Dpto. Bioquímica y Biología Molecular y Fisiología

Neuroprotective Attributes of Gut-derived Urolithins in Parkinson’s Disease

Wed, 01 Jan 2025 00:00:00 GMT

Urolithins, a class of gut microbiota-derived metabolites, are produced from dietary ellagitannins and ellagic acid. Their pleiotropic activities, including antioxidant, anti-inflammatory, and mitophagy-enhancing effects, position them as promising candidates for Parkinson's disease (PD), a disorder increasingly understood through the lens of gut-brain axis dysfunction. Mounting evidence implicates gastrointestinal disturbances, including dysbiosis, increased intestinal permeability, and aberrant microbial signaling, as early events that may initiate or exacerbate neuropathological cascades in PD. In this context, urolithins represent a unique class of neuromodulatory agents operating at the intersection of host-microbiota co-metabolism and neuroprotection. This review synthesizes mechanistic insights into urolithin biosynthesis and interindividual variability in bioavailability, followed by a critical appraisal of their efficacy in preclinical PD models. We outline their relevance across key pathogenic dimensions, including preservation of dopaminergic neurons, inhibition of pathological α-synuclein aggregation and propagation, suppression of oxidative stress via nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway activation and enhancement of endogenous antioxidant defenses, attenuation of neuroinflammation through downregulation of pro-inflammatory cytokines and glial reactivity, rescue of mitochondrial dysfunction, and promotion of autophagy-lysosomal pathways to mitigate proteostatic failure. By translating mechanistic insights into a coherent therapeutic framework, this review highlights the promise of urolithins as microbiota-derived interventions capable of modifying the course of PD.

Interplay Between Fibroblast Growth Factor-19, Beta-Klotho, and Receptors Impacts Cardiovascular Risk in Chronic Kidney Disease

Thu, 01 Jan 2026 00:00:00 GMT

Background: Chronic kidney disease (CKD) markedly increases the risk of cardiovascular events (CVE), yet conventional biomarkers often fail to capture this excess risk. We evaluated whether circulating levels and genetic variability within the FGF19/β-Klotho/FGFR axis contribute to CV risk stratification in CKD. Methods: In 579 CKD patients, plasma FGF19 and β-Klotho concentrations were quantified, and 64 genetic variants across FGF19, KLB, FGFR1, and FGFR4 genes were analyzed. Results: Cluster analysis identified three distinct biomarker profiles, with one cluster—characterized by low/intermediate FGF19 and markedly elevated β-Klotho—showing significantly reduced CV event-free survival. After adjustment for clinical covariates, this cluster was independently associated with higher CV risk [HR = 2.97 (1.12–7.92), p = 0.029]. Two genetic variants also showed independent associations: FGFR1 rs2288696 (protective) [HR = 0.51 (0.27–0.95), p = 0.029] and KLB rs2687971 (risk-increasing) [HR = 2.03 (0.97–4.27), p = 0.046]. A combined CV risk model incorporating biomarker clusters, relevant SNPs, and traditional risk factors achieved good discriminative ability (C-index = 0.80), with the FGF19/β-Klotho cluster showing predictive importance comparable to diabetes and previous CV history. Conclusions: These results indicate that integrating FGF19-Klotho biomarkers with genetic information may improve CV risk prediction in CKD.

Sex Disparities in the Processes Underlying Aging: Mitochondrial DNA Copy Number Associations with Dynapenia, 25-Hydroxyvitamin D3 Levels and Quality of Life in Older Adults

