José Manuel Pérez-Ortiz | Universidad Camilo José Cela (original) (raw)

Papers by José Manuel Pérez-Ortiz

Pharmaceutics

Molecular hybridization consists of the combination of two or more non-identical pharmacophores i... more Molecular hybridization consists of the combination of two or more non-identical pharmacophores in a single molecule. It has emerged as a promising strategy that allows the design of molecular frameworks with enhanced activity and affinity compared to their parent drugs. In this work, two novel hybrids that combine the well-known anticancer chemotherapeutic agent 5-fluorouracil with antioxidant coumarin derivatives have been synthesized and characterized by means of a copper-catalyzed azide-alkyne cycloaddition (CuAAC). The conjugates showed good antioxidant properties and a high tendency to aggregate and form stable nanoparticles in aqueous media, with regular shape and uniform size. These materials have proven to be preferential cytotoxic agents in vitro against human pancreatic cancer cells PANC-1, with an activity superior to free 5-fluorouracil. These results open up the possibility of exploiting the synergistic combination between 5-fluorouracil and coumarin derivatives and wa...

Journal of Drug Delivery Science and Technology

International Journal of Molecular Sciences, 2020

In this work, we sought to investigate the effects of a thiosulfinate-enriched garlic extract, co... more In this work, we sought to investigate the effects of a thiosulfinate-enriched garlic extract, co-administered with 5-fluorouracil (5-FU) or oxaliplatin chemotherapy, on the viability of colon cancer cells (Caco-2 and HT-29). We also addressed the economic feasibility of a new combined treatment of this thiosulfinate-enriched garlic extract, with oxaliplatin that could reduce the dosage and costs of a monotherapy. The thiosulfinate-enriched garlic extract not only enhanced the impact of 5-FU and oxaliplatin (500 µM) in decreasing Caco-2 and HT-29 viability, but also showed a higher effect than standard 5-FU and oxaliplatin chemotherapy as anti-cancer agents. These results provided evidences for the combination of lyophilized garlic extract and 5-FU or oxaliplatin as a novel chemotherapy regimen in colon cancer cells that may also reduce the clinical therapy costs.

Revista Española de Quimioterapia, 2021

Este estudio pretende hacer un análisis comparativo de los pacientes ingresados en el Hospital Ge... more Este estudio pretende hacer un análisis comparativo de los pacientes ingresados en el Hospital General Universitario de Ciudad Real (HGUCR) durante la primera y la segunda onda de COVID-19, con la intención de mejorar la comprensión de esta enfermedad para futuras ondas. El HGUCR atiende a una población de aproximadamente 200.000 habitantes. Se incluyó en el estudio a los adultos in

European Journal of Clinical Investigation, 2022

BackgroundSARS‐CoV‐2 virus requires host proteases to cleave its spike protein to bind to its ACE... more BackgroundSARS‐CoV‐2 virus requires host proteases to cleave its spike protein to bind to its ACE2 target through a two‐step furin‐mediated entry mechanism. Aprotinin is a broad‐spectrum protease inhibitor that has been employed as antiviral drug for other human respiratory viruses. Also, it has important anti‐inflammatory properties for inhibiting the innate immunity contact system.MethodsThis was a multicentre, double‐blind, randomized trial performed in four Spanish hospitals comparing standard treatment versus standard treatment + aprotinin for patients with COVID‐19 between 20 May 2020 and 20 October 2021. The primary efficacy outcomes were length of hospital stay and ICU admission. The secondary endpoints were each of the primary efficacy outcomes and a composite of oxygen therapy, analytical parameters and death. Safety outcomes included adverse reactions to treatment during a 30‐day follow‐up period. Treatment was given for 11 days or till discharge.ResultsWith almost identi...

