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Highlights • TRAF6 binds to both WT and the mutant form A30 P asyn in SH-SY5Y cell model. • The activation of NF-κB leads to changes in cytokines levels induced by TRAF6 - WT asyn interaction decreasing cell viability. • The interaction between TRAF6 and A30P asyn does not induce NF-κB activation and cytokine regulation in SH-SY5Y cells. • The present work demonstrates a novel role of TRAF6 in the pathophysiology of Parkinson's disease., Background Parkinson's disease (PD) is a neurodegenerative disease characterized by intracellular inclusions named Lewy bodies (LB), and alpha-synuclein (asyn) is the major component of these protein aggregates. The precise physiological and pathological roles of asyn are not fully understood. Nevertheless, asyn present in LB is ubiquitinated but fails to reach the 26S proteasome. The mutation A30 P is related to an aggressive and early-onset form of PD. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an E3 ubiquitin ligase, and it interacts and ubiquitinates the asyn in atypical chains (lysine K6, K27, K29, and K33). Methods: Here, we investigated the role of TRAF6 interaction with asyn and the involvement of nuclear factor κB (NF-κB), a key transcription factor in pro-inflammatory signaling pathway activation. Results and Conclusion We demonstrated that TRAF6 binds to both WT and the mutant form A30 P asyn in an SH-SY5Y cell model. Additionally, the interaction between TRAF6 and WT asyn induced an increase in the activation of NF-κB, leading to changes in TNF, IL-1β and IL-10 levels and culminating in reduced cell viability. Interestingly, the activation of NF-κB and gene regulation were not found in A30 P asyn. These data point to a novel role of TRAF6 in the pathophysiology of PD.

Due to the limited options for topical management of skin cancer, this study aimed at developing and evaluating nanoemulsions (NE) for topical delivery of the cytotoxic agent piplartine (piperlongumine). NEs were modified with chitosan or sodium alginate, and the effects on the physicochemical properties, piplartine delivery and formulation efficacy were evaluated. The nanoemulsion droplets displayed similar size (96–112 nm), but opposite charge; the polysaccharides improved piplartine penetration into and across the skin (1.3–1.9-fold) in a similar manner, increasing the ratio “drug in the skin/receptor phase” by 1.4–1.5-fold compared to the plain NE and highlighting their relevance for cutaneous localization. Oleic acid addition to the chitosan-containing NE further increased drug penetration (~1.9–2.0-fold), as did increases in drug content from 0.5 to 1%. The cytotoxicity of piplartine was ~2.8-fold higher when the drug was incorporated in the chitosan-containing NE compared to its solution (IC50 = 14.6 μM) against melanoma cells. The effects of this nanocarrier on 3D melanoma tissues were concentration-related; at 1%, piplartine elicited marked epidermis destruction. These results support the potential applicability of the chitosan-modified nanoemulsion containing piplartine as a new strategy for local management of skin cancer.

espanolStrongiloides stercoralis es un parasito nematodo de distribucion global y el principal agente causal de la Estrongiloidiasis. La infeccion cronica presenta un curso asintomatico, sin embargo, puede producir Sindrome de Hiperinfeccion en pacientes inmunodeprimidos. En la actualidad, la falta de un diagnostico estandarizado genera una subestimacion de la prevalencia de la enfermedad. El analisis coprologico, considerado como el gold-standard, presenta una muy baja sensibilidad. Una alternativa es el metodo LAMP especifico y sensible para la deteccion de S.stercoralis, el Strong-LAMP. En el presente estudio, se ha utilizado un total de 100 muestras de heces recolectadas de una poblacion de Porto Iguazu, Misiones (Argentina) y almacenadas en papel de filtro hasta su analisis. Cuando se aplico el Strong-LAMP para la deteccion de ADN de Strongyloides spp., hasta 39 muestras (39%) resultaron positivas, incluyendo 5 positivas al analisis coprologico, frente a 7 muestras(7%) positivas obtenidas por analisis parasitologico. Por tanto, el Strong-LAMP ha demostrado ser un metodo mas sensible para la deteccion de Strongyloides stercoralis en muestras de heces almacenadas en papel de filtro que los metodos de diagnostico parasitologicos y podria utilizarse en combinacion con los metodos parasitologicos en areas endemicas para establecer con mayor fiabilidad la prevalencia real de la enfermedad. EnglishStrongiloides stercoralis is a nematode globally distributed and the chief causative agent of human Strongyloidiasis. Chronic infection is clinically asymptomatic, but, it can cause Hyperinfection Syndrome in immunocompromised patients. At present, the lack of a standardized diagnosis generates an underestimation of the prevalence of the disease. Coprological test, considered as the gold-standard, has a very low sensitivity. An alternative is the specific and sensitive LAMP method for the detection of S.stercoralis, the Strong-LAMP. In the present study, it have been used a total of 100 stool samples collected from a population of Porto Iguazu, Misiones (Argentina) and stored on filter paper until analysis. When Strong-LAMP was applied for the detection of Strongyloides spp. DNA, up to 39 samples (39%) were positive, including 5 positive obtained by coprological test, compared to 7 positive samples (7%) obtained by parasitological test. Therefore, Strong-LAMP has demonstrated more sensitive method for the detection of Strongyloides stercoralis in stool samples stored in filter paper than parasitological diagnostic methods and could be used in combination with parasitological methods in endemic areas to establish with greater reliability the real prevalence of the disease.

Background and Purpose Klotho is a membrane‐bound or soluble protein, originally identified as an age‐suppressing factor and regulator of mineral metabolism. Klotho deficiency is associated with the development of renal disease, but its role in cardiac function in the context of uraemic cardiomyopathy is unknown. Experimental Approach We explored the effects of Klotho on cardiac Ca2+ cycling. We analysed Ca2+ handling in adult cardiomyocytes from Klotho‐deficient (kl/kl) mice and from a murine model of 5/6 nephrectomy (Nfx). We also studied the effect of exogenous Klotho supplementation, by chronic recombinant Klotho treatment, or endogenous Klotho overexpression, using transgenic mice overexpressing Klotho (Tg‐Kl), on uraemic cardiomyopathy. Hearts from Nfx mice were used to study Ca2+ sensitivity of ryanodine receptors and their phosphorylation state. Key Results Cardiomyocytes from kl/kl mice showed decreased amplitude of intracellular Ca2+ transients and cellular shortening together with an increase in pro‐arrhythmic Ca2+ events compared with cells from wild‐type mice. Cardiomyocytes from Nfx mice exhibited the same impairment in Ca2+ cycling as kl/kl mice. Changes in Nfx cardiomyocytes were explained by higher sensitivity of ryanodine receptors to Ca2+ and their increased phosphorylation at the calmodulin kinase type II and protein kinase A sites. Ca2+ mishandling in Nfx‐treated mice was fully prevented by chronic recombinant Klotho administration or transgenic Klotho overexpression. Conclusions and Implications Klotho emerges as an attractive therapeutic tool to improve cardiac Ca2+ mishandling observed in uraemic cardiomyopathy. Strategies that improve Klotho availability are good candidates to protect the heart from functional cardiac alterations in renal disease. Sin financiación 8.740 JCR (2020) Q1, 12/276 Pharmacology & Pharmacy 2.432 SJR (2020) Q1, 16/314 Pharmacology No data IDR 2020 UEM

Background: Leishmaniasis is a neglected tropical disease associated with several clinical manifestations, including cutaneous, mucocutaneous, and visceral forms. As currently available drugs have some limitations (toxicity, resistance, among others), the target-based identification has been an important approach to develop new leads against leishmaniasis. The present study aims to identify targets involved in the pharmacological action of potent antileishmanial compounds. Methods: The literature information regarding molecular interactions of antileishmanial compounds studied over the past half-decade is discussed. The information was obtained from databases such as Wiley, SciFinder, Science Direct, National Library of Medicine, American Chemical Society, Scientific Electronic Library Online, Scopus, Springer, Google Scholar, Web of Science, etc. Results: Numerous in vitro antileishmanial compounds showed affinity and selective interactions with enzymes such as arginase, pteridine reductase 1, trypanothione reductase, pyruvate kinase, among others, which are crucial for the survival and virulence of the Leishmania parasite. Conclusion: The in-silico activity of small molecules (enzymes, proteins, among others) might be used as pharmacological tools to develop candidate compounds for the treatment of leishmaniasis. As some pharmacologically active compounds may act on more than one target, additional studies of the mechanism (s) of action of potent antileishmanial compounds might help to better understand their pharmacological action. Also, the optimization of promising antileishmanial compounds might improve their biological activity.

Introduction: improper use of medication is becoming more frequent and can cause physical or physiological damage. Objective: to determine the frequency of potentially inappropriate prescriptions of cardiovascular drugs according to Beers' criteria in a population of colombian patients. Method: cross-sectional study conducted during november 2016 using a population database of 326,192 adults over 65 years of age who were eligible to receive drugs included in the cardiovascular system category according to the Beers' criteria. The frequency of potentially inappropriate prescriptions was determined and investigated in relation to sociodemographic variables. Results: the mean subject age was 74.6±7.6 years (range:65-100 years). It was found that 11.3% (n=36894) of the elderly presented at least one potentially inappropriate prescription for cardiovascular conditions. The most frequent finding was the use of aspirin in patients older than 80 years of age followed by the use of prazosin for hypertension in patients over 65 years of age or in patients who consulted emergency services for syncope. The other criteria were present in less than 1% of patients, and in 16 out of 33 treatment drugs, no patients exposed to potentially inappropriate prescriptions were found. Within the criteria based on drug-drug interactions, the most frequent were loop diuretics along with prazosin (6.4%). Conclusions: the prevalence of potentially inappropriate prescriptions in an elderly population of patients in Colombia is lower than that reported worldwide. In addition, there is a need to re-evaluate the Beers' criteria in this population and adjust the guidelines according to results of pharmacovigilance of active pharmaceutical substances available in Colombia. Resumen Introducción: el uso incorrecto de medicamentos es cada vez más frecuente y puede causar daños físicos o fisiológicos. Objetivo: determinar la frecuencia de las prescripciones de medicamentos de uso cardiovascular potencialmente inapropiadas según criterios de Beers en una población de pacientes colombianos. Métodos: estudio de corte transversal, a partir de una base de datos de una población de 326.192 adultos mayores de 65 años, durante el mes de noviembre de 2016, susceptibles de recibir medicamentos incluidos en los criterios de Beers en la categoría de sistema cardiovascular, determinando la frecuencia de prescripciones potencialmente inapropiadas, así como la identificación de variables sociodemográficas. Resultados: la edad promedio fue de 74,6±7,6 años (rango 65-100 años). Se halló que el 11,3% (n=36894) de los ancianos tuvo al menos una prescripción potencialmente inapropiada para condiciones cardiovasculares. El criterio más frecuente fue el uso de aspirina en mayores de 80 años, seguido del empleo de prazosín para la hipertensión arterial en mayores de 65 años, o en pacientes que consultaron por síncope a los servicios de urgencias. Los demás criterios se presentaban en menos del 1% de pacientes y en 16 de 33 fármacos de cuidado no se halló ningún paciente expuesto. Entre los criterios basados en interacciones fármaco-fármaco, el más frecuente fue diuréticos de asa junto con prazosín (6,4%). Conclusiones: la prevalencia de prescripciones potencialmente inapropiadas en una población de ancianos colombianos es menor a la reportada en el mundo. Además, se plantea la necesidad de reevaluar los criterios de Beers en dicha población y ajustarlos de acuerdo con los informes de farmacovigilancia y principios activos disponibles en Colombia.

