María C. Ovejero‐Benito

Universidad San Pablo CEU

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Francisco Abad‐Santos

Universidad Autónoma de Madrid

E. Daudén

Hospital Universitario de La Princesa

Mar Llamas‐Velasco

Hospital Universitario de La Princesa

Ester Muñoz‐Aceituno

Hospital Universitario de La Princesa

Alejandra Reolid

Hospital Universitario de La Princesa

Miriam Saiz‐Rodríguez

Hospital Universitario de Burgos

Manuel Román

Hospital Universitario de La Princesa

Ancor Sanz‐García

University of Castilla-La Mancha

José M. Frade

Instituto Cajal

Patricia Sánchez‐Jiménez

Hospital Universitario de La Princesa

Cooperative Institutions

Hospital Universitario de La Princesa

Universidad Autónoma de Madrid

Instituto de Salud Carlos III

Universidad San Pablo CEU

Universidad Complutense de Madrid

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

Centro de Investigación Biomédica en Red

Hospital Universitario 12 De Octubre

Spanish Clinical Research Network

Consejo Superior de Investigaciones Científicas

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Histone modifications associated with biological drug response in moderate‐to‐severe psoriasis

Experimental Dermatology (2018)

María C. Ovejero‐Benito Alejandra Reolid Patricia Sánchez‐Jiménez Miriam Saiz‐Rodríguez Ester Muñoz‐Aceituno

Abstract Introduction Epigenetic factors play an important role in psoriasis onset and development. Biological drugs are used to treat moderate‐to‐severe psoriasis patients resistant to conventional systemic drugs. Although they are safe and effective, some patients do not respond to them. Therefore, it is necessary to find biomarkers that could predict response to these therapies. Objective To find epigenetic biomarkers that could predict response to biological drugs (ustekinumab, secukinumab, adalimumab, ixekizumab). Materials and methods Peripheral blood mononuclear cells ( PBMC s) were isolated from 39 psoriasis patients treated with biological therapies before and after drug administration and from 42 healthy subjects. Afterwards, histones were extracted from PBMC s. Four histone modifications (H3 and H4 acetylation, H3K4 and H3K27 methylation) were determined by ELISA . Data were analysed by IBM ‐ SPSS v.23. Results and conclusions Psoriasis patients presented reduced levels of acetylated H3 and H4 and increased levels of methylated H3K4 compared to controls. Non‐significant changes were observed after treatment administration in any of the histone modifications analysed. Nevertheless, significant changes in methylated H3K27 were found between responders and non‐responders to biological drugs at 3 months. As 28% of these patients also presented psoriatic arthritis (PsA), the former analysis was repeated in the subsets of patients with or without PsA. In patients without PsA, significant changes in methylated H3K4 were found between responders and non‐responders to biological drugs at 3 and 6 months. Although further studies should confirm these results, these findings suggest that H3K27 and H3K4 methylation may contribute to patients’ response to biological drugs in psoriasis.

Ixekizumab

Ustekinumab

10.1111/exd.13790

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Citations (62)

p27^Kip1participates in the regulation of endoreplication in differentiating chick retinal ganglion cells

Cell Cycle (2015)

María C. Ovejero‐Benito José M. Frade

Nuclear DNA duplication in the absence of cell division (i.e. endoreplication) leads to somatic polyploidy in eukaryotic cells. In contrast to some invertebrate neurons, whose nuclei may contain up to 200,000-fold the normal haploid DNA amount (C), polyploid neurons in higher vertebrates show only 4C DNA content. To explore the mechanism that prevents extra rounds of DNA synthesis in these latter cells we focused on the chick retina, where a population of tetraploid retinal ganglion cells (RGCs) has been described. We show that differentiating chick RGCs that express the neurotrophic receptors p75 and TrkB while lacking retinoblastoma protein, a feature of tetraploid RGCs, also express p27Kip1. Two different short hairpin RNAs (shRNA) that significantly downregulate p27Kip1 expression facilitated DNA synthesis and increased ploidy in isolated chick RGCs. Moreover, this forced DNA synthesis could not be prevented by Cdk4/6 inhibition, thus suggesting that it is triggered by a mechanism similar to endoreplication. In contrast, p27Kip1 deficiency in mouse RGCs does not lead to increased ploidy despite previous observations have shown ectopic DNA synthesis in RGCs from p27Kip1−/− mice. This suggests that a differential mechanism is used for the regulation of neuronal endoreplication in mammalian versus avian RGCs.

