Publications by authors named "Santiago Vázquez"

83 Publications

Inhibition of Soluble Epoxide Hydrolase Ameliorates Phenotype and Cognitive Abilities in a Murine Model of Niemann Pick Type C Disease.

Int J Mol Sci 2021 Mar 26;22(7). Epub 2021 Mar 26.

Pharmacology and Toxicology Section and Institute of Neuroscience, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain.

Niemann-Pick type C (NPC) disease is a rare autosomal recessive inherited childhood neurodegenerative disease characterized by the accumulation of cholesterol and glycosphingolipids, involving the autophagy-lysosome system. Inhibition of soluble epoxide hydrolase (sEH), an enzyme that metabolizes epoxy fatty acids (EpFAs) to 12-diols, exerts beneficial effects in modulating inflammation and autophagy, critical features of the NPC disease. This study aims to evaluate the effects of UB-EV-52, an sEH inhibitor (sEHi), in an NPC mouse model (Npc) by administering it for 4 weeks (5 mg/kg/day). Behavioral and cognitive tests (open-field test (OF)), elevated plus maze (EPM), novel object recognition test (NORT) and object location test (OLT) demonstrated that the treatment produced an improvement in short- and long-term memory as well as in spatial memory. Furthermore, UB-EV-52 treatment increased body weight and lifespan by 25% and reduced gene expression of the inflammatory markers (i.e., and ) and enhanced oxidative stress (OS) markers () in the treated Npc mice group. As for autophagic markers, surprisingly, we found significantly reduced levels of LC3B-II/LC3B-I ratio and significantly reduced brain protein levels of lysosomal-associated membrane protein-1 (LAMP-1) in treated Npc mice group compared to untreated ones in hippocampal tissue. Lipid profile analysis showed a significant reduction of lipid storage in the liver and some slight changes in homogenated brain tissue in the treated NPC mice compared to the untreated groups. Therefore, our results suggest that pharmacological inhibition of sEH ameliorates most of the characteristic features of NPC mice, demonstrating that sEH can be considered a potential therapeutic target for this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22073409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036710PMC
March 2021

Incommensurability: An Obstacle to the Integration of Psychotherapy and Spirituality. The Desert Fathers as an Overcoming Epistemological Paradigm.

Rev Colomb Psiquiatr 2021 Mar 23. Epub 2021 Mar 23.

Conicet, Mendoza, Argentina.

In recent years, the body of literature that deals with trying different ways of integrating spirituality into psychotherapeutic practice has grown exponentially. Probably the interest in this topic has arisen with regard to the inclusion in the DSM-IV of the new category "Religious or Spiritual Problem" (Code V62.89). Until then, religious or spiritual issues had been viewed in the clinical practice as symptoms of some mental illnesses like, for example, the delusions with religious content typical of schizophrenics. But with the fourth edition of the aforementioned manual, there began to be an interest in the study of spirituality as it expresses a fundamental aspect of personality. In this vein, various models of integration of spirituality and psychotherapy have been formulated. Our intention is to study the problem of incommensurability as one of the epistemological and methodological problems that supposes a project of this type. We present the writings of the Desert Fathers as an explanatory model that guarantees an epistemologically legitimate integration of spiritual traditions with psychotherapeutic practice. And for that reason, we argue that their writings could constitute a way to overcome the relationship of mutual incommensurability that apparently exists between scientific rationality and spirituality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.rcp.2020.12.003DOI Listing
March 2021

Rebuild the Academy: Supporting academic mothers during COVID-19 and beyond.

PLoS Biol 2021 03 9;19(3):e3001100. Epub 2021 Mar 9.

Department of Animal Ecology and Systematics, Justus Liebig University Giessen, Giessen, Germany.

The issues facing academic mothers have been discussed for decades. Coronavirus Disease 2019 (COVID-19) is further exposing these inequalities as womxn scientists who are parenting while also engaging in a combination of academic related duties are falling behind. These inequities can be solved by investing strategically in solutions. Here we describe strategies that would ensure a more equitable academy for working mothers now and in the future. While the data are clear that mothers are being disproportionately impacted by COVID-19, many groups could benefit from these strategies. Rather than rebuilding what we once knew, let us be the architects of a new world.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pbio.3001100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942998PMC
March 2021

Synthesis, Characterization and HPLC Analysis of the (1,2,5)-Diastereomer and the Enantiomer of the Clinical Candidate AR-15512.

Molecules 2021 Feb 9;26(4). Epub 2021 Feb 9.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació, Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain.