Heart failure (HF) represents a leading cause of morbidity and mortality. However, HF trials highlighted many differences between men and women with HF. Thus, women represent approximately a quarter of people with HF with reduced ejection fraction (HFrEF), while they account for over half of those with HF with preserved EF (HFpEF). There are also sex-related differences (SRDs) in the pharmacokinetics, pharmacodynamics and safety profile of some guideline-recommended drugs for the treatment of HF. As compared with men, women with HFrEF are less often treated with guideline-recommended HF drugs, experience more frequent and severe adverse reactions when these drugs are prescribed at the same doses in both sexes, and recent evidence suggests that women might need lower doses than men, bringing into question which are the optimal doses of HF drugs in women and men separately. However, information on SRDs in drug efficacy and safety in patients with HFrEF is very limited due to the underrepresentation of women and the lack of sex-specific evaluations of drug efficacy and safety in HF clinical trials. As a consequence, current clinical guidelines do not provide sex-specific recommendations, even when significant differences exist, at least, in drug safety. The aim of this article is to review the SRDs in the pharmacokinetics, efficacy and safety of guideline-recommended HF drugs and to identify emerging areas of research to improve our understanding of the SRDs, because a better understanding of these differences is the first step to achieve a personalized treatment of HF in women and men.

Childhood maltreatment is one of the biggest social and economic problems worldwide. Among people affected by Childhood maltreatment there is a high prevalence, inter alia, of violence, drugs abuse and psychiatric disorders. At the physiological level, the Hypothalamic-Pituitary-Adrenal axis and the stress response are key to this prevalence. Moreover, in recent years, pollution has become an important issue because it affects directly human health. The objective of this experiment is to elucidate the effect of a chronic exposure to pollution, in particular ozone, on some biomarkers in a maternal deprivation animal model. We will measure how ozone exposure affects cognitive ability as well as anxiety state. Besides, the plasma variation of corticosterone and ACTH after an acute stressor will be analysed. We will also see if hippocampus and hippocampal subareas volume is altered in the animal model after the exposure to ozone. Finally, we will evaluate the methylation state of the exon promotor of glucocorticoid – receptor 1F and the exon promotor of vasopressin. This study is thought to start looking for the answer to how pollution affects the cognitive development of children who have suffered from Childhood maltreatment. El maltrato infantil es uno de los mayores problemas sociales y económicos a nivel mundial. Entre las personas que han sido víctimas del MI existe una alta prevalencia de violencia, abuso de drogas y enfermedades psiquiátricas, entre otros. A nivel fisiológico, el eje hipotálamo-pituitaria-adrenal y la respuesta al estrés están directamente relacionados con esta prevalencia. Además, en los últimos años, ha aumentado la preocupación por el efecto de la contaminación sobre la salud humana. El objetivo de este proyecto es determinar el efecto de la exposición crónica a un ambiente contaminado con ozono, sobre algunos biomarcadores, en un modelo animal de privación materna. Se medirá cómo afecta la exposición a ozono sobre la capacidad cognitiva y el estado de ansiedad. Además, se analizará la variación de corticosterona y ACTH en plasma tras la exposición a un estresor agudo. Por último, se analizará el volumen del hipocampo y sus subáreas, así como el grado de metilación del exón promotor del receptor de glucocorticoides 1F y del exón promotor de vasopresina. Con el presente trabajo se pretende ampliar el conocimiento sobre el desarrollo cognitivo de niños que han sufrido maltrato infantil./n

Hyperhidrosis is the production of sweat abnormally greater than that required to regulate body temperature. The symptoms are manifested mainly in the palms of the hands, soles of the feet, armpits and craniofacial regions. Currently, there are various treatments for hyperhidrosis, being the topical treatment with metal salts, and specifically, with aluminum chloride hexahydrate, the most used for its effectiveness, safety and ease of application, however, some people may experience sensitivity reactions to the aforementioned salts. The formulation proposed in this study provides an effective and safe alternative for the treatment of hyperhidrosis, using as essential ingredients of the formulation essential oil of tea tree, apple cider vinegar, sage and thyme extracts and menthol in individualized cellulose wipes. After testing different formulations in three volunteers with hyperhidrosis, the results were satisfactory when rapid absorption of the formulation, freshness and prolongation in time of the dryness of the treated área was perceived. The result of the study shows that cosmetic preparations with natural compounds can be a satisfactory research path in the search for the treatment of hyperhidrosis/n La hiperhidrosis es la producción de sudor anormalmente mayor a la requerida para regular la temperatura corporal. Los síntomas se manifiestan principalmente en las palmas de las manos, plantas de los pies, axilas y regiones craneofaciales. Actualmente, existen diversos tratamientos para la hiperhidrosis, siendo el tratamiento tópico con sales metálicas y, en concreto, con cloruro de aluminio hexahidratado, el más empleado por su eficacia, seguridad y facilidad de aplicación, sin embargo, algunas personas pueden experimentar reacciones de sensibilidad a las citadas sales. La formulación propuesta en este estudio proporciona una alternativa eficaz y segura para el tratamiento de la hiperhidrosis, empleando como principios activos de la formulación aceite esencial de árbol de té, vinagre de manzana, extractos de salvia y tomillo y mentol en toallitas de celulosa individualizadas. Tras probar distintas formulaciones en tres voluntarios con hiperhidrosis, las impresiones fueron satisfactorias al percibirse rápida absorción de la formulación, frescor y prolongación en el tiempo de la sequedad de la zona tratada. El resultado del estudio refleja que los preparados cosméticos con compuestos naturales pueden ser una vía de investigación satisfactoria en la búsqueda del tratamiento de la hiperhidrosis./n

Objectives: Bacterial viability and enrichment of resistance resulting from three different amikacin administration schedules with respect to haemodialysis (HD) were assessed against three OXA-48-producing Klebsiella pneumoniae isolated during an outbreak in a Spanish hospital. Methods: A previously described two-compartment dynamic system was used. Three possible amikacin administration schedules were simulated: (i) haemodialysis immediately after amikacin infusion (pre-HD); (ii) infusion immediately after haemodialysis (post-HD); and (iii) infusion at 50% interdialytic period. Amikacin standard dose (SD) and double dose (DD) were simulated for each schedule. Values of Cmax/MIC, Cmax/MPC (mutant prevention concentration), AUC0-48h/MIC, AUC0-48h/MPC and %TMSW (percentage of time that the concentration was inside the mutant selection window) were determined with experimental data and were correlated with the area under the bacterial killing curve of the total population and the resistant subpopulation. Results: Both with SD and DD, the pre-HD schedule resulted in increases at 48h in bacterial counts of the total population at the expense of enrichment of pre-existing resistant subpopulations from 12h onwards for all strains. The estimated %TMSW that prevented enrichment of resistant mutants was

Dientamoeba fragilis is a trichomonad parasite of the human intestine that is found worldwide. However, the biological cycle and transmission of this parasite have yet to be elucidated. Although its pathogenic capacity has been questioned, there is increasing evidence that clinical manifestations vary greatly. Different therapeutic options with antiparasitic drugs are currently available; however, very few studies have compared the effectiveness of these drugs. In the present longitudinal study, we evaluate 13,983 copro-parasitological studies using light microscopy of stools, during 2013–2015, in Terrassa, Barcelona (Spain). A total of 1150 (8.2%) presented D. fragilis. Of these, 739 episodes were finally analyzed: those that involved a follow-up parasitology test up to 3 months later, corresponding to 586 patients with gastrointestinal symptoms (53% under 15 years of age). Coinfection by Blastocystis hominis was present in 33.6% of the subjects. Our aim was to compare therapeutic responses to different antiparasitic drugs and the factors associated with the persistence of D. fragilis post-treatment. Gender, age, and other intestinal parasitic coinfections were not associated with parasite persistence following treatment. Metronidazole was the therapeutic option in most cases, followed by paromomycin: 65.4% and 17.5% respectively. Paromomycin was found to be more effective at eradicating parasitic infection than metronidazole (81.8% vs. 65.4%; p = 0.007), except in children under six years of age (p = 0.538). Although Dientamoeba fragilis mainly produces mild clinical manifestations, the high burden of infection means we require better understanding of its epidemiological cycle and pathogenicity, as well as adequate therapeutic guidelines in order to adapt medical care and policies to respond to this health problem., Graphical abstract Figure: Binucleate form of a trophozoite of D. fragilis, stained with trichrome Image courtesy of DPDx (Centers for Disease Control and Prevention).Image 1, Highlights • A high prevalence of D. fragilis was detected in individuals with gastrointestinal symptoms. • Paromomycin was more effective than metronidazole in the eradication of D. fragilis. • Persistence of infection by D. fragilis was not associated with age, gender or other parasitic coinfections.

La malformación vascular más común del tracto digestivo son las angiodisplasias gastrointestinales. Se caracterizan por una dilatación venocapilar con elevada fragilidad vascular, estado patológico que deriva en sangrados gastrointestinales. La prevalencia aumenta en pacientes de edad avanzada y pluripatológicos, lo que condiciona el tratamiento y pronóstico de las angiodisplasias./nEl objetivo es evaluar la eficacia del tratamiento de las angiodisplasias con análogos de somatostatina, siendo estos el Octreótido y el Lanreótido (fuera de ficha técnica para la indicación), en condiciones de práctica clínica habitual. Además, se tratará de relacionar la respuesta terapéutica con la localización de las lesiones, comorbilidades, reingresos, transfusiones sanguíneas y prescripción de anticoagulantes. /nSe llevó a cabo un estudio observacional retrospectivo con datos obtenidos de pacientes tratados en el Complejo Asistencial Universitario de León. Tras el análisis estadístico de los datos, se concluyó que no existen diferencias significativas entre los fármacos. Tampoco se encontró asociación significativa del éxito con las localizaciones de las angiodisplasias, ni con las comorbilidades coexistentes, ni con la toma de anticoagulantes. Sólo tratamientos de larga duración (> 11 meses) se relacionan con indicadores objetivos de éxito, como la reducción del número de transfusiones y de reingresos. The most common vascular malformation of the digestive tract are gastrointestinal angiodysplasias. They are characterized by a venocapillary dilation with high vascular fragility, a pathological state that results in gastrointestinal bleeding. The prevalence increases in elderly and multi-pathological patients, which conditions the treatment and prognosis of angiodysplasias./nThe objective is to evaluate the efficacy of the treatment of angiodysplasias with somatostatin analogues, being these Octreotide and Lanreotide (outside of the technical data sheet for the indication), under conditions of usual clinical practice. In addition, we will try to relate the therapeutic response with the location of the lesions, comorbidities, readmissions, blood transfusions and prescription of anticoagulants. /nA retrospective observational study was carried out with data obtained from patients treated at the Complejo Asistencial Universitario de León. After the statistical analysis of the data, it was concluded that there are no significant differences between the drugs. There was also no significant association of success with the locations of the angiodysplasias, nor with the coexisting comorbidities, nor with the taking of anticoagulants. Only long-term treatments (> 11 months) are related to objective indicators of success, such as reducing the number of transfusions and re-admissions.

