Targets, Mechanisms and Cytotoxicity of Half-Sandwich Ir(III) Complexes Are Modulated by Structural Modifications on the Benzazole Ancillary Ligand

Cancers are driven by multiple genetic mutations but evolve to evade treatments targeting specific mutations. Nonetheless, cancers cannot evade a treatment that targets mitochondria, which are essential for tumor progression. Iridium complexes have shown anticancer properties, but they lack specificity for their intracellular targets, leading to undesirable side effects. Herein we present a systematic study on structure-activity relationships of eight arylbenzazole-based Iridium(III) complexes of type [IrCl(Cp*)], that have revealed the role of each atom of the ancillary ligand in the physical chemistry properties, cytotoxicity and mechanism of biological action. Neutral complexes, especially those bearing phenylbenzimidazole (HL1 and HL2), restrict the binding to DNA and albumin. One of them, complex 1[C,NH-Cl], is the most selective one, does not bind DNA, targets exclusively the mitochondria, disturbs the mitochondria membrane permeability inducing proton leak and increases ROS levels, triggering the molecular machinery of regulated cell death. In mice with orthotopic lung tumors, the administration of complex 1[C,NH-Cl] reduced the tumor burden. Cancers are more vulnerable than normal tissues to a treatment that harnesses mitochondrial dysfunction. Thus, complex 1[C,NH-Cl] characterization opens the way to the development of new compounds to exploit this vulnerabilityWe acknowledge the “la Caixa” Foundation (LCF/PR/PR12/11070003), Ministerio de Ciencia Innovación y Universidades-FEDER (RTI2018-102040-B-100) and Junta de Castilla y León-FEDER (BU305P18) for financial support. Networking support by COST Action CA18202 (NECTAR) is also acknowledged

Relationship Between Osteoporosis and Marginal Bone Loss in Osseointegrated Implants: A 2-Year Retrospective Study

Background: Fitting implants in osteoporotic patients has raditionally been controversial, and there is little scientific evidence relating osteoporosis to marginal bone loss (MBL). The aims of this study are as follows: 1) to evaluate the possibility of a correlation between osteoporosis, as measured by the mandibular cortical index (MCI), and MBL and 2) to assess how various systemic diseases, periodontitis, and placement of implants in regenerated bone are correlated with MBL and MCI. Methods: This retrospective study examines 212 implants inserted in 67 patients. To take a possible cluster failure into account, an implant for each patient was selected (n = 67 implants). MBL was assessed. Osteoporosis was evaluated using the MCI. Both MBL and MCI were assessed from panoramic radiographs. x2 test was performed (Haberman post hoc test). Significance was P <0.05. Results: When the total sample implant (N = 212) was evaluated, a significant association was found between the presence of osteoporosis and MCI (P <0.001) and between the presence of diabetes mellitus and MCI (P <0.01). Significant associations were also found between MBL and placement of implants in regenerated sites (P <0.001) and between MBL and a previous history of periodontitis (P <0.05). When the sample is evaluated only in selected implants (one per patient, n = 67), significant differences appear to relate only to the MBL with the placement of implants in regenerated bone sites (P <0.001). Conclusions: Osteoporosis (as evaluated by MCI) does not pose a risk for the development of greater MBL. Parameters adversely affecting the development of increased MBL are a previous history of periodontitis and especially the placement of implants at sites of bone regeneration

Azure A embedded in carbon dots as NADH electrocatalyst: Development of a glutamate electrochemical biosensor

Carbon nanodots modified with azure A (AA-CDs) have been synthesized and applied as redox mediator of bioelectrocatalytic reactions. A deep characterization of AA-CDs nanomaterial has been carried out, proving the covalent attachment of azure A molecules into the carbon dots nanostructure. Disposable screen-printed carbon electrodes (SPCE) have been modified with AA-CDs, through the action of chitosan polymer (Chit-AA-CDs/SPCE). The Chit-AA-CDs/SPCE electrocatalytic activity towards the oxidation of NADH has been proved, obtaining excellent results regarding the low oxidation potential achieved (−0.15 V vs. Ag) and low detection and quantification limits (LOD and LOQ) for NADH, 16 and 53 µM, respectively. The developed electrochemical platform has been applied for the construction of a glutamate biosensor by immobilizing L-glutamic dehydrogenase (GLDH/Chit-AA-CDs/SPCE). The morphology of GLDH/Chit-AA-CDs/SPCE platform was analysed by AFM at each different step of the electrode modification process. The resulting biosensing platform is capable of detect NADH enzymatically generated by GLDH in the presence of glutamate and NAD+. Good analytical parameters were obtained for glutamate analysis using GLDH/Chit-AA-CDs/SPCE, as LOD and LOQ of 3.3 and 11 µM, respectively. The biosensor has been successfully applied to the analysis of food and biological samplesThis work has been supported by the Spanish Ministerio de Ciencia e Innovacion (PID2020–116728RB-I00) and Comunidad Autonoma de Madrid (SI3/PJI/2021–00341, P2018/NMT-4349 TRANSNANOAVANSENS Program