AR-15512 (formerly known as AVX-012 and WS-12) is a TRPM8 receptor agonist currently in phase 2b clinical trials for the treatment of dry eye. This bioactive compound with menthol-like cooling activity has three stereogenic centers, and its final structure and absolute configuration, (1,2,5), have been previously solved by cryo-electron microscopy. The route of synthesis of AR-15512 has also been reported, revealing that epimerization processes at the C-1 can occur at specific stages of the synthesis. In order to confirm that the desired configuration of AR-15512 does not change throughout the process and to discard the presence of the enantiomer in the final product due to possible contamination of the initial starting material, both the enantiomer of AR-15512 and the diastereomer at the C-1 were synthesized and fully characterized. In addition, the absolute configuration of the (1,2,5)-diastereomer was determined by X-ray crystallographic analysis, and new HPLC methods were designed and developed for the identification of the two stereoisomers and their comparison with the clinical candidate AR-15512.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules26040906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914790PMC
February 2021

Bilateral hypopyon in syphilitic uveitis.

Am J Ophthalmol Case Rep 2021 Mar 31;21:101007. Epub 2020 Dec 31.

University of Puerto Rico, Medical Sciences Campus, School of Medicine, Department of Ophthalmology, San Juan, PR, USA.

Purpose: To report an atypical bilateral hypopyon presentation of syphilitic uveitis.

Observations: A 38-year-old male presented with a 2-day history of bilateral progressive visual loss, conjunctival hyperemia, and photophobia. Initial ophthalmologic examination revealed bilateral hypopyon and vitritis that limited the examination of the posterior segment. The physical exam revealed cervical lymphadenopathy, glossal leukoplakia, erythematous maculae on the hard palate, erythematous macular lesions on both palms, onychodystrophy, onycholysis, and psoriasiform plaques on both plantar surfaces, testicular tenderness, and hypopigmented patches on the scrotal and perianal skin. A therapeutic and diagnostic vitrectomy was performed on the right eye, and the intraoperative findings were consistent with severe vitritis and pre-retinal precipitates. The cytopathologic analysis of the right vitreous revealed a mixed inflammatory process composed of lymphocytes, histiocytes, and neutrophils in a proteinaceous background. Laboratory testing revealed positive serum RPR, CSF FTA-Abs and VDRL, and HIV serology. Treatment with a 2-week course of intravenous penicillin G 4 million units every 4 hours and topical corticosteroids resulted in complete resolution of the uveitis.

Conclusions And Importance: Bilateral hypopyon uveitis may be a rare presentation of syphilitic uveitis. As with most forms of uveitis, syphilis should be considered in the differential diagnosis of patients presenting with bilateral hypopyon.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajoc.2020.101007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788489PMC
March 2021

2-Oxaadamant-1-yl Ureas as Soluble Epoxide Hydrolase Inhibitors: Evaluation in a Murine Model of Acute Pancreatitis.

J Med Chem 2020 09 25;63(17):9237-9257. Epub 2020 Aug 25.

Laboratori de Quı́mica Farmacèutica (Unitat Associada al CSIC), Departament de Farmacologia, Toxicologia i Quı́mica Terapèutica, Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain.

pharmacological inhibition of soluble epoxide hydrolase (sEH) reduces inflammatory diseases, including acute pancreatitis (AP). Adamantyl ureas are very potent sEH inhibitors, but the lipophilicity and metabolism of the adamantane group compromise their overall usefulness. Herein, we report that the replacement of a methylene unit of the adamantane group by an oxygen atom increases the solubility, permeability, and stability of three series of urea-based sEH inhibitors. Most of these oxa-analogues are nanomolar inhibitors of both the human and murine sEH. Molecular dynamics simulations rationalize the molecular basis for their activity and suggest that the presence of the oxygen atom on the adamantane scaffold results in active site rearrangements to establish a weak hydrogen bond. The 2-oxaadamantane , which has a good solubility, microsomal stability, and selectivity for sEH, was selected for further and studies in models of cerulein-induced AP. Both in prophylactic and treatment studies, diminished the overexpression of inflammatory and endoplasmic reticulum stress markers induced by cerulein and reduced the pancreatic damage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c00310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755424PMC
September 2020

Chemical Probes for Blocking of Influenza A M2 Wild-type and S31N Channels.

ACS Chem Biol 2020 09 27;15(9):2331-2337. Epub 2020 Aug 27.

Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis-Zografou, Athens 15771, Greece.

We report on using the synthetic aminoadamantane-CH-aryl derivatives - as sensitive probes for blocking M2 S31N and influenza A virus (IAV) M2 wild-type (WT) channels as well as virus replication in cell culture. The binding kinetics measured using electrophysiology (EP) for M2 S31N channel are very dependent on the length between the adamantane moiety and the first ring of the aryl headgroup realized in and and the girth and length of the adamantane adduct realized in and . Study of - shows that, according to molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations, all bind in the M2 S31N channel with the adamantyl group positioned between V27 and G34 and the aryl group projecting out of the channel with the phenyl (or isoxazole in ) embedded in the V27 cluster. In this outward binding configuration, an elongation of the ligand by only one methylene in rimantadine or using diamantane or triamantane instead of adamantane in and , respectively, causes incomplete entry and facilitates exit, abolishing effective block compared to the amantadine derivatives and . In the active M2 S31N blockers and , the phenyl and isoxazolyl head groups achieve a deeper binding position and high /low and high /high rate constants, compared to inactive -, which have much lower and higher . Compounds - block the M2 WT channel by binding in the longer area from V27-H37, in the inward orientation, with high and low rate constants. Infection of cell cultures by influenza virus containing M2 WT or M2 S31N is inhibited by - or - and , respectively. While and block infection through the M2 block mechanism in the S31N variant, - may block M2 S31N virus replication in cell culture through the lysosomotropic effect, just as chloroquine is thought to inhibit SARS-CoV-2 infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acschembio.0c00553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051587PMC
September 2020