Endoreduplication

10.1080/15384101.2015.1044175

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Citations (7)

Transcriptomic Profiling Unveils Novel Therapeutic Options for Drug-Resistant Temporal Lobe Epilepsy

medRxiv (Cold Spring Harbor Laboratory) (2024)

Patricia Sánchez‐Jiménez Lola Alonso Laura Cerrada-Gálvez Marcos Elizalde-Horcada Inmaculada Granero‐Cremades

ABSTRACT Background Epilepsy drug treatments fail in 25-30% of patients, who then develop drug resistance. Temporal lobe epilepsy is the most prevalent subtype associated with drug resistance. Classical drug discovery is a long and extremely costly process with a high rate of failure in clinical trials. Drug repurposing is a more cost- and time-effective strategy. Hence, the main objective of this study is to propose drug candidates for the treatment of drug-resistant temporal lobe epilepsy (DR-TLE) through drug repurposing based on transcriptomic profiling. Methods Total RNA-sequencing (RNA-Seq) was performed on 45 formalin-fixed paraffin-embedded (FFPE) hippocampi of DR-TLE patients and 36 FFPE hippocampi of post-mortem biobank donors. RNA-Seq was carried out in an Illumina NovaSeq 6000 platform in 100bp paired-end. Drug repurposing based on transcriptomic analysis top candidates was performed against these databases: Pandrugs2, PharmOmics, DGIdb, ToppGene, L1000CDS 2 and Connectivity Map. Results We found 887 genes differentially expressed between DR-TLE patients and post-mortem controls. We observed 74 potential drug candidates in at least two independent databases. Of these, we selected only the 11 which can cross the blood-brain barrier: cobimetinib, panobinostat, melphalan, rucaparib, alectinib, ponatinib, danazol, carboplatin, vandetanib, erlotinib, and gefitinib. After analyzing their safety and efficacy profile based on previous publications, we provide a list of the top 5 candidates. Conclusions We therefore propose erlotinib, danazol, rucaparib, ponatinib, and panobinostat as potential therapies for DR-TLE based on differential RNA-Seq profiling.

Profiling (computer programming)

Drug Resistant Epilepsy

10.1101/2024.06.26.24309519

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Growth Arrest and DNA Damage-Inducible Proteins (GADD45) in Psoriasis

Research Square (Research Square) (2020)

Pedro Rodríguez‐Jiménez Lola Fernández‐Messina María C. Ovejero‐Benito P. Chicharro Alicia Vara

Abstract The interplay between T cells, dendritic cells and keratinocytes is crucial in the development and maintenance of inflammation in psoriasis. GADD45 proteins mediate DNA repair in many cells including keratinocytes. In the immune system, GADD45a and GADD45b regulate the function and activation of both T lymphocytes and dendritic cells and GADD45a links DNA repair and epigenetic regulation by mediating demethylation. Here, we analyzed the expression of GADD45a and GADD45b in the skin, dendritic cells and circulating T cells from psoriasis patients and their regulation by inflammatory signals. Psoriasis patients exhibited a lower expression of GADD45a at the epidermis but a higher expression in dermal infiltrating T cells in lesional skin. Expression of GADD45a and GADD45b was also higher in peripheral T cells from psoriasis patients, although no differences were observed in p38 activation. The expression and methylation state of the GADD45a target UCHL1 were evaluated, revealing a hypermethylation of its promoter in lesional skin compared to non-lesional skin and controls. Furthermore, hypermethylation correlated with lower levels of both GADD45a and UCHL1 in lesional skin. The demethylase function of GADD45a may account for its pleiotropic effects, and the complex and heterogeneous pattern of expression observed in psoriatic disease.

DNA demethylation

Epidermis (zoology)

Demethylase

10.21203/rs.3.rs-111019/v1

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Pharmacogenetics of Trazodone in Healthy Volunteers: Association with Pharmacokinetics, Pharmacodynamics and Safety

Pharmacogenomics (2017)

Miriam Saiz‐Rodríguez Carmen Belmonte Nieves Derqui Teresa Cabaleiro Manuel Román

The aim was to evaluate the effect of polymorphisms in metabolizing enzymes and transporters on the pharmacokinetics, pharmacodynamics and adverse effects of trazodone in healthy volunteers.36 healthy volunteers receiving a single 100-mg oral dose of trazodone were genotyped for 11 variants in CYP3A4, CYP3A5, CYP2D6 and ABCB1 by real-time PCR. Plasma concentrations were measured using liquid chromatography-tandem mass spectrometry method.Sex affected the pharmacokinetics of trazodone with higher clearance in women. Polymorphisms in ABCB1, but not in CYP3A or CYP2D6, influenced trazodone pharmacokinetics. Trazodone decreased blood pressure and prolonged the corrected QT interval interval. CYP2D6 and ABCB1 polymorphisms were associated with the incidence of dizziness and prolonged corrected QT interval, respectively. Subjects with adverse drug reactions had lower concentrations of trazodone suggesting its metabolite (m-chlorophenylpiperazine) could be responsible for these effects.

