Search

El seguimiento del punto de máxima potencia (MPPT) es una etapa esencial en la operación de las turbinas eólicas para garantizar una generación de energía eficiente. En los últimos años se han diseñado y aplicado técnicas de control avanzadas para lograr este objetivo, solventando algunas de las limitaciones de los métodos clásicos. Este artículo proporciona una visión general de las estrategias existentes y describe con más detalle algunas configuraciones de control específicas, explicando su utilidad y proporcionando una base para futuros desarrollos. En concreto incluye técnicas de control basadas en inteligencia artificial para el estudio del control MPPT en aerogeneradores. Se ejemplifican dos estrategias de control inteligente: una red neuronal y un controlador de lógica borrosa. Estos enfoques se enmarcan en la regulación del par electromagnético del generador y, en consecuencia, de la velocidad angular del sistema, mejorando la generación de potencia. Los resultados evidencian los beneficios de estos controladores inteligentes para maximizar la potencia y mejorar el proceso de conversión de energía.

Cu2ZnSnSe4 (CZTSe) nanoparticles (NPs) were successfully synthesized via a solvothermal method. Their structural, compositional, morphological, optoelectronic, and electrochemical properties have been characterized by X-ray diffraction (XRD), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), Field-emission scanning electron microscopy (FE-SEM), transmission electron microscope (TEM), UV–vis absorption spectroscopy, and electrochemical impedance spectroscopy (EIS) techniques. Porosimetry and specific surface area in terms of the Brunauer–Emmett–Teller (BET) technique have also been studied. XRD indicates the formation of a polycrystalline kesterite CZTSe phase. Raman peaks at 173 and 190 cm−1 confirm the formation of a pure phase. TEM micrographs revealed the presence of nanoparticles with average sizes of ~90 nm. A BET surface area of 7 m2/g was determined. The CZTSe NPs showed a bandgap of 1.0 eV and a p-type semiconducting behavior. As a proof of concept, for the first time, the CZTSe NPs have been used as a visible-light-driven photocatalyst to Congo red (CR) azo dye degradation. The nanophotocatalyst material under simulated sunlight results in almost complete degradation (96%) of CR dye after 70 min, following a pseudo-second-order kinetic model (rate constant of 0.334 min−1). The prepared CZTSe was reusable and can be repeatedly used to remove CR dye from aqueous solutions.

Cimicifuga racemosa extracts (CREs) have gained well-established use for the treatment of menopausal symptoms such as hot flushes and excessive sweating, and weight gain. While the clinical effects of CREs have been well documented, the mechanisms underlying these effects are largely unknown. More recently, the metabolic effects of the CRE Ze 450 were demonstrated in cultured cells in vitro and in mouse models of obesity in vivo. At the molecular level, metabolic regulation, enhanced insulin sensitivity, and increased glucose uptake were linked to the activation of AMP-activated protein kinase (AMPK). Therefore, we tested the effects of Ze 450 on AMPK phosphorylation and thus activation in cells from different tissues, i.e., murine C2C12 myoblast cells, human HEPG2 liver cells, mouse HT22 neuronal cells, and in murine 3T3L1 adipocytes. Using a FRET-based HTRF-assay, we found that Ze 450 induced AMPK phosphorylation and the activation of this key enzyme of metabolic regulation in cells from various different tissues including C2C12 (muscle), HEPG2 (liver), HT22 (hippocampal), and 3T3-L1 (adipocyte) cells. In C2C12 muscle cells, enhanced AMPK activation was accompanied by reduced mitochondrial respiration and enhanced glucose uptake. Further, Ze 450 enhanced the resilience of the cells against oxidative death induced by ferroptosis inducers erastin or RSL3. Our findings suggest a general effect of Cimicifuga racemosa on AMPK activation in different tissues and across species. This may have a significant impact on expanded therapeutic applications of Ze 450, since AMPK activation and the related metabolic effects have been previously associated with anti-aging effects and the prevention of the metabolic syndrome.

La presente investigación aborda la campaña permanente llevada a cabo durante una década por el Partido Demócrata de Georgia, Estados Unidos. Cómo lograron tras veinte años de mayoría republicana, convertir al Estado en un campo de batalla político y competitivo. Se realiza una exposición del razonamiento y análisis que se ha desarrollado con el fin de entender desde la planificación hasta su ejecución. La investigación emplea bibliografía, así como entrevistas a expertos y miembros del partido. Por último, se exponen los resultados que ha tenido, así como los futuros retos.

Introduction: Home hemodialysis (HDD) is implemented in the Valencian Community with a higher prevalence than to the rest of the national territory, with a prevalence of 13.4 patients pmp in December 2018. We carried out an assessment of the patients characteristics and the overall and technical survival in HDD depending on the historical moment of onset and its origin. Material and methods: We conducted a retrospective and descriptive study including patients of the Valencian Registry of Renal Patients from the beginning of data reported until December 2020. We calculated overall survival (combined event death-technical failure, censoring transplantation) and technical survival (event technical failure, censoring exitus and transplantation). Comparing technical survival according to the starting era: ancient (1976−2000) vs modern (2001−2020) and according to the modality of origin. We performed univariate and multivariate Cox regression in the total series for both overall and technical survival. Results: 236 patients on HDD (611.4 patient-years of follow-up), mean age 49.7 ± 16.3 years; median time of prior renal replacement therapy 0.2 years. The ratio of transplantation, death, and technical failure were 13.2, 4.4, and 7 events per 100 patient-years, respectively. In the comparison by ancient (n = 57) vs modern (n = 179) eras, age (37.5 vs 53.5 years), DM (3.5 vs 13.4%) and chronic tubuleinterstitial nephropathy (24.6 vs 8.9%) as a cause of chronic kidney disease were statistically significant. The probability of coming from outpatient consultation (33.3 vs 48.6%) and peritoneal dialysis (1.8 vs 12.8%) were higher in modern era with statistical significance. In the ancient era a single hospital centralized 57.9% of the patients, and in the modern era between two hospitals centralized 55.8% of the patients. Overall survival in the ancient era was 83.7% at 1 year, 77.4% at 2 years, and 61% at 5 years; and in the modern era 87.3% per year, 83% 2 years and 47.8% 5 years (Log Rank 0.521). Technical survival in the ancient era was 85.4% at 1 year, 79% 2 years, and 64.1% 5 years; and in the modern era 91.4% per year, 88.5% 2 years and 74.5% 5 years (Log Rank 0.195). There were no statistical differences in the comparison based on technical of provenance. In the Cox regression it was statistically significant for overall survival: the age and being diagnosed with heart disease, vascular disease or active neoplasia and for technical survival liver disease or social problem, both in univariate and multivariate. Conclusions: In the modern era there is a considerable increase in HDD patients in the Valencian Community. There was a center effect in the development of HDD programs, most of the patients depended on few healthcare centers. The patients were older and had greater comorbidity in the modern era, despite this without affecting the technical and overall survival of the HDD. Resumen: Introducción: La hemodiálisis (HD) domiciliaria (HDD) está especialmente implementada en la Comunidad Valenciana en comparación al resto del territorio nacional, con una prevalencia de 13,4 pacientes pmp a diciembre del 2018. Realizamos una valoración de las características de los pacientes y de la supervivencia global y técnica del paciente en HDD en función del momento histórico de inicio y de su procedencia. Material y métodos: Pacientes incluidos en el Registro de Enfermos Renales de la Comunidad Valenciana desde que se reportan datos al mismo hasta diciembre del 2020. Estudio descriptivo y retrospectivo, calculando supervivencia global (evento combinado muerte-fallo técnico, censurando trasplante) y supervivencia técnica (evento fallo técnico, censurando muerte y trasplante). Comparamos la supervivencia de la técnica en función de era de inicio: antigua (1976−2000) vs moderna (2001−2020), y en función de la modalidad de procedencia. Realizamos regresión de Cox uni y multivariante en el total de la serie tanto para supervivencia global como técnica. Resultados: 236 pacientes en HDD (611,4 pacientes-año de seguimiento), edad media 49,7 ± 16,3 años; tiempo terapia renal sustitutiva previa 0,2 años de mediana. Los ratios de trasplante, muerte y fallo técnico fueron 13,2; 4,4 y 7 eventos por 100 pacientes-año respectivamente. En la comparación por eras según inicio en HDD, antigua (n = 57) vs moderna (n = 179) fue estadísticamente significativo la edad (37,5 vs 53,5 años), la DM (3,5 vs 13,4%) y la nefropatía tubulointersiticial crónica (24,6 vs 8,9%) como causa de enfermedad renal crónica Hubo en la era moderna mayor probabilidad de provenir de consulta externa (33,3 vs 48,6%) y de diálisis peritoneal (1,8 vs 12,8%) con significación estadística. En era antigua un único hospital centralizaba el 57,9% de los pacientes, y en era moderna entre dos hospitales centralizaban el 55,8% de los pacientes. La supervivencia global en era antigua fue de 83,7% al año, 77,4% 2 años y 61% 5 años; y en era moderna 87,3% al año, 83% 2 años y 47,8% 5 años (Log Rank 0,521). La supervivencia técnica en era antigua fue 85,4% al año, 79% 2 años y 64,1% 5 años; y en era moderna 91,4% al año, 88,5% 2 años y 74,5% 5 años (Log Rank 0,195). No hubieron diferencias estadísticas en la comparación en función de la procedencia. En la regresión de Cox fue estadísticamente significativo para supervivencia global la edad y estar diagnosticado de cardiopatía, enfermedad vascular o neoplasia activa y para la supervivencia técnica hepatopatía o problema social, tanto en análisis uni como en multivariante. Conclusión: En la era moderna existe un incremento considerable de pacientes en HDD en la Comunidad Valenciana. Existió un efecto centro en el desarrollo de los programas de HDD, la mayoría de los pacientes dependían de pocos centros asistenciales. Los pacientes fueron de mayor edad y mayor comorbilidad en la era moderna, pese a ello sin afectar ni la supervivencia técnica y ni global de la HDD.