Toxicological analysis of serious drug-related harm among electronic dance music festival attendees in New South Wales, Australia: A consecutive case series.

Drug Alcohol Depend 2020 May 28;213:108070. Epub 2020 May 28.

Clinical Quality and Safety, Centre for Population Health, New South Wales Ministry of Health, St Leonards 2065, NSW, Australia.

Background: A substantial increase in drug-related harm was observed during the 2018-2019 music festival season in New South Wales, Australia, including the deaths of five young people. As part of a rapid public health response, the New South Wales Ministry of Health referred samples from patients with suspected severe drug-related illness for forensic toxicological testing to identify the type and concentration of substances associated with the presentations.

Methods: Cases were identified through a variety of active and passive surveillance systems, and selected consecutively based on indicators of clinical severity. Comprehensive toxicology testing of blood and urine samples was expedited for all cases. Demographic and clinical characteristics were collated, together with quantitative toxicology results. Results were analysed using descriptive statistics.

Results: Forty cases from eleven different music festivals were included. The majority of cases (80.0%) were aged 25 years and under. There were five fatalities, and 62.5% of cases were admitted to intensive care units. MDMA was the most frequent substance, detected in 87.5% of cases. In 82.9% of cases with MDMA, blood concentrations were above thresholds that have been associated with toxicity. Multiple substances were detected in 60.0% of cases. Novel psychoactive substances were not detected.

Conclusions: Our findings strongly suggest that MDMA-related toxicity was a major factor in the severity of the clinical presentations among these cases. Other substances may have enhanced MDMA toxicity but appear unlikely to have caused severe toxicity in isolation. These findings have important implications for harm reduction strategies targeted to music festival settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.drugalcdep.2020.108070DOI Listing
May 2020

Pharmacological Inhibition of Soluble Epoxide Hydrolase as a New Therapy for Alzheimer's Disease.

Neurotherapeutics 2020 10;17(4):1825-1835

Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine, University of Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain.

The inhibition of the enzyme soluble epoxide hydrolase (sEH) has demonstrated clinical therapeutic effects in several peripheral inflammatory-related diseases, with 3 compounds in clinical trials. However, the role of this enzyme in the neuroinflammation process has been largely neglected. Herein, we disclose the pharmacological validation of sEH as a novel target for the treatment of Alzheimer's disease (AD). Evaluation of cognitive impairment and pathological hallmarks were used in 2 models of age-related cognitive decline and AD using 3 structurally different and potent sEH inhibitors as chemical probes. sEH is upregulated in brains from AD patients. Our findings supported the beneficial effects of central sEH inhibition, regarding reducing cognitive impairment, neuroinflammation, tau hyperphosphorylation pathology, and the number of amyloid plaques. This study suggests that inhibition of inflammation in the brain by targeting sEH is a relevant therapeutic strategy for AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13311-020-00854-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851240PMC
October 2020

Soluble Epoxide Hydrolase Inhibition to Face Neuroinflammation in Parkinson's Disease: A New Therapeutic Strategy.

Biomolecules 2020 05 1;10(5). Epub 2020 May 1.

Pharmacology Section, Department of Pharmacology, Toxicology, and Therapeutic Chemistry. Faculty of Pharmacy and Food Sciences. Institute of Neuroscience, University of Barcelona (NeuroUB), Av. Joan XXIII 27-31, 08028 Barcelona, Spain.

Neuroinflammation is a crucial process associated with the pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD). Several pieces of evidence suggest an active role of lipid mediators, especially epoxy-fatty acids (EpFAs), in the genesis and control of neuroinflammation; 14,15-epoxyeicosatrienoic acid (14,15-EET) is one of the most commonly studied EpFAs, with anti-inflammatory properties. Soluble epoxide hydrolase (sEH) is implicated in the hydrolysis of 14,15-EET to its corresponding diol, which lacks anti-inflammatory properties. Preventing EET degradation thus increases its concentration in the brain through sEH inhibition, which represents a novel pharmacological approach to foster the reduction of neuroinflammation and by end neurodegeneration. Recently, it has been shown that sEH levels increase in brains of PD patients. Moreover, the pharmacological inhibition of the hydrolase domain of the enzyme or the use of sEH knockout mice reduced the deleterious effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. This paper overviews the knowledge of sEH and EETs in PD and the importance of blocking its hydrolytic activity, degrading EETs in PD physiopathology. We focus on imperative neuroinflammation participation in the neurodegenerative process in PD and the putative therapeutic role for sEH inhibitors. In this review, we also describe highlights in the general knowledge of the role of sEH in the central nervous system (CNS) and its participation in neurodegeneration. We conclude that sEH is one of the most promising therapeutic strategies for PD and other neurodegenerative diseases with chronic inflammation process, providing new insights into the crucial role of sEH in PD pathophysiology as well as a singular opportunity for drug development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biom10050703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277900PMC
May 2020

Treatment of erythrodermic psoriasis with biologics: A systematic review.

