Oscar Fraile‐Martínez

Instituto Ramón y Cajal de Investigación Sanitaria

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Co-Authors

MÁ

Miguel Á. Ortega

Universidad de Alcalá

120

MÁ

Melchor Álvarez‐Mon

Universidad de Alcalá

115

Cielo García‐Montero

Instituto Ramón y Cajal de Investigación Sanitaria

108

Natalio García‐Honduvilla

Instituto Cajal

Julia Buján

Universidad de Alcalá

MÁ

Miguel Ángel Álvarez-Mon

Hospital Universitario Infanta Leonor

Miguel A. Sáez

Universidad de Alcalá

Luis G. Guijarro

Universidad de Alcalá

Jorge Monserrat

Instituto Cajal

Raúl Dı́az

Instituto Ramón y Cajal de Investigación Sanitaria

Cooperative Institutions

Universidad de Alcalá

142

Instituto Cajal

Instituto Ramón y Cajal de Investigación Sanitaria

Hospital Universitario Príncipe de Asturias

Universidad Complutense de Madrid

Hospital General Universitario Gregorio Marañón

Haute École de Bruxelles

Gdańsk Medical University

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

Instituto de Salud Carlos III

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Elevated tissue expression of RANKL and RANK is associated with poorer survival rates in pancreatic cancer patients.

PubMed (2023)

Miguel Á. Ortega Laura Jiménez‐Alvárez Oscar Fraile‐Martínez Cielo García‐Montero Diego De León-Oliva

Pancreatic cancer is a highly lethal malignancy with a growing incidence reported worldwide. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, which is often diagnosed at advanced stages, making its prognosis and medical management difficult. The identification of histopathological biomarkers has allowed a more precise stratification of pancreatic cancer patients, providing additional information about their prognosis and offering possible therapeutic targets to be explored. The prognostic value of the receptor activator of nuclear factor-kappa B (RANK) and its ligand (RANKL) has been evaluated in breast and prostate tumors, however, their usefulness has not been assessed in pancreatic cancer. In the present work, we analyzed the relationship between the protein expression of RANK and RANKL with the survival of 41 patients with pancreatic cancer followed for 60 months, by performing immunohistochemistry and Kaplan-Meier curves. Our results demonstrate a direct association of high expression levels of RANK and RANKL with poorer survival of pancreatic cancer patients in comparison to those with low/medium and null expression levels of both markers. Further studies should be conducted to explore the carcinogenic role of both components in this type of tumor, as well as additional promising translational uses.

10.14670/hh-18-700

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Evidence of Increased Oxidative Stress in the Placental Tissue of Women Who Suffered an Episode of Psychosis during Pregnancy

Antioxidants (2023)

Miguel Á. Ortega Oscar Fraile‐Martínez Cielo García‐Montero Sonia Rodriguez-Martín Rosa M. Funes Moñux

Psychosis is a complex clinical syndrome resulting in a loss of contact with reality and alterations in behavior and sensorial and motor functions. Although the onset of psychosis can be related to any medical condition, most cases of psychosis are not fully understood. Psychosis may manifest for the first time during pregnancy, which is detrimental to maternofetal well-being. The impact of having a first episode of psychosis during pregnancy on the placenta has not yet been explored. Oxidative stress is thought to take part in the etiopathogenesis of this complex disorder, and this condition can also affect the placenta as it is highly sensitive to changes in the maternal environment. In this sense, the aim of the present work was to study the gene and protein expression through RT-qPCR and immunohistochemistry, respectively, of oxidative stress markers (NOX-1, NOX-2, iNOS, eNOS and PARP) in the placental tissue of women who underwent a first episode of psychosis during pregnancy (FE-PW) in comparison to healthy pregnant women. Our results showed augmented gene and protein expression of NOX-1, NOX-2, iNOS and PARP in the placental tissue of FE-PW. For the first time, we demonstrated that oxidative stress may have an important pathophysiological role in this tissue, aiding in explaining the impact of psychosis on pregnancy and the need for future studies in this field to guide better clinical management of these patients.