Resumen: Introducción: La hemodiálisis domiciliaria (HDD) está especialmente implementada en la Comunidad Valenciana en comparación con el resto del territorio nacional, con una prevalencia de 13,4 pacientes pmp a diciembre de 2018. Realizamos una valoración de las características de los pacientes y de la supervivencia global y técnica del paciente en HDD en función del momento histórico de inicio y de su procedencia. Material y métodos: Pacientes incluidos en el Registro de Enfermos Renales de la Comunidad Valenciana desde que se reportan datos al mismo hasta diciembre de 2020. Estudio descriptivo y retrospectivo, calculando supervivencia global (evento combinado muerte-fallo técnico, censurando trasplante) y supervivencia técnica (evento fallo técnico, censurando muerte y trasplante). Comparamos la supervivencia de la técnica en función de era de inicio: antigua (1976-2000) vs. moderna (2001-2020), y en función de la modalidad de procedencia. Realizamos regresión de Cox uni- y multivariante en el total de la serie tanto para supervivencia global como técnica. Resultados: Doscientos treinta y seis pacientes en HDD (611,4 pacientes-año de seguimiento), edad media 49,7 ±16,3 años; tiempo terapia renal sustitutiva previa 0,2 años de mediana. Los ratios de trasplante, muerte y fallo técnico fueron 13,2; 4,4 y 7 eventos por 100 pacientes-año respectivamente. En la comparación por eras según inicio en HDD, antigua (n = 57) vs. moderna (n = 179) fue estadísticamente significativa la edad (37,5 vs. 53,5 años), la DM (3,5 vs. 13,4%) y la nefropatía tubulointersiticial crónica (24,6 vs. 8,9%) como causa de enfermedad renal crónica. Hubo en la era moderna mayor probabilidad de provenir de consulta externa (33,3 vs. 48,6%) y de diálisis peritoneal (1,8 vs. 12,8%) con significación estadística. En era antigua un único hospital centralizaba el 57,9% de los pacientes, y en era moderna entre 2 hospitales centralizaban el 55,8% de los pacientes. La supervivencia global en era antigua fue del 83,7% al año, del 77,4% a 2 años y del 61% a 5 años; y en era moderna del 87,3% al año, del 83% a 2 años y del 47,8% a 5 años (Log Rank: 0,521). La supervivencia técnica en era antigua fue 85,4% al año, 79% a 2 años y 64,1% a 5 años; y en era moderna 91,4% al año, 88,5% a 2 años y 74,5% a 5 años (Log Rank: 0,195). No hubo diferencias estadísticas en la comparación en función de la procedencia. En la regresión de Cox fueron estadísticamente significativos para supervivencia global la edad y estar diagnosticado de cardiopatía, enfermedad vascular o neoplasia activa, y para la supervivencia técnica hepatopatía o problema social, tanto en análisis univariante como en multivariante. Conclusión: En la era moderna existe un incremento considerable de pacientes en HDD en la Comunidad Valenciana. Hubo un efecto centro en el desarrollo de los programas de HDD, la mayoría de los pacientes dependían de pocos centros asistenciales. Los pacientes fueron de mayor edad y mayor comorbilidad en la era moderna, pese a ello sin afectar ni la supervivencia técnica y ni global de la HDD. Abstract: Introduction: Home hemodialysis (HDD) is implemented in the Valencian Community with a higher prevalence than to the rest of the national territory, with a prevalence of 13.4 patients’ pmp in December 2018. We carried out an assessment of the patients’ characteristics and the overall and technical survival in HDD depending on the historical moment of onset and its origin. Material and methods: We conducted a retrospective and descriptive study including patients of the Valencian Registry of Renal Patients from the beginning of data reported until December 2020. We calculated overall survival (combined event death-technical failure, censoring transplantation) and technical survival (event technical failure, censoring exitus and transplantation). Comparing technical survival according to the starting era: ancient (1976–2000) vs modern (2001–2020) and according to the modality of origin. We performed univariate and multivariate Cox regression in the total series for both overall and technical survivals. Results: 236 patients on HDD (611.4 patient-years of follow-up), mean age 49.7 ± 16.3 years; median time of prior renal replacement therapy 0.2 years. The ratio of transplantation, death, and technical failure were 13.2, 4.4, and 7 events per 100 patient-years, respectively. In the comparison by ancient (n = 57) vs modern (n = 179) eras, age (37.5 vs 53.5 years), DM (3.5 vs 13.4%) and chronic tubuleinterstitial nephropathy (24.6 vs 8.9%) as a cause of chronic kidney disease were statistically significant. The probability of coming from outpatient consultation (33.3 vs 48.6%) and peritoneal dialysis (1.8 vs 12.8%) were higher in modern era with statistical significance. In the ancient era a single hospital centralized 57.9% of the patients, and in the modern era between two hospitals centralized 55.8% of the patients. Overall survival in the ancient era was 83.7% at 1 year, 77.4% at 2 years, and 61% at 5 years; and in the modern era 87.3% per year, 83% 2 years and 47.8% 5 years (Log Rank 0.521). Technical survival in the ancient era was 85.4% at 1 year, 79% 2 years, and 64.1% 5 years; and in the modern era 91.4% per year, 88.5% 2 years and 74.5% 5 years (Log Rank 0.195). There were no statistical differences in the comparison based on technical of provenance. In the Cox regression it was statistically significant for overall survival: the age and being diagnosed with heart disease, vascular disease or active neoplasia and for technical survival liver disease or social problem, both in univariate and multivariate. Conclusion: In the modern era there is a considerable increase in HDD patients in the Valencian Community. There was a center effect in the development of HDD programs, most of the patients depended on few healthcare centers. The patients were older and had greater comorbidity in the modern era, despite this without affecting the technical and overall survival of the HDD.