Objectives To assess the association between oral mucosa hyperpigmentation in patients with leukemia and imatinib mesylate use. Additionally, we compared our data to those obtained from a systematic review. Materials and methods A cross-sectional study was conducted with 74 patients undergoing treatment with imatinib mesylate. Sociodemographic characteristics, oral mucosa alterations, and medical history were evaluated. Oral hyperpigmentation was scored. The use of imatinib mesylate and hydroxyurea was evaluated. Association between oral hyperpigmentation and imatinib mesylate was assessed. A systematic review was also conducted to retrieve case reports or case series of patients with oral hyperpigmentation associated with imatinib mesylate. Results Among the 74 participants, 41 were male (55.4%) and 33 were female (44.6%). Participants’ mean age was 49.3 years. Sixty-six (89.2%) patients developed hyperpigmented lesions in the hard palate mucosa. In multivariate analysis, patients who had used imatinib mesylate for > 72 months had a hyperpigmentation score 1.62 times higher than those who had used this medication during a shorter period. Patients who had used hydroxyurea for > 30 days had a hyperpigmentation score 1.43 times higher than those who had used this medication during a shorter period. The systematic review retrieved 20 clinical cases of patients undergoing imatinib mesylate treatment and exhibiting oral hyperpigmentation. Conclusions The development of oral hyperpigmentation is associated with imatinib mesylate use. Hydroxyurea seems to increment such an association. Clinical relevance To assist providers in the differential diagnosis of hyperpigmented lesions associated with imatinib mesylate, as well as in the clinical management of such lesions. Objetivos Avaliar a associação entre hiperpigmentação da mucosa oral em pacientes com leucemia e mesilato de imatinibe usar. Além disso, comparamos nossos dados com os obtidos em uma revisão sistemática. Materiais e métodos Foi realizado um estudo transversal com 74 pacientes em tratamento com mesilato de imatinibe. Foram avaliadas características sociodemográficas, alterações da mucosa oral e histórico médico. A hiperpigmentação oral foi marcou. Foi avaliado o uso de mesilato de imatinibe e hidroxiureia. Associação entre hiperpigmentação oral e imatinibe mesilato foi avaliado. Uma revisão sistemática também foi realizada para recuperar relatos de casos ou séries de casos de pacientes com hiperpigmentação associada ao mesilato de imatinibe. Resultados Entre os 74 participantes, 41 eram do sexo masculino (55,4%) e 33 do sexo feminino (44,6%). A média de idade dos participantes foi de 49,3 anos. Sessenta e seis (89,2%) pacientes desenvolveram lesões hiperpigmentadas na mucosa do palato duro. Na análise multivariada, os pacientes que usaram mesilato de imatinibe por > 72 meses tiveram um escore de hiperpigmentação 1,62 vezes maior do que aqueles que usaram este medicação durante um período mais curto. Pacientes que usaram hidroxiureia por > 30 dias apresentaram escore de hiperpigmentação 1,43 vezes maior do que aqueles que usaram esse medicamento por um período menor. A revisão sistemática recuperou 20 casos clínicos de pacientes submetidos a tratamento com mesilato de imatinibe e exibindo hiperpigmentação oral. Conclusões O desenvolvimento de hiperpigmentação oral está associado ao uso de mesilato de imatinibe. A hidroxiureia parece incrementar tal associação. Relevância clínica Para auxiliar os profissionais no diagnóstico diferencial de lesões hiperpigmentadas associadas ao mesilato de imatinibe, bem como no manejo clínico dessas lesões.

Soft-tissue sarcomas (STS) are an uncommon and heterogeneous group of malignancies that result in high mortality. Metastatic STS have very bad prognosis due to the lack of effective treatments. Dinaciclib is a model drug for the family of CDK inhibitors. Its main targets are cell cycle regulator CDK1 and protein synthesis controller CDK9. We present data supporting Dinaciclib ability to inactivate in vitro different STS models at nanomolar concentrations. Moreover, the different rhythms of cell death induction allow us to further study into the mechanism of action of the drug. Cell death was found to respond to the mitochondrial pathway of apoptosis. Anti-apoptotic Bcl-xL was identified as the key regulator of this process. Already natural low levels of pro-apoptotic proteins BIM and PUMA in tolerant cell lines were insufficient to inhibit Bcl-xL as this anti-apoptotic protein showed a slow decay curve after Dinaciclib-induced protein synthesis disruption. Combination of Dinaciclib with BH3-mimetics led to quick and massive apoptosis induction in vitro, but in vivo assessment was prevented due to liver toxicity. Additionally, Bcl-xL inhibitor A-1331852 also synergized with conventional chemotherapy drugs as Gemcitabine. Thus, Bcl-xL targeted therapy arises as a major opportunity to the treatment of STS.

Objective: To determine the pharmacological measures implemented for secondary prevention in patients with acute coronary syndrome in order to identify whether the implemented management corresponds to recommended clinical practice guidelines and to intervene in those cases where incomplete treatments are found. Methods: A pre- and post-quasi-experimental study was performed in patients with acute coronary syndrome who were affiliated with the Colombian health system. The patients were monitored for one year from the occurrence of acute coronary syndrome, and all dispensed medications were reviewed. For those patients in whom a lack of a prescription (β-blockers + renin-angiotensin-aldosterone system inhibitors (RAASi) + dual antiaggregation + statin) was identified, an intervention was performed with their treating physicians, showing the analysis of each case, the missing medication, and the evidence supporting the recommendation. The results were measured three months later. Results: A total of 829 patients with acute coronary syndrome who underwent percutaneous coronary intervention (90.1%) or coronary bypass (9.9%) were identified. The mean age was 63.8 ± 10.6 years and 73.1% were men. The recommended pharmacological therapy was completed in 729 patients (87.9% of cases). The intervention performed on the remaining 100 patients was able to add the missing drug in 23.0% of the cases. Statistical analysis showed no significant differences with the drug that should have been initiated nor with the success of the intervention. Conclusion: The majority of patients with acute coronary syndrome are adequately treated after percutaneous intervention with medications recommended by the guidelines. Limited success in the adjustment of the management acute coronary syndrome was achieved following the recommendations given to the responsible physicians. Resumen: Objetivo: Determinar las medidas de prevención secundaria implementadas en pacientes que sufrieron un síndrome coronario agudo para identificar si corresponden con guías de práctica clínica e intervenir casos con tratamientos incompletos. Métodos: Estudio cuasiexperimental, antes y después, en todos los niveles de atención, en el que se incluyeron pacientes que sufrieron un síndrome coronario agudo, afiliados al sistema de salud de Colombia. Se hizo seguimiento un año (1 enero y 31 diciembre de 2014) a partir del episodio del síndrome coronario agudo y se revisó toda la medicación dispensada. En quienes se identificó falta de prescripción (β-bloqueadores + ISRAA + antiagregación dual + estatina) se realizó una intervención sobre sus médicos tratantes mostrando el análisis de cada caso, el medicamento faltante y la evidencia que avala la recomendación. Tres meses después se midieron los resultados. Resultados: Se hallaron 829 pacientes con síndrome coronario agudo sometidos a intervención coronaria percutánea (90,1%) o baipás coronario (9,9%). La media de edad fue 63,8 ± 10,6 años y 73,1% fueron hombres. La terapia farmacológica recomendada se cumplió en 729 pacientes (87,9% de casos). La intervención hecha sobre los 100 pacientes restantes logró que agregaran el fármaco faltante en 23,0% de casos. El análisis estadístico no mostró diferencias significativas con el fármaco que debía iniciarse ni con el éxito de la intervención. Conclusión: La mayoría de pacientes que sufrieron un síndrome coronario agudo están tratados de manera adecuada después de la intervención percutánea, con medicamentos recomendados por las guías. Se logró un limitado éxito en el ajuste del manejo tras las recomendaciones dadas a los médicos responsables. Keywords: Acute coronary syndrome, Primary prevention, Optimal medical treatment, Guideline, Pharmacology, Palabras clave: Síndrome coronario agudo, Prevención primaria, Tratamiento médico óptimo, Guía terapéutica, Farmacología

Introduction In the European Union companies only need to demonstrate that the risk-benefit balance of the new drug is favourable to obtain the authorization to sell new drugs. Hence a comparison with available treatments, a cost-effectiveness analysis and the place in the therapy of the new drug are not required. Therefore, it is necessary to carry out these analyses in an additional study. In Spain there is no national government agency, which conducts a centralized evaluation and makes decisions on funding and are the Pharmacy and Therapeutics committees that take mandatory decisions for the entire region. Objectives To identify all drug assessments and health technology assessment reports of the enzymatic replacement treatments for the four LSD considered in this study, including Mucopolysaccharidosis (MPS), Gaucher, Fabry and Pompe disease at the national, regional and hospital level; and to summarize the efficacy in terms of outcome measures, adverse events, economic impact and final recommendations and indicate potential improvements. Methods 19 reviews at the regional and hospital level and one therapeutic positioning report at national level for MPS were considered for this. Results In general, the drugs evaluated in LSD have proved to be effective in the most frequent clinical forms of disease. However, there are clinical phenotypes that still do not have available an effective treatment. Conclusions It is expected that new therapies, such as intrathecal therapies or gene therapy could be evaluated in the different types of LSD demonstrating positive effects, especially in the previous phenotypes.

Within the scope of SAMPL7 challenge for predicting physical properties, the Integral Equation Formalism of the Miertus-Scrocco-Tomasi (IEFPCM/MST) continuum solvation model has been used for the blind prediction of n-octanol/water partition coefficients and acidity constants of a set of 22 and 20 sulfonamide-containing compounds, respectively. The log P and pKa were computed using the B3LPYP/6-31G(d) parametrized version of the IEFPCM/MST model. The performance of our method for partition coefficients yielded a root-mean square error of 1.03 (log P units), placing this method among the most accurate theoretical approaches in the comparison with both globally (rank 8th) and physical (rank 2nd) methods. On the other hand, the deviation between predicted and experimental pKa values was 1.32 log units, obtaining the second best-ranked submission. Though this highlights the reliability of the IEFPCM/MST model for predicting the partitioning and the acid dissociation constant of drug-like compounds compound, the results are discussed to identify potential weaknesses and improve the performance of the method.