10.3390/antiox12010179

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Prognostic Value of Malondialdehyde (MDA) in the Temporal Progression of Chronic Spinal Cord Injury

Journal of Personalized Medicine (2023)

Sergio Haro Jorge Monserrat Miguel Á. Ortega Cielo García‐Montero Oscar Fraile‐Martínez

Oxidative stress is a major signature of spinal cord injury (SCI). The altered levels of various oxidative stress markers have been demonstrated in acute and chronic SCI. However, the variation of these markers in patients with chronic SCI depending on the time since the initial injury has not been explored yet.Our aim was to measure plasma levels of malondialdehyde (MDA), a marker of lipid peroxidation in patients with SCI stratified in different periods of suffering the injury (0-5 years, 5-10 years, and more than 10 years).This cross-sectional study enrolled patients with SCI (N = 105) from different periods of the lesion and healthy control (HC) subjects (N = 38): short period (SCI SP, N = 31, time of evolution less than 5 years); early chronic (SCI ECP, N = 32, time of evolution 5-15 years); and late chronic (SCI LCP, N = 42, time of evolution more than 15 years). The plasma levels of MDA were measured using a commercially available colorimetric assay.Patients with SCI had significantly higher plasma levels of MDA than HC subjects. Receiver operating characteristic (ROC) curve analysis for plasma MDA levels in patients with SCI demonstrated areas under the curve (AUC) of 1 (HC vs. SCI-SP); 0.998 (HC vs. SCI-ECP); and 0.964 (HC vs. SCI-LCP). Additionally, three ROC curves were used to compare the different concentrations of MDA between the subgroups of patients with SCI, and the resulting AUCs were: 0.896 (SCI-SP vs. SCI-ECP); 0.840 (SCI-ECP vs. SCI-LCP); and 0.979 (SCI-SP vs. SCI-LCP).Plasma concentration of MDA can be considered as an oxidative stress biomarker to assess the prognosis of SCI in chronic stages.

Malondialdehyde

10.3390/jpm13040626

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Connecting epigenetics and inflammation in vascular senescence: state of the art, biomarkers and senotherapeutics

Frontiers in Genetics (2024)

Oscar Fraile‐Martínez Diego De León-Oliva Diego Liviu Boaru Patricia De Castro-Martinez Cielo García‐Montero

Vascular diseases pose major health challenges, and understanding their underlying molecular mechanisms is essential to advance therapeutic interventions. Cellular senescence, a hallmark of aging, is a cellular state characterized by cell-cycle arrest, a senescence-associated secretory phenotype macromolecular damage, and metabolic dysregulation. Vascular senescence has been demonstrated to play a key role in different vascular diseases, such as atherosclerosis, peripheral arterial disease, hypertension, stroke, diabetes, chronic venous disease, and venous ulcers. Even though cellular senescence was first described in 1961, significant gaps persist in comprehending the epigenetic mechanisms driving vascular senescence and its subsequent inflammatory response. Through a comprehensive analysis, we aim to elucidate these knowledge gaps by exploring the network of epigenetic alterations that contribute to vascular senescence. In addition, we describe the consequent inflammatory cascades triggered by these epigenetic modifications. Finally, we explore translational applications involving biomarkers of vascular senescence and the emerging field of senotherapy targeting this biological process.

Senescence

Cellular senescence

10.3389/fgene.2024.1345459

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Assessment of Tissue Expression of the Oxytocin–Vasopressin Pathway in the Placenta of Women with a First-Episode Psychosis during Pregnancy

International Journal of Molecular Sciences (2023)

Miguel Á. Ortega Cielo García‐Montero Oscar Fraile‐Martínez Diego De León-Oliva Diego Liviu Boaru

