María Mulet

Hospital Universitari Arnau de Vilanova

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Xavier Gallart‐Palau

Biomedical Research Institute of Lleida

Aida Serra

Biomedical Research Institute of Lleida

Cristina Lorca

Hospital Universitari Arnau de Vilanova

José Antonio Sánchez Milán

Biomedical Research Institute of Lleida

Julia Lisa

Hospital Universitari Arnau de Vilanova

Catalina Arévalo‐Caro

Universidad Nacional de Colombia

Elisabet Vilella

Universidad Rovira i Virgili

José Miguel Blasco‐Ibáñez

Universitat de València

Alicia Aguilar

University of the Philippines Manila

María Fernández‐Rhodes

Biomedical Research Institute of Lleida

Cooperative Institutions

Universitat de Lleida

Instituto de Salud Carlos III

Biomedical Research Institute of Lleida

Universidad Autónoma de Madrid

Universitat de València

Centro de Investigación Biomédica en Red de Salud Mental

Hospital Universitari Arnau de Vilanova

Centro de Investigación Biomédica en Red

Nanyang Technological University

IMDEA Food

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Altered ureido protein modification profiles in seminal plasma extracellular vesicles of non-normozoospermic men

Frontiers in Endocrinology (2023)

R. Roy Cristina Lorca María Mulet José Antonio Sánchez Milán Alejandro Baratas

Extracellular vesicles (EVs) have been recognized as key players in numerous physiological functions. These vesicles alter their compositions attuned to the health and disease states of the organism. In men, significant changes in the proteomic composition(s) of seminal plasma EVs (sEVs) have already been found to be related to infertility. Methods: In this study, we analyze the posttranslational configuration of sEV proteomes from normozoospermic (NZ) men and non-normozoospermic (non-NZ) men diagnosed with teratozoospermia and/or asthenozoospermia by unbiased, discovery-driven proteomics and advanced bioinformatics, specifically focusing on citrulline (Cit) and homocitrulline (hCit) posttranscriptional residues, both considered product of ureido protein modifications. Significant increase in the proteome-wide cumulative presence of hCit together with downregulation of Cit in specific proteins related to decisive molecular functions have been encountered in sEVs of non-NZ subjects. These findings identify novel culprits with a higher chance of affecting fundamental aspects of sperm functional quality and define potential specific diagnostic and prognostic non-invasive markers for male infertility.

Asthenozoospermia

Proteome

Extracellular Vesicles

10.3389/fendo.2023.1113824

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Citations (8)

Trioxidized cysteine in the aging proteome mimics the structural dynamics and interactome of phosphorylated serine

Aging Cell (2023)

José Antonio Sánchez Milán María Fernández‐Rhodes Xue Guo María Mulet SoFong Cam Ngan

Abstract Aging is the primary risk factor for the development of numerous human chronic diseases. On a molecular level, it significantly impacts the regulation of protein modifications, leading to the accumulation of degenerative protein modifications (DPMs) such as aberrant serine phosphorylation (p‐Ser) and trioxidized cysteine (t‐Cys) within the proteome. The altered p‐Ser is linked to abnormal cell signaling, while the accumulation of t‐Cys is associated with chronic diseases induced by oxidative stress. Despite this, the potential cross‐effects and functional interplay between these two critical molecular factors of aging remain undisclosed. This study analyzes the aging proteome of wild‐type C57BL/6NTac mice over 2 years using advanced proteomics and bioinformatics. Our objective is to provide a comprehensive analysis of how t‐Cys affects cell signaling and protein structure in the aging process. The results obtained indicate that t‐Cys residues accumulate in the aging proteome, interact with p‐Ser interacting enzymes, as validated in vitro, and alter their structures similarly to p‐Ser. These findings have significant implications for understanding the interplay of oxidative stress and phosphorylation in the aging process. Additionally, they open new venues for further research on the role(s) of these protein modifications in various human chronic diseases and aging, wherein exacerbated oxidation and aberrant phosphorylation are implicated.

