Gramine derivatives targeting Ca2+ channels and Ser/Thr phosphatases: A new dual strategy for the treatment of neurodegenerative diseases

This document is the unedited author's version of a Submitted Work that was subsequently accepted for publication in Journal of Medicinal Chemistry , copyright © American Chemical Society after peer review. To access the final edited and published work, see http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00478We describe the synthesis of gramine derivatives and their pharmacological evaluation as multipotent drugs for the treatment of Alzheimer’s disease. An innovative multitarget approach is presented, targeting both voltage-gated Ca2+ channels, classically studied for neurodegenerative diseases, and Ser/Thr phosphatases, which have been marginally aimed, even despite their key role in protein τ dephosphorylation. Twenty-five compounds were synthesized, and mostly their neuroprotective profile exceeded that offered by the head compound gramine. In general, these compounds reduced the entry of Ca2+ through VGCC, as measured by Fluo-4/AM and patch clamp techniques, and protected in Ca2+ overload-induced models of neurotoxicity, like glutamate or veratridine exposures. Furthermore, we hypothesize that these compounds decrease τ hyperphosphorylation based on the maintenance of the Ser/Thr phosphatase activity and their neuroprotection against the damage caused by okadaic acid. Hence, we propose this multitarget approach as a new and promising strategy for the treatment of neurodegenerative diseasesThis work was supported by the following grant: Proyectos de Investigación en Salud (PI13/00789, IS Carlos III). R.L.C is granted by Universidad Autónoma de Madri

Development of subtype-selective photoswitchable positive allosteric modulators for mGlu receptors

Positive allosteric modulators (PAMs) for metabotropic glutamate receptors have been postulated to treat neuropsychiatric diseases. Besides, obtaining a reversible and efficient spatiotemporal control of mGlu activity would be therapeutically advantageous. Photopharmacology may provide a solution on this topic, since it is based on the use of light and photoswitchable ligands to modulate a protein activity. This approach offers new perspectives for drug discovery and promises a better drug action control reducing side effects to unattained levels.Peer reviewe

Theoretical Determination of the pK a Values of Betalamic Acid Related to the Free Radical Scavenger Capacity: Comparison Between Empirical and Quantum Chemical Methods

Health benefits of dietary phytochemicals have been suggested in recent years. Among 1000s of different compounds, Betalains, which occur in vegetables of the Cariophyllalae order (cactus pear fruits and red beet), have been considered because of reducing power and potential to affect redox-modulated cellular processes. The antioxidant power of Betalains is strictly due to the dissociation rate of the acid moieties present in all the molecules of this family of phytochemicals. Experimentally, only the pK a values of betanin were determined. Recently, it was evidenced it was evidenced as the acid dissociation, at different environmental pHs, affects on its electron-donating capacity, and further on its free radical scavenging power. The identical correlation was studied on another Betalains family compound, Betalamic Acid. Experimental evidences showed that the free radical scavenging capacity of this compound drastically decreases at pH > 5, but pK a values were experimentally not measured. With the aim to justify the Betalamic Acid behavior as free radical scavenger, in this paper we tried to predict in silico the pK a values by means different approaches. Starting from the known experimental pK as of acid compounds, both phytochemicals and small organic, two empirical approaches and quantum-mechanical calculation were compared to give reliable prediction of the pK as of Betalamic Acid. Results by means these computational approaches are consistent with the experimental evidences. As shown herein, in silico, the totally dissociated species, at the experimental pH > 5 in solution, is predominant, exploiting the higher electron-donating capability (HOMO energy). Therefore, the computational estimated pK a values of Betalamic Acid resulted very reliable

Productivity trends and collaboration patterns: A diachronic study in the eating disorders field