Age-related neurodegenerative disorders are an increasing public health problem. Oxidative stress is one of the major causes. Medicinal plant-based functional foods can be effective for these diseases. The aim of this work is to investigate the neuroprotective role of methanol extracts of Moringa oleifera leaf powder on antioxidant/oxidant imbalance and mitochondrial regulation in a H2O2-induced oxidative stress model in human neuroblastoma cells. On nutritional analysis, results showed that moringa contained 28.50% carbohydrates, 25.02% proteins, 10.42% fat, 11.83% dietary fiber, 1.108 mg β-carotene, 326.4 µg/100 g vitamin B1 and 15.2 mg/100 g vitamin C. In-vitro assays revealed that moringa methanol extracts had more phenolic content and higher antioxidant activity than acetone extracts. Moreover, pretreatments with methanol extracts showed a protective effect against H2O2-induced oxidative damage through increasing cell viability and reducing free radicals. Furthermore, the extract decreased lipid peroxidation and enhanced glutathione levels and antioxidant enzyme activity. Finally, moringa also prevented mitochondrial dysfunction by regulating calcium levels and increasing mitochondrial membrane potential. The most active concentration was 25 µg/mL. In summary, the nutritional and functional properties of Moringa oleifera as a neuroprotective agent could be beneficial to protect against oxidative stress and provide necessary nutrients for a healthy diet.

Dalbavancin (DAL) is a lipoglycopeptide with bactericidal activity against a very wide range of Gram-positive microorganisms. It also has unique pharmacokinetic properties, namely a prolonged half-life (around 181 h), which allows a convenient weekly dosing regimen, and good diffusion in bone tissue. These features have led to off-label use of dalbavancin in the setting of bone and joint infection, including prosthetic joint infections (PJI). In this narrative review, we go over the pharmacokinetic and pharmacodynamic characteristics of DAL, along with published in vitro and in vivo experimental models evaluating its activity against biofilm-embedded bacteria. We also examine published experience of osteoarticular infection with special attention to DAL and PJI.

Antibiotic resistance in Streptococcus pneumoniae has increased worldwide, making fluoroquinolones an alternative therapeutic option. Fluoroquinolones inhibit the type II DNA topoisomerases (topoisomerase IV and gyrase). In this study we have evaluated the in vivo activity of seconeolitsine, an inhibitor of topoisomerase I. Levofloxacin (12.5 to 50 mg/kg) or seconeolitsine (5 to 40 mg/kg) were administered every 12 h during two days in mice infected with a serotype 8-resistant strain. At 48 h, a 70% protection was obtained with seconeolitsine (40 mg/kg, p &lt, 0.001). However, survival with levofloxacin was 20%, regardless of the dose. In addition, seconeolitsine decreased bacteremia efficiently. Levofloxacin had higher levels in serum than seconeolitsine (Cmax of 14.7 vs. 1.6, 0.01) and higher values of area under the serum concentration-time curve (AUC0-12h of 17.3 vs. 5, 0.01). However, seconeolitsine showed higher levels of time to peak concentration and elimination half-life. This is consistent with the higher binding of seconeolitsine to plasma proteins (40% and 80% when used at 1 µg/mL and 50 µg/mL, respectively) in comparison to levofloxacin (12% at 5 µg/mL and 33% at 50 µg/mL). Our results suggest that seconeolitsine would be a promising therapeutic alternative against pneumococcal isolates with high fluoroquinolone resistance levels.

Type-2 diabetes mellitus (T2DM) is a major systemic disease which involves impaired pancreatic function and currently affects half a billion people worldwide. Diet is considered the cornerstone to reduce incidence and prevalence of this disease. Algae contains fiber, polyphenols, ω-3 PUFAs, and bioactive molecules with potential antidiabetic activity. This review delves into the applications of algae and their components in T2DM, as well as to ascertain the mechanism involved (e.g., glucose absorption, lipids metabolism, antioxidant properties, etc.). PubMed, and Google Scholar databases were used. Papers in which whole alga, algal extracts, or their isolated compounds were studied in in vitro conditions, T2DM experimental models, and humans were selected and discussed. This review also focuses on meat matrices or protein concentrate-based products in which different types of alga were included, aimed to modulate carbohydrate digestion and absorption, blood glucose, gastrointestinal neurohormones secretion, glycosylation products, and insulin resistance. As microbiota dysbiosis in T2DM and metabolic alterations in different organs are related, the review also delves on the effects of several bioactive algal compounds on the colon/microbiota-liver-pancreas-brain axis. As the responses to therapeutic diets vary dramatically among individuals due to genetic components, it seems a priority to identify major gene polymorphisms affecting potential positive effects of algal compounds on T2DM treatment.

Introduction: Tacrolimus is the backbone immunosuppressant after solid organ transplantation. Tacrolimus has a narrow therapeutic window with large intra- and inter-patient pharmacokinetic variability leading to frequent over- and under-immunosuppression. While routine therapeutic drug monitoring (TDM) remains the standard of care, tacrolimus pharmacokinetic variability may be influenced by circadian rhythms. Our aim was to analyze tacrolimus pharmacokinetic/pharmacodynamic profiles on circadian rhythms comparing morning and night doses of a twice-daily tacrolimus formulation.Methods: This is a post-hoc analysis from a clinical trial to study the area under curve (AUC) and the area under effect (AUE) profiles of calcineurin inhibition after tacrolimus administration in twenty-five renal transplant patients. Over a period of 24 h, an intensive sampling (0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 12.5, 13, 13.5, 14, 15, 20, and 24 h) was carried out. Whole blood and intracellular tacrolimus concentrations and calcineurin activity were measured by UHPLC-MS/MS.Results: Whole blood and intracellular AUC12–24 h and Cmax achieved after tacrolimus night dose was significantly lower than after morning dose administration (AUC0–12 h) (p < 0.001 for both compartments). AUE0–12 h and AUE12–24 h were not statistically different after morning and night doses. Total tacrolimus daily exposure (AUC0–24 h), in whole blood and intracellular compartments, was over-estimated when assessed by doubling the morning AUC0–12 h data.Conclusion: The lower whole blood and intracellular tacrolimus concentrations after night dose might be influenced by a distinct circadian clock. This significantly lower tacrolimus exposure after night dose was not translated into a significant reduction of the pharmacodynamic effect. Our study may provide conceptual bases for better understanding the TDM of twice-daily tacrolimus formulation.

Importance Type I interferon (IFN)-mediated monogenic autoinflammatory disorders (interferonopathies) are childhood-onset rare multisystemic diseases with limited treatment options. The Janus kinase (JAK) inhibitors are promising potential therapeutic candidates for immune-mediated chronic inflammatory skin diseases. Objective To review the use of JAK inhibitors to improve decision-making when treating interferonopathies with cutaneous manifestations. Evidence Review The MEDLINE, EMBASE, CINAHL, Scopus, and Web of Science databases were searched for studies that used JAK protein inhibitors to treat IFN-related monogenic diseases with cutaneous manifestations in humans. The search results are reported using the scoping review approach. Findings Seventeen open-label studies assessing the efficacy of ruxolitinib, baricitinib, or tofacitinib reported variable responses in patients with chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) and related syndromes, stimulator of IFN genes [STING]-associated vasculopathy with onset in infancy (SAVI), familial chilblain lupus (FCh-L), gain-of-function mutations of STAT1 (GOF-STAT1), or Aicardi-Goutiéres syndrome. JAK inhibitors improved clinical and analytical parameters and decreased flare numbers, plasma inflammatory markers, and expression of IFN-stimulated genes. BK viremia and upper respiratory infections were the most frequent and severe adverse events. Significant heterogeneity in efficacy assessment methods and poor reporting of safety events were detected. Conclusions and Relevance Evidence of the use of JAK inhibitors in patients with interpheronopathies is scarce and of low methodological quality. Future clinical trials should use validated scales and report drug safety in a more accurate way. Supplementary Information The online version contains supplementary material available at 10.1007/s13555-021-00517-9.

Background: KPC-producing Klebsiella pneumoniae (KPCKP) is a threat for patients admitted to healthcare institutions.Objectives: To assess the efficacy of several decolonization strategies for KPCKP rectal carriage.Methods: Observational study performed in a 750-bed university center from July to October 2018 on the efficacy of a 10-day non-absorbable oral antibiotic (NAA) regimen (colistin 10 mg/ml, amikacin 8 mg/ml, and nystatin 30 mg/ml, 10 ml/6 h) vs. the same regimen followed by a probiotic (Vivomixx®) for 20 days in adult patients with KPCKP rectal colonization acquired during an outbreak.Results: Seventy-three patients colonized by KPCKP were included, of which 21 (29%) did not receive any treatment and 52 (71.2%) received NAA either alone (n = 26, 35.6%) or followed by a probiotic (n = 26, 35.6%). Eradication was observed in 56 (76.7%) patients and the only variable significantly associated with it was not receiving systemic antibiotics after diagnosis of rectal carriage [22/24 (91.6%) vs. 34/49 (69.3%), p = 0.04]. Eradication in patients receiving NAA plus probiotic was numerically but not significantly higher than that of controls [23/26 (88.4%) vs. 15/21 (71.4%), p = 0.14] and of those receiving only NAA (OR = 3.4, 95% CI = 0.78–14.7, p = 0.09).Conclusion: In an outbreak setting, rectal carriage of KPCKP persisted after a mean of 36 days in about one quarter of patients. The only factor associated with eradication was not receiving systemic antibiotic after diagnosis. A 10-day course of NAA had no impact on eradication. Probiotics after NAA may increase the decolonization rate, hence deserving further study.

Vegetable oils such as palm oil (enriched in saturated fatty acids, SFA) and high‐oleic‐acid sunflower oil (HOSO, containing mainly monounsaturated fatty acids, MUFA) have emerged as the most common replacements for trans‐fats in the food industry. The aim of this study is to analyze the impact of SFA and MUFA‐enriched high‐fat (HF) diets on endothelial function, vascular remodeling, and arterial stiffness compared to commercial HF diets. Five‐week‐old male C57BL6J mice were fed a standard (SD), a HF diet enriched with SFA (saturated oil‐enriched Food, SOLF), a HF diet enriched with MUFA (unsaturated oil‐enriched Food, UOLF), or a commercial HF diet for 8 weeks. Vascular function was analyzed in the thoracic aorta. Structural and mechanical parameters were assessed in mesenteric arteries by pressure myography. SOLF, UOLF, and HF diet reduced contractile responses to phenylephrine and induced endothelial dysfunction in the thoracic aorta. A significant increase in the β‐index, and thus in arterial stiffness, was also detected in mesenteric arteries from the three HF groups, due to enhanced deposition of collagen in the vascular wall. SOLF also induced hypotrophic inward remodeling. In conclusion, these data demonstrate a deleterious effect of HF feeding on obesity‐related vascular alterations that is exacerbated by SFA., This research was funded by Ministerio de Economía y Competitividad (BFU2017-82565- C2-2-R, BFU2017-82565-C2-1-R and BFU2016-78556-R), FUSP-CEU and Grupos Universidad Complutense de Madrid (GR-921641).

