, rendering them suitable for ocular topical administration. Furthermore, APG-NLC showed non-toxicity in an epithelial corneal cell line and exhibited fast cell internalization. Therapeutic benefits were demonstrated using an in vivo model of DED, where APG-NLC effectively reversed DED by reducing ocular surface cellular damage and increasing tear volume. Anti-inflammatory assays in vivo also showcased its potential to treat and prevent ocular inflammation, particularly relevant in DED patients. Hence, APG-NLC represent a promising system for the treatment and prevention of DED and its associated inflammation.
Chitosan-based delivery of fish codon-optimised Caenorhabditis elegans FAT-1 and FAT-2 boosts EPA and DHA biosynthesis in Sparus aurata
(Springer Verlag, 2024-04-09) Wu, Yuanbing; Rashidpour, Ania; Fàbregas, Anna; Almajano Pablos, Ma. Pilar (María Pilar); Metón Teijeiro, Isidoro
Omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) are essential fatty acids required in healthy balanced diets for humans. To induce sustained production of n-3 LC-PUFA in gilthead seabream (Sparus aurata), chitosan-tripolyphosphate (TPP) nanoparticles encapsulating plasmids expressing fish codon-optimised Caenorhabditis elegans FAT-1 and FAT-2 were intraperitoneally administered every 4 weeks (3 doses in total, each of 10 μg plasmid per g of body weight). Growth performance and metabolic effects of chitosan-TPP complexed with pSG5 (empty plasmid), pSG5-FAT-1, pSG5-FAT-2 and pSG5-FAT-1 + pSG5-FAT-2 were assessed 70 days post-treatment. Tissue distribution analysis showed high expression levels of fish codon-optimised FAT-1 and FAT-2 in the liver (> 200-fold). Expression of fat-1 and fat-1 + fat-2 increased weight gain. Fatty acid methyl esters assay revealed that co-expression of fat-1 and fat-2 increased liver production and muscle accumulation of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and total n-3 LC-PUFA, while decreased the n-6/n-3 ratio. Co-expression of fat-1 and fat-2 downregulated srebf1 and genes encoding rate-limiting enzymes for de novo lipogenesis in the liver, leading to decreased circulating triglycerides and cholesterol. In contrast, FAT-2 and FAT-1 + FAT-2 upregulated hepatic hnf4a, nr1h3 and key enzymes in glycolysis and the pentose phosphate pathway. Our findings demonstrate for the first time efficient and sustained production of EPA and DHA in animals after long-term treatment with chitosan-TPP-DNA nanoparticles expressing FAT-1 and FAT-2, which enabled the production of functional fish rich in n-3 LC-PUFA for human consumption.
Maternal diet shapes infant microbiota and defensive capacity against infections in early life via differential human milk composition
(Elsevier, 2025-08-01) Rio Aige, Karla; Selma-Royo, Marta; Cabrera-Rubio, Raúl; Gonzalez, Sergi; Martínez Costa, Cecilia; Castell, Margarida; Rodríguez Lagunas, María José; Collado, Maria Carmen; Pérez-Cano, Francisco J.
Maternal nutritional status and dietary profile during pregnancy and lactation have short- and long-term impacts on offspring health. However, there is an incomplete understanding of the mechanisms behind these health effects. This study aims to assess the effect of maternal diet on the health of offspring by examining to unravel the impact of maternal diet on offspring health outcomes and evaluate the link between maternal nutrition, human milk immune components and neonatal colonisation as potential mechanisms that mediate the influence of maternal diet in the incidence of infant infections.
Methods: To assess this objective, we used two complementary approaches by which a clinical observational study based on the MAMI birth cohort guided a preclinical interventional analysis using a neonatal rat model of rotavirus-induced gastroenteritis.
Findings: The findings in both approaches demonstrated that a maternal diet rich in plant-based protein, fibre and polyunsaturated fatty acids, was linked to reduced incidence and severity of infections in offspring that would be mediated by beneficial modulation of the gut microbiota and immune system. Specifically, in the suckling rats, a predominant Th1 immune response and an enhanced virus-specific response were observed. Moreover, human milk IgA and rat milk IgG2c played a key protective role that complemented the effects of maternal diet.