Emergencias : revista de la Sociedad Espanola de Medicina de Emergencias, 2022

Food and Chemical Toxicology, 2021

High-fat diets (HFDs) can lead to pathological changes in the brain underlying several behavioral... more High-fat diets (HFDs) can lead to pathological changes in the brain underlying several behavioral disturbances (e.g., reward deficiency). To further increase our knowledge of these associations, we studied the sucrose reward and the brain expression of clusterin, a protein that is overexpressed after several kind of brain damaging conditions. C57BL/6J male mice were differentially fed on an HFD or standard chow for 41 days and underwent 11 sucrose place conditioning sessions followed by 4 extinction sessions to monitor the effects of HFD on sucrose reward by means of free choice tests. We quantified clusterin expression by immunochemistry in the nucleus accumbens, dorsal striatum and cingulate cortex. HFD tended to provoke a transient potentiation in the acquisition of sucrose-conditioned place preference, but this effect was followed by a much more consistent reduction in sucrose preference, which spontaneously disappeared after 31 days of an HFD with no need for extinction learning. The HFD mice showed higher clusterin expression in the nucleus accumbens but not in the other brain areas studied. The results confirm that HFDs strongly influence the rewarding properties of palatable foods and suggest a direct connection with neurotoxic alterations in the brain reward system tagged by clusterin overexpression.

Cancers, 2021

Chronic ultraviolet B (UV-B) irradiation is known to be one of the most important hazards acting ... more Chronic ultraviolet B (UV-B) irradiation is known to be one of the most important hazards acting on the skin and poses a risk of developing photoaging, skin with cutaneous field cancerization (CFC), actinic keratosis (AKs), and squamous cell carcinomas (SCCs). Most of the UV-B light is absorbed in the epidermis, affecting the outermost cell layers, the stratum corneum, and the stratum granulosum, which protects against this radiation and tries to maintain the permeability barrier. In the present work, we show an impairment in the transepidermal water loss, stratum corneum hydration, and surface pH after chronic UV-B light exposure in an immunologically intact mouse model (SKH1 aged mice) of skin with CFC. Macroscopic lesions of AKs and SCCs may develop synchronically or over time on the same cutaneous surface due to both the presence of subclinical AKs and in situ SCC, but also the accumulation of different mutations in keratinocytes. Focusing on skin with CFC, yet without the patho...

Nutrition, 2021

OBJECTIVE The aim of this study was to explore the influence of an enrolled degree course on heal... more OBJECTIVE The aim of this study was to explore the influence of an enrolled degree course on health and eating habits in a population of Spanish university students (17-26 y of age). METHODS A cross-sectional observational study was carried out with 648 students. Volunteers were stratified into biomedical (medicine and nursing, 48%) and non-biomedical students (other fields of study, 52%). Data were collected using previously self-reported questionnaires focused on anthropometric and sociodemographic profile, lifestyle practices, body image perception, health consciousness, eating habits, physical activity, and food addiction. Mann-Whitney U tests and Pearson's χ2 tests were applied to identify associations between the two groups. RESULTS Self-reported body mass index was higher for the non-biomedical group (22.1 ± 3.1 versus 23 ± 5 kg/m2; P < 0.05), which also reported less regularity in taking meals (91 versus 95%; P < 0.05), eating fewer colored vegetables and fruits (65 versus 77%; P < 0.001) and a higher alcohol intake (27 versus 20%; P < 0.001). In contrast, the proportion of students that showed more interest in the diet-health duality (92 versus 85%; P < 0.001) and a desire to adopt healthier habits (80 versus 78%; P < 0.05) was larger in the biomedical group. Dietary habits, obtained by means of a food frequency questionnaire, suggested that biomedical students make healthier food choices. Additionally, the group of biomedical students took more walks per week (5.8 ± 1.8 versus 5.5 ± 1.9; P < 0.05). CONCLUSIONS Healthier lifestyle factors cluster into the biomedical group in various components of the study, except food addiction where no differences were observed. The data presented here suggest the necessity to develop health promotion strategies targeting university students.