Angiogenesis pathway genes show substantial genetic variability causing inter-individual differences in responses to anti-angiogenic drugs. We examined 20 single nucleotide polymorphisms (SNPs) in 13 of these genes to predict tumour response and clinical outcome measured as progression free survival (PFS) and overall survival (OS) in 57 patients with metastatic colorectal cancer (mCRC) given bevacizumab plus chemotherapy. SNPs were detected (iPLEX&reg, Assay) in genomic DNA extracted from formalin-fixed paraffin-embedded tumour specimens. The variant allele CD39 rs11188513 was associated with a good tumour response (p = 0.024). Patients homozygous for the wild-type allele FGF2 rs1960669 showed a median PFS of 10.95 months versus 5.44 months for those with at least one variant allele-A (HR 3.30, 95% CI: 1.52&ndash, 7.14, p = 0.001). Patients homozygous for wild-type MMP9 rs2236416 and rs2274755 showed a median PFS of 9.48 months versus 6 and 6.62 months, respectively, for those with at least one variant allele (p = 0.022, p = 0.043, respectively). OS was also lengthened to 30.92 months (p = 0.034) in carriers of wild-type ANGPT1 rs2445365 versus 22.07 months for those carrying at least one variant allele-A. These gene variants were able to predict clinical outcome and tumour response in mCRC patients given bevacizumab-based therapy.

Valganciclovir (VGCV) and ganciclovir (GCV) doses must be adjusted according to indication, renal function and weight. No specific therapeutic exposure values have been established. We aimed to evaluate the adequacy of VGCV/GCV doses, to assess the interpatient variability in GCV serum levels, to identify predictive factors for this variability and to assess the clinical impact. This is a prospective study at a tertiary institution including hospitalized patients receiving VGCV/GCV prophylaxis or treatment. Adequacy of the antiviral dose was defined according to cytomegalovirus guidelines. Serum levels were determined using High-Performance Liquid Chromatography. Blood samples were drawn at least 3 days after antiviral initiation. Outcome was considered favorable if there was no evidence of cytomegalovirus infection during prophylaxis or when a clinical and microbiological resolution was attained within 21 days of treatment and no need for drug discontinuation due to toxicity. Seventy consecutive patients [74.3% male/median age: 59.2 years] were included. VGCV was used in 25 patients (35.7%) and GCV in 45 (64.3%). VGCV/GCV initial dosage was deemed adequate in 47/70 cases (67.1%), lower than recommended in 7/70 (10%) and higher in 16/70 (22.9%). Large inter-individual variability of serum levels was observed, with median trough levels of 2.3 mg/L and median peak levels of 7.8 mg/L. Inadequate dosing of VGCV/GCV and peak levels lower than 8.37 or greater than 11.86 mg/L were related to poor outcome. Further studies must be performed to confirm these results and to conclusively establish if VGCV/GCV therapeutic drug monitoring could be useful to improve outcomes in specific clinical situations.

The article aims to analyze the progress of the evolution of cinnamic acid derivatives through a bibliographic review, describing the main synthetic routes in obtaining this class, as well as remarkable biological applications and application of the structure-activity relationship (SAR) as a strategy for design pharmacologically active molecules. The methodology used consists of reading and analyzing articles, whose approach is descriptive, with data being collected regarding the therapeutic potential of derivatives of cinnamic acid and its relationship with structural scaffolding, as well as the most widely used synthetic approaches. As a result, it was observed that cinnamic acid and its derivatives from natural sources can be synthesized in appreciable quantities with varied synthetic routes, as well as being candidates for therapeutic agents, since they have several therapeutic applications against diabetes, infectious and degenerative diseases, among others, in addition to presenting activity such as pest control, which has attracted the attention of academic and industrial researchers. These compounds are highly versatile since their activity is intrinsically associated with the mode of interaction between the structure and its molecular target. However, in nature they are obtained in small quantities, therefore, the development of new approaches of synthetic methodologies to obtain such compounds in substantial quantities and linked to medicinal chemistry can contribute to the development of very effective bioactive molecules in comparison with their precursors. El artículo tiene como objetivo analizar el avance de la evolución de los derivados del ácido cinámico a través de una revisión bibliográfica, describiendo las principales vías sintéticas en la obtención de esta clase, así como las aplicaciones biológicas destacables y la aplicación de la relación estructura-actividad (SAR) como estrategia para diseñar moléculas farmacológicamente activas. La metodología empleada consiste en la lectura y análisis de artículos, cuyo abordaje es descriptivo, recogiéndose datos sobre el potencial terapéutico de los derivados del ácido cinámico y su relación con el andamiaje estructural, así como los abordajes sintéticos más utilizados. Como resultado, se observó que el ácido cinámico y sus derivados de fuentes naturales pueden sintetizarse en cantidades apreciables con variadas rutas sintéticas, además de ser candidatos a agentes terapéuticos, ya que tienen varias aplicaciones terapéuticas contra la diabetes, enfermedades infecciosas y degenerativas, entre otros, además de presentar actividades como el control de plagas, que ha llamado la atención de investigadores académicos e industriales. Estos compuestos son muy versátiles ya que su actividad está intrínsecamente asociada con el modo de interacción entre la estructura y su objetivo molecular. Sin embargo, en la naturaleza se obtienen en pequeñas cantidades, por lo que el desarrollo de nuevos enfoques de metodologías sintéticas para obtener dichos compuestos en cantidades sustanciales y vinculados a la química médica puede contribuir al desarrollo de moléculas bioactivas muy efectivas en comparación con sus precursores. O artigo tem por objetivo analisar o progresso da evolução dos derivados do ácido cinâmico por meio de uma revisão bibliográfica, descrevendo as principais rotas sintéticas na obtenção dessa classe, bem como as notáveis aplicações biológicas e aplicação da relação estrutura-atividade (SAR) como estratégia para projetar moléculas farmacologicamente ativas. A metodologia empregada consistiu na leitura e análise de artigos, cuja abordagem foi descritiva, sendo feito o levantamento de dados no que tange as potencialidades terapêuticas dos derivados do ácido cinâmico e sua relação estrutural, assim como as abordagens sintéticas mais utilizadas. Como resultado observou-se que o ácido cinâmico e seus derivados oriundos de fontes naturais podem ser sintetizados em quantidades apreciáveis por rotas sintéticas variadas, e que são bons candidatos a agentes terapêuticos, já que apresentam diversas aplicações terapêuticas contra diabetes, doenças infecciosas, degenerativas entre outras. Além disso, apresentam atividades como controle de pragas, o que vem chamando a atenção de pesquisadores do meio acadêmico e industrial. Esses compostos são altamente versáteis visto que sua atividade está intrinsecamente associada ao modo de interação entre a estrutura e seu alvo molecular. Contudo, na natureza são obtidos em pequenas quantidades, portanto, o desenvolvimento de novas abordagens de metodologias sintéticas visando obter tais compostos em quantidades substanciais e ligadas à química medicinal podem contribuir para o desenvolvimento de moléculas bioativas eficazes em comparação aos seus precursores.

We assessed the sustained delivery effect of poly (lactic-co-glycolic) acid (PLGA)/vitamin E (VitE) microspheres (MSs) loaded with glial cell-derived neurotrophic factor (GDNF) alone (GDNF-MSs) or combined with brain-derived neurotrophic factor (BDNF, GDNF/BDNF-MSs) on migration of the human adult retinal pigment epithelial cell-line-19 (ARPE-19) cells, primate choroidal endothelial (RF/6A) cells, and the survival of isolated mouse retinal ganglion cells (RGCs). The morphology of the MSs, particle size, and encapsulation efficiencies of the active substances were evaluated. In vitro release, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability, terminal deoxynucleotidyl transferase (TdT) deoxyuridine dUTP nick-end labelling (TUNEL) apoptosis, functional wound healing migration (ARPE-19, migration), and (RF/6A, angiogenesis) assays were conducted. The safety of MS intravitreal injection was assessed using hematoxylin and eosin, neuronal nuclei (NeuN) immunolabeling, and TUNEL assays, and RGC in vitro survival was analyzed. MSs delivered GDNF and co-delivered GDNF/BDNF in a sustained manner over 77 days. The BDNF/GDNF combination increased RPE cell migration, whereas no effect was observed on RF/6A. MSs did not alter cell viability, apoptosis was absent in vitro, and RGCs survived in vitro for seven weeks. In mice, retinal toxicity and apoptosis was absent in histologic sections. This delivery strategy could be useful as a potential co-therapy in retinal degenerations and glaucoma, in line with future personalized long-term intravitreal treatment as different amounts (doses) of microparticles can be administered according to patients&rsquo, needs.

The 2015/16 Zika virus (ZIKV) epidemic led to almost 1 million confirmed cases in 84 countries and was associated to the development of congenital microcephaly and Guillain-Barre syndrome. More recently, a ZIKV African lineage was identified in Brazil raising concerns about a future outbreak. The long-term consequences of viral infection emphasizes the need for the development of effective anti-ZIKV drugs. In this study, we developed and characterized a ZIKV replicon cell line for the screening of viral replication inhibitors. The replicon system was developed by engineering the IRES-Neo cassette into the 3’ UTR terminus of the ZIKV Rluc DNA construct. After in vitro transcription, replicon RNA was used to transfect BHK-21 cells, that were selected with G418, thus generating the BHK-21-RepZIKV_IRES-Neo cell line. Through this replicon-based cell system, we identified two molecules with potent anti-ZIKV activities, an imidazonaphthyridine and a riminophenazine, both from the MMV/DNDi Pandemic Response Box library of 400 drug-like compounds. The imidazonaphthyridine, known as RO8191, showed remarkable selectivity against ZIKV, while the riminophenazine, the antibiotic Clofazimine, could act as a non-nucleoside analog inhibitor of viral RNA-dependent RNA polymerase (RdRp), as evidenced both in vitro and in silico. The data showed herein supports the use of replicon-based assays in high-throughput screening format as a biosafe and reliable tool for antiviral drug discovery.