J Am Acad Dermatol 2020 Jul 2;83(1):151-158. Epub 2020 Apr 2.

Department of Dermatology, University of Puerto Rico School of Medicine, San Juan, Puerto Rico.

Background: Biologic medications for plaque psoriasis have been used to treat erythrodermic psoriasis (EP). Since the guidelines for management of EP were published, new biologic medications have been approved for the treatment of plaque psoriasis.

Objective: To analyze the evidence of biologic medications in the treatment of EP based on response and tolerability.

Methods: A comprehensive search was conducted with the PubMed, Cochrane Library, Embase, and Scopus databases through December 31, 2018. Studies reporting 1 or more cases of EP, defined as >75% body surface area involvement, in patients aged ≥18 years treated with biologics were included. Baseline Psoriasis Area and Severity Index score, score improvement, and adverse events were documented. Adequate response to treatment was defined as Psoriasis Area and Severity Index ≥50.

Results: Included were 43 articles, yielding a total of 179 patients. Most patients responded at some point during treatment, with a higher level of evidence for infliximab, ustekinumab, ixekizumab, and guselkumab. Infection was the most common adverse event (n = 35).

Limitations: Data are limited to case reports, case series, and uncontrolled studies.

Conclusion: Patients with EP treated with biologics demonstrated positive responses and treatment was well-tolerated, with a weak recommendation and limited quality of evidence in favor of infliximab, ustekinumab, ixekizumab, and guselkumab.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaad.2020.03.073DOI Listing
July 2020

A Novel NMDA Receptor Antagonist Protects against Cognitive Decline Presented by Senescent Mice.

Pharmaceutics 2020 Mar 22;12(3). Epub 2020 Mar 22.

Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, University of Barcelona (NeuroUB), Av. Joan XXIII 27-31, 08028 Barcelona, Spain.

Alzheimer's disease (AD) is the leading cause of dementia. Non-competitive N-Methyl-D-aspartate (NMDA) receptor antagonist memantine improved cognition and molecular alterations after preclinical treatment. Nevertheless, clinical results are discouraging. In vivo efficacy of the RL-208, a new NMDA receptor blocker described recently, with favourable pharmacokinetic properties was evaluated in Senescence accelerated mice prone 8 (SAMP8), a mice model of late-onset AD (LOAD). Oral administration of RL-208 improved cognitive performance assessed by using the three chamber test (TCT), novel object recognition test (NORT), and object location test (OLT). Consistent with behavioural results, RL-208 treated-mice groups significantly changed NMDAR2B phosphorylation state levels but not NMDAR2A. Calpain-1 and Caspase-3 activity was reduced, whereas B-cell lymphoma-2 (BCL-2) levels increased, indicating reduced apoptosis in RL-208 treated SAMP8. Superoxide Dismutase 1 (SOD1) and Glutathione Peroxidase 1 (GPX1), as well as a reduction of hydrogen peroxide (HO), was also determined in RL-208 mice. RL-208 treatment induced an increase in mature brain-derived neurotrophic factor (mBDNF), prevented Tropomyosin-related kinase B full-length (TrkB-FL) cleavage, increased protein levels of Synaptophysin (SYN) and Postsynaptic density protein 95 (PSD95). In whole, these results point out to an improvement in synaptic plasticity. Remarkably, RL-208 also decreased the protein levels of Cyclin-Dependent Kinase 5 (CDK5), as well as p25/p35 ratio, indicating a reduction in kinase activity of CDK5/p25 complex. Consequently, lower levels of hyperphosphorylated Tau (p-Tau) were found. In sum, these results demonstrate the neuroprotectant role of RL-208 through NMDAR blockade.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/pharmaceutics12030284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151078PMC
March 2020

Pharmacological inhibition of G9a/GLP restores cognition and reduces oxidative stress, neuroinflammation and β-Amyloid plaques in an early-onset Alzheimer's disease mouse model.

Aging (Albany NY) 2019 12 4;11(23):11591-11608. Epub 2019 Dec 4.

Pharmacology Section, Department of Pharmacology, Toxicology, and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, University of Barcelona (NeuroUB), Barcelona 08028, Spain.