Thu, 01 Jan 2026 00:00:00 GMT

Background/Objectives: Mitochondrial dysfunction, often reflected by a decline in mitochondrial DNA copy number (mtDNA-CN) in peripheral blood cells (PMBCs), is a key hallmark of biological aging and is linked to numerous adverse health outcomes, including frailty and cardiovascular disease. Furthermore, emerging evidence suggests that vitamin D may influence mitochondrial dysfunction. This cross-sectional study aims to investigate the associations of mtDNA-CN with muscular strength, self-rated health, and serum 25-hydroxyvitamin D3 (25(OH)D3) levels in a community-dwelling elderly population. Methods: A total of 149 elderly outpatients (≥65 years) from Soria, Spain, were included in this cross-sectional study. Muscular strength was assessed using the hand grip strength (HGS) test, and self-rated health-related quality of life (QoL) was measured using the EuroQoL five-dimension questionnaire (EQ-5D). Genomic DNA was extracted from peripheral blood, and mtDNA-CN was quantified using quantitative real-time PCR (qPCR). Serum 25(OH)D3, intact parathyroid hormone (iPTH), phosphorus, calcium, albumin and other mineral metabolism markers were measured. Statistical analyses, including Spearman correlations and multivariate logistic regression, were performed to assess associations, with stratification by sex. Results: In the total population, a marginally significant positive correlation was observed between mtDNA copy number (mtDNA-CN) and serum 25(OH)D3 levels (r = 0.210; p = 0.010), which did not remain significant after Bonferroni correction. Among women, lower mtDNA-CN was significantly linked to muscle weakness (p = 0.005), mobility problems (p = 0.009), and a trend toward self-care difficulties (p = 0.016). Multivariate analysis confirmed an independent association with increased mobility impairment risk (adjusted OR = 0.983; 95% CI: 0.97–1.00; p = 0.009). No significant associations were observed between mtDNA-CN and dynapenia or QoL components in the male group. Conclusions: This study identified a marginally significant positive correlation between serum 25(OH)D3 levels and mtDNA-CN in the total population (r = 0.210; p = 0.010), which did not persist after Bonferroni correction, suggesting an exploratory link between vitamin D status and mitochondrial homeostasis in older adults. In addition, these results highlight sex-specific differences in mtDNA-CN as a potential biomarker of functional decline, particularly of mobility, in women. These findings support the idea that mtDNA-CN could serve as an integrated biomarker and that sex-specific nutrition could be used to promote healthy aging.

Quality of life, grip strength, health indicators, and clinical risk in older adults: A cross-sectional study

Thu, 01 Jan 2026 00:00:00 GMT

Aim: To examine the relationship between functional status, self-perceived quality of life and other health indicators, and their association with clinical risk and assignment to Clinical Risk Groups (CRGs) in older adults (≥65 years). Design: Cross-sectional study conducted among older patients attending primary care in a city in Spain. Methods: Data from 384 community-dwelling older adults were analysed in groups <80 and ≥80 years. Functional status (Barthel Index), hand grip strength (HGS), quality of life (EuroQol-5D-5 L and EQ-VAS), medications and polypharmacy were recorded, together with CRG (G0-G3) from clinical records. Correlation and comparison analyses explored associations between health indicators and CRG assignment. Results: In both age groups, a higher number of medications was associated with lower Barthel Index, EQ-5D and EQ-VAS scores, and older age with lower HGS. Among patients aged <80 years, Barthel Index, number of medications, polypharmacy and EQ-VAS were significantly associated with CRG assignment. In those aged ≥80 years, CRG classification was mainly related to functional status and medication burden, with no clear association with quality of life. In both age groups, HGS was positively correlated with quality of life but showed no association with CRG category. Conclusion: Functional dependency, medication burden and, in those under 80 years, self-perceived health-related quality of life were key correlates of clinical risk classification. Incorporating simple indicators such as the Barthel Index, HGS and EQ-5D into CRG-based approaches could improve identification of high-risk older adults in primary care.

Sex Disparities in the Processes Underlying Aging: Mitochondrial DNA Copy Number Associations with Dynapenia, 25-Hydroxyvitamin D3 Levels and Quality of Life in Older Adults

Thu, 01 Jan 2026 00:00:00 GMT

In vitro anti-inflammatory activity of phenolic rich extracts from white and red common beans

Wed, 01 Jan 2014 00:00:00 GMT

According to epidemiological evidence, diets rich in fruits and vegetables can reduce the incidence of several chronic diseases that share an inflammatory component. These protective effects are attributed, in part, to the occurrence of different antioxidant components, mainly phenolic compounds. Our aim was to characterise phenolic composition, and to determine antioxidant and anti-inflammatory activities of phenolic rich extracts obtained from two kinds of common beans, white kidney beans (WKB) and round purple beans (RPB). Phenolic acids were the predominant component in WKB extracts, whereas RPB extracts presented higher concentrations of phenolic compounds, mainly catechin derivatives, proanthocyanidins and catechin glucoside. In addition, RPB extracts showed higher antioxidant capacity and higher anti-inflammatory activity by the reduction of NO production and cytokine mRNA expression of LPS stimulated macrophages. These results suggest that common bean extracts may be used as a source of anti-inflammatory agents as well as a dietary complement for health promotion.