Current approved therapies for pulmonary hypertension (PH) aim to restore the balance between endothelial mediators in the pulmonary circulation. These drugs may exert vasodilator effects on poorly oxygenated vessels. This may lead to the derivation of blood perfusion towards low ventilated alveoli, i.e., producing ventilation-perfusion mismatch, with detrimental effects on gas exchange. The aim of this study is to analyze the oxygen-sensitivity in vitro of 25 drugs currently used or potentially useful for PH. Additionally, the study analyses the effectiveness of these vasodilators in the pulmonary vs. the systemic vessels. Vasodilator responses were recorded in pulmonary arteries (PA) and mesenteric arteries (MA) from rats and in human PA in a wire myograph under different oxygen concentrations. None of the studied drugs showed oxygen selectivity, being equally or more effective as vasodilators under conditions of low oxygen as compared to high oxygen levels. The drugs studied showed low pulmonary selectivity, being equally or more effective as vasodilators in systemic than in PA. A similar behavior was observed for the members within each drug family. In conclusion, none of the drugs showed optimal vasodilator profile, which may limit their therapeutic efficacy in PH. This work was supported by grants from Mineco (SAF2011-28150, SAF2016-77222, PID2019- 107363RB-I00), Instituto de Salud Carlos III (PI15/01100, FIS PI14/01733) with funds from the European Union (Fondo Europeo de Desarrollo Regional FEDER) and Fundación contra la Hipertensión Pulmonar (Empathy project). D.M.-C., M.C., G.M.-P. and S.E.-R. were funded by a Formación de Personal Investigador grant (BES-2012-051904), Universidad Complutense, Ciberes grant and a FPU grant from Ministerio de Educación, respectively. Sí

3,4-Methylenedioxypyrovalerone (MDPV) is a new psychoactive substance (NPS) and the most widespread and life-threatening synthetic cathinone of the "bath salts". Preclinical research has proven the cocaine-like psychostimulant effects of MDPV and its potential for abuse. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid that has emerged as a new potential treatment for drug addiction. Here, we tested the effects of CBD (20 mg/kg) on MDPV (2 mg/kg)-induced conditioned place preference and MDPV (0.05 and 0.075 mg/kg/infusion) self-administration paradigms. In addition, we assessed the effects of the co-administration of CBD and MDPV (3 and 4 mg/kg) on anxiety-like behaviour using the elevated plus maze (EPM). CBD mitigated the MDPV-induced conditioned place preference. On the contrary, CBD administration throughout the MDPV (0.075 mg/kg/infusion) self-administration increased drug-seeking and taking behaviours, but only in the high-responders group of mice. Furthermore, CBD exerted anxiolytic-like effects, exclusively in MDPV-treated mice. Taken together, our results indicate that CBD modulation of MDPV-induced motivational responses in mice varies depending on the requirements of the learning task, resulting in a complex response. Therefore, further research attempting to decipher the behavioural and molecular interactions between CBD and MDPV is needed. This work was supported by Ministerio de Economía y Competitividad (grant number SAF2016-75966-R-FEDER and PID2019-104077-RB-100), Ministerio de Sanidad, Asuntos Sociales e Igualdad (Retic-ISCIII-RD/16/0017/0010-FEDER and Plan Nacional Sobre Drogas (#2018/007). L.A.-Z. received FPI grant (BES-2017-080066) from the Ministerio de Economía y Competitividad. The Department of Experimental and Health Sciences (UPF) is a “Unidad de Excelencia María de Maeztu” funded by the AEI (CEX2018-000792-M).

Graphical abstract, Introduction Natural products of pharmaceutical interest often do not reach the drug market due to the associated low yields and difficult extraction. Knowledge of biosynthetic pathways is a key element in the development of biotechnological strategies for plant specialized metabolite production. Erythrina species are mainly used as central nervous system depressants in folk medicine and are important sources of bioactive tetracyclic benzylisoquinoline alkaloids (BIAs), which can act on several pathology-related biological targets. Objectives In this sense, in an unprecedented approach used with a non-model Fabaceae species grown in its unique arid natural habitat, a combined transcriptome and metabolome analyses (seeds and leaves) is presented. Methods The Next Generation Sequencing-based transcriptome (de novo RNA sequencing) was carried out in a NextSeq 500 platform. Regarding metabolite profiling, the High-resolution Liquid Chromatography was coupled to DAD and a micrOTOF-QII mass spectrometer by using electrospray ionization (ESI) and Time of Flight (TOF) analyzer. The tandem MS/MS data were processed and analyzed through Molecular Networking approach. Results This detailed macro and micromolecular approach applied to seeds and leaves of E. velutina revealed 42 alkaloids, several of them unique. Based on the combined evidence, 24 gene candidates were put together in a putative pathway leading to the singular alkaloid diversity of this species. Conclusion Overall, these results could contribute by indicating potential biotechnological targets for modulation of erythrina alkaloids biosynthesis as well as improve molecular databases with omic data from a non-model medicinal plant, and reveal an interesting chemical diversity of Erythrina BIA harvested in Caatinga.

Adenosine A2A receptor mediates the promotion of wound healing and revascularization of injured tissue, in healthy and animals with impaired wound healing, through a mechanism depending upon tissue plasminogen activator (tPA), a component of the fibrinolytic system. In order to evaluate the contribution of plasmin generation in the proangiogenic effect of adenosine A2A receptor activation, we determined the expression and secretion of t-PA, urokinase plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1) and annexin A2 by human dermal microvascular endothelial cells stimulated by the selective agonist CGS-21680. The plasmin generation was assayed through an enzymatic assay and the proangiogenic effect was studied using an endothelial tube formation assay in Matrigel. Adenosine A2A receptor activation in endothelial cells diminished the release of PAI-1 and promoted the production of annexin A2, which acts as a cell membrane co-receptor for plasminogen and its activator tPA. Annexin A2 mediated the increased cell membrane-associated plasmin generation in adenosine A2A receptor agonist treated human dermal microvascular endothelial cells and is required for tube formation in an in vitro model of angiogenesis. These results suggest a novel mechanism by which adenosine A2A receptor activation promotes angiogenesis: increased endothelial expression of annexin A2, which, in turn, promotes fibrinolysis by binding tPA and plasminogen to the cell surface.

Introduction: The role of Olanzapine therapeutic drug monitoring is controversial. The present study explores the associations of Olanzapine plasma concentrations with clinical response and metabolic side effects in first episode psychosis (FEP) after 2 months of treatment. Methods: Forty-seven patients were included. Improvement in clinical symptomatology was assessed using the PANSS. Metabolic assessment included weight, blood pressure, waist circumference, blood glucose, total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides. Results: The Olanzapine plasma concentrations after 2 months of treatment were positively correlated with weight gain (r = 0.49, p = 0.003), and a concentration > 23.28 ng/mL was identified as a positive predictor of weight gain (≥ 7%). The Olanzapine concentration to dose (C/D) ratio was positively correlated with the percentage of improvement in the total PANSS (r = 0.46, p = 0.004), and a C/D ratio > 2.12 was identified as a positive predictor of a good response (percentage of improvement > 30%) after 2 months of treatment. We also identified several factors that could alter Olanzapine pharmacokinetics: gender (p = 0.03), diagnosis (p = 0.05), smoking habit (p = 0.05), and co-medications such as valproic acid (p = 0.05) and anxiolytics (p = 0.01). Discussion: In conclusion, our results suggest that therapeutic drug monitoring of Olanzapine could be helpful to evaluate therapeutic efficacy and metabolic dysfunction in FEP patients treated with Olanzapine.

Alzheimers disease (AD) is a chronic neurodegenerative disorder that accounts for about 60% of all diagnosed cases of dementia worldwide. Although there are currently several drugs marketed for its treatment, none are capable of slowing down or stopping the progression of AD. The role of the blood-brain barrier (BBB) plays a key role in the design of a successful treatment for this neurodegenerative disease. Nanosized particles have been proposed as suitable drug delivery systems to overcome BBB with the purpose of increasing bioavailability of drugs in the brain. Biodegradable poly (lactic-co-glycolic acid) nanoparticles (PLGA-NPs) have been particularly regarded as promising drug delivery systems as they can be surface-tailored with functionalized molecules for site-specific targeting. In this review, a thorough discussion about the most recent functionalization strategies based on PLGA-NPs for AD and their mechanisms of action is provided, together with a description of AD pathogenesis and the role of the BBB in brain targeting., A.C. [Amanda Cano] acknowledges the support of the Spanish Ministry of Science, Innovation and Universities under the grant Juan de la Cierva (FJC2018-036012-I). Authors acknowledge the support of the Spanish Ministry of Economy and Competitiveness under the project SAF2017-84283-R; Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED, CB06/05/0024) and Portuguese Science and Technology Foundation (FCT) for the strategic fund (UIDB/04469/2020)., info:eu-repo/semantics/publishedVersion

Despite the high incidence of breast cancer, there are few pharmacological prevention strategies for the high-risk population and those that are available have low adherence. Strategies that deliver drugs directly to the breasts may increase drug local concentrations, improving efficacy, safety and acceptance. The skin of the breast has been proposed as an administration route for local transdermal therapy, which may improve drug levels in the mammary tissue, due to both deep local penetration and percutaneous absorption. In this review, we discuss the application of nanotechnology-based strategies for the delivery of well established and new agents as well as drug repurposing using the topical transdermal route to improve the outcomes of preventive therapy for breast cancer.

N-Propargylamines are useful synthetic scaffolds for the synthesis of bioactive molecules, and in addition, they possess important pharmacological activities. We obtained several neuroprotective molecules, chiral 1,2-amino alcohols and 1,2-diamines, able to reduce by almost 70% the rotenone and oligomycin A-induced damage in SH-SY5Y cells. Furthermore, some molecules assessed also counteracted the toxicity evoked by the Ser/Thr phosphatase inhibitor okadaic acid. Before extrapolating these data to preclinical studies, we analyze the molecules through an in silico prediction system to detect carcinogenicity risk or other toxic effects. In light of these promising results, these molecules may be considered as a lead family of neuroprotective and relatively safe compounds.

Background: Patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) are at risk of atrial fibrillation or flutter (AFF) due to cardiac remodeling and kidney complications. Finerenone, a novel, selective, nonsteroidal mineralocorticoid receptor antagonist, inhibited cardiac remodeling in preclinical models. Objectives: This work aims to examine the effect of finerenone on new-onset AFF and cardiorenal effects by history of AFF in the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) study. Methods: Patients with CKD and T2D were randomized (1:1) to finerenone or placebo. Eligible patients had a urine albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g, an estimated glomerular filtration rate (eGFR) ≥25 to 2 and received optimized doses of renin–angiotensin system blockade. Effect on new-onset AFF was evaluated as a pre-specified outcome adjudicated by an independent cardiologist committee. The primary composite outcome (time to first onset of kidney failure, a sustained decrease of ≥40% in eGFR from baseline, or death from renal causes) and key secondary outcome (time to first onset of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) were analyzed by history of AFF. Results: Of 5,674 patients, 461 (8.1%) had a history of AFF. New-onset AFF occurred in 82 (3.2%) patients on finerenone and 117 (4.5%) patients on placebo (hazard ratio: 0.71; 95% confidence interval: 0.53–0.94; p = 0.016). The effect of finerenone on primary and key secondary kidney and cardiovascular outcomes was not significantly impacted by baseline AFF (interaction p value: 0.16 and 0.85, respectively). Conclusions: In patients with CKD and T2D, finerenone reduced the risk of new-onset AFF. The risk of kidney or cardiovascular events was reduced irrespective of history of AFF at baseline. (EudraCT 2015-000990-11 [A randomized, double-blind, placebo-controlled, parallel-group, multicenter, event-driven Phase III study to investigate the efficacy and safety of finerenone, in addition to standard of care, on the progression of kidney disease in subjects with type 2 diabetes mellitus and the clinical diagnosis of diabetic kidney disease]; Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease [FIDELIO-DKD]; NCT02540993)