The implication of epigenetic mechanisms in Alzheimer's disease (AD) has been demonstrated in several studies. UNC0642, a specific and potent inhibitor of methyltransferase activity G9a/GLP (G9a-like) complex, was evaluated in the 5XFAD mouse model. UNC0642 treatment rescued 5XFAD cognition impairment, reduced DNA-methylation (5-mC), increased hydroxymethylation (5-hmC), and decreased the di-methylation of lysine 9 of histone H3 (H3K9me2) levels in the hippocampus. Increases in the Nuclear Factor erythroid-2-Related Factor 2 (NRF2), ( gene expression, and diminution in Reactive Oxygen Species (ROS) were also reported. Moreover, neuroinflammatory markers, such as () gene expression, and Glial fibrillary acidic protein (GFAP) immunofluorescence were reduced by UNC0642 treatment. An increase in gene expression, Brain-derived neurotrophic factor (BDNF), and Synaptophysin (SYN) were found after UNC0642 treatment. Importantly, a reduction in β-amyloid plaques was also observed. In conclusion, our work demonstrates that the inhibition of the G9a/GLP complex by UNC0642 delivered significant neuroprotective effects in 5XFAD mice, point out G9a/GLP as a new target for AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.102558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6932909PMC
December 2019

Comparative Study of Coupling Techniques in Lamb Wave Testing of Metallic and Cementitious Plates.

Sensors (Basel) 2019 Sep 20;19(19). Epub 2019 Sep 20.

Instituto de Ciencia y Tecnología del Hormigón (ICITECH), Universitat Politècnica de València, Camino de Vera, s/n, 46022 Valencia, Spain.

Lamb waves have emerged as a valuable tool to examine long plate-like structures in a faster way compared to conventional bulk wave techniques, which make them attractive in non-destructive testing. However, they present a multimodal and dispersive nature, which hinders signal identification. Oblique incidence is one of the most known methods to generate and receive Lamb waves and it is applied in different experimental arrangements with different types of sensors. In this work, several setups were conducted and compared to determine the optimal ones to launch and detect ultrasonic Lamb waves, especially in non-homogeneous specimens. The chosen arrangements were contact with angle beam transducers, immersion in a water tank, localised water coupling using conical containers and air coupling. Plates of two different materials were used, stainless steel and Portland cement mortar. Theoretical and experimental dispersion curves were compared to verify the existence of Lamb modes and good correspondence was achieved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/s19194068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806287PMC
September 2019

Exploring the size of the lipophilic unit of the soluble epoxide hydrolase inhibitors.

Bioorg Med Chem 2019 10 26;27(20):115078. Epub 2019 Aug 26.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII 27-31, Barcelona E-08028, Spain. Electronic address:

Soluble epoxide hydrolase (sEH) inhibitors are potential drugs for several diseases. Adamantyl ureas are excellent sEH inhibitors but have limited metabolic stability. Herein, we report the effect of replacing the adamantane group by alternative polycyclic hydrocarbons on sEH inhibition, solubility, permeability and metabolic stability. Compounds bearing smaller or larger polycyclic hydrocarbons than adamantane yielded all good inhibition potency of the human sEH (0.4 ≤ IC ≤ 21.7 nM), indicating that sEH is able to accommodate inhibitors of very different size. Human liver microsomal stability of diamantane containing inhibitors is lower than that of their corresponding adamantane counterparts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2019.115078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892585PMC
October 2019

11β-HSD1 Inhibition Rescues SAMP8 Cognitive Impairment Induced by Metabolic Stress.

Mol Neurobiol 2020 Jan 9;57(1):551-565. Epub 2019 Aug 9.

Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av Joan XXIII 27-31, 08028, Barcelona, Spain.

Ageing and obesity have been shown to increase the risk of cognitive decline and Alzheimer's disease (AD). Besides, elevated glucocorticoid (GCs) levels cause metabolic stress and have been associated with the neurodegenerative process. Direct pieces of evidence link the reduction of GCs caused by the inhibition of 11β-HSD type 1 (11β-HSD1) with cognitive improvement. In the present study, we investigated the beneficial effects of 11β-HSD1 inhibitor (i) RL-118 after high-fat diet (HFD) treatment in the senescence-accelerated mouse prone 8 (SAMP8). We found an improvement in glucose intolerance induced by HFD in mice treated with RL-118, a significant reduction in 11β-HSD1 and glucocorticoid receptor (GR) protein levels. Furthermore, specific modifications in the FGF21 activation after treatment with 11β-HSD1i, RL-118, which induced changes in SIRT1/PGC1α/AMPKα pathway, were found. Oxidative stress (OS) and reactive oxygen species (ROS), as well as inflammatory markers and microglial activation, were significantly diminished in HFD mice treated with 11β-HSD1i. Remarkably, treatment with 11β-HSD1i altered PERK pathway in both diet groups, increasing autophagy only in HFD mice group. After RL-118 treatment, a decrease in glycogen synthase kinase 3 (GSK3β) activation, Tau hyperphosphorylation, BACE1 protein levels and the product β-CTF were found. Increases in the non-amyloidogenic secretase ADAM10 protein levels and the product sAPPα were found in both treated mice, regardless of the diet. Consequently, beneficial effects on social behaviour and cognitive performance were found in treated mice. Thus, our results support the therapeutic strategy of selective 11β-HSD1i for the treatment of age-related cognitive decline and AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12035-019-01708-4DOI Listing
January 2020

A novel class of multitarget anti-Alzheimer benzohomoadamantane‒chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors.