Storage temperature and UV-irradiation influence on the ergosterol content in edible mushrooms

Wed, 01 Jan 2014 00:00:00 GMT

Ergosterol (5,7,22-ergostatrien-3β-ol) and ergosteryl derivatives from different genera of edible mushrooms were separated and quantified by an isocratic reversed-phase high performance liquid chromatography (HPLC) method. The technique allowed a rapid separation of free ergosterol and two ergosteryl derivatives occurring in mushrooms. The ergosterol content varied considerably depending on the fungus. Thus, the species Agaricus bisporus and Hygrophorus marzuolus presented high quantities of ergosterol (6.4–6.8 mg/g, dry matter) followed by Pleurotus ostreatus, Calocybe gambosa, Lentinus edodes, and Boletus edulis (3.3–4.0 mg/g). In contrast, other species, such as Cantharellus cibarius, Lactarius deliciosus and Craterellus cornucopioides, contained significantly lower ergosterol amounts (0.2–0.4 mg/g). Two ergosteryl derivatives were found in mushrooms and also the content depended on the fungus. The stability of ergosterol, in terms of the formation of ergosterol peroxide, was evaluated under different storage temperatures and UV radiation. The lower the temperature (−20 °C) and the radiation time (10 min), the lower ergosterol oxidation was observed.

Insulin-degrading enzyme (IDE) as a modulator of microglial phenotypes in the context of Alzheimer’s disease and brain aging

Sun, 01 Jan 2023 00:00:00 GMT

The insulin-degrading enzyme (IDE) is an evolutionarily conserved zinc-dependent metallopeptidase highly expressed in the brain, where its specific functions remain poorly understood. Besides insulin, IDE is able to cleave many substrates in vitro, including amyloid beta peptides, making this enzyme a candidate pathophysiological link between Alzheimer's disease (AD) and type 2 diabetes (T2D). These antecedents led us to address the impact of IDE absence in hippocampus and olfactory bulb. A specific induction of microgliosis was found in the hippocampus of IDE knockout (IDE-KO) mice, without any effects in neither hippocampal volume nor astrogliosis. Performance on hippocampal-dependent memory tests is influenced by IDE gene dose in 12-month-old mice. Furthermore, a comprehensive characterization of the impact of IDE haploinsufficiency and total deletion in metabolic, behavioral, and molecular parameters in the olfactory bulb, a site of high insulin receptor levels, reveals an unambiguous barcode for IDE-KO mice at that age. Using wildtype and IDE-KO primary microglial cultures, we performed a functional analysis at the cellular level. IDE absence alters microglial responses to environmental signals, resulting in impaired modulation of phenotypic states, with only transitory effects on amyloid-β management. Collectively, our results reveal previously unknown physiological functions for IDE in microglia that, due to cell-compartment topological reasons, cannot be explained by its enzymatic activity, but instead modulate their multidimensional response to various damaging conditions relevant to aging and AD conditions.

Dual role of Apolipoprotein D as long-term instructive factor and acute signal conditioning microglial secretory and phagocytic responses

Sun, 01 Jan 2023 00:00:00 GMT

Microglial cells are recognized as very dynamic brain cells, screening the environment and sensitive to signals from all other cell types in health and disease. Apolipoprotein D (ApoD), a lipid-binding protein of the Lipocalin family, is required for nervous system optimal function and proper development and maintenance of key neural structures. ApoD has a cell and state-dependent expression in the healthy nervous system, and increases its expression upon aging, damage or neurodegeneration. An extensive overlap exists between processes where ApoD is involved and those where microglia have an active role. However, no study has analyzed the role of ApoD in microglial responses. In this work, we test the hypothesis that ApoD, as an extracellular signal, participates in the intercellular crosstalk sensed by microglia and impacts their responses upon physiological aging or damaging conditions. We find that a significant proportion of ApoD-dependent aging transcriptome are microglia-specific genes, and show that lack of ApoD in vivo dysregulates microglial density in mouse hippocampus in an age-dependent manner. Murine BV2 and primary microglia do not express ApoD, but it can be internalized and targeted to lysosomes, where unlike other cell types it is transiently present. Cytokine secretion profiles and myelin phagocytosis reveal that ApoD has both long-term pre-conditioning effects on microglia as well as acute effects on these microglial immune functions, without significant modification of cell survival. ApoD-triggered cytokine signatures are stimuli (paraquat vs. Aβ oligomers) and sex-dependent. Acute exposure to ApoD induces microglia to switch from their resting state to a secretory and less phagocytic phenotype, while long-term absence of ApoD leads to attenuated cytokine induction and increased myelin uptake, supporting a role for ApoD as priming or immune training factor. This knowledge should help to advance our understanding of the complex responses of microglia during aging and neurodegeneration, where signals received along our lifespan are combined with damage-triggered acute signals, conditioning both beneficial roles and limitations of microglial functions.