Abstract Background Traumatic brain injury (TBI) is characterized by a primary mechanical injury and a secondary injury associated with neuroinflammation, blood–brain barrier (BBB) disruption and neurodegeneration. We have developed a novel cannabidiol aminoquinone derivative, VCE-004.8, which is a dual PPARγ/CB2 agonist that also activates the hypoxia inducible factor (HIF) pathway. VCE-004.8 shows potent antifibrotic, anti-inflammatory and neuroprotective activities and it is now in Phase II clinical trials for systemic sclerosis and multiple sclerosis. Herein, we investigated the mechanism of action of VCE-004.8 in the HIF pathway and explored its efficacy in a preclinical model of TBI. Methods Using a phosphoproteomic approach, we investigated the effects of VCE-004.8 on prolyl hydroxylase domain-containing protein 2 (PHD2) posttranslational modifications. The potential role of PP2A/B55α in HIF activation was analyzed using siRNA for B55α. To evaluate the angiogenic response to the treatment with VCE-004.8 we performed a Matrigel plug in vivo assay. Transendothelial electrical resistance (TEER) as well as vascular cell adhesion molecule 1 (VCAM), and zonula occludens 1 (ZO-1) tight junction protein expression were studied in brain microvascular endothelial cells. The efficacy of VCE-004.8 in vivo was evaluated in a controlled cortical impact (CCI) murine model of TBI. Results Herein we provide evidence that VCE-004.8 inhibits PHD2 Ser125 phosphorylation and activates HIF through a PP2A/B55α pathway. VCE-004.8 induces angiogenesis in vivo increasing the formation of functional vessel (CD31/α-SMA) and prevents in vitro blood–brain barrier (BBB) disruption ameliorating the loss of ZO-1 expression under proinflammatory conditions. In CCI model VCE-004.8 treatment ameliorates early motor deficits after TBI and attenuates cerebral edema preserving BBB integrity. Histopathological analysis revealed that VCE-004.8 treatment induces neovascularization in pericontusional area and prevented immune cell infiltration to the brain parenchyma. In addition, VCE-004.8 attenuates neuroinflammation and reduces neuronal death and apoptosis in the damaged area. Conclusions This study provides new insight about the mechanism of action of VCE-004.8 regulating the PP2A/B55α/PHD2/HIF pathway. Furthermore, we show the potential efficacy for TBI treatment by preventing BBB disruption, enhancing angiogenesis, and ameliorating neuroinflammation and neurodegeneration after brain injury.

One of the main global causes of mortality and morbidity is traumatic brain injury (TBI). Neuroinflammation and brain-blood barrier (BBB) disruption play a pivotal role in the pathogenesis of acute and chronic TBI onset. The activation of the hypoxia pathway is a promising approach for CNS neurodegenerative diseases, including TBI. Herein, we have studied the efficacy of VCE-005.1, a betulinic acid hydroxamate, against acute neuroinflammation in vitro and on a TBI mouse model. The effect of VCE-005.1 on the HIF pathway in endothelial vascular cells was assessed by western blot, gene expression, in vitro angiogenesis, confocal analysis and MTT assays. In vivo angiogenesis was evaluated through a Matrigel plug model and a mouse model of TBI induced by a controlled cortical impact (CCI) was used to assess VCE-005.1 efficacy. VCE-005.1 stabilized HIF-1α through a mechanism that involved AMPK and stimulated the expression of HIF-dependent genes. VCE-005.1 protected vascular endothelial cells under prooxidant and pro-inflammatory conditions by enhancing TJ protein expression and induced angiogenesis both in vitro and in vivo. Furthermore, in CCI model, VCE-005.1 greatly improved locomotor coordination, increased neovascularization and preserved BBB integrity that paralleled with a large reduction of peripheral immune cells infiltration, recovering AMPK expression and reducing apoptosis in neuronal cells. Taken together, our results demonstrate that VCE-005.1 is a multitarget compound that shows anti-inflammatory and neuroprotective effects mainly by preventing BBB disruption and has the potential to be further developed pharmacologically in TBI and maybe other neurological conditions that concur with neuroinflammation and BBB disruption.

(1) Background: A cannabigerol aminoquinone derivative, so-called VCE-003.2, has been found to behave as a neuroprotective agent (administered both i.p. and orally) in different experimental models of Parkinson’s disease (PD) in mice. These effects were exerted through mechanisms that involved the activation of a regulatory site within the peroxisome proliferator-activated receptor-γ (PPAR-γ). (2) Methods: We are now interested in comparing such neuroprotective potential of VCE-003.2, orally administered, with the effect of the classic dopaminergic replacement therapy with L-DOPA/benserazide in similar conditions, using 6-hydroxydopamine-lesioned mice. (3) Results: The oral administration of VCE-003.2 during 14 days at the dose of 20 mg/kg improved, as expected, the neurological status (measured in motor tests) in these mice. This correlated with a preservation of TH-labelled neurons in the substantia nigra. By contrast, the treatment with L-DOPA/benserazide (during 7 days at 2 mg/kg) was significantly less active in these experimental conditions, in concordance with their profile as a mere symptom-alleviating agent. (4) Conclusions: Our results confirmed again the therapeutic profile of VCE-003.2 in experimental PD and revealed a different and more relevant effect, as a disease modifier, compared to the classic symptom-alleviating L-DOPA treatment. This reinforces the interest in VCE-003.2 for a future clinical development in this disease.

Cannabidiol (CBD) has been suggested as a potential therapy for inflammatory and fibrotic diseases. Cannabidiol was demonstrated to reduce alcohol-induced liver inflammation and steatosis but its specific activity on the fibrotic process was not investigated. Herein, the antifibrotic effects of cannabidiol in the skin were analysed in vitro using NIH-3T3 fibroblasts and human dermal fibroblasts and in vivo using the bleomycin-induced model of skin fibrosis. In a second model, non-alcoholic liver fibrosis was induced in mice by CCl4 exposure. Cannabidiol was administered daily, intraperitoneally in mice challenged with bleomycin and orally in CCl4 mice, and skin and liver fibrosis and inflammation were assessed by immunochemistry. Cannabidiol inhibited collagen gene transcription and synthesis and prevented TGFβ-and IL-4 induced fibroblast migration. In the bleomycin model, cannabidiol prevented skin fibrosis and collagen accumulation around skin blood vessels, and in the CCl4 model cannabidiol significantly attenuated liver fibrosis measured by picrosirius red and Tenascin C staining and reduced T cell and macrophage infiltration. Altogether, our data further support the rationale of the medicinal use of this cannabinoid, as well as cannabis preparations containing it, in the management of fibrotic diseases including Systemic Sclerosis and Non-Alcoholic Fatty Liver Disease.

The existence of the nucleus distinguishes prokaryotes and eukaryotes. Apart from containing most of the genetic material, the nucleus possesses several nuclear bodies composed of protein and RNA molecules. The nucleus is separated from the cytoplasm by a double membrane, regulating the trafficking of molecules in- and outwards. Here, we investigate the composition and function of the different plant nuclear bodies and molecular clues involved in nuclear trafficking. The behavior of the nucleolus, Cajal bodies, dicing bodies, nuclear speckles, cyclophilin-containing bodies, photobodies and DNA damage foci is analyzed in response to different abiotic stresses. Furthermore, we research the literature to collect the different protein localization signals that rule nucleocytoplasmic trafficking. These signals include the different types of nuclear localization signals (NLSs) for nuclear import, and the nuclear export signals (NESs) for nuclear export. In contrast to these unidirectional-movement signals, the existence of nucleocytoplasmic shuttling signals (NSSs) allows bidirectional movement through the nuclear envelope. Likewise, nucleolar signals are also described, which mainly include the nucleolar localization signals (NoLSs) controlling nucleolar import. In contrast, few examples of nucleolar export signals, called nucleoplasmic localization signals (NpLSs) or nucleolar export signals (NoESs), have been reported. The existence of consensus sequences for these localization signals led to the generation of prediction tools, allowing the detection of these signals from an amino acid sequence. Additionally, the effect of high temperatures as well as different post-translational modifications in nuclear and nucleolar import and export is discussed.

A hydrothermal method was successfully employed to synthesize kesterite Cu2ZnSnS4 (CZTS) nanoparticles. X-ray diffraction (XRD), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), field-emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy (EDS), transmission electron microscopy (TEM), and optical ultraviolet-visible (UV-vis) spectroscopy were used for characterization of structural, chemical, morphological, and optical properties. XRD results confirmed that a nanocrystalline CZTS phase corresponding to the kesterite structure was formed. Raman analysis confirmed the existence of single pure phase CZTS. XPS results revealed the oxidation states as Cu+, Zn2+, Sn4+, and S2−. FESEM and TEM micrograph images revealed the presence of nanoparticles with average sizes between 7 nm to 60 nm. The synthesized CZTS nanoparticles bandgap was found to be 1.5 eV which is optimal for solar photocatalytic degradation applications. The properties as a semiconductor material were evaluated through the Mott–Schottky analysis. The photocatalytic activity of CZTS has been investigated through photodegradation of Congo red azo dye solution under solar simulation light irradiation, proving to be an excellent photo-catalyst for CR where 90.2% degradation could be achieved in just 60 min. Furthermore, the prepared CZTS was reusable and can be repeatedly used to remove Congo red dye from aqueous solutions.