Interpretation: These results strengthen the importance of maternal diet during pregnancy and lactation supporting infant health.
Lighting conditions during suckling modify rat pupillary light responses but not entrainment to 24-hour sawtooth dim light-dark cycles
(Swets & Zeitlinger, BV, 2025-10-22) Cambras Riu, Trinitat; Díez Noguera, Antoni
Early-life experiences have lasting consequences on future health. This study examined the impact of bright light exposure during suckling on non-image-forming system responses, specifically the pupillary light reflex (PLR) and circadian entrainment. Wistar rats were exposed to either constant bright light (SLL-rats) or 24-hour light-dark cycles (SLD-rats) during suckling. After weaning, all rats were maintained under identical conditions, experiencing different 24-hour sawtooth light-dark cycles (light: dim light, 1 µW/cm2; dark: 0.03 µW/cm2 red light) for three months. PLR was tested using 30-second blue light pulses at intensities of 3, 10, 30, 100, and 300 µW/cm2. Results showed that PLR was influenced by early-life lighting conditions. SLL-rats exhibited a linear response across all light intensities, with significantly reduced pupillary contraction compared to SLD-rats at 3, 10, 30, and 100 µW/cm2, while no differences were observed at 300 µW/cm2. Additionally, exposure to different 24-hour sawtooth cycles led to minor differences in circadian rhythm shape and entrainment, which did not correspond to the PLR differences or the manifestation of rhythms under LL in adulthood. These findings suggest that early-life lighting conditions may induce functional alterations in specific aspects of the non-image-forming system, potentially affecting physiology and behavior in adulthood.
Mevalonate biosynthesis in plants
(CRC Press, 1999) Bach, Thomas J.; Boronat i Margosa, Albert; Campos Martínez, Narciso; Ferrer i Prats, Albert; Vollack, Kai-Uwe
The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR, R-mevalonate: NADP+ oxidoreductase, CoA-acylating, EC 1.1.1.34) catalyzes the reductive conversion of HMG-CoA to mevalonic acid (MVA). This reaction is generally considered as a key controlling step in plant isoprenoid biosynthesis.1–4 However, the role of HMGR in the overall control of plant isoprenoid biosynthesis has not yet been unequivocally established. In spite of the interest in plant HMGR, the molecular characterization of this enzyme was hampered by the fact that it is membrane bound and difficult to purify (see Bach et al.3,5 for literature). That is why many of the molecular properties of plant HMGR did not emerge until the genes encoding the enzyme had been cloned. After characterization of a considerable number of HMGR genes (for literature see Stermer et al.4), it now seems clear that plant HMGR is encoded by multigene families. The number of genes comprising each multigene family varies, depending on the species, ranging from the two genes found in Arabidopsis thaliana6,7 to the at least seven genes reported to occur in potato.4 This is in sharp contrast with animal systems in which the enzyme is encoded by a single gene. The presence of multiple plant HMGR isozymes is consistent with the proposed key role of this enzyme in plant isoprenoid biosynthesis. Up to now, Arabidopsis is the only plant species from which all the HMGR genes have been cloned and characterized.6,7 The simplicity of the Arabidopsis HMGR gene family, together with the well recognized advantages of this plant for molecular and genetic studies, make Arabidopsis an attractive model system to elucidate the regulatory role of HMGR in plant isoprenoid biosynthesis.
Expression and molecular analysis of the Arabidopsis DXR gene encoding 1-Deoxy-D-Xylulose 5-phosphate reductoisomerase, the first commited enzyme of the 2-C-methyl-D-erythritol 4-phosphate pathway.