Proteome

Interactome

10.1111/acel.14062

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Citations (8)

Plant-derived nootropics and human cognition: A systematic review

Critical Reviews in Food Science and Nutrition (2022)

Cristina Lorca María Mulet Catalina Arévalo‐Caro Marco A. Piña Sánchez Ainhoa Perez

Substances with modulatory capabilities on certain aspects of human cognition have been revered as nootropics from the dawn of time. The plant kingdom provides most of the currently available nootropics of natural origin. Here, in this systematic review, we aim to provide state-of-the-art information regarding proven and unproven effects of plant-derived nootropics (PDNs) on human cognition in conditions of health and disease. Six independent searches, one for each neurocognitive domain (NCD), were performed in parallel using three independent scientific library databases: PubMed, Cochrane and Scopus. Only scientific studies and systematic reviews with humans published between January 2000 and November 2021 were reviewed, and 256 papers were included. Ginkgo biloba was the most relevant nootropic regarding perceptual and motor functions. Bacopa monnieri improves language, learning and memory. Withania somnifera (Ashwagandha) modulates anxiety and social-related cognitions. Caffeine enhances attention and executive functions. Together, the results from the compiled studies highlight the nootropic effects and the inconsistencies regarding PDNs that require further research.Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2021.2021137

Nootropic

Neurocognitive

10.1080/10408398.2021.2021137

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Citations (25)

Trioxidized cysteine and aging: a molecular binomial that extends far beyond classical proteinopathic paradigms

Aging (2024)

José Antonio Sánchez Milán María Mulet Aida Serra Xavier Gallart‐Palau

Increased oxidative stress (OS) and the disruption of the equilibrium between the production of reactive oxygen species and antioxidants are key molecular features of unhealthy aging. OS results in the formation of oxidative posttranslational modifications (PTMs), some of which involve cysteine (Cys) residues in aging proteomes, and specifically, the formation of trioxidized Cys (t-Cys), which leads to permanent protein damage. Recent findings in rodents have uncovered that irregular regulation of t-Cys residues in the aging proteome disrupts homeostatic phosphorylation signaling, resulting in alterations to proteins that are analogous to those caused by phosphorylated serine (p-Ser) residues. This work contextualizes these significant findings and discusses the implications and molecular role(s) of t-Cys in the aging proteome. Furthermore, we present novel data, validating the increase of specific t-Cys sites associated with aging in a blood-related circulating human proteome. The scope and findings included here support the hypothesis that t-Cys residues may serve as important mechanistic and biological markers, warranting further exploration in the context of unhealthy aging and age-related major diseases.

Binomial (polynomial)

10.18632/aging.206036

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Citations (6)

Periodontal Indices as Predictors of Cognitive Decline: Insights from the PerioMind Colombia Cohort

Biomedicines (2025)

Catalina Arévalo‐Caro Diego López José Antonio Sánchez Milán Cristina Lorca María Mulet

Background: Poor oral health and periodontitis have been epidemiologically linked to cognitive decline and mild cognitive impairment (MCI) in older adults. However, specific metrics directly linking these clinical signs are exceedingly limited. Methods: To address this gap and develop novel tools to help clinicians identify individuals at risk of cognitive decline, we established the PerioMind Colombia Cohort, comprising elderly Colombian subjects who underwent comprehensive neurocognitive and periodontal evaluations. Results: The results revealed that subjects diagnosed with MCI exhibited significantly higher scores in specific periodontal indices, including gingival erythema and pocket depth parameters. The predictive model identified positive associations with MCI, with gingival erythema showing the strongest correlation, followed by the presence of periodontitis and variations in pocket depth measurements. Additionally, lower educational attainment was associated with a higher likelihood of being classified in the periodontitis-MCI group. Conclusions: Here, we show that specific altered periodontal metrics are associated with MCI diagnosis, and the generated results provide defined metric ranges for identifying individuals at risk. Upon validation in larger cohorts, the findings reported here could offer dental practitioners and clinicians innovative tools to identify individuals at risk of MCI and age-related dementias through routine oral health assessments, thereby enabling more accessible and highly sought-after early intervention strategies in both developing and developed countries.

Neurocognitive

Cognitive Decline

10.3390/biomedicines13010205

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Citations (0)

Plant-derived nootropics and human cognition: A systematic review

Figshare (2022)

Cristina Lorca María Mulet Catalina Arévalo‐Caro Marco A. Piña Sánchez Ainhoa Perez

Substances with modulatory capabilities on certain aspects of human cognition have been revered as nootropics from the dawn of time. The plant kingdom provides most of the currently available nootropics of natural origin. Here, in this systematic review, we aim to provide state-of-the-art information regarding proven and unproven effects of plant-derived nootropics (PDNs) on human cognition in conditions of health and disease. Six independent searches, one for each neurocognitive domain (NCD), were performed in parallel using three independent scientific library databases: PubMed, Cochrane and Scopus. Only scientific studies and systematic reviews with humans published between January 2000 and November 2021 were reviewed, and 256 papers were included. Ginkgo biloba was the most relevant nootropic regarding perceptual and motor functions. Bacopa monnieri improves language, learning and memory. Withania somnifera (Ashwagandha) modulates anxiety and social-related cognitions. Caffeine enhances attention and executive functions. Together, the results from the compiled studies highlight the nootropic effects and the inconsistencies regarding PDNs that require further research.