Eur J Med Chem 2019 Oct 17;180:613-626. Epub 2019 Jul 17.

Laboratory of Pharmaceutical Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII 27-31, E-08028, Barcelona, Spain. Electronic address:

The development of multitarget compounds against multifactorial diseases, such as Alzheimer's disease, is an area of very intensive research, due to the expected superior therapeutic efficacy that should arise from the simultaneous modulation of several key targets of the complex pathological network. Here we describe the synthesis and multitarget biological profiling of a new class of compounds designed by molecular hybridization of an NMDA receptor antagonist fluorobenzohomoadamantanamine with the potent acetylcholinesterase (AChE) inhibitor 6-chlorotacrine, using two different linker lengths and linkage positions, to preserve or not the memantine-like polycyclic unsubstituted primary amine. The best hybrids exhibit greater potencies than parent compounds against AChE (IC 0.33 nM in the best case, 44-fold increased potency over 6-chlorotacrine), butyrylcholinesterase (IC 21 nM in the best case, 24-fold increased potency over 6-chlorotacrine), and NMDA receptors (IC 0.89 μM in the best case, 2-fold increased potency over the parent benzohomoadamantanamine and memantine), which suggests an additive effect of both pharmacophoric moieties in the interaction with the primary targets. Moreover, most of these compounds have been predicted to be brain permeable. This set of biological properties makes them promising leads for further anti-Alzheimer drug development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2019.07.051DOI Listing
October 2019

Stevens-Johnson syndrome and toxic epidermal necrolysis: a retrospective descriptive study.

Int J Dermatol 2019 Nov 5;58(11):1293-1299. Epub 2019 Jun 5.

Department of Dermatology, University of Puerto Rico School of Medicine, San Juan, Puerto Rico.

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and potentially life-threatening mucocutaneous reactions. Given their rarity, limited cohort studies have been done. The aim of this study is to evaluate and compare the demographics, etiology, management, clinical and laboratory characteristics, complications, and outcome of SJS/TEN patients seen by the inpatient dermatology service at the University of Puerto Rico.

Methods: A retrospective review of 30 cases with identified diagnosis of SJS, overlap SJS/TEN, or TEN who were consulted to the Dermatology Department of the University of Puerto Rico from 2006 to 2017.

Results: A total of 24 adult and six pediatric cases were reviewed. Females were predominant with a female to male ratio of 1.3 : 1. The most frequent offending drugs identified were antibiotics (56.7%), anticonvulsants (23.3%), and nonsteroidal anti-inflammatory drugs (NSAIDs) (16.7%) with the most frequent antibiotic identified being trimethoprim/sulfamethoxazole (23.3%). Seventy percent of patients experienced at least one complication, most often of infectious etiology (80.1%). During hospital course, 73% received pharmacologic therapy (23% received IVIG alone, 17% received steroids alone, and 33% both) versus 27% which received only supportive care. Mortality rate in this study was 13.8%. When comparing SCORTEN at day one of admission, deceased cases had a mean SCORTEN at day 1 of 4.0, while survivors had an average of 1.54 (P < 0.001).

Conclusion: Antibiotics followed by anticonvulsants were the most frequently offending drugs identified within this study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ijd.14493DOI Listing
November 2019

Oral administration of a new HRI activator as a new strategy to improve high-fat-diet-induced glucose intolerance, hepatic steatosis, and hypertriglyceridaemia through FGF21.

Br J Pharmacol 2019 07 23;176(13):2292-2305. Epub 2019 May 23.

Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain.

Background And Purpose: FGF21 has emerged as a therapeutic strategy for treating type 2 diabetes mellitus due to its antidiabetic effects, and this has led to the development of long-acting analogues of FGF21. However, these compounds have some limitations, including a need to be administered by s.c. injection and their prolonged pharmacodynamic effect compared with native FGF21, which might be responsible for their reported side effects.

Experimental Approach: We have previously demonstrated that i.p. administration of haem-regulated eukaryotic translation initiation factor 2α kinase (HRI) activators increases hepatic and circulating levels of FGF21. In this study, we examined the effects of p.o. administration of a new HRI activator, EPB-53, on high-fat diet (HFD)-induced glucose intolerance, hepatic steatosis, and hypertriglyceridaemia, and compared them with those of metformin.