Applied Sciences, 2021

Up to now, there are no studies that have shown a decrease in morbidity and mortality in the cont... more Up to now, there are no studies that have shown a decrease in morbidity and mortality in the context of sepsis and septic shock, except for antibiotic therapy and the objective-guided resuscitation strategy. The goal was to evaluate the use of thiosulfinate-enriched Allium sativum extract (TASE) as an adjuvant in the management of sepsis. An experimental in vivo study was carried out with male Sprague Dawley® rats. Animals were randomized in three treatment groups: the control group (I), antibiotic (ceftriaxone) treatment group (II) and ceftriaxone plus TASE treatment group (III). All animals were housed and inoculated with 1 × 1010 CFU/15 mL of intraperitoneal Escherichia coli ATCC 25922. Subsequently, they received a daily treatment according to each group for 7 days. Clinical, analytical, microbiological, and histopathological parameters were evaluated. Statistically significant clinical improvement was observed in the ceftriaxone plus TASE vs. ceftriaxone group in weight, ocular...

Chinese Journal of Integrative Medicine, 2020

Cutaneous wound is a common health issue not only in the elderly, but also in younger people beca... more Cutaneous wound is a common health issue not only in the elderly, but also in younger people because of the rise of obesity and diabetes. (1-3) A delay in wound healing (WH) can result in an increased risk for infections and worsened scarring, leading to increased morbidity and medical costs. (1,4) Despite signifi cant improvements in wound dressings, topical treatments, and management of risk factors, such as obesity, diabetes or chronic venous insufficiency, cutaneous wound remains an important cause of morbidity, infections and scarring, even in the developed nations. (4) Hence, development of effective therapeutic approaches for accelerating wound closure, modulating infl ammation, preventing infection, and ultimately restoration of epidermal permeability barrier are of utmost importance. (5) Although wound dressings, silicone gels, and topical hyaluronic acid ABSTRACT ABSTRACT Objective Objective: To determine whether topical applications of thiosulfi nate-enriched : To determine whether topical applications of thiosulfi nate-enriched Allium sativum Allium sativum extract extract (TASE) can accelerate acute cutaneous wound healing (WH) in a murine model. (TASE) can accelerate acute cutaneous wound healing (WH) in a murine model. Methods Methods: Keratinocyte viability : Keratinocyte viability and and in vitro in vitro wound closure were assessed in keratinocyte cultures. Effects of topical TASE (0.5 wound closure were assessed in keratinocyte cultures. Effects of topical TASE (0.5 μg/mL of allicin g/mL of allicin in 97% ethanol) on acute cutaneous WH were determined in a murine model of acute cutaneous wound. Twelve in 97% ethanol) on acute cutaneous WH were determined in a murine model of acute cutaneous wound. Twelve mice were alternately assigned to the vehicle-and TASE-treated groups (mice were alternately assigned to the vehicle-and TASE-treated groups (n=6 per group). Expression levels of =6 per group). Expression levels of mRNA for keratinocyte differentiation marker-related proteins (fi laggrin, loricrin and involucrin) and lipid synthetic mRNA for keratinocyte differentiation marker-related proteins (fi laggrin, loricrin and involucrin) and lipid synthetic enzymes (elongation of very long chain fatty acids protein 4 (ELOVL4), fatty acid synthase (FA2H), 3-hydroxy-enzymes (elongation of very long chain fatty acids protein 4 (ELOVL4), fatty acid synthase (FA2H), 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCoA), and serine palmitoyltransferase (SPT)) were assessed 3-methyl-glutaryl-coenzyme A reductase (HMGCoA), and serine palmitoyltransferase (SPT)) were assessed using real-time quantitative polymerase chain reaction on day 3 and 8 after wounding, while transepidermal water using real-time quantitative polymerase chain reaction on day 3 and 8 after wounding, while transepidermal water loss (TEWL) rates were measured in wounded areas. loss (TEWL) rates were measured in wounded areas. Results Results: TASE accelerated WH both : TASE accelerated WH both in vivo in vivo (40% (40% vs vs. 22%. 22% reduction in wound area, reduction in wound area, P<0.01) and <0.01) and in vitro in vitro (90% (90% vs vs. 65% reduction in wound area,. 65% reduction in wound area, P<0.01). Moreover, topical <0.01). Moreover, topical applications of TASE upregulated the expression levels of epidermal mRNA for ELOVL4, HMGCoA, SPT, fi laggrin, applications of TASE upregulated the expression levels of epidermal mRNA for ELOVL4, HMGCoA, SPT, fi laggrin, loricrin and involucrin (loricrin and involucrin (P<0.05 <0.05 vs vs. vehicle-treated controls) on day 3 after wounding. Likewise, TASE signifi cantly. vehicle-treated controls) on day 3 after wounding. Likewise, TASE signifi cantly lowered TEWL rates in comparison with vehicle alone on day 8 (33.06±2.09 g/(m lowered TEWL rates in comparison with vehicle alone on day 8 (33.06±2.09 g/(m 2 • h) h) vs vs. 24.60±2.04 g/(m. 24.60±2.04 g/(m 2 • h), h), P<0.01). <0.01). Conclusions Conclusions: Topical applications of TASE stimulated keratinocyte proliferation and formation of epidermal : Topical applications of TASE stimulated keratinocyte proliferation and formation of epidermal permeability barrier function, leading to acceleration of acute cutaneous WH. Topical products containing TASE permeability barrier function, leading to acceleration of acute cutaneous WH. Topical products containing TASE could be used to manage acute cutaneous WH. could be used to manage acute cutaneous WH.