10.6084/m9.figshare.17727297.v1

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Citations (0)

Brain extracellular vesicles in psychoticism display novel molecular clues associated to higher prevalence of age-related dementia

Journal of the Neurological Sciences (2023)

Fenghe Zhang Cristina Lorca José María Sánchez María Mulet Julia Lisa

Psychoticism

Extracellular Vesicles

10.1016/j.jns.2023.121393

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Citations (0)

Morphological alterations in the hippocampus of the Ts65Dn mouse model for Down Syndrome correlate with structural plasticity markers.

PubMed (2018)

Olga Villarroya Raúl Ballestín Rosa López‐Hidalgo María Mulet José Miguel Blasco‐Ibáñez

Down syndrome (DS) is the most common chromosomal aneuploidy. Although trisomy on chromosome 21 can display variable phenotypes, there is a common feature among all DS individuals: the presence of intellectual disability. This condition is partially attributed to abnormalities found in the hippocampus of individuals with DS and in the murine model for DS, Ts65Dn. To check if all hippocampal areas were equally affected in 4-5 month adult Ts65Dn mice, we analysed the morphology of dentate gyrus granule cells and cornu ammonis pyramidal neurons using Sholl method on Golgi-Cox impregnated neurons. Structural plasticity has been analysed using immunohistochemistry for plasticity molecules followed by densitometric analysis (Brain Derived Neurotrophic Factor (BDNF), Polysialylated form of the Neural Cell Adhesion Molecule (PSA-NCAM) and the Growth Associated Protein 43 (GAP43)). We observed an impairment in the dendritic arborisation of granule cells, but not in the pyramidal neurons in the Ts65Dn mice. When we analysed the expression of molecules related to structural plasticity in trisomic mouse hippocampus, we observed a reduction in the expression of BDNF and PSA-NCAM, and an increment in the expression of GAP43. These alterations were restricted to the regions related to dentate granule cells suggesting an interrelation. Therefore the impairment in dendritic arborisation and molecular plasticity is not a general feature of all Down syndrome principal neurons. Pharmacological manipulations of the levels of plasticity molecules could provide a way to restore granule cell morphology and function.

Granule cell

10.14670/hh-11-894

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Citations (5)

Early increased density of cyclooxygenase-2 (COX-2) immunoreactive neurons in Down syndrome

Folia Neuropathologica (2017)

María Mulet José Miguel Blasco‐Ibáñez Carlos Crespo Juan Nácher Emilio Varea

Neuroinflammation is one of the hallmarks of Alzheimer's disease. One of the enzymes involved in neuroinflammation, even in early stages of the disease, is COX-2, an inducible cyclooxygenase responsible for the generation of eicosanoids and for the generation of free radicals. Individuals with Down syndrome develop Alzheimer's disease early in life. Previous studies pointed to the possible overexpression of COX-2 and correlated it to brain regions affected by the disease. We analysed the COX-2 expression levels in individuals with Down syndrome and in young, adult and old mice of the Ts65Dn mouse model for Down syndrome. We have observed an overexpression of COX-2 in both, Down syndrome individuals and mice. Importantly, mice already presented an overexpression of COX-2 at postnatal day 30, before neurodegeneration begins; which suggests that neuroinflammation may underlie the posterior neurodegeneration observed in individuals with Down syndrome and in Ts65Dn mice and could be a factor for the premature appearance of Alzheimer's disease..

10.5114/fn.2017.68582

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Citations (7)

Phenotypic characterization of MCP-1 expressing neurons in the rat cerebral cortex

Journal of Chemical Neuroanatomy (2020)

María Mulet José Miguel Blasco‐Ibáñez Martina Kirstein Carlos Crespo Juan Nácher

Neocortex

Neurochemical

Interneuron

10.1016/j.jchemneu.2020.101785

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Citations (2)