Key Results: EPB-53 administration for the last 2 weeks, to mice fed a HFD for 10 weeks, reduced body weight gain, improved glucose intolerance, and prevented hepatic steatosis and hypertriglyceridaemia, whereas metformin only ameliorated glucose intolerance. Moreover, EPB-53, similar to the reported effects of FGF21, reduced lipogenesis in cultured human hepatocytes and in the liver of mice fed a HFD. Administration of EPB-53 to Fgf21-knockout mice had no effects, demonstrating that its efficacy is dependent on this hormone.

Conclusions And Implications: Overall, the findings of this study demonstrate that p.o. administration of HRI activators, by increasing FGF21, is a promising strategy for the treatment of type 2 diabetes mellitus and non-alcoholic fatty liver disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bph.14678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555855PMC
July 2019

Pentafluorosulfanyl-containing Triclocarban Analogs with Potent Antimicrobial Activity.

Molecules 2018 Nov 2;23(11). Epub 2018 Nov 2.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain.

Concerns have been raised about the long-term accumulating effects of triclocarban, a polychlorinated diarylurea widely used as an antibacterial soap additive, in the environment and in human beings. Indeed, the Food and Drug Administration has recently banned it from personal care products. Herein, we report the synthesis, antibacterial activity and cytotoxicity of novel ,'-diarylureas as triclocarban analogs, designed by reducing one or more chlorine atoms of the former and/or replacing them by the novel pentafluorosulfanyl group, a new bioisostere of the trifluoromethyl group, with growing importance in drug discovery. Interestingly, some of these pentafluorosulfanyl-bearing ureas exhibited high potency, broad spectrum of antimicrobial activity against Gram-positive bacterial pathogens, and high selectivity index, while displaying a lower spontaneous mutation frequency than triclocarban. Some lines of evidence suggest a bactericidal mode of action for this family of compounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules23112853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278391PMC
November 2018

Pigmented Lesions of the Nail Unit.

Am J Dermatopathol 2018 Nov;40(11):793-804

Faculty in Dermatopathology, Department of Dermatology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.

Pigmented lesions of the nail unit are commonly encountered in the clinical setting. Yet, they often present a unique challenge to clinicians because of a broad differential diagnosis or unfamiliarity with clinical and histopathologic features. A wide variety of causes exist ranging from benign lesions such as subungual hemorrhage to malignant lesions such as subungual melanoma. Identifying the underlying cause is key to appropriate management and follow-up in these patients. Although emerging clinical tools such as dermoscopy can be very useful in evaluation of these lesions, histopathologic analysis remains the gold standard. In this review, we discuss and provide a summary of important clinical and histopathological concepts of pigmented lesions of the nail unit with special focus on longitudinal melanonychia, melanotic macule, melanocytic nevus, subungual melanoma, along with discussion of some nonmelanocytic lesions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/DAD.0000000000001106DOI Listing
November 2018

Novel Quinazolinone Inhibitors of ALK2 Flip between Alternate Binding Modes: Structure-Activity Relationship, Structural Characterization, Kinase Profiling, and Cellular Proof of Concept.

J Med Chem 2018 08 7;61(16):7261-7272. Epub 2018 Aug 7.

Institute of Cancer Research , 15 Cotswold Road , Sutton , Surrey SM2 5NG , United Kingdom.

Structure-activity relationship and crystallographic data revealed that quinazolinone-containing fragments flip between two distinct modes of binding to activin receptor-like kinase-2 (ALK2). We explored both binding modes to discover potent inhibitors and characterized the chemical modifications that triggered the flip in binding mode. We report kinase selectivity and demonstrate that compounds of this series modulate ALK2 in cancer cells. These inhibitors are attractive starting points for the discovery of more advanced ALK2 inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.8b00782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109843PMC
August 2018

Palladium-catalyzed cocyclotrimerization of arynes with a pyramidalized alkene.

Chem Commun (Camb) 2018 Jun;54(47):5996-5999

Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Departamento de Química Orgánica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain.

The metal-catalyzed [2+2+2] cocycloaddition of arynes with pyramidalized alkenes is presented. The generation of a highly reactive pyramidalized alkene in the presence of a large excess of in situ-produced arynes led to the corresponding cocyclotrimerization (1 : 2)-adducts in good yields, establishing the first example of a palladium-based reaction of a pyramidalized alkene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c8cc03188fDOI Listing
June 2018

Pharmacological and Electrophysiological Characterization of Novel NMDA Receptor Antagonists.

ACS Chem Neurosci 2018 11 1;9(11):2722-2730. Epub 2018 Jun 1.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació i Institut de Biomedicina (IBUB) , Universitat de Barcelona , Av. Joan XXIII, 27-31 , 08028 Barcelona , Spain.

This work reports the synthesis and pharmacological and electrophysiological evaluation of new N-methyl-d-aspartic acid receptor (NMDAR) channel blocking antagonists featuring polycyclic scaffolds. Changes in the chemical structure modulate the potency and voltage dependence of inhibition. Two of the new antagonists display properties comparable to those of memantine, a clinically approved NMDAR antagonist.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acschemneuro.8b00154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249113PMC
November 2018

11β-HSD1 Inhibition by RL-118 Promotes Autophagy and Correlates with Reduced Oxidative Stress and Inflammation, Enhancing Cognitive Performance in SAMP8 Mouse Model.