[EN] Objective The present study seeks to extend previous bibliometric studies on eating disorders (EDs) by including a time-dependent analysis of the growth and evolution of multi-author collaborations and their correlation with ED publication trends from 1980 to 2014 (35 years). Methods Using standardized practices, we searched Web of Science (WoS) Core Collection (WoSCC) (indexes: Science Citation Index-Expanded [SCIE], & Social Science Citation Index [SSCI]) and Scopus (areas: Health Sciences, Life Sciences, & Social Sciences and Humanities) to identify a large sample of articles related to EDs. We then submitted our sample of articles to bibliometric and graph theory analyses to identify co-authorship and social network patterns. Results We present a large number of detailed findings, including a clear pattern of scientific growth measured as number of publications per five-year period or quinquennium (Q), a tremendous increase in the number of authors attracted by the ED subject, and a very high and steady growth in collaborative work. Conclusions We inferred that the noted publication growth was likely driven by the noted increase in the number of new authors per Q. Social network analyses suggested that collaborations within ED follow patters of interaction that are similar to well established and recognized disciplines, as indicated by the presence of a ¿giant cluster¿, high cluster density, and the replication of the ¿small world¿ phenomenon¿the principle that we are all linked by short chains of acquaintances.This work was performed with a subsidy from Universidad Catolica de Valencia "San Vicente Martir" to resarch group INDOTEI: Evaluacion de la Ciencia, for the years 2016-2017. This work is benefited from Spanish Government assistance through Government Delegation for the National Drugs Plan of the Ministry of Health, Social Services and Equality (project 2016/028); and National R+D+I (projects: CS02012-39632-C02-01 and CS02015-65594-C2-2-R) and 2015-Networks of Excellence Call (project CS02015-71867-REDT) of the Ministry of Economy and Competitiveness.Valderrama Zurian, JC.; Aguilar-Moya, R.; Cepeda-Benito, A.; Melero-Fuentes, D.; Navarro-Moreno, MÁ.; Gandía-Balaguer, A.; Aleixandre-Benavent, R. (2017). Productivity trends and collaboration patterns: A diachronic study in the eating disorders field. PLoS ONE. 12(8):1-17. https://doi.org/10.1371/journal.pone.0182760S117128McClelland, J., Bozhilova, N., Campbell, I., & Schmidt, U. (2013). A Systematic Review of the Effects of Neuromodulation on Eating and Body Weight: Evidence from Human and Animal Studies. 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Revista española de Documentación Científica, 34(3), 301-333. doi:10.3989/redc.2011.3.804Valderrama-Zurián, J.-C., Aguilar-Moya, R., Melero-Fuentes, D., & Aleixandre-Benavent, R. (2015). A systematic analysis of duplicate records in Scopus. Journal of Informetrics, 9(3), 570-576. doi:10.1016/j.joi.2015.05.002Guardiola-Wanden-Berghe, R., Sanz-Valero, J., & Wanden-Berghe, C. (2012). Medical subject headings versus American Psychological Association Index Terms: indexing eating disorders. Scientometrics, 94(1), 305-311. doi:10.1007/s11192-012-0866-7Soh, N., Walter, G., Touyz, S., Russell, J., Malhi, G. S., & Hunt, G. E. (2012). Food for thought: Comparison of citations received from articles appearing in specialized eating disorder journals versus general psychiatry journals. International Journal of Eating Disorders, 45(8), 990-994. doi:10.1002/eat.22036Theander, S. S. (2004). 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Neurosurgical emergency management during the lockdown period in health care regions in Spain with different COVID-19 impact: lessons learned to improve outcomes on the future waves

Background COVID-19 has overloaded health care systems, testing the capacity and response in every European region. Concerns were raised regarding the impact of resources’ reorganization on certain emergency pathology management. The aim of the present study was to assess the impact of the outbreak (in terms of reduction of neurosurgical emergencies) during lockdown in different regions of Spain. Methods We analyzed the impact of the outbreak in four different affected regions by descriptive statistics and univariate comparison with same period of two previous years. These regions differed in their incidence level (high/low) and in the time of excess mortality with respect to lockdown declaration. That allowed us to analyze their influence on the characteristics of neurosurgical emergencies registered for every region. Results 1185 patients from 18 neurosurgical centers were included. Neurosurgical emergencies that underwent surgery dropped 24.41% and 28.15% in 2020 when compared with 2019 and 2018, respectively. A higher reduction was reported for the most affected regions by COVID-19. Non-traumatic spine experienced the most significant decrease in number of cases. Life-threatening conditions did not suffer a reduction in any health care region. Conclusions COVID-19 affected dramatically the neurosurgical emergency management. The most significant reduction in neurosurgical emergencies occurred on those regions that were hit unexpectedly by the pandemic, as resources were focused on fighting the virus. As a consequence, life-threating and non-life-threatening conditions’ mortality raised. Results in regions who had time to prepare for the hit were congruent with an organized and sensible neurosurgical decision-making.Peer reviewe

Synthetic biology to access and expand nature's chemical diversity

Bacterial genomes encode the biosynthetic potential to produce hundreds of thousands of complex molecules with diverse applications, from medicine to agriculture and materials. Accessing these natural products promises to reinvigorate drug discovery pipelines and provide novel routes to synthesize complex chemicals. The pathways leading to the production of these molecules often comprise dozens of genes spanning large areas of the genome and are controlled by complex regulatory networks with some of the most interesting molecules being produced by non-model organisms. In this Review, we discuss how advances in synthetic biology — including novel DNA construction technologies, the use of genetic parts for the precise control of expression and for synthetic regulatory circuits — and multiplexed genome engineering can be used to optimize the design and synthesis of pathways that produce natural products