Background: Metabolic myopathies are a heterogenous group of muscle diseases typically characterized by exercise intolerance, myalgia and progressive muscle weakness. Effective treatments for some of these diseases are available, but while our understanding of the pathogenesis of metabolic myopathies related to glycogen storage, lipid metabolism and β-oxidation is well established, evidence linking treatments with the precise causative genetic defect is lacking. Objective: The objective of this study was to collate all published evidence on pharmacological therapies for the aforementioned metabolic myopathies and link this to the genetic mutation in a format amenable to databasing for further computational use in line with the principles of the "treatabolome" project. Methods: A systematic literature review was conducted to retrieve all levels of evidence examining the therapeutic efficacy of pharmacological treatments on metabolic myopathies related to glycogen storage and lipid metabolism. A key inclusion criterion was the availability of the genetic variant of the treated patients in order to link treatment outcome with the genetic defect. Results: Of the 1,085 articles initially identified, 268 full-text articles were assessed for eligibility, of which 87 were carried over into the final data extraction. The most studied metabolic myopathies were Pompe disease (45 articles), multiple acyl-CoA dehydrogenase deficiency related to mutations in the ETFDH gene (15 articles) and systemic primary carnitine deficiency (8 articles). The most studied therapeutic management strategies for these diseases were enzyme replacement therapy, riboflavin, and carnitine supplementation, respectively. Conclusions: This systematic review provides evidence for treatments of metabolic myopathies linked with the genetic defect in a computationally accessible format suitable for databasing in the treatabolome system, which will enable clinicians to acquire evidence on appropriate therapeutic options for their patient at the time of diagnosis. AM received a Summer Studentship stipend from the Faculty of Medicine at the University of Ottawa. HL receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant NG2-170044 for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). RT receives support from the Canadian Institutes of Health Research (postdoctoral fellowship award MFE-171275). This review is part of the Solve-RD treatabolome initiative. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257

Background: Mitochondrial DNA (mtDNA) diseases are a group of maternally inherited genetic disorders caused by a lack of energy production. Currently, mtDNA diseases have a poor prognosis and no known cure. The chance to have unaffected offspring with a genetic link is important for the affected families, and mitochondrial replacement techniques (MRTs) allow them to do so. MRTs consist of transferring the nuclear DNA from an oocyte with pathogenic mtDNA to an enucleated donor oocyte without pathogenic mtDNA. This paper aims to determine the efficacy, associated risks, and main ethical and legal issues related to MRTs. Methods: A bibliographic review was performed on the MEDLINE and Web of Science databases, along with searches for related clinical trials and news. Results: A total of 48 publications were included for review. Five MRT procedures were identified and their efficacy was compared. Three main risks associated with MRTs were discussed, and the ethical views and legal position of MRTs were reviewed. Conclusions: MRTs are an effective approach to minimizing the risk of transmitting mtDNA diseases, but they do not remove it entirely. Global legal regulation of MRTs is required.

A Bauhinia variegata Linn pertence à família Fabaceae e é utilizada popularmente como hipoglicemiante. Estudos fitoquímicos isolaram flavonoides, terpenos, esteroides e derivados do naftaleno, e por essa razão, este artigo objetiva descrever os resultados de farmacocinética, toxicidade e atividades biológicas obtidos em estudos in silico das moléculas isoladas para B. variegata. As bases de dados online para coleta dos dados foram: PreADMET e PASS online. Para o desenho das estruturas químicas e caracterização físico-química: MarvinSketch, Mcule property calculator e Chemicalize. Os resultados sugeriram que o Caempferol, 2'-hidroxi-4',6'- dimetoxi-3,4-metilenodioxichalcona, Campferol3-O-α-L-ramnosídeo, (2S)-5,7-dimetóxi-3’,4’-metilenodioxiflavanona e 5,6-dihidro-1,7-dihidroxi-3,4-dimetóxi-2-metildibenz[b,f]oxepina apresentaram melhor padrão farmacocinético, devido as características físico-químicas serem alinhadas com Lipinsk, entretanto, todos os compostos apresentaram inibição sobre o citocromo P450 (CYP). O Lupeol foi o mais favorável enquanto antineoplásico; o β-Sitosterol e o Heptatricontan-12, 13-diol capacidade antiviral; os flavonoides (Campferol3-O-α-L-ramnosídeo e 2'-hidroxi-4',6'- dimetoxi-3,4-metilenodioxichalcona) e o Lupeol atividade antiparasitária; o Campferol3-O-α-L-ramnosídeo e o Lupeol potencial anti-inflamatório. A ação hipoglicemiante não foi encontrada, mas a via de liberação do hormônio pode ser outra. Os compostos obtiveram resultados tóxicos nos diferentes níveis tróficos e em relação à avaliação da carcinogenicidade e mutagenicidade. Com base nestes aspectos, o Campferol3-O-α-L-ramnosídeo e o Lupeol parecem ser as moléculas mais promissoras em atividades biológicas, podendo atuar como antimaláricos, com modificações necessárias na sua estrutura para a diminuição dos seus efeitos tóxicos, bem como apresentando aspectos farmacocinéticos aceitáveis caso sejam candidatos à fármacos.

Folkloric or galenic preparations of valerian roots and rhizomes have been used as sedatives/anxiolytics and sleep inducers since ancient times. “Valerianas” are plants that naturally grow in our region. Although some of them are used in folk medicine, they lack scientific information. We performed a comparative study of the phytochemical composition and the potential in vivo effects of ethanolic extracts of argentine valerian species: Valeriana carnosa Sm., V. clarionifolia Phil. and V. macrorhiza Poepp. ex DC., from “Patagonia Argentina”; V. ferax (Griseb.) Hock and V. effusa Griseb., from the central part of our country, and V. officinalis (as the reference plant). All these plants were rich in phenolic compounds, evidenced the presence of ligands for the benzodiazepine binding site of the GABAA receptor and were able to induce sedation as assessed by loss-of-righting reflex assays (500 mg/kg, i.p.). Mice treated with V. macrorhiza, V. carnosa and V. ferax extracts showed reduced exploratory behaviors while V. clarionifolia produced anxiolytic-like activities (500 mg/kg, i.p.) in the Hole board test. Oral administrations (300 mg/kg and 600 mg/kg, p.o.) evidenced sedative effects for V. ferax and anxiolytic-like properties for V. macrorhiza, V. carnosa and V. clarionifolia extracts. Our native valerian species are active on the CNS, validating its folkloric use as anxiolytic/sedative and sleep enhancers., Facultad de Ciencias Exactas, Instituto de Estudios Inmunológicos y Fisiopatológicos

Introduction A prospective evaluation of outcomes in a series of patients with post-prostatectomy incontinence (PPI) treated with two different devices is presented. Methods Consecutive patients with PPI underwent interventions with an adjustable transobturator male system (ATOMS) or artificial urinary sphincter (AUS). Decisions were based on patient preference after physician counselling. Patient characteristics and operative and postoperative parameters including dryness, satisfaction, complications, revision and device durability were evaluated. Results One hundred twenty-nine patients were included: 102 (79.1%) received ATOMS and 27 (20.9%) AUS. Mean follow-up was 34.9 ± 15.9 months. No difference was observed between patient age (p = 0.56), ASA score (p = 0.13), Charlson index (p = 0.57) and radiation (p = 0.3). BMI was higher for AUS (27.1 vs. 29.7; p = 0.003) and also baseline incontinence severity (7.9% mild, 44.1% moderate and 48% severe for ATOMS vs. 11.1% moderate and 88.9% severe for AUS; p = 0.0007). Differential pad test was higher for AUS (− 470 vs. − 1000 ml; p

CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior A complex intracellular signaling governs different cellular responses in inflammation. Extracellular stimuli are sensed, amplified, and transduced through a dynamic cellular network of messengers converting the first signal into a proper response: production of specific mediators, cell activation, survival, or death. Several overlapping pathways are coordinated to ensure specific and timely induction of inflammation to neutralize potential harms to the tissue. Ideally, the inflammatory response must be controlled and self-limited. Resolution of inflammation is an active process that culminates with termination of inflammation and restoration of tissue homeostasis. Comparably to the onset of inflammation, resolution responses are triggered by coordinated intracellular signaling pathways that transduce the message to the nucleus. However, the key messengers and pathways involved in signaling transduction for resolution are still poorly understood in comparison to the inflammatory network. cAMP has long been recognized as an inducer of anti-inflammatory responses and cAMP-dependent pathways have been extensively exploited pharmacologically to treat inflammatory diseases. Recently, cAMP has been pointed out as coordinator of key steps of resolution of inflammation. Here, we summarize the evidence for the role of cAMP at inducing important features of resolution of inflammation. Uma sinalização intracelular complexa governa diferentes respostas celulares na inflamação. Estímulos extracelulares são detectados, amplificados e transduzidos através de uma rede celular dinâmica de mensageiros convertendo o primeiro sinal em uma resposta adequada: produção de mediadores específicos, ativação celular, sobrevivência ou morte. Várias vias sobrepostas são coordenadas para garantir a indução específica e oportuna da inflamação para neutralizar possíveis danos ao tecido. Idealmente, a resposta inflamatória deve ser controlada e autolimitada. A resolução da inflamação é um processo ativo que culmina com o término da inflamação e restauração da homeostase tecidual. Comparativamente ao início da inflamação, as respostas de resolução são desencadeadas por vias de sinalização intracelular coordenadas que transduzem a mensagem para o núcleo. No entanto, os principais mensageiros e vias envolvidos na transdução de sinalização para resolução ainda são pouco compreendidos em comparação com a rede inflamatória. O cAMP tem sido reconhecido há muito tempo como um indutor de respostas anti-inflamatórias e as vias dependentes de cAMP têm sido extensivamente exploradas farmacologicamente para tratar doenças inflamatórias. Recentemente, o AMPc tem sido apontado como coordenador das principais etapas de resolução da inflamação. Aqui, resumimos as evidências do papel do AMPc na indução de características importantes da resolução da inflamação.