(American Society of Plant Biologists, 2002-08) Carretero Paulet, Lorenzo; Ahumada, Iván; Cunillera i Segarra, Núria; Rodríguez Concepción, Manuel; Ferrer i Prats, Albert; Boronat i Margosa, Albert; Campos Martínez, Narciso
1-Deoxy-d-xylulose 5-phosphate reductoisomerase (DXR) catalyzes the first committed step of the 2-C-methyl-d-erythritol 4-phosphate pathway for isoprenoid biosynthesis. In Arabidopsis, DXR is encoded by a single-copy gene. We have cloned a full-length cDNA corresponding to this gene. A comparative analysis of all plant DXR sequences known to date predicted an N-terminal transit peptide for plastids, with a conserved cleavage site, and a conserved proline-rich region at the N terminus of the mature protein, which is not present in the prokaryotic DXR homologs. We demonstrate that Arabidopsis DXR is targeted to plastids and localizes into chloroplasts of leaf cells. The presence of the proline-rich region in the mature Arabidopsis DXR was confirmed by detection with a specific antibody. A proof of the enzymatic function of this protein was obtained by complementation of anEscherichia coli mutant defective in DXR activity. The expression pattern of β-glucuronidase, driven by theDXR promoter in Arabidopsis transgenic plants, together with the tissue distribution of DXR transcript and protein, revealed developmental and environmental regulation of theDXR gene. The expression pattern of theDXR gene parallels that of the Arabidopsis 1-deoxy-d-xylulose 5-phosphate synthase gene, but the former is slightly more restricted. These genes are expressed in most organs of the plant including roots, with higher levels in seedlings and inflorescences. The block of the 2-C-methyl-d-erythritol 4-phosphate pathway in Arabidopsis seedlings with fosmidomycin led to a rapid accumulation of DXR protein, whereas the 1-deoxy-d-xylulose 5-phosphate synthase protein level was not altered. Our results are consistent with the participation of the Arabidopsis DXR gene in the control of the 2-C-methyl-d-erythritol 4-phosphate pathway.
Subcellular localization of Arabidopsis 3-hydroxy-3-methylglutaryl-coenzyme A reductase
(American Society of Plant Biologists, 2005-06-11) Leivar, Pablo; Gonzalez, Victor Manuel; Castel i Gil, Susanna; Trelease, Richard N.; López Iglesias, Carmen; Arró i Plans, Montserrat; Boronat i Margosa, Albert; Campos Martínez, Narciso; Ferrer i Prats, Albert; Fernàndez Busquets, Xavier
Plants produce diverse isoprenoids, which are synthesized in plastids, mitochondria, endoplasmic reticulum (ER), and the nonorganellar cytoplasm. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) catalyzes the synthesis of mevalonate, a rate-limiting step in the cytoplasmic pathway. Several branches of the pathway lead to the synthesis of structurally and functionally varied, yet essential, isoprenoids. Several HMGR isoforms have been identified in all plants examined. Studies based on gene expression and on fractionation of enzyme activity suggested that subcellular compartmentalization of HMGR is an important intracellular channeling mechanism for the production of the specific classes of isoprenoids. Plant HMGR has been shown previously to insert in vitro into the membrane of microsomal vesicles, but the final in vivo subcellular localization(s) remains controversial. To address the latter in Arabidopsis (Arabidopsis thaliana) cells, we conducted a multipronged microscopy and cell fractionation approach that included imaging of chimeric HMGR green fluorescent protein localizations in transiently transformed cell leaves, immunofluorescence confocal microscopy in wild-type and stably transformed seedlings, immunogold electron microscopy examinations of endogenous HMGR in seedling cotyledons, and sucrose density gradient analyses of HMGR-containing organelles. Taken together, the results reveal that endogenous Arabidopsis HMGR is localized at steady state within ER as expected, but surprisingly also predominantly within spherical, vesicular structures that range from 0.2- to 0.6-µm diameter, located in the cytoplasm and within the central vacuole in differentiated cotyledon cells. The N-terminal region, including the transmembrane domain of HMGR, was found to be necessary and sufficient for directing HMGR to ER and the spherical structures. It is believed, although not directly demonstrated, that these vesicle-like structures are derived from segments of HMGR-ER. Nevertheless, they represent a previously undescribed subcellular compartment likely capable of synthesizing mevalonate, which provides new evidence for multiorganelle compartmentalization of the isoprenoid biosynthetic pathways in plants.