Research on the plant growth promoting microorganisms (PGPM) is increasing strongly due to the biotechnological potential for the agricultural, forestry, and food industry. The benefits of using PGPM in crop production are well proven; however, their incorporation in agricultural management is still limited. Therefore, we wanted to explore the gaps and challenges for the transfer of biotechnological innovations based on PGPM to the agricultural sector. Our systematic review of the state of the art of PGPM research and knowledge transfer takes Chile as an example. Several transfer limiting aspects are identified and discussed. Our two main conclusions are: neither academia nor industry can meet unfounded expectations during technology transfer, but mutually clarifying their needs, capabilities, and limitations is the starting point for successful collaborations; the generation of a collaborative innovation environment, where academia as well as public and private stakeholders (including the local community) take part, is crucial to enhance the acceptance and integration of PGPM on the way to sustainable agriculture.

This study reports CdTe quantum dots synthesis in an aqueous medium using cadmium chloride and sodium tellurite as precursors and sodium borohydride and mercaptosuccinic acid as reducing and capping agents, respectively. The synthesis process was optimized through experimental design, and particle characterization was carried out by UV-Vis spectroscopy and molecular fluorescence. In the first stage, a factorial design was used to establish the significance of each of the synthesis variables; i.e., the temperature, pH, reaction time and precursor molar ratios. In the second stage, a multivariate design was constructed to relate the synthesis variables with the maximum absorbance wavelengths, which allowed for predictions of the diameters of the CdTe quantum dots, which were compared with direct measurements of the particles analyzed by high-resolution transmission electron microscopy, HR-TEM and X-ray diffraction, XRD. Finally, there is a brief discussion regarding the existing models predicting particle sizes. Keywords: Experimental design, Quantum dots, Cadmium telluride, Synthesis and characterization

An emerging number of studies address the involvement of neuroinflammation and oxidative stress in the pathophysiology of central nervous system (CNS) disorders such as depression, schizophrenia, anxiety, and neurodegenerative diseases. Different cytokines and molecules, such as prostaglandin (PG) E2, are associated with neuroinflammatory processes. The active acetaminophen metabolite AM404 has been shown to prevent inflammation and neuroinflammation in primary microglia and organotypic hippocampal slice cultures. However, its effects on pathophysiological conditions in the CNS and especially on neurons are still poorly understood. In this study, we therefore evaluated the effects of AM404 and acetaminophen on the arachidonic acid cascade and oxidative stress induced by interleukin (IL)-1β in human SK-N-SH neuronal cells. We observed that AM404 and acetaminophen significantly and concentration-dependent inhibited IL-1β-induced release of PGE2, independent of cyclooxygenases (COX)-1 and COX-2 enzymatic activity as well as COX-2 mRNA and protein levels in SK-N-SH-cells. The reduction of IL-1β-induced PGE2-release by AM404 and acetaminophen treatment might be mediated by the 8-iso-PGF2α pathway since IL-1β-induced synthesis of this free radical marker is dose-dependently reduced by both compounds, respectively. Therefore, understanding of the potential therapeutic properties of AM404 in neuroinflammation and oxidative stress might lead to future treatment options of different neurological disorders.

Some cannabinoids showed anti-inflammatory and antifibrotic activities. EHP-101 is an oral lipidic formulation of the novel non-psychotropic cannabidiol aminoquinone VCE-004.8, which showed antifibrotic activity in murine models of systemic sclerosis induced by bleomycin. We herein examined the effect of EHP-101 on cardiac and other organ fibrosis in a mouse model induced by Angiotensin II. VCE-004.8 inhibited TGFβ- and Ang II-induced myofibroblast differentiation in cardiac fibroblasts detected by α-SMA expression. VCE-004.8 also inhibited Ang II-induced ERK 1 + 2 phosphorylation, NFAT activation and mRNA expression of IL1β, IL6, Col1A2 and CCL2 in cardiac fibroblasts. Mice infused with Ang II resulted in collagen accumulation in left ventricle, aortic, dermal, renal and pulmonary tissues; oral administration of EHP-101, Ajulemic acid and Losartan improved these phenotypes. In myocardial tissue, Ang II induced infiltration of T cells and macrophages together with the accumulation of collagen and Tenascin C; those were all reduced by either EHP-101 or Losartan treatment. Cardiac tissue RNA-Seq analyses revealed a similar transcriptomic signature for both treatments for inflammatory and fibrotic pathways. However, the gene set enrichment analysis comparing data from EHP-101 vs Losartan showed specific hallmarks modified only by EHP-101. Specifically, EHP-101 inhibited the expression of genes such as CDK1, TOP2A and MKi67 that are regulated to the E2 factor family of transcription factors. This study suggests that the oral administration of EHP-101 prevents and inhibits cardiac inflammation and fibrosis. Furthermore, EHP-101 inhibits renal, pulmonary and dermal fibrosis. EHP-101 could offer new opportunities in the treatment of cardiac fibrosis and other fibrotic diseases.

Intraventricular hemorrhage (IVH) is an important cause of long-term disability in extremely preterm infants, with no current treatment. We aimed to study in an IVH model in immature rats the neuroprotective effect of betulinic acid hydroxamate (BAH), a B55α/PP2A activator that inhibits the activity of the hypoxia-inducing factor prolyl-hydroxylase type 2. IVH was induced in 1-day-old (P1) Wistar rats by the left periventricular injection of Clostridial collagenase. Then, pups received i.p. vehicle or BAH 3 mg/kg single dose. At P6, P14 and P45, brain damage (area of damage, neurobehavioral deficits, Lactate/N-acetylaspartate ratio), white matter injury (WMI: corpus callosum atrophy and myelin basic protein signal reduction) and inflammation (TLR4, NF-κB and TNFα expression), excitotoxicity (Glutamate/N-acetylspartate) and oxidative stress (protein nitrosylation) were evaluated. BAH treatment did not reduce the volume of brain damage, but it did reduce perilesional tissue damage, preventing an IVH-induced increase in Lac/NAA. BAH restored neurobehavioral performance at P45 preventing WMI. BAH prevented an IVH-induced increase in inflammation, excitotoxicity and oxidative stress. In conclusion, in immature rats, BAH reduced IVH-induced brain damage and prevented its long-term functional consequences, preserving normal myelination in a manner related to the modulation of inflammation, excitotoxicity and oxidative stress.

Fosfomycin is currently a viable option against urinary tract infections, particularly against extended-spectrum β-lactamases (ESBL)-producing E. coli, due to its unique mechanism of action and its low resistance among bacteria. The objective of this study was to investigate two of the three most common mechanisms of resistance against this antibiotic among 350 ESBL-producing E. coli strains isolated from the urine of Mexican patients. The prevalence of fosfomycin resistance in our study was 10.9% (38/350). Of all resistant isolates analyzed, 23 (60.5%) were identified as fos-producing organisms, with 14 strains carrying fosA3 and 9, fosA1. Additionally, 11 (28.9%) fosfomycin-resistant isolates presented resistance due to impaired antibiotic transport and 8 (21.0%) both mechanisms. No resistance mechanism investigated in the study was found on 12 strains. All 38 confirmed ESBL-producing isolates carried a blaCTX-M subtype, 36 (94.5%) belonged to the O25b-ST131 clone, and all of them were able to transfer the fosfomycin resistance trait to recipient strains horizontally. This is the first study in Mexico demonstrating a plasmid-mediated fosfomycin resistance mechanism among clinical E. coli strains. Since our results suggest a strong association among fos and blaCTX-M genes and ST131 clones in uropathogenic E. coli, plasmid-mediated fosfomycin resistance should be closely monitored.

In the present work, a control strategy for Maximum Power Point Tracking (MPPT) of a wind turbine based on a Doubly Fed Induction Generator (DFIG) is described. This strategy is developed according to the theory of Di-rect Speed Control (DSC) which includes a state observer. This strategy con-siders the Low Shaft Speed (LSS) as an input and the Iqr reference current as the output. This control mechanism allows monitoring the MPPT; thus, changing the Power coefficient (Cp) to its optimal value during the operation of the wind turbine. The controller, among its main features, is configured to work with the incorporation of different wind inputs; fact that permits evaluating the system response to disturbances and variations. For simulations tests, a 1,5 MW wind turbine has been modeled in Matlab and Fatigue, Aero-dynamics, and Structures and Turbulence FAST software. The strategy has been compared to a PI MPPT controller and has demonstrated improvements in terms of speed and output power extraction.