Anxiety participates in the body's natural defense, however, it can be pathological, when symptoms start to interfere in the individual's routine, causing loss of quality of life. Essential oils (EOs) are secondary metabolites with numerous pharmacological and biological activities, where we can highlight anxiolytic activity. Thus, the objective was to carry out a systematic review of the last 9 years in the large area of ​​pharmacology and toxicology, and to verify which EOs have anxiolytic activity, which tests were performed and the possible mechanisms involved. A bibliographic review with a qualitative and quantitative nature was carried out, using the Scopus database, where original studies were published, published between January 2010 and August 10, 2019, of the pre-clinical and clinical trial type that present results referring to anxiolytic activity of EOs, excluding those studies that did not understand the area of ​​pharmacology and / or toxicology. At the end of this analysis, of the 71 papers found, 18 were selected to compose this review. This review made it possible to visualize the panorama of preclinical and clinical studies for assessing anxiety with the use of OEs in the last 9 years, pointing out that in addition to the EO of Lavandula angustifolia, other EOs can also be promising, such as the EOs obtained from species of the genus Citrus. However, there is a scarcity of clinical studies to prove the efficacy and safety of the use of these EOs in the treatment of anxiety, which allows the opening of research in this area for the development and launch of new natural anxiolytics. La ansiedad participa en la defensa natural del organismo, sin embargo, puede ser patológica, cuando los síntomas comienzan a interferir en la rutina del individuo, provocando pérdida de calidad de vida. Los aceites esenciales (AEs) son metabolitos secundarios con numerosas actividades farmacológicas y biológicas, entre las que podemos destacar la actividad ansiolítica. Assim, o objetivo era realizar uma revisión sistemática dos últimos 9 anos no amplio ámbito de la farmacología y toxicología, y comprobar qué AE tienen actividad ansiolítica, qué pruebas se han realizado y los posibles mecanismos implicados. Se realizó uma revisión bibliográfica de carácter cualitativo y cuantitativo, utilizando a base de dados Scopus, donde se publicaron estudios originales, publicado entre enero de 2010 e 10 de agosto de 2019, del tipo de ensayo clínico y preclínico que apresenta resultados referidos a la atividade ansiolítica de los AEs, excluindo aquellos estudios que não comprendem a área de farmacología y / o toxicología. A final desta análise, dos 71 artigos encontrados, 18 foram selecionados para componer esta revisión. Esta revisión permite visualizar o panorama dos estudos preclínicos e clínicos para avaliar la ansiedad con el uso de AEs nos últimos 9 anos, señalando que además de la AE deLavandula angustifolia , otras AEs también pueden ser prometedoras, como los AEs obtenidas de especies del género Citrus . No entanto, existe um escasso de estudos clínicos que demonstram a eficiência e segurança do uso de estos AEs no tratamento da ansiedade, o que permite a abertura da investigação nesta área para o desenvolvimento e desenvolvimento de novos ansiolíticos naturais. A ansiedade participa da defesa natural do organismo, no entanto, ela pode ser patológica, quando os sintomas passam a interferir na rotina do indivíduo, causando perda da qualidade de vida. Os óleos essenciais (OEs) são metabólitos secundários com inúmeras atividades farmacológicas e biológicas, onde podemos destacar a atividade ansiolítica. Desta forma, objetivou-se realizar uma revisão sistemática dos últimos 9 anos na grande área de farmacologia e toxicologia, e verificar quais OEs apresentam atividade ansiolítica, quais os ensaios foram realizados e os possíveis mecanismos envolvidos. Realizou-se uma revisão bibliográfica com natureza quali-quantitativa, utilizando-se a base de dados Scopus, onde foram selecionados estudos originais, publicados entre janeiro de 2010 a 10 de agosto de 2019, do tipo ensaio pré-clínico e clínico que apresentam resultados referentes à atividade ansiolítica de EOs, sendo excluídos aqueles estudos que não compreendiam a área de farmacologia e/ou toxicologia. Ao final desta análise, dos 71 trabalhos encontrados, 18 foram selecionados para compor esta revisão. Esta revisão possibilitou visualizar o panorama dos estudos pré-clínicos e clínicos para avaliação da ansiedade com a utilização de OEs dos últimos 9 anos, apontando que além do OE de Lavandula angustifolia, outros OEs também podem ser promissores, como por exemplo os OEs obtidos de espécies do gênero Citrus. No entanto, verifica-se a escassez de estudos clínicos para a comprovação da eficácia e segurança do uso destes OEs no tratamento da ansiedade, o que possibilita a abertura de pesquisas nesta área para o desenvolvimento e lançamento de novos ansiolíticos naturais.

Purpose: Retinitis pigmentosa (RP) is a blinding neurodegenerative disease of the retina that can be affected by many factors. The present study aimed to analyze the effect of different environmental light intensities in rd10 mice retina. Methods: C57BL/6J and rd10 mice were bred and housed under three different environmental light intensities: scotopic (5 lux), mesopic (50 lux), and photopic (300 lux). Visual function was studied using electroretinography and optomotor testing. The structural and morphological integrity of the retinas was evaluated by optical coherence tomography imaging and immunohistochemistry. Additionally, inflammatory processes and oxidative stress markers were analyzed by flow cytometry and western blotting. Results: When the environmental light intensity was higher, retinal function decreased in rd10 mice and was accompanied by light-dependent photoreceptor loss, followed by morphological alterations, and synaptic connectivity loss. Moreover, light-dependent retinal degeneration was accompanied by an increased number of inflammatory cells, which became more activated and phagocytic, and by an exacerbated reactive gliosis. Furthermore, light-dependent increment in oxidative stress markers in rd10 mice retina pointed to a possible mechanism for light-induced photoreceptor degeneration. Conclusions: An increase in rd10 mice housing light intensity accelerates retinal degeneration, activating cell death, oxidative stress pathways, and inflammatory cells. Lighting intensity is a key factor in the progression of retinal degeneration, and standardized lighting conditions are advisable for proper analysis and interpretation of experimental results from RP animal models, and specifically from rd10 mice. Also, it can be hypothesized that light protection could be an option to slow down retinal degeneration in some cases of RP. Supported by grants from the Spanish Ministry of Economy and Competitiveness (MINECO-FEDER BFU2015-67139-R); Spanish Ministry of Education (FPU16/04114); Instituto de Salud Carlos III co-financed by European Regional Development funds (RETICS-FEDER RD16/0008/0016); and Asociación Retina Asturias, FARPE-FUNDALUCE, Generalitat Valenciana (PROMETEO/2016/158, ACIF/2016/055 and FEDER IDIFEDER/2017/064).

Neurodegenerative diseases (NDDs) represent a huge social burden, particularly in Alzheimer's disease (AD) in which all proposed treatments investigated in murine models have failed during clinical trials (CTs). Thus, novel therapeutic strategies remain crucial. Neuroinflammation is a common pathogenic feature of NDDs. As purinergic P2X7 receptors (P2X7Rs) are gatekeepers of inflammation, they could be developed as drug targets for NDDs. Herein, we review this challenging hypothesis and comment on the numerous studies that have investigated P2X7Rs, emphasizing their molecular structure and functions, as well as their role in inflammation. Then, we elaborate on research undertaken in the field of medicinal chemistry to determine potential P2X7R antagonists. Subsequently, we review the state of neuroinflammation and P2X7R expression in the brain, in animal models and patients suffering from AD, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and retinal degeneration. Next, we summarize the in vivo studies testing the hypothesis that by mitigating neuroinflammation, P2X7R blockers afford neuroprotection, increasing neuroplasticity and neuronal repair in animal models of NDDs. Finally, we reviewed previous and ongoing CTs investigating compounds directed toward targets associated with NDDs; we propose that CTs with P2X7R antagonists should be initiated. Despite the high expectations for putative P2X7Rs antagonists in various central nervous system diseases, the field is moving forward at a relatively slow pace, presumably due to the complexity of P2X7Rs. A better pharmacological approach to combat NDDs would be a dual strategy, combining P2X7R antagonism with drugs targeting a selective pathway in a given NDD., We would like to acknowledge the support received from the EU Horizon 2020 Research and Innovation Programme under Maria Sklodowska-Curie Grant Agreement N. 766124. We would also like to thank the support received from the Ministerio de Economía y Competitividad (MINECO, Spain; grant SAF2016-78892-R to Luis Gandía and Antonio G. García) and Fundación Teófilo Hernando

Introdução: Anacardium occidentale, conhecida popularmente como cajueiro, é uma planta nativa do Brasil e tem sido amplamente utilizada pela população devido suas propriedades medicinais. Objetivo: Realizar uma pesquisa bibliográfica para se evidenciar o perfil de utilização de A. occidentale como planta medicinal e correlacionar essas informações com pesquisas experimentais que evidenciem os potenciais biológicos desse vegetal. Metodologia: Trata-se de uma revisão de literatura do tipo narrativa. A busca de artigos ocorreu nas bases de dados Lilacs, Scielo e Periódicos Capes, por meio dos termos: 1) Anacardium occidentale; 2) Cajueiro e 3) Atividades Biológicas, utilizando-se os operadores booleanos “AND” e “OR”. Resultados: De 40 estudos analisados, 17 foram utilizados para compor os resultados. Evidenciou-se, o uso do cajueiro por diferentes populações para o tratamento de inflamações, acidente cerebrovascular, ferimentos, diarreia, infecções, cefaleia, odontalgia, ressaca, como adstringente, anticoagulante, antigripal, antitérmico e cicatrizante. Dentre essas indicações, destacam-se anti-inflamatória, cicatrizante, antidiarreica, antigripal e antimicrobiana, devido a existência de estudos experimentais comprovando esses diferentes potenciais biológicos. Extratos de frutos, folhas e caule, demostram potencial anti-inflamatório. O extrato de cascas apresenta potencial cicatrizante, devido a presença de compostos fenólicos, que parecem favorecer a reconstrução tecidual, por seus efeitos cicatrizante, antibacteriano e por exercer influência sobre mediadores envolvidos na inflamação. Com relação ao potencial antidiarreico, estudos com extrato de cascas de caule e com goma de A. occidentale demonstraram redução do trânsito gastrintestinal, aumento da reabsorção de água e eletrólitos e retardo do início da diarreia. Ademais, foram obtidas quantidades elevadas de flavonoides e moderada de alcaloides e taninos. Quanto à atividade antigripal, observou-se uma promissora atividade anti-influenza, mediante a capacidade de inibir a enzima neuraminidase e inibir a replicação viral em camundongos. A atividade antimicrobiana, foi verificada em bactérias Gram-positivas e negativas e fungos, sendo associada à presença de alcaloides e taninos. Conclusão: Assim, compreende-se que o cajueiro apresenta uma gama de indicações terapêuticas no uso popular, entre as quais se destaca o seu potencial nos processos anti-inflamatórios, cicatriciais, antidiarreicos, antigripais e antimicrobianos, contudo cabe ressaltar que são necessárias mais pesquisas que esclareçam melhor os possíveis mecanismos envolvidos.

Glaucoma is an optical neuropathy associated to a progressive degeneration of retinal ganglion cells with visual field loss and is the main cause of irreversible blindness in the world. The treatment has the aim to reduce intraocular pressure. The first therapy option is to instill drugs on the ocular surface. The main limitation of this is the reduced time of the drug staying on the cornea. This means that high doses are required to ensure its therapeutic effect. A drug-loaded contact lens can diffuse into the post lens tear film in a constant and prolonged flow, resulting in an increased retention of the drug on the surface of the cornea for up to 30 min and thus providing a higher drug bioavailability, increasing the therapeutic efficacy, reducing the amount of administered drug, and thereby provoking fewer adverse events. Several different systems of drug delivery have been studied in recent decades; ranging from more simple methods of impregnating the lenses, such as soaking, to more complex ones, such as molecular imprinting have been proposed. Moreover, different drugs, from those already commercially available to new substances such as melatonin have been studied to improve the glaucoma treatment efficacy. This review describes the role of contact lenses as an innovative drug delivery system to treat glaucoma.