Statin use and the risk of colorectal cancer in a population-based electronic health records study

There is extensive debate regarding the protective effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) on colorectal cancer (CRC). We aimed to assess the association between CRC risk and exposure to statins using a large cohort with prescription data. We carried out a case-control study in Catalonia using the System for Development of Primary Care Research (SIDIAP) database that recorded patient diseases history and linked data on reimbursed medication. The study included 25 811 cases with an incident diagnosis of CRC between 2010 and 2015 and 129 117 frequency-matched controls. Subjects were classified as exposed to statins if they had ever been dispensed statins. Analysis considering mean daily defined dose, cumulative duration and type of statin were performed. Overall, 66 372 subjects (43%) were exposed to statins. There was no significant decrease of CRC risk associated to any statin exposure (OR = 0.98; 95% CI: 0.95-1.01). Only in the stratified analysis by location a reduction of risk for rectal cancer was observed associated to statin exposure (OR = 0.87; 95% CI: 0.81-0.92). This study does not support an overall protective effect of statins in CRC, but a protective association with rectal cancer merits further research

PREVALENCIA DE PATOLOGÍA RESPIRATORIA CRÓNICA EN PACIENTES MAYORES DE 75 AÑOS EN TRATAMIENTO CON GABAPENTINOIDES Y OPIOIDES

Introducción: Tras la reciente publicación de la alerta de la Food and Drug Administration (FDA) que advierte sobre la posible aparición de dificultades respiratorias en pacientes con fármacos gabapentinoides y factores de riesgo respiratorio, se plantea un estudio cuyo objetivo principal es conocer la prevalencia de patología respiratoria crónica en mayores de 75 años, en tratamiento concomitante con gabapentinoides y opioides potentes. Material y métodos: Estudio transversal descriptivo realizado en pacientes >75 años con prescripción concomitante de gabapentinoides y opioides potentes, y al menos 3 envases dispensados en un periodo de 6 meses (julio-diciembre 2019), en 40 centros de salud. Resultados: Tras realizar muestreo, se analizaron 57 pacientes. Edad media=84,1 (DE 5,0) años; 82,5%mujeres. Un 25,3% de la población presentaba patología respiratoria crónica asociada. El promedio del Índice de comorbilidad Charlson fue=6,4 (DE 1,88). La indicación para patología lumbar se detectó en el 50,9% de la prescripción con gabapentinoides y 47,3% con opioides. Un 68,4% tenían incluido en su tratamiento otro depresor. Conclusiones: Los resultados muestran una población mayor frágil, con una elevada carga de comorbilidad. Alrededor de un cuarto de la muestra analizada ya presentaba patología respiratoria crónica, con lo que en estos pacientes el riesgo se incrementa notablemente. El uso de gabapentinoides y de opioides fue para la indicación de dolor lumbar en casi la mitad de los pacientes. La evidencia disponible en esta indicación es cuestionable y limitada.  Por otro lado, el abordaje de tratamiento para dolor de tipo lumbar es complejo, y requiere un planteamiento global

PREVALENCIA DE PATOLOGÍA RESPIRATORIA CRÓNICA EN PACIENTES MAYORES DE 75 AÑOS EN TRATAMIENTO CON GABAPENTINOIDES Y OPIOIDES