Esta investigación propone una metodología de control aplicada a una técnica en Sistemas de Generación de Energía Eólica (WEGS) para el Seguimiento del Punto de Máxima Potencia (MPPT) basada en un observador Fuzzy y complementada con un controlador PI mediante el método de Control Directo de Velocidad (DSC). Este enfoque permite controlar la corriente de referencia del lado del rotor a través de las variaciones de par y potencia eléctrica en un modelo de Generador de Inducción Doblemente Alimentado (DFIG). En consecuencia, la velocidad del generador se controla para obtener una respuesta rápida del máximo Coeficiente de Potencia (). La construcción de esta estrategia comienza con mediciones directas de las variables eléctricas y mecánicas utilizando herramientas computacionales como FAST y Matlab-Simulink para las simulaciones del modelo del aerogenerador. Esta estrategia DSC presenta un rápido desempeño en el seguimiento del considerando la dinámica de un aerogenerador de 1,5MW; esta estrategia ha sido comparada con un controlador PI tradicional mejorando la extracción de la potencia de salida.

Despite the very large number of phytocannabinoids isolated from Cannabis (Cannabis sativa L.), bioactivity studies have long remained focused on the so called “Big Four” [Δ9-THC (1), CBD (2), CBG (3) and CBC (4)] because of their earlier characterization and relatively easy availability via isolation and/or synthesis. Bioactivity information on the chemical space associated with the remaining part of the cannabinome, a set of ca 150 compounds traditionally referred to as “minor phytocannabinoids”, is scarce and patchy, yet promising in terms of pharmacological potential. According to their advancement stage, we sorted the bioactivity data available on these compounds, better referred to as the “dark cannabinome”, into categories: discovery (in vitro phenotypical and biochemical assays), preclinical (animal models), and clinical. Strategies to overcome the availability issues associated with minor phytocannabinoids are discussed, as well as the still unmet challenges facing their development as mainstream drugs.

The renewed interest in dimeric salicylates as broad-spectrum anti-inflammatory and anti-diabetic agents provided a rationale to investigate the dimerization of the substituted salicylate Δ9-tetrahydrocannabinolic acid (THCA-A, 3a) as a strategy to solve its instability to decarboxylation and to generate analogues and/or pro-drugs of this native pre-cannabinoid. Activation of the carboxylic group with the DCC-HOBt-DMAP protocol afforded a high yield of the OBt ester 4, that was next converted into the highly crystalline di-depsidic dimer 5 upon treatment with DMAP. The mono-depsidic dimer 6 was also formed when the reaction was carried out with partially decarboxylated THCA-A samples. The structure of the depsidic dimers was established by spectroscopic methods and by aminolysis of 5 into the pre-cannabinoid amide 7. Both dimers showed excellent shelf stability and did not generate significant amounts of Δ9-THC upon heating. However, only the didepsidic dimer 5 activated PPAR-γ, the major target of pre-cannabinoids, but strong binding to serum proteins abolished this activity, also shielding it from the action of esterases. Key words: Phytocannabinoids, Dimerization, Δ9-Tetrahydrocannabinolic acid A, Δ9-Tetrahydrocannabinol, PPAR-γ

Abstract Background The major obstacle impeding human immunodeficiency virus-1 (HIV-1) eradication in antiretroviral treatment (ART) treated HIV-1 subjects is the establishment of long-lived latently infected resting CD4+ T cells. Due to the fact that no drug has been effective, the search for new drugs and combinations are a priority in the HIV cure. Treatments based on nanotechnology have emerged as an innovative and promising alternative to current and conventional therapies. In this respect, nanotechnology opens up a new door for eliminating latent HIV infection. We studied the role of G1-S4, G2-S16 and G3-S16 polyanionic carbosilane dendrimers in the context of latent HIV-1 persistence. Moreover, we study the efficiency of these dendrimers in combination with latency reversal agents (LRAs) against HIV-1 infection. Methods J89GFP lymphocyte and THP89GFP monocyte derived cell lines latently infected with HIV-1 p89GFP were used as an in vitro model of latency for our study. Viability assays by 3-(4-5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) were performed to determine the working concentrations of dendrimers and LRAs. Both cell lines were treated with G1-S4, G2-S16 and G3-S16 either alone or in combination with bryostatin (BRY), romidepsin (RMD) or panobinostat (PNB) for 24 and 48 h. The expression pattern of GFP was measured by flow cytometry and referred as measure of viral reactivation. Results and discussion The combination treatment of the dendrimers with the protein kinase C (PKC) agonist did not modify the antilatency activity in J89GFP lymphocyte cell line. Interestingly enough, G3-S16 dendrimer alone and its combination with BRY, RMD or PNB showed a significant increased expression of GFP in the THP89GFP monocyte cell line. Conclusion We showed for the first time that nanoparticles, in this case, G3-S16 anionic carbosilan dendrimer may play an important role in new treatments against HIV-1 infection.

Abstract Background The administration of certain cannabinoids provides neuroprotection in models of neurodegenerative diseases by acting through various cellular and molecular mechanisms. Many cannabinoid actions in the nervous system are mediated by CB1 receptors, which can elicit psychotropic effects, but other targets devoid of psychotropic activity, including CB2 and nuclear PPARγ receptors, can also be the target of specific cannabinoids. Methods We investigated the pro-neurogenic potential of the synthetic cannabigerol derivative, VCE-003.2, in striatal neurodegeneration by using adeno-associated viral expression of mutant huntingtin in vivo and mouse embryonic stem cell differentiation in vitro. Results Oral administration of VCE-003.2 protected striatal medium spiny neurons from mutant huntingtin-induced damage, attenuated neuroinflammation and improved motor performance. VCE-003.2 bioavailability was characterized and the potential undesired side effects were evaluated by analyzing hepatotoxicity after chronic treatment. VCE-003.2 promoted subventricular zone progenitor mobilization, increased doublecortin-positive migrating neuroblasts towards the injured area, and enhanced effective neurogenesis. Moreover, we demonstrated the proneurogenic activity of VCE-003.2 in embryonic stem cells. VCE-003.2 was able to increase neuroblast formation and striatal-like CTIP2-mediated neurogenesis. Conclusions The cannabigerol derivative VCE-003.2 improves subventricular zone-derived neurogenesis in response to mutant huntingtin-induced neurodegeneration, and is neuroprotective by oral administration.

Although metabolomics has attracted considerable attention in the field of lung cancer (LC) detection and management, only a very limited number of works have applied it to tissues. As such, the aim of this study was the thorough analysis of metabolic profiles of relevant LC tissues, including the most important histological subtypes (adenocarcinoma and squamous cell lung carcinoma). Mass spectrometry‐based metabolomics, along with genetic expression and histological analyses, were performed as part of this study, the widest to date, to identify metabolic alterations in tumors of the most relevant histological subtypes in lung. A total of 136 lung tissue samples were analyzed and 851 metabolites were identified through metabolomic analysis. Our data show the existence of a clear metabolic alteration not only between tumor vs. nonmalignant tissue in each patient, but also inherently intrinsic changes in both AC and SCC. Significant changes were observed in the most relevant biochemical pathways, and nucleotide metabolism showed an important number of metabolites with high predictive capability values. The present study provides a detailed analysis of the metabolomic changes taking place in relevant biochemical pathways of the most important histological subtypes of LC, which can be used as biomarkers and also to identify novel targets.

MIGNON is a workflow for the analysis of RNA-Seq experiments, which not only efficiently manages the estimation of gene expression levels from raw sequencing reads, but also calls genomic variants present in the transcripts analyzed. Moreover, this is the first workflow that provides a framework for the integration of transcriptomic and genomic data based on a mechanistic model of signaling pathway activities that allows a detailed biological interpretation of the results, including a comprehensive functional profiling of cell activity. MIGNON covers the whole process, from reads to signaling circuit activity estimations, using state-of-the-art tools, it is easy to use and it is deployable in different computational environments, allowing an optimized use of the resources available.