Psychosis refers to a mental health condition characterized by a loss of touch with reality, comprising delusions, hallucinations, disorganized thought, disorganized behavior, catatonia, and negative symptoms. A first-episode psychosis (FEP) is a rare condition that can trigger adverse outcomes both for the mother and newborn. Previously, we demonstrated the existence of histopathological changes in the placenta of pregnant women who suffer an FEP in pregnancy. Altered levels of oxytocin (OXT) and vasopressin (AVP) have been detected in patients who manifested an FEP, whereas abnormal placental expression of these hormones and their receptors (OXTR and AVPR1A) has been proven in different obstetric complications. However, the precise role and expression of these components in the placenta of women after an FEP have not been studied yet. Thus, the purpose of the present study was to analyze the gene and protein expression, using RT-qPCR and immunohistochemistry (IHC), of OXT, OXTR, AVP, and AVPR1a in the placental tissue of pregnant women after an FEP in comparison to pregnant women without any health complication (HC-PW). Our results showed increased gene and protein expression of OXT, AVP, OXTR, and AVPR1A in the placental tissue of pregnant women who suffer an FEP. Therefore, our study suggests that an FEP during pregnancy may be associated with an abnormal paracrine/endocrine activity of the placenta, which can negatively affect the maternofetal wellbeing. Nevertheless, additional research is required to validate our findings and ascertain any potential implications of the observed alterations.

Oxytocin receptor

10.3390/ijms241210254

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Nutritional Components in Western Diet Versus Mediterranean Diet at the Gut Microbiota–Immune System Interplay. Implications for Health and Disease

Nutrients (2021)

Cielo García‐Montero Oscar Fraile‐Martínez Ana M. Gómez-Lahoz Leonel Pekarek Alejandro J. Castellanos

The most prevalent diseases of our time, non-communicable diseases (NCDs) (including obesity, type 2 diabetes, cardiovascular diseases and some types of cancer) are rising worldwide. All of them share the condition of an “inflammatory disorder”, with impaired immune functions frequently caused or accompanied by alterations in gut microbiota. These multifactorial maladies also have in common malnutrition related to physiopathology. In this context, diet is the greatest modulator of immune system–microbiota crosstalk, and much interest, and new challenges, are arising in the area of precision nutrition as a way towards treatment and prevention. It is a fact that the westernized diet (WD) is partly responsible for the increased prevalence of NCDs, negatively affecting both gut microbiota and the immune system. Conversely, other nutritional approaches, such as Mediterranean diet (MD), positively influence immune system and gut microbiota, and is proposed not only as a potential tool in the clinical management of different disease conditions, but also for prevention and health promotion globally. Thus, the purpose of this review is to determine the regulatory role of nutritional components of WD and MD in the gut microbiota and immune system interplay, in order to understand, and create awareness of, the influence of diet over both key components.

Mediterranean Diet

10.3390/nu13020699

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Citations (279)

The RANK–RANKL–OPG System: A Multifaceted Regulator of Homeostasis, Immunity, and Cancer

Medicina (2023)

Diego De León-Oliva Silvestra Barrena-Blázquez Laura Jiménez‐Alvárez Oscar Fraile‐Martínez Cielo García‐Montero

The RANK-RANKL-OPG system is a complex signaling pathway that plays a critical role in bone metabolism, mammary epithelial cell development, immune function, and cancer. RANKL is a ligand that binds to RANK, a receptor expressed on osteoclasts, dendritic cells, T cells, and other cells. RANKL signaling promotes osteoclast differentiation and activation, which leads to bone resorption. OPG is a decoy receptor that binds to RANKL and inhibits its signaling. In cancer cells, RANKL expression is often increased, which can lead to increased bone resorption and the development of bone metastases. RANKL-neutralizing antibodies, such as denosumab, have been shown to be effective in the treatment of skeletal-related events, including osteoporosis or bone metastases, and cancer. This review will provide a comprehensive overview of the functions of the RANK-RANKL-OPG system in bone metabolism, mammary epithelial cells, immune function, and cancer, together with the potential therapeutic implications of the RANK-RANKL pathway for cancer management.

Denosumab

Bone remodeling

Osteoimmunology

10.3390/medicina59101752

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An Updated View of the Importance of Vesicular Trafficking and Transport and Their Role in Immune-Mediated Diseases: Potential Therapeutic Interventions

Membranes (2022)

Miguel Á. Ortega Oscar Fraile‐Martínez Cielo García‐Montero Miguel Ángel Álvarez-Mon Ana M. Gómez-Lahoz

Cellular trafficking is the set of processes of distributing different macromolecules by the cell. This process is highly regulated in cells, involving a system of organelles (endomembranous system), among which are a great variety of vesicles that can be secreted from the cell, giving rise to different types of extracellular vesicles (EVs) that can be captured by other cells to modulate their function. The cells of the immune system are especially sensitive to this cellular traffic, producing and releasing different classes of EVs, especially in disease states. There is growing interest in this field due to the therapeutic and translational possibilities it offers. Different ways of taking advantage of the understanding of cell trafficking and EVs are being investigated, and their use as biomarkers or therapeutic targets is being investigated. The objective of this review is to collect the latest results and knowledge in this area with a specific focus on immune-mediated diseases. Although some promising results have been obtained, further knowledge is still needed, at both the basic and translational levels, to understand and modulate cellular traffic and EVs for better clinical management of these patients.