Mirabegron induces selective changes in the faecal microbiota of HFHFr rats without altering bile acid composition
(Frontiers Media, 2025-04-14) Bentanachs Raset, Roger; Miró Martí, Ma. Lluïsa; Ramírez-Carrasco, Patricia; Sánchez, Rosa María; Bernabeu Lorenzo, Manuel; Amat, Concepció; Alegret i Jordà, Marta; Pérez Bosque, Anna; Roglans i Ribas, Núria; Laguna Egea, Juan Carlos
In the present work, we analyse stored liver, adipose tissue (perigonadal
and brown), serum and faecal samples from our previous study and present new
biochemical, faecal metabolomic and microbiome data.
We show that oral administration of mirabegron
significantly increases the expression of uncoupling protein 1 in brown
adipose tissue and β3-Adrenergic receptor protein in perigonadal white
adipose and liver tissues. Furthermore, mirabegron treatment changes the
relative abundance of several genus and families of rat faecal microbiota,
albeit without restoring the global biodiversity and evenness indexes observed
in control rats, as well as faecal bile acids composition. These changes are
probably due to a direct effect of mirabegron on the gut microbiome, rather
than being mediated by changes in bile acid induced by drug treatment.
Arabidopsis thaliana contains two differentially expressed 3-hydroxy-3-methylglutaryl-CoA reductase genes, wich encode microsomal forms of the enzyme
(National Academy of Sciences, 1994-02-01) Enjuto, Montserrat; Balcells i Argemí, Lluís; Campos Martínez, Narciso; Caelles Franch, Carme; Arró i Plans, Montserrat; Boronat i Margosa, Albert
The enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR; EC 1.1.1.34) catalyzes the first rate-limiting step in plant isoprenoid biosynthesis. Arabidopsis thaliana contains two genes, HMG1 and HMG2, that encode HMGR. We have cloned these two genes and analyzed their structure and expression. HMG1 and HMG2 consist of four exons and three small introns that interrupt the coding sequence at equivalent positions. The two genes share sequence similarity in the coding regions but not in the 5'- or 3'-flanking regions. HMG1 mRNA is detected in all tissues, whereas the presence of HMG2 mRNA is restricted to young seedlings, roots, and inflorescences. The similarity between the two encoded proteins (HMGR1 and HMGR2) is restricted to the regions corresponding to the membrane and the catalytic domains. Arabidopsis HMGR2 represents a divergent form of the enzyme that has no counterpart among plant HMGRs characterized so far. By using a coupled in vitro transcription-translation assay, we show that both HMGR1 and HMGR2 are cotranslationally inserted into endoplasmic reticulum-derived microsomal membranes. Our results suggest that the endoplasmic reticulum is the only cell compartment for the targeting of HMGR in Arabidopsis and support the hypothesis that in higher plants the formation of mevalonate occurs solely in the cytosol.
Circadian Patterns of Patients with Type 2 Diabetes and Obstructive Sleep Apnea.
(MDPI, 2021) Cambras Riu, Trinitat; Romero, Odile; Díez Noguera, Antoni; Lecube, Albert; Sampol, Gabriel
Sleep apnea, a condition that modifies sleep and circadian rhythms, is highly prevalent in patients with diabetes. However, it is not known if there is an association between sleep apnea, circadian alterations and glycemic regulation in this type of patient. Here, a polysomnographic study was carried out on 21 women and 25 men (mean age = 64.3 ± 1.46 years) with diagnoses of type 2 diabetes to detect the presence of sleep apnea. Moreover, patients wore an actigraph and a temperature sensor on the wrist for one week, to study the manifestation of the circadian rhythms. The correlations of circadian and polysomnographic variables with the severity of apnea, measured by the apnea-hypopnea index, and with glycemic dysregulation, measured by the percentage of glycated hemoglobin, were analyzed. The mean apnea-hypoapnea index of all the participants was 39.6 ± 4.3. Apnea-hypoapnea index correlated with % N1, negatively with % N3, and also the stability of the active circadian rhythm. However, no significant correlation was found between the apnea-hypopnea index and wrist temperature rhythm and glycated hemoglobin. Glycated hemoglobin levels were negatively associated with the percentage of variance explained by the wrist temperature circadian rhythm (calculated via 24 and 12 h rhythms). This association was independent of body mass index and was strongest in patients with severe apnea. In conclusion, patients with diabetes showed altered circadian rhythms associated with a poor glycemic control and this association could partially be related to the coexistence of sleep apnea.