In this In this article, a control strategy for Maximum Power Point Tracking (MPPT) of a wind turbine system based on a Doubly Fed Induction Generator (DFIG) is presented. The proposed strategy consists of the Indirect Speed Control (ISC) taking the Low Speed Shaft (LSS) as variable input. This implementation allows the MPPT to optimize the Power coefficient (Cp). The controller has been designed in order to allow the wind turbine to reach the MPPT along the partial load operation. For these experiments, a 1.5 MW wind turbine was modeled and simulated by using Matlab and Fatigue, Aerodynamic, Structure and Turbulence (FAST) software. In order to present the achieved results, a comparison between the ISC and a classical PI controller is made. The Cp curves as well as the output power display an important improvement in terms of stability. These results are possible because the appropriate values of optimal Tip Speed Ratio (TSR) and maximum Cp have been properly established. article, a control strategy for Maximum Power Point Tracking (MPPT) of a wind turbine system based on a Doubly Fed Induction Generator (DFIG) is presented. The proposed strategy consists of the Indirect Speed Control (ISC) taking the Low Speed Shaft (LSS) as variable input. This implementation allows the MPPT to optimize the Power coefficient (Cp). The controller has been designed in order to allow the wind turbine to reach the MPPT along the partial load operation. For these experiments, a 1.5 MW wind turbine was modeled and simulated by using Matlab and Fatigue, Aerodynamic, Structure and Turbulence (FAST) software. In order to present the achieved results, a comparison between the ISC and a classical PI controller is made. The Cp curves as well as the output power display an important improvement in terms of stability. These results are possible because the appropriate values of optimal Tip Speed Ratio (TSR) and maximum Cp have been properly established.

Oxidative stress and inflammation in the brain are two key hallmarks of neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's, Huntington's and multiple sclerosis. The axis NRF2-BACH1 has anti-inflammatory and anti-oxidant properties that could be exploited pharmacologically to obtain neuroprotective effects. Activation of NRF2 or inhibition of BACH1 are, individually, promising therapeutic approaches for NDs. Compounds with dual activity as NRF2 activators and BACH1 inhibitors, could therefore potentially provide a more robust antioxidant and anti-inflammatory effects, with an overall better neuroprotective outcome. The phytocannabinoid cannabidiol (CBD) inhibits BACH1 but lacks significant NRF2 activating properties. Based on this scaffold, we have developed a novel CBD derivative that is highly effective at both inhibiting BACH1 and activating NRF2. This new CBD derivative provides neuroprotection in cell models of relevance to Huntington's disease, setting the basis for further developments in vivo.

Anti-neuroinflammatory treatment has gained importance in the search for pharmacological treatments of different neurological and psychiatric diseases, such as depression, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. Clinical studies demonstrate a reduction of the mentioned diseases’ symptoms after the administration of anti-inflammatory drugs. Novel coumarin derivates have been shown to elicit anti-neuroinflammatory effects via G-protein coupled receptor GPR55, with possibly reduced side-effects compared to the known anti-inflammatory drugs. In this study, we, therefore, evaluated the anti-inflammatory capacities of the two novel coumarin-based compounds, KIT C and KIT H, in human neuroblastoma cells and primary murine microglia. Both compounds reduced PGE2-concentrations likely via the inhibition of COX-2 synthesis in SK-N-SH cells but only KIT C decreased PGE2-levels in primary microglia. The examination of other pro- and anti-inflammatory parameters showed varying effects of both compounds. Therefore, the differences in the effects of KIT C and KIT H might be explained by functional selectivity as well as tissue- or cell-dependent expression and signal pathways coupled to GPR55. Understanding the role of chemical residues in functional selectivity and specific cell- and tissue-targeting might open new therapeutic options in pharmacological drug development and might improve the treatment of the mentioned diseases by intervening in an early step of their pathogenesis.

Multiple Sclerosis (MS) is characterized by a combination of inflammatory and neurodegenerative processes in the spinal cord and the brain. Natural and synthetic cannabinoids such as VCE-004.8 have been studied in preclinical models of MS and represent promising candidates for drug development. VCE-004.8 is a multitarget synthetic cannabidiol (CBD) derivative acting as a dual Peroxisome proliferator-activated receptor-gamma/Cannabinoid receptor type 2 (PPARγ/CB2) ligand agonist that also activates the Hypoxia-inducible factor (HIF) pathway. EHP-101 is an oral lipidic formulation of VCE-004.8 that has shown efficacy in several preclinical models of autoimmune, inflammatory, fibrotic, and neurodegenerative diseases. EHP-101 alleviated clinical symptomatology in EAE and transcriptomic analysis demonstrated that EHP-101 prevented the expression of many inflammatory genes closely associated with MS pathophysiology in the spinal cord. EHP-101 normalized the expression of several genes associated with oligodendrocyte function such as Teneurin 4 (Tenm4) and Gap junction gamma-3 (Gjc3) that were downregulated in EAE. EHP-101 treatment prevented microglia activation and demyelination in both the spinal cord and the brain. Moreover, EAE was associated with a loss in the expression of Oligodendrocyte transcription factor 2 (Olig2) in the corpus callosum, a marker for oligodendrocyte differentiation, which was restored by EHP-101 treatment. In addition, EHP-101 enhanced the expression of glutathione S-transferase pi (GSTpi), a marker for mature oligodendrocytes in the brain. We also found that a diet containing 0.2% cuprizone for six weeks induced a clear loss of myelin in the brain measured by Cryomyelin staining and Myelin basic protein (MBP) expression. Moreover, EHP-101 also prevented cuprizone-induced microglial activation, astrogliosis and reduced axonal damage. Our results provide evidence that EHP-101 showed potent anti-inflammatory activity, prevented demyelination, and enhanced remyelination. Therefore, EHP-101 represents a promising drug candidate for the potential treatment of different forms of MS.

Cannabidiol (CBD) is a major non-psychotropic phytocannabinoid that attracted a great attention for its therapeutic potential against different pathologies including skin diseases. However, although the efficacy in preclinical models and the clinical benefits of CBD in humans have been extensively demonstrated, the molecular mechanism(s) and targets responsible for these effects are as yet unknown. Herein we characterized at the molecular level the effects of CBD on primary human keratinocytes using a combination of RNA sequencing (RNA-Seq) and sequential window acquisition of all theoretical mass spectrometry (SWATH-MS). Functional analysis revealed that CBD regulated pathways involved in keratinocyte differentiation, skin development and epidermal cell differentiation among other processes. In addition, CBD induced the expression of several NRF2 target genes, with heme oxygenase 1 (HMOX1) being the gene and the protein most upregulated by CBD. CRISPR/Cas9-mediated genome editing, RNA interference and biochemical studies demonstrated that the induction of HMOX1 mediated by CBD, involved nuclear export and proteasomal degradation of the transcriptional repressor BACH1. Notably, we showed that the effect of BACH1 on HMOX1 expression in keratinocytes is independent of NRF2. In vivo studies showed that topical CBD increased the levels of HMOX1 and of the proliferation and wound-repair associated keratins 16 and 17 in the skin of mice. Altogether, our study identifies BACH1 as a molecular target for CBD in keratinocytes and sets the basis for the use of topical CBD for the treatment of different skin diseases including atopic dermatitis and keratin disorders. Keywords: Cannabidiol/ BACH1/ HMOX1/ NRF2/ Keratinocytes