Extracellular Vesicles

Cell type

Organelle

10.3390/membranes12060552

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Citations (17)

Placentas from Women with Late-Onset Preeclampsia Exhibit Increased Expression of the NLRP3 Inflammasome Machinery

Biomolecules (2023)

Luis M. García-Puente Oscar Fraile‐Martínez Cielo García‐Montero Julia Buján Juan A. De León-Luis

Pre-eclampsia is a harmful and potentially lethal medical condition during pregnancy clinically diagnosed by hypertension and commonly accompanied by proteinuria and multiorgan affections. According to the time of diagnosis, it is differentiated between early-onset (EO-PE) and late-onset preeclampsia (LO-PE). Despite being less dangerous and presenting distinct pathophysiological signatures, LO-PE has a greater prevalence than EO-PE, both having significant consequences on the placenta. Previous works have evidenced that exacerbated inflammation in this organ might play a potential pathogenic role in the development of pre-eclampsia, and there is some preliminary evidence that the hyperactivation of inflammasomes can be related to the altered immunoinflammatory responses observed in the placentas of these patients. However, the precise role of inflammasomes in the placentas of women with LO-PE remains to be fully understood. In this work, we have studied the gene and protein expression of the main components related to the canonical and non-canonical pathways of the inflammasome NLRP3 (NLRP3, ASC, caspase 1, caspase 5, caspase 8, interleukin 1β, and interleukin 18) in the placental tissue of women with LO-PE. Our results show a marked increase in all these components in the placentas of women who have undergone LO-PE, suggesting that NLRP3 inflammasome plays a potentially pathophysiological role in the development of this entity. Future works should aim to evaluate possible translational approaches to this dysregulation in these patients.

Pyrin domain

Pathophysiology

Pyroptosis

10.3390/biom13111644

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An Overview of the Role of MicroRNAs on Carcinogenesis: A Focus on Cell Cycle, Angiogenesis and Metastasis

International Journal of Molecular Sciences (2023)

Leonel Pekarek Diego Torres‐Carranza Oscar Fraile‐Martínez Cielo García‐Montero Tatiana Pekarek

In recent years, the importance of epigenetic markers in the carcinogenesis of different malignant neoplasms has been demonstrated, also demonstrating their utility for understanding metastatic spread and tumor progression in cancer patients. Among the different biomarkers, microRNAs represent a set of non-coding RNAs that regulate gene expression, having been involved in a wide variety of neoplasia acting in different oncogenic pathways. Both the overexpression and downregulation of microRNAs represent a complex interaction with various genes whose ultimate consequence is increased cell proliferation, tumor invasion and interaction with various driver markers. It should be noted that in current clinical practice, even though the combination of different microRNAs has been shown to be useful by different authors at diagnostic and prognostic levels, there are no diagnostic kits that can be used for the initial approach or to assess recurrences of oncological diseases. Previous works have cited microRNAs as having a critical role in several carcinogenic mechanisms, ranging from cell cycle alterations to angiogenesis and mechanisms of distant metastatic dissemination. Indeed, the overexpression or downregulation of specific microRNAs seem to be tightly involved in the modulation of various components related to these processes. For instance, cyclins and cyclin-dependent kinases, transcription factors, signaling molecules and angiogenic/antiangiogenic products, among others, have been recognized as specific targets of microRNAs in different types of cancer. Therefore, the purpose of this article is to describe the main implications of different microRNAs in cell cycle alterations, metastasis and angiogenesis, trying to summarize their involvement in carcinogenesis.

Tumor progression

10.3390/ijms24087268

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Citations (32)