Modulation of Glial Responses by Furanocembranolides: Leptolide Diminishes Microglial Inflammation in Vitro and Ameliorates Gliosis In Vivo in a Mouse Model of Obesity and Insulin Resistance

Wed, 01 Jan 2020 00:00:00 GMT

Neurodegenerative diseases are age-related disorders caused by progressive neuronal death in different regions of the nervous system. Neuroinflammation, modulated by glial cells, is a crucial event during the neurodegenerative process; consequently, there is an urgency to find new therapeutic products with anti-glioinflammatory properties. Five new furanocembranolides (1−5), along with leptolide, were isolated from two different extracts of Leptogorgia sp., and compound 6 was obtained from chemical transformation of leptolide. Their structures were determined based on spectroscopic evidence. These seven furanocembranolides were screened in vitro by measuring their ability to modulate interleukin-1β (IL-1β) production by microglial BV2 cells after LPS (lipopolysaccharide) stimulation. Leptolide and compounds 3, 4 and 6 exhibited clear anti-inflammatory effects on microglial cells, while compound 2 presented a pro-inflammatory outcome. The in vitro results prompted us to assess anti-glioinflammatory effects of leptolide in vivo in a high-fat diet-induced obese mouse model. Interestingly, leptolide treatment ameliorated both microgliosis and astrogliosis in this animal model. Taken together, our results reveal a promising direct biological effect of furanocembranolides on microglial cells as bioactive anti-inflammatory molecules. Among them, leptolide provides us a feasible therapeutic approach to treat neuroinflammation concomitant with metabolic impairment.

Lipid-Binding Proteins in Brain Health and Disease

Tue, 01 Jan 2019 00:00:00 GMT

A proper lipid management is paramount for a healthy brain. Lipid homeostasis alterations are known to be causative or risk factors for many neurodegenerative diseases, or key elements in the recovery from nervous system injuries of different etiology. In addition to lipid biogenesis and catabolism, non-enzymatic lipid-binding proteins play an important role in brain function and maintenance through aging. Among these types of lipoproteins, apolipoprotein E has received much attention due to the relationship of particular alleles of its gene with the risk and progression of Alzheimer's disease. However, other lipid-binding proteins whose role in lipid homeostasis and control are less known need to be brought to the attention of both researchers and clinicians. The aim of this review is to cover the knowledge of lipid-managing proteins in the brain, with particular attention to new candidates to be relevant for brain function and health.

Elastin‐like recombinamers as substrates for retinal pigment epithelial cell growth

Sat, 01 Jan 2011 00:00:00 GMT

The aim of this study is to investigate the use of elastin-like recombinamers (ELRs) as a substrate that can maintain the growth, phenotype, and functional characteristics of retinal pigment epithelial (RPE) cells efficiently and as a suitable carrier for the transplantation of autologous RPE cells for treatment of age-related macular degeneration (AMD). ELR films containing a bioactive sequence, RGD (ELR-RGD), and one with no specific sequence (ELR-IK) as control, were obtained by solvent-casting onto glass and subsequent cross-linking. ARPE19 cells were seeded on sterilized ELR films as well as on the control surfaces. Cells were analysed after 4, 24, 72, and 120 h to study cell adhesion, proliferation, cell viability, morphology, and specificity by staining with Trypan blue, DAPI, Rhodamin-Phalloidin and RPE65, ZO-1 antibodies and observing under fluorescence as well as electron microscope. ARPE19 cells seeded on both ELR films and controls were 100% viable and maintained their morphology and set of characteristics at the different time points studied. Cell proliferation on ELR-RGD was significantly higher than that found on ELR-IK at all time points, although it was less than the growth rate on polystyrene. ARPE19 cells grow well on ELR-RGD maintaining their phenotype. These results should be extended to further studies with fresh human RPE cells and in vivo studies to determine whether this ELR-RGD matrix could be used as a Bruch's membrane prosthesis and carrier for transplantation of RPE cells in patients suffering with AMD.