Mol Neurobiol 2018 Dec 2;55(12):8904-8915. Epub 2018 Apr 2.

Secció de Farmacologia i Toxicologia and Institut de Neurociències, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028, Barcelona, Spain.

Elevated glucocorticoid (GC) exposure is widely accepted as a key factor in the age-related cognitive decline in rodents and humans. 11β-HSD1 is a key enzyme in the GCs pathway, catalyzing the conversion of 11β-dehydrocorticosterone to corticosterone in mice, with possible implications in neurodegenerative processes and cognitive impairment. Here, we determined the effect of a new 11β-HSD1 inhibitor, RL-118, administered to 12-month-old senescence-accelerated mouse-prone 8 (SAMP8) mice with neuropathological AD-like hallmarks and widely used as a rodent model of cognitive dysfunction. Behavioral tests (open field and object location) and neurodegeneration molecular markers were studied. After RL-118 treatment, increased locomotor activity and cognitive performance were found. Likewise, we found changes in hippocampal autophagy markers such as Beclin1, LC3B, AMPKα, and mTOR, indicating a progression in the autophagy process. In line with autophagy increase, a diminution in phosphorylated tau species (Ser 396 and Ser 404) jointly with an increase in ADAM10 and sAPPα indicated that an improvement in removing the abnormal proteins by autophagy might be implicated in the neuroprotective role of the 11β-HSD1 inhibitor. In addition, gene expression of oxidative stress (OS) and inflammatory markers, such as Hmox1, Aldh2, Il-1β, and Ccl3, were reduced in old treated mice in comparison to that of the control group. Consistent with this, we further demonstrate a significant correlation with autophagy markers and cognitive improvement and significant inverse correlation with autophagy, OS, and neuroinflammation markers. We concluded that inhibition of 11β-HSD1 by RL-118 prevented neurodegenerative processes and cognitive decline, acting on autophagy process, being an additional neuroprotective mechanism not described previously.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12035-018-1026-8DOI Listing
December 2018

Rare Variant of Agminated Spitz Nevi on a Hypopigmented Background and Segmental Distribution: Case Report and Review of Literature.

Am J Dermatopathol 2018 Sep;40(9):686-689

Departments of Dermatology, and.

Spitz nevus is a type of melanocytic nevus that can arise as a solitary lesion or as multiple lesions either disseminated or agminated (grouped) in different skin backgrounds (eg, grossly normal, hyperpigmented, or hypopigmented). Agminated Spitz nevi have been rarely reported and are even rarer in a background of hypopigmented skin. We present the case of a 2-month-old girl with multiple, grouped, dome-shaped, red papules arising on a hypopigmented patch with a segmental distribution. Biopsy of 2 lesions showed findings characteristic of Spitz nevus, confirming the diagnosis. We also review 4 other cases of agminated Spitz nevi arising on hypopigmented skin reported in the literature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/DAD.0000000000001135DOI Listing
September 2018

Exploring N-acyl-4-azatetracyclo[5.3.2.0.0]dodec-11-enes as 11β-HSD1 Inhibitors.

Molecules 2018 Feb 28;23(3). Epub 2018 Feb 28.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain.

We recently found that a cyclohexanecarboxamide derived from 4-azatetracyclo[5.3.2.0.0]dodec-11-ene displayed low nanomolar inhibition of 11β-HSD1. In continuation of our efforts to discover potent and selective 11β-HSD1 inhibitors, herein we explored several replacements for the cyclohexane ring. Some derivatives exhibited potent inhibitory activity against human 11β-HSD1, although with low selectivity over the isoenzyme 11β-HSD2, and poor microsomal stability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules23030536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017749PMC
February 2018

Towards a Novel Class of Multitarget-Directed Ligands: Dual P2X7-NMDA Receptor Antagonists.

Molecules 2018 Jan 21;23(1). Epub 2018 Jan 21.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII 27-31, E-08028 Barcelona, Spain.

Multi-target-directed ligands (MTDLs) offer new hope for the treatment of multifactorial complex diseases such as Alzheimer's Disease (AD). Herein, we present compounds aimed at targeting the NMDA and the P2X7 receptors, which embody a different approach to AD therapy. On one hand, we are seeking to delay neurodegeneration targeting the glutamatergic NMDA receptors; on the other hand, we also aim to reduce neuroinflammation, targeting P2X7 receptors. Although the NMDA receptor is a widely recognized therapeutic target in treating AD, the P2X7 receptor remains largely unexplored for this purpose; therefore, the dual inhibitor presented herein-which is open to further optimization-represents the first member of a new class of MTDLs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules23010230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017257PMC
January 2018