Revista de Neurología, 2008

Introduccion. El aumento de la prevalencia de la disfuncion cognitiva y la demencia, asociado, en... more Introduccion. El aumento de la prevalencia de la disfuncion cognitiva y la demencia, asociado, entre otros factores, al envejecimiento de la poblacion en los paises desarrollados, ha despertado un gran interes por el estudio de la etiopatogenesis del deficit cognitivo y de las posibles dianas farmacologicas para mejorar la funcion intelectual o frenar la neurodegeneracion subyacente en estos sintomas. Desarrollo y conclusiones. Un instrumento esencial a tal fin es la utilizacion de modelos animales de las enfermedades humanas que cursan clinicamente con deterioro cognitivo y demencia. En esta revision analizamos los modelos animales de estos trastornos y las principales pruebas que, mediante la observacion de la evolucion de la conducta del animal de experimentacion, permiten valorar sus funciones cognitivas y su modificacion por los tratamientos experimentales que se quieran ensayar, de cara a su posible aplicacion a los pacientes.

Addiction biology, Jan 21, 2016

A mouse model has been developed to study the effect of dietary fat combined with food deprivatio... more A mouse model has been developed to study the effect of dietary fat combined with food deprivation periods on palatable food seeking and on the expression of three potential addiction biomarkers in the nucleus accumbens: fumarate hydratase (FH), ATP synthase subunit alpha (ATP5a1) and transketolase (TKT). Forty C57BL/6 J male mice, four-week old, were fed either with a high-fat (HF) diet or standard diet along the experiment. After 3 weeks of differential feeding, animals underwent a two-week training period of two daily sessions where visual cues were paired either to palatable food (chocolate cereals) or no food at all. This training was prolonged one more week with similar, one daily sessions preceded by 12 hours of food deprivation. A behavioural test was finally conducted where mice were confined for 30 minutes either in food unpaired compartments or in compartments previously paired with cereals, but now with empty food trays. Total activity during this behavioural test and se...