Cellular uptake of multilayered capsules produced with natural and genetically engineered biomimetic macromolecules

Wed, 01 Jan 2014 00:00:00 GMT

Multilayered microcapsules of chitosan and biomimetic elastin-like recombinamers (ELRs) were prepared envisaging the intracellular delivery of active agents. Two ELRs containing either a bioactive RGD sequence or a scrambled non-functional RDG were used to construct two types of functionalized polymeric microcapsules, both of spherical shape ∼4 μm in diameter. Cell viability studies with human mesenchymal stem cells (hMSCs) were performed using microcapsule/cell ratios between 5:1 and 100:1. After 3 and 72 h of co-incubation, no signs of cytotoxicity were found, but cells incubated with RGD-functionalized microcapsules exhibited higher viability values than RDG cells. The internalization efficacy and bioavailability of encapsulated DQ-ovalbumin were assessed by monitoring the fluorescence changes in the cargo. The data show that surface functionalization did not significantly influence internalization by hMSCs, but the bioavailability of DQ-ovalbumin degraded faster when encapsulated within RGD-functionalized microcapsules. The microcapsules developed show promise for intracellular drug delivery with increased drug efficacy.

Soft Hydrogel Inspired by Elastomeric Proteins

Fri, 01 Jan 2021 00:00:00 GMT

Elastin polypeptides based on -VPGVG- repeated motifs are widely used in the production of biomaterials because they are stimuli-responsive systems. On the other hand, glycine-rich sequences, mainly present in tropoelastin terminal domains, are responsible for the elastin self-assembly. In a previous study, we have recombinantly expressed a chimeric polypeptide, named resilin, elastin, and collagen (REC), inspired by glycine-rich motifs of elastin and containing resilin and collagen sequences as well. Herein, a three-block polypeptide, named (REC)3, was expressed starting from the previous monomer gene by introducing key modifications in the sequence. The choice was mandatory because the uneven distribution of the cross-linking sites in the monomer precluded the hydrogel production. In this work, the cross-linked polypeptide appeared as a soft hydrogel, as assessed by rheology, and the linear un-cross-linked trimer self-aggregated more rapidly than the REC monomer. The absence of cell-adhesive sequences did not affect cell viability, while it was functional to the production of a material presenting antiadhesive properties useful in the integration of synthetic devices in the body and preventing the invasion of cells.

Elastin‐like recombinamers: Biosynthetic strategies and biotechnological applications

Sat, 01 Jan 2011 00:00:00 GMT

The past few decades have witnessed the development of novel naturally inspired biomimetic materials, such as polysaccharides and proteins. Likewise, the seemingly exponential evolution of genetic-engineering techniques and modern biotechnology has led to the emergence of advanced protein-based materials with multifunctional properties. This approach allows extraordinary control over the architecture of the polymer, and therefore, monodispersity, controlled physicochemical properties, and high sequence complexity that would otherwise be impossible to attain. Elastin-like recombinamers (ELRs) are emerging as some of the most prolific of these protein-based biopolymers. Indeed, their inherent properties, such as biocompatibility, smart nature, and mechanical qualities, make these recombinant polymers suitable for use in numerous biomedical and nanotechnology applications, such as tissue engineering, “smart” nanodevices, drug delivery, and protein purification. Herein, we present recent progress in the biotechnological applications of ELRs and the most important genetic engineering-based strategies used in their biosynthesis.

A comparative study of cell behavior on different energetic and bioactive polymeric surfaces made from elastin-like recombinamers

Sun, 01 Jan 2012 00:00:00 GMT

This work explores cell behavior as a function of the topographic (fibers vs. films) and bioactive (RGD inclusion) design of multifunctional surfaces obtained from elastin-like recombinamers (ELRs). The surfaces have been analyzed for their differential roughness, wettability, and surface free-energy, as their precise contribution and importance of controlling critical aspects of cell behavior were investigated. The results suggest that the highest proliferative capacity of cells on the highly hydrophilic surfaces is more closely related to the surface properties than to the presence of adhesion sequences, although they act as an accelerating factor. However, on energetically unfavorable surfaces, bioactivity acquires decisive significance in ensuring cell adhesion and proliferation.