Introducción: Tras la reciente publicación de la alerta de la Food and Drug Administration (FDA) que advierte sobre la posible aparición de dificultades respiratorias en pacientes con fármacos gabapentinoides y factores de riesgo respiratorio, se plantea un estudio cuyo objetivo principal es conocer la prevalencia de patología respiratoria crónica en mayores de 75 años, en tratamiento concomitante con gabapentinoides y opioides potentes. Material y métodos: Estudio transversal descriptivo realizado en pacientes >75 años con prescripción concomitante de gabapentinoides y opioides potentes, y al menos 3 envases dispensados en un periodo de 6 meses (julio-diciembre 2019), en 40 centros de salud. Resultados: Tras realizar muestreo, se analizaron 57 pacientes. Edad media=84,1 (DE 5,0) años; 82,5%mujeres. Un 25,3% de la población presentaba patología respiratoria crónica asociada. El promedio del Índice de comorbilidad Charlson fue=6,4 (DE 1,88). La indicación para patología lumbar se detectó en el 50,9% de la prescripción con gabapentinoides y 47,3% con opioides. Un 68,4% tenían incluido en su tratamiento otro depresor. Conclusiones: Los resultados muestran una población mayor frágil, con una elevada carga de comorbilidad. Alrededor de un cuarto de la muestra analizada ya presentaba patología respiratoria crónica, con lo que en estos pacientes el riesgo se incrementa notablemente. El uso de gabapentinoides y de opioides fue para la indicación de dolor lumbar en casi la mitad de los pacientes. La evidencia disponible en esta indicación es cuestionable y limitada.  Por otro lado, el abordaje de tratamiento para dolor de tipo lumbar es complejo, y requiere un planteamiento global

Galectin-3 Deletion Reduces LPS and Acute Colitis-Induced Pro-Inflammatory Microglial Activation in the Ventral Mesencephalon

Parkinson’s disease is a highly prevalent neurological disorder for which there is currently no cure. Therefore, the knowledge of risk factors as well as the development of new putative molecular targets is mandatory. In this sense, peripheral inflammation, especially the originated in the colon, is emerging as a predisposing factor for suffering this disease. We have largely studied the pleiotropic roles of galectin-3 in driving microglia-associated immune responses. However, studies aimed at elucidating the role of galectin-3 in peripheral inflammation in terms of microglia polarization are lacking. To achieve this, we have evaluated the effect of galectin-3 deletion in two different models of acute peripheral inflammation: intraperitoneal injection of lipopolysaccharide or gut inflammation induced by oral administration of dextran sodium sulfate. We found that under peripheral inflammation the number of microglial cells and the expression levels of pro-inflammatory mediators take place specifically in the dopaminergic system, thus supporting causative links between Parkinson’s disease and peripheral inflammation. Absence of galectin-3 highly reduced neuroinflammation in both models, suggesting an important central regulatory role of galectin-3 in driving microglial activation provoked by the peripheral inflammation. Thus, modulation of galectin-3 function emerges as a promising strategy to minimize undesired microglia polarization states.This work was supported by grants from the Spanish Ministerio de Ciencia, Innovación y Universidades (RTI 2018-098830-B-I00), from the Consejería de Economía y Conocimiento of Junta de Andalucía (P18-RT-1372 and US-1264806). MJP, MDVC and PGM were supported by a grant from the Junta de Andalucía (CTS 5884) and AEC by an associated post-doctoral grant

The Absence of Caspase-8 in the Dopaminergic System Leads to Mild Autism-like Behavior

In the last decade, new non-apoptotic roles have been ascribed to apoptotic caspases. This family of proteins plays an important role in the sculpting of the brain in the early stages of development by eliminating excessive and nonfunctional synapses and extra cells. Consequently, impairments in this process can underlie many neurological and mental illnesses. This view is particularly relevant to dopamine because it plays a pleiotropic role in motor control, motivation, and reward processing. In this study, we analyze the effects of the elimination of caspase-8 (CASP8) on the development of catecholaminergic neurons using neurochemical, ultrastructural, and behavioral tests. To do this, we selectively delete the CASP8 gene in cells that express tyrosine hydroxylase with the help of recombination through the Cre-loxP system. Our results show that the number of dopaminergic neurons increases in the substantia nigra. In the striatum, the basal extracellular level of dopamine and potassium-evoked dopamine release decreased significantly in mice lacking CASP8, clearly showing the low dopamine functioning in tissues innervated by this neurotransmitter. This view is supported by electron microscopy analysis of striatal synapses. Interestingly, behavioral analysis demonstrates that mice lacking CASP8 show changes reminiscent of autism spectrum disorders (ASD). Our research reactivates the possible role of dopamine transmission in the pathogenesis of ASD and provides a mild model of autism.Ministerio de Economía y Competitividad RTI2018-098645-B-I00, PID2019-109569GB-I00, RTI2018-099778-B-I00Junta de Andalucía P18-RT-1372, US-1264806, PI-0080-2017, PI-0009-2017, PI-0134-2018, PEMP-0008-2020, P20_00958, CTS-510Instituto de Salud Carlos III PI18/01691Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz-INiBICA LI19/06IN-CO22, IN-C09European Union 95568