Background: As a library of cannabinoid (CB) derivatives with (-)-trans-cannabidiol (CBD) or (-)-trans-cannabidivarin (CBDV) scaffold, we synthesized nine novel cannabinoids: 2-hydroxyethyl cannabidiolate (2-HEC), 2-hydroxypentyl cannabidiolate (2-HPC), 2,3-dihydroxypropyl cannabidiolate (GCBD), cyclohexyl cannabidiolate (CHC), n-hexyl-cannabidiolate (HC), 2-(methylsulfonamido)ethyl cannabidiolate (NMSC), 2-hydroxyethyl cannabidivarinolate (2-HECBDV), cyclohexyl cannabidivarinolate (CHCBDV), and n-hexyl cannabidivarinolate (HCBDV). Their binding and intrinsic effects at the CB1- and CB2-receptors and the effects on inflammatory signaling cascades were investigated in in vitro and ex vivo cell models.Materials and Methods: Binding affinity was studied in membranes isolated from CB-receptor-transfected HEK293EBNA cells, intrinsic functional activity in Chinese hamster ovary (CHO) cells, and activation of nuclear factor κB (NF-κB) and nuclear factor of activated T-cells (NFAT) in phorbol 12-myristate 13-acetate (PMA)/ionomycin (IO)-treated Jurkat T-cells. Inhibition of interleukin (IL)-17-induced pro-inflammatory cytokines and chemokines [IL-6, IL-1β, CC-chemokine ligand 2 (CCL2), and tumor necrosis factor (TNF)-α] was studied in RAW264.7 macrophages at the RNA level. Pro-inflammatory cytokine (IL-1β, IL-6, IL-8, and TNF-α) expression and prostaglandin E2 (PGE2) expression were investigated at the protein level in lipopolysaccharide (LPS)-treated primary human monocytes.Results: Derivatives with long aliphatic side chains at the ester position at R1 [HC (5)] as well as the ones with polar side chains [2-HECBDV (7), NMSC (6), and 2-HEC (1)] can be selective for CB2-receptors. The CBDV-derivatives HCBDV and CHCBDV demonstrated specific binding at CB1- and CB2-receptors at nanomolar concentrations. 2-HEC, 2-HPC, GCBD, and NMSC were agonists at CB2-receptor and antagonists at CB1-receptor. CHC bound both receptors at submicromolar ranges and was an agonist for these receptors. 2-HECBDV was an agonist at CB2-receptor and an antagonist at the CB1-receptor despite its modest affinity at this receptor (micromolar range). NMSC inhibited NF-κB and NFAT activity, and 2-HEC, 2-HPC, and GCBD dose-dependently inhibited PMA/IO-stimulated NFAT activation. CHC and HC dose-dependently reduced IL-1β and CCL2 messenger RNA (mRNA) expression. NMSC inhibited IL-1β, CCL2, and TNF-α at lower doses. At higher doses, it induced a pronounced increase in IL-6 mRNA. 2-HEC, 2-HPC, and GCBD dose-dependently inhibited LPS-induced IL-1β, TNF-α, and IL-6 synthesis. NMSC further increased LPS-stimulated IL-1β release but inhibited IL-8, TNF-α, and PGE2.Conclusion: The CBD- and CBDV-derivatives studied are suitable for targeting CB-receptors. Some may be used as selective CB2 agonists. The length of the aliphatic rest at R2 of CBD (pentyl) and CBDV (propyl) did not correlate with the binding affinity. Higher polarity at R1 appeared to favor the agonistic activity at CB2-receptors.

Abstract Background Multiple sclerosis (MS) is characterized by a combination of inflammatory and neurodegenerative processes variously dominant in different stages of the disease. Thus, immunosuppression is the goal standard for the inflammatory stage, and novel remyelination therapies are pursued to restore lost function. Cannabinoids such as 9Δ-THC and CBD are multi-target compounds already introduced in the clinical practice for multiple sclerosis (MS). Semisynthetic cannabinoids are designed to improve bioactivities and druggability of their natural precursors. VCE-004.8, an aminoquinone derivative of cannabidiol (CBD), is a dual PPARγ and CB2 agonist with potent anti-inflammatory activity. Activation of the hypoxia-inducible factor (HIF) can have a beneficial role in MS by modulating the immune response and favoring neuroprotection and axonal regeneration. Methods We investigated the effects of VCE-004.8 on the HIF pathway in different cell types. The effect of VCE-004.8 on macrophage polarization and arginase 1 expression was analyzed in RAW264.7 and BV2 cells. COX-2 expression and PGE2 synthesis induced by lipopolysaccharide (LPS) was studied in primary microglia cultures. The efficacy of VCE-004.8 in vivo was evaluated in two murine models of MS such as experimental autoimmune encephalomyelitis (EAE) and Theiler’s virus-induced encephalopathy (TMEV). Results Herein, we provide evidence that VCE-004.8 stabilizes HIF-1α and HIF-2α and activates the HIF pathway in human microvascular endothelial cells, oligodendrocytes, and microglia cells. The stabilization of HIF-1α is produced by the inhibition of the prolyl-4-hydrolase activity of PHD1 and PDH2. VCE-004.8 upregulates the expression of HIF-dependent genes such as erythropoietin and VEGFA, induces angiogenesis, and enhances migration of oligodendrocytes. Moreover, VCE-004.8 blunts IL-17-induced M1 polarization, inhibits LPS-induced COX-2 expression and PGE2 synthesis, and induces expression of arginase 1 in macrophages and microglia. In vivo experiments showed efficacy of VCE-004.8 in EAE and TMEV. Histopathological analysis revealed that VCE-004.8 treatments prevented demyelination, axonal damage, and immune cells infiltration. In addition, VCE-004.8 downregulated the expression of several genes closely associated with MS physiopathology, including those underlying the production of chemokines, cytokines, and adhesion molecules. Conclusions This study provides new significant insights about the potential role of VCE-004.8 for MS treatment by ameliorating neuroinflammation and demyelination.

Abstract Background Neuroprotection with cannabinoids in Parkinson’s disease (PD) has been afforded predominantly with antioxidant or anti-inflammatory cannabinoids. In the present study, we investigated the anti-inflammatory and neuroprotective properties of VCE-003.2, a quinone derivative of the non-psychotrophic phytocannabinoid cannabigerol (CBG), which may derive its activity at the peroxisome proliferator-activated receptor-γ (PPARγ). The compound is also an antioxidant. Methods We evaluated VCE-003.2 in an in vivo [mice subjected to unilateral intrastriatal injections of lipopolysaccharide (LPS)] model of PD, as well as in in vitro (LPS-exposed BV2 cells and M-213 cells treated with conditioned media generated from LPS-exposed BV2 cells) cellular models. The type of interaction of VCE-003.2 at the PPARγ receptor was furtherly investigated in bone marrow-derived human mesenchymal stem cells (MSCs) and sustained with transcriptional assays and in silico docking studies. Results VCE-003.2 has no activity at the cannabinoid receptors, a fact that we confirmed in this study using competition studies. The administration of VCE-003.2 to LPS-lesioned mice attenuated the loss of tyrosine hydroxylase (TH)-containing nigrostriatal neurons and, in particular, the intense microgliosis provoked by LPS in the substantia nigra, measured by Iba-1/Cd68 immunostaining. The analysis by qPCR of proinflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and inducible nitric oxide synthase (iNOS) in the striatum showed they were markedly elevated by the LPS lesion and strongly reduced by the treatment with VCE-003.2. The effects of VCE-003.2 in LPS-lesioned mice implied the activation of PPARγ receptors, as they were attenuated when VCE-003.2 was co-administered with the PPARγ inhibitor T0070907. We then moved to some in vitro approaches, first to confirm the anti-inflammatory profile of VCE-003.2 in cultured BV2 cells exposed to LPS. VCE-003.2 was able to attenuate the synthesis and release of TNF-α and IL-1β, as well as the induction of iNOS and cyclooxygenase-2 (COX-2) elicited by LPS in these cells. However, we found such effects were not reversed by GW9662, another classic PPARγ antagonist. Next, we investigated the neuroprotective effects of VCE-003.2 in cultured M-213 neuronal cells exposed to conditioned media generated from LPS-exposed cultured BV2 cells. VCE-003.2 reduced M-213 cell death, but again, such effects were not reversed by T0070907. Using docking analysis, we detected that VCE-003.2 binds both the canonical and the alternative binding sites in the PPARγ ligand-binding pocket (LBP). Functional assays further showed that T0070907 almost abolished PPARγ transcriptional activity induced by rosiglitazone (RGZ), but it did not affect the activity of VCE-003.2 in a Gal4-Luc system. However, T0070907 inhibited the effects of RGZ and VCE-003.2 on the expression of PPARγ-dependent genes upregulated in MSCs. Conclusions We have demonstrated that VCE-003.2 is neuroprotective against inflammation-driven neuronal damage in an in vivo model of PD and in in vitro cellular models of neuroinflammation. Such effects might involve PPARγ receptors, although in silico and in vitro experiments strongly suggest that VCE-003.2 targets PPARγ by acting through two binding sites at the LBP, one that is sensitive to T0070907 (canonical binding site) and other that is not affected by this PPARγ antagonist (alternative binding site).