British journal of pharmacology, 2014

BACKGROUND AND PURPOSE Heteromerization of GPCRs is key to the integration of extracellular signa... more BACKGROUND AND PURPOSE Heteromerization of GPCRs is key to the integration of extracellular signals and the subsequent cell response via several mechanisms including heteromer-selective ligand binding, trafficking and/or downstream signalling. As the lysophosphatidylinositol GPCR 55 (GPR55) has been shown to affect the function of the cannabinoid receptor subtype 2 (CB2 receptor) in human neutrophils, we investigated the possible heteromerization of CB2 receptors with GPR55. EXPERIMENTAL APPROACH The direct interaction of human GPR55 and CB2 receptors heterologously expressed in HEK293 cells was assessed by co-immunoprecipitation and bioluminescence resonance energy transfer assays. The effect of cross-talk on signalling was investigated at downstream levels by label-free real-time methods (Epic dynamic mass redistribution and CellKey impedance assays), ERK1/2-MAPK activation and gene reporter assays. KEY RESULTS GPR55 and CB2 receptors co-localized on the surface of HEK293 cells, co-precipitated in membrane extracts and formed heteromers in living HEK293 cells. Whereas heteromerization led to a reduction in GPR55-mediated activation of transcription factors (nuclear factor of activated T-cells, NF-κB and cAMP response element), ERK1/2-MAPK activation was potentiated in the presence of CB2 receptors. CB2 receptor-mediated signalling was also affected by co-expression with GPR55. Label-free assays confirmed cross-talk between the two receptors.

The Open Neuropsychopharmacology Journal, 2009

Neurobiology of Aging, 2012

The role of CB2 cannabinoid receptors in the behavioral and neurochemical changes induced by intr... more The role of CB2 cannabinoid receptors in the behavioral and neurochemical changes induced by intracaudate administration of 6-hydroxydopamine (6-OHDA) was evaluated. 6-OHDA (12 μg/4 μL) or its vehicle was injected in the caudate-putamen (CPu) of mice overexpressing the CB2 cannabinoid receptor (CB2xP) and wild type (WT) mice. Motor impairment, emotional behavior, and cognitive alterations were evaluated. Tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), and ionized calcium-binding adapter molecule 1 (Iba-1) were measured by immunocytochemistry in the CPu and/or substantia nigra (SN) of CB2xP mice and WT mice. Oxidative/nitrosative and neuroinflammatory parameters were also measured in the CPu and cortex of 6-OHDA-treated and sham-treated mice. 6-OHDA-treated CB2xP mice presented significantly less motor deterioration than 6-OHDA-treated WT mice. Immunocytochemical analysis of tyrosine hydroxylase in the SN and CPu revealed significantly fewer lesions in CB2xP mice than in WT mice. GFAP and Iba-1 immunostaining revealed less astrocyte and microglia recruitment to the treated area of the CPu in CB2xP mice. Malonyldialdehyde (MDA) concentrations were lower in the striatum and cerebral cortex of sham-treated CB2xP mice than in sham-treated WT mice. The administration of 6-OHDA increased MDA levels in both WT mice and CB2xP mice; it increased the oxidized (GSSG)/reduced (GSH) glutathione ratio in the striatum in WT mice alone compared with matched sham-treated controls. The results revealed that overexpression of CB2 cannabinoid receptors decreased the extent of motor impairment and dopaminergic neuronal loss, reduced the recruitment of astrocytes and microglia to the lesion, and decreased the level of various oxidative parameters. These results suggest that CB2 receptors offer neuroprotection against dopaminergic injury.

Psychoneuroendocrinology, 2013

Recent reports suggest that FKBP5 gene and its corresponding FKBP5 protein play a relevant role i... more Recent reports suggest that FKBP5 gene and its corresponding FKBP5 protein play a relevant role in the regulation of anxiety and depression in animal models and human stress-related disorders. In the present study, FKBP5 and glucocorticoid receptor (GR) gene and protein expression were analyzed in the amygdala (AMY) of suicide victims (n=13 males, without clinical psychiatric history and non-treated with anxiolytic or antidepressant drugs) and its corresponding controls (n=13 males) by real-time PCR and Western blotting. The results revealed that FKBP5 and GR gene expression were significantly reduced in the AMY (-38% and -48%, respectively) of suicide victims compared with controls. Interestingly, FKBP5 and GR protein expression were also significantly decreased (-41% and -42%, respectively) in the AMY of suicide victims compared with controls. These results suggest that the FKBP5 plays a relevant role in human emotional responses and suggest this receptor as a new promising target in the treatment of suicide behavior.

Metabolic Brain Disease, 2012

European Neuropsychopharmacology, 2010

European Neuropsychopharmacology, 2011