JNK signaling and its impact on neural cell maturation and differentiation
(Elsevier, 2024-05-25) Castro-Torres, Rubén Darío; Olloquequi, Jordi; Parcerisas, Antoni; Ureña, Jesús; Ettcheto Arriola, Miren; Beas Zárate, Carlos; Camins Espuny, Antoni; Verdaguer, Ester; Auladell i Costa, M. Carme
C-Jun-N-terminal-kinases (JNKs), members of the mitogen-activated-protein-kinase family, are significantly linked with neurological and neurodegenerative pathologies and cancer progression. However, JNKs serve key roles under physiological conditions, particularly within the central-nervous-system (CNS), where they are critical in governing neural proliferation and differentiation during both embryogenesis and adult stages. These processes control the development of CNS, avoiding neurodevelopment disorders. JNK are key to maintain the proper activity of neural-stem-cells (NSC) and neural-progenitors (NPC) that exist in adults, which keep the convenient brain plasticity and homeostasis. This review underscores how the interaction of JNK with upstream and downstream molecules acts as a regulatory mechanism to manage the self-renewal capacity and differentiation of NSC/NPC during CNS development and in adult neurogenic niches. Evidence suggests that JNK is reliant on non-canonical Wnt components, Fbw7-ubiquitin-ligase, and WDR62-scaffold-protein, regulating substrates such as transcription factors and cytoskeletal proteins. Therefore, understanding which pathways and molecules interact with JNK will bring knowledge on how JNK activation orchestrates neuronal processes that occur in CNS development and brain disorders.
GPR88 impairs the signaling of kappa opioid receptors in a heterologous system and in primary striatal neurons
(Elsevier Ltd., 2025-03-01) Rivas‐Santisteban, Rafael; Lillo, Jaume; Garrigós, Claudia; Navarro Brugal, Gemma; Franco Fernández, Rafael
The physiological role of GPR88, an orphan G protein-coupled receptor (GPCR) predominantly expressed in the striatum, remains unclear, despite its altered expression in parkinsonian animal models. GPR88 is known to interact with other GPCRs. Specifically, GPR88 expression inhibits signaling mediated by the μ-opioid receptor in cells coexpressing both receptors. The effect of GPR88 on the kappa-opioid receptor (KOR) is less understood. In this study, we examine the interaction between GPR88 and KOR, and the impact of GPR88 expression on KOR-mediated signaling in heterologous cells and primary striatal neurons. Bioluminescence resonance energy transfer and proximity ligation assays revealed an interaction between GPR88 and KOR. Functional assays showed that GPR88 antagonized the effects of U69,593, a selective KOR agonist, on forskolin-stimulated cAMP levels, β-arrestin-2 recruitment, and phosphorylation of extracellular signal-regulated kinases (ERK1/2) in HEK-293T cells coexpressing both receptors. In primary striatal neurons, GPR88 and KOR complexes were observed, with KOR activation effects enhanced when GPR88 expression was suppressed using RNA interference. These results suggest that GPR88 and KOR are coexpressed in striatal neurons, where GPR88 inhibits KOR activation. Notably, the GPR88-KOR heteromer was more prevalent in dopamine D1-receptor-containing neurons of the direct pathway of the basal ganglia. Given the roles of KORs in dopamine release, motor function regulation, and pain and reward perception, the GPR88-KOR interaction warrants further investigation in the context of neuropathic pain, Parkinson's disease, and neuropsychiatric disorders.