Trazodone

Pharmacodynamics

CYP3A

Active metabolite

10.2217/pgs-2017-0116

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Citations (17)

Neuronal cell cycle: the neuron itself and its circumstances

Cell Cycle (2015)

José M. Frade María C. Ovejero‐Benito

Neurons are usually regarded as postmitotic cells that undergo apoptosis in response to cell cycle reactivation. Nevertheless, recent evidence indicates the existence of a defined developmental program that induces DNA replication in specific populations of neurons, which remain in a tetraploid state for the rest of their adult life. Similarly, de novo neuronal tetraploidization has also been described in the adult brain as an early hallmark of neurodegeneration. The aim of this review is to integrate these recent developments in the context of cell cycle regulation and apoptotic cell death in neurons. We conclude that a variety of mechanisms exists in neuronal cells for G1/S and G2/M checkpoint regulation. These mechanisms, which are connected with the apoptotic machinery, can be modulated by environmental signals and the neuronal phenotype itself, thus resulting in a variety of outcomes ranging from cell death at the G1/S checkpoint to full proliferation of differentiated neurons.

10.1080/15384101.2015.1004937

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Citations (224)

Polymorphisms Associated with Etanercept Response in Moderate-To-Severe Plaque Psoriasis

Pharmacogenomics (2017)

María C. Ovejero‐Benito Rocío Prieto‐Pérez Mar Llamas‐Velasco Carmen Belmonte Teresa Cabaleiro

Aim: Few studies have evaluated the influence of pharmacogenetics in psoriatic patients treated with etanercept. Materials & methods: We evaluated the association between 124 polymorphisms with the response to etanercept in patients with moderate-to-severe plaque psoriasis at 3 months (n = 78) and 6 months of treatment (n = 68). Results: The results of the multivariate analysis showed an association between polymorphisms rs13437088 (HLA-B/MICA), rs96844 (MAP3K1), rs2431697 (PTTG1), rs9304742 (ZNF816A) and the response to etanercept at 3 months. Besides polymorphisms rs928655 (GBP6) and rs2546890 (IL12B) were associated to response at 6 months. Conclusions. Nevertheless, these biomarkers should be validated in large-scale studies before its implementation in clinical practice.

10.2217/pgs-2017-0014

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Citations (31)

CNVs Associated with Different Clinical Phenotypes of Psoriasis and Anti-TNF-Induced Palmoplantar Pustulosis

Journal of Personalized Medicine (2022)

Alejandra Reolid Antonio Sahuquillo‐Torralba Ancor Sanz‐García Rafael Botella‐Estrada Ester Muñoz‐Aceituno

Background: Psoriasis can present different phenotypes and could affect diverse body areas. In contrast to the high effectiveness of biological drugs in the treatment of trunk and extremities plaque psoriasis, in palmoplantar phenotypes and in plaque scalp psoriasis, these same drugs usually have reduced efficacy. Anti-TNF drugs could induce the appearance of palmoplantar pustulosis (PPP) in patients with other inflammatory diseases. The objective of this study is to identify if there are DNA Copy Number Variations (CNVs) associated with these different clinical phenotypes, which could justify the differences found in clinical practice. Moreover, we intend to elucidate if anti-TNF-induced PPP has a similar genetic background to idiopathic PPP. Methods: Skin samples were collected from 39 patients with different patterns of psoriasis and six patients with anti-TNF-induced PPP. The CNVs were obtained from methylation array data (Illumina Infinium Human Methylation) using the conumee R package. Results: No significant CNVs were found between the different phenotypes and the locations of psoriasis compared. Nevertheless, we found two significant bins harboring five different genes associated with anti-TNF-induced PPP in patients with a different background other than psoriasis. Conclusions: Our results may help to predict which patients could develop anti-TNF-induced PPP.

Palmoplantar pustulosis

10.3390/jpm12091452

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Citations (1)

DNA Methylation Description of Hippocampus, Cortex, Amygdala, and Blood of Drug-Resistant Temporal Lobe Epilepsy

Molecular Neurobiology (2023)

Patricia Sánchez‐Jiménez Marcos Elizalde-Horcada Ancor Sanz‐García Inmaculada Granero‐Cremades María de Toledo

10.1007/s12035-022-03180-z

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Citations (9)

Epigenetics in Non-tumor Immune-Mediated Skin Diseases

Molecular Diagnosis & Therapy (2021)

Alejandra Reolid Ester Muñoz‐Aceituno Francisco Abad‐Santos María C. Ovejero‐Benito E. Daudén

10.1007/s40291-020-00507-1

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Citations (5)