Chitosan-Mediated Expression of Caenorhabditis elegans fat-1 and fat-2 in Sparus aurata: Short-Term Effects on the Hepatic Fatty Acid Profile, Intermediary Metabolism, and Proinflammatory Factors
(MDPI, 2025-11-13) Wu, Yuanbing; Rashidpour, Ania; Duan, Wenwen; Fábregas, A. (Anna); Almajano Pablos, Ma. Pilar (María Pilar); Metón Teijeiro, Isidoro
A single dose of chitosan-tripolyphosphate (TPP) nanoparticles carrying expression plasmids for fish codon-optimized Caenorhabditis elegans fat-1 and fat-2 was intraperitoneally administered to gilthead seabream (Sparus aurata) to stimulate the biosynthesis of omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) and evaluate subsequent short-term effects on liver intermediary metabolism and immunity. Seventy-two hours post-injection, the upregulation of fat-1 elevated eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and total n-3 fatty acids in the liver, while fat-2 enhanced DHA and n-3 fatty acids. Co-expression of fat-1 and fat-2 increased EPA, DHA, PUFA, and the total n-6 and n-3 LC-PUFA, while reducing plasma triglycerides. The expression of fat-1 and fat-2 suppressed hepatic lipogenesis by downregulating srebf1 and pparg, and consequently key genes in fatty acid synthesis (acaca, acacb, fasn, scd1, and fads2). In contrast, the co-expression of fat-1 and fat-2 upregulated hnf4a, chrebp, and pfkl, a rate-limiting enzyme in glycolysis. Furthermore, fat-1 and fat-2 reduced hepatic proinflammatory markers such as tnfa and nfkb1. In addition to enhancing EPA and DHA biosynthesis, promoting glycolysis, and suppressing lipogenesis, our findings suggest that the short-term expression of C. elegans fat-1 and fat-2 in the liver may also reduce inflammation and, therefore, could impact the health and growth performance of cultured fish.
Glycosylated Sterols Enhance Cold Tolerance in Tomato Via Membrane Stabilization and Jasmonate Signaling
(American Society of Plant Biologists, 2025-10-31) Deng, Cuiyun; Garcia-Molina, Antoni; Gómez-Cadenas, Aurelio; Vives-Peris, Vicente; Alcázar Hernández, Rubén; Ferrer i Prats, Albert; Altabella Artigas, Teresa
Free and glycosylated sterols play a central role in maintaining the structural integrity and proper functioning of the plasma membrane, which serves as the primary sensor of cold and initiates signaling cascades to mitigate chilling-induced damage. Here, we characterize the cold-response of tomato (Solanum lycopersicum cv. Micro-Tom) mutants with higher and lower ratios of glycosylated to free sterols than wild-type plants, resulting from the overexpression and silencing of the STEROL GLYCOSYLTRANSFERASES 1 and 2 (SlSGT2 and SlSGT1), respectively. The SlSGT2 overexpressing mutants show increased cold tolerance, membrane stability, and oxidative stress responses, while silencing of the SlSGT1 gene causes the opposite phenotypes. Furthermore, changes in the glycosylated to free sterols ratio activate distinct transcriptional programs that establish a preconditioned stress-responsive state under basal conditions and trigger a more efficient response to cold in the SlSGT2 overexpressing mutants, as well as compromise the capacity to withstand the effects of cold stress in the SlSGT1-silenced mutants. The SlSGT2 overexpressing mutants also contain higher levels of jasmonates under basal conditions and display enhanced biosynthesis of these hormones under cold stress compared to SlSGT1-silenced and control plants. The facilitating effect of elevated glycosylated to free sterols ratio on jasmonic acid (JA) biosynthesis and signaling leads to theactivation of cold-responsive genes, including those of the CBF–COR pathway, antioxidant defenses, and polyamine biosynthesis. Our findings provide key insights into the mechanisms by which glycosylated sterols help improve cold tolerance in tomato.
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.

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