Cannabinoids act as pleiotropic compounds exerting, among others, a broad-spectrum of neuroprotective effects. These effects have been investigated in the last years in different preclinical models of neurodegeneration, with the cannabinoid type-1 (CB1) and type-2 (CB2) receptors concentrating an important part of this research. However, the issue has also been extended to additional targets that are also active for cannabinoids, such as the orphan G-protein receptor 55 (GPR55). In the present study, we investigated the neuroprotective potential of VCE-006.1, a chromenopyrazole derivative with biased orthosteric and positive allosteric modulator activity at GPR55, in murine models of two neurodegenerative diseases. First, we proved that VCE-006.1 alone could induce ERK1/2 activation and calcium mobilization, as well as increase cAMP response but only in the presence of lysophosphatidyl inositol. Next, we investigated this compound administered chronically in two neurotoxin-based models of Parkinson’s disease (PD), as well as in some cell-based models. VCE-006.1 was active in reversing the motor defects caused by 6-hydroxydopamine (6-OHDA) in the pole and the cylinder rearing tests, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity detected in the substantia nigra. Similar cytoprotective effects were found in vitro in SH-SY5Y cells exposed to 6-OHDA. We also investigated VCE-006.1 in LPS-lesioned mice with similar beneficial effects, except against glial reactivity and associated inflammatory events, which remained unaltered, a fact confirmed in BV2 cells treated with LPS and VCE-006.1. We also analyzed GPR55 in these in vivo models with no changes in its gene expression, although GPR55 was down-regulated in BV2 cells treated with LPS, which may explain the lack of efficacy of VCE-006.1 in such an assay. Furthermore, we investigated VCE-006.1 in two genetic models of amyotrophic lateral sclerosis (ALS), mutant SOD1, or TDP-43 transgenic mice. Neither the neurological decline nor the deteriorated rotarod performance were prevented with this compound, and the same happened with the elevated microglial and astroglial reactivities, albeit modest spinal motor neuron preservation was achieved in both models. We also analyzed GPR55 in these in vivo models and found no changes in both TDP-43 transgenic and mSOD1 mice. Therefore, our findings support the view that targeting the GPR55 may afford neuroprotection in experimental PD, but not in ALS, thus stressing the specificities for the development of cannabinoid-based therapies in the different neurodegenerative disorders.

Abstract Background N-arachidonoylphenolamine (AM404), a paracetamol metabolite, is a potent agonist of the transient receptor potential vanilloid type 1 (TRPV1) and low-affinity ligand of the cannabinoid receptor type 1 (CB1). There is evidence that AM404 exerts its pharmacological effects in immune cells. However, the effect of AM404 on the production of inflammatory mediators of the arachidonic acid pathway in activated microglia is still not fully elucidated. Method In the present study, we investigated the effects of AM404 on the eicosanoid production induced by lipopolysaccharide (LPS) in organotypic hippocampal slices culture (OHSC) and primary microglia cultures using Western blot, immunohistochemistry, and ELISA. Results Our results show that AM404 inhibited LPS-mediated prostaglandin E2 (PGE2) production in OHSC, and LPS-stimulated PGE2 release was totally abolished in OHSC if microglial cells were removed. In primary microglia cultures, AM404 led to a significant dose-dependent decrease in the release of PGE2, independent of TRPV1 or CB1 receptors. Moreover, AM404 also inhibited the production of PGD2 and the formation of reactive oxygen species (8-iso-PGF2 alpha) with a reversible reduction of COX-1- and COX-2 activity. Also, it slightly decreased the levels of LPS-induced COX-2 protein, although no effect was observed on LPS-induced mPGES-1 protein synthesis. Conclusions This study provides new significant insights about the potential anti-inflammatory role of AM404 and new mechanisms of action of paracetamol on the modulation of prostaglandin production by activated microglia.

Una de las instituciones educativas nivel superior más representativas de este estado es la (UAEH) la misma que sostiene ser la institución de enseñanza más antigua de esta entidad federativa. El plantel nació con el estado; en sus distintas etapas de desarrollo se reflejan las correspondientes épocas de la historia hidalguense. Así mismo establece que durante 48 años de vida institucional, la Universidad ha vivido múltiples e importantes cambios caracterizados por un rápido crecimiento y expansión de cada una de sus funciones sustantivas. El presente artículo presenta los resultados de la investigación Perspectiva de aceptación del Marketing musical en una Universidad El Caso: Universidad Autónoma del Estado de Hidalgo (UAEH) Instituto de Ciencias Económico Administrativas (ICEA), encontrándose como antecedentes que las instituciones de educación superior tienen como objetivo formar competencias en los individuos de acuerdo a su área del conocimiento, de tal forma que desarrolle armónicamente las facultades cognitivas, afectivas y psicomotoras, a fin de propiciar continuamente su mejoramiento intelectual, físico, social, moral y cultural. El diseño de la investigación fue de corte cuantitativo, transversal, descriptivo y Correlacional, teniendo como Hipótesis: H1: Los alumnos tienen una Actitud positiva hacia la conducta al emplear marketing musical dentro del proceso enseñanza-aprendizaje. H2: Los alumnos tienen creencias subjetivas de manera positiva aplicables al marketing musical dentro del proceso enseñanza-aprendizaje. De acuerdo a los resultados obtenidos el notable la aceptación de reproducción de música por parte del estudiante dentro su formación académica sin embargo, la mayoría señala que no se les ha dado la oportunidad de incorporar la música dentro de sus actividades académicas así como en su proceso de aprendizaje dentro de su escuela, por tanto se propone a los directivos de la institución desarrollar programas o asignar espacios que peritan al alumno estar en contacto con la ambientación musical pertinente para maximizar su aprovechamiento académico.

Anti-inflammatory and antidiabetogenic properties have been ascribed to cannabidiol (CBD). CBD-based medicinal drugs have been approved for over a lustrum, and a boom in the commercialization of CBD products started in parallel. Herein, we explored the efficacy of CBD in streptozotocin (STZ)-induced diabetic mice to prevent diabetic nephropathy at onset. Eight-to-ten-week-old C57BL6J male mice were treated daily intraperitoneally with 10 mg/kg of CBD or vehicle for 14 days. After 8 days of treatment, mice were challenged with STZ or vehicle (healthy-control). At the end of the study, non-fasting blood glucose (FBG) level was 276 ± 42 mg/dL in vehicle-STZ-treated compared to 147 ± 9 mg/dL (p ≤ 0.01) in healthy-control mice. FBG was 114 ± 8 mg/dL in vehicle-STZ-treated compared to 89 ± 4 mg/dL in healthy-control mice (p ≤ 0.05). CBD treatment did not prevent STZ-induced hyperglycemia, and non-FBG and FBG levels were 341 ± 40 and 133 ± 26 mg/dL, respectively. Additionally, treatment with CBD did not avert STZ-induced glucose intolerance or pancreatic beta cell mass loss compared to vehicle-STZ-treated mice. Anatomopathological examination showed that kidneys from vehicle-STZ-treated mice had a 35% increase of glomerular size compared to healthy-control mice (p ≤ 0.001) and presented lesions with a 43% increase in fibrosis and T cell infiltration (p ≤ 0.001). Although treatment with CBD prevented glomerular hypertrophy and reduced T cell infiltration, it significantly worsened overall renal damage (p ≤ 0.05 compared to vehicle-STZ mice), leading to a more severe renal dysfunction than STZ alone. In conclusion, we showed that CBD could be detrimental for patients with type 1 diabetes, particularly those undergoing complications such as diabetic nephropathy.

Neutral cannabinoids are oxidatively unstable and are converted into quinone derivatives by atmospheric- and/or chemical oxidative dearomatization. The study of cannabinoquinones has long been plagued by their lability toward additional oxidative degradation, but full substitution of the quinone ring, as well as the introduction of steric hindrance on the alkyl substituent, have provided sufficient stability for a systematic investigation of their bioactivity and for further clinical development. These studies culminated in the discovery of the aminocannabinoquinone VCE-004.8 (5), a compound under phase 2 clinical development with orphan drug status by EMA and FDA for the management of scleroderma. The synthesis and rich chemistry of these compounds will be described, summarizing their biological profile and clinical potential.

The 3-hydroxyquinone derivative of the non-psychotrophic phytocannabinoid cannabigerol, so-called VCE-003.2, and some other derivatives have been recently investigated for neuroprotective properties in experimental models of Parkinson’s disease (PD) in mice. The pharmacological effects in those models were related to the activity on the peroxisome proliferator-activated receptor-γ (PPAR-γ) and possibly other pathways. In the present study, we investigated VCE-004.8 (formulated as EHP-101 for oral administration), the 3-hydroxyquinone derivative of cannabidiol (CBD), with agonist activity at the cannabinoid receptor type-2 (CB2) receptor in addition to its activity at the PPAR-γ receptor. Studies were conducted in both in vivo (lesioned-mice) and in vitro (SH-SY5Y cells) models using the classic parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). Our data confirmed that the treatment with VCE-004.8 partially reduced the loss of tyrosine hydroxylase (TH)-positive neurons measured in the substantia nigra of 6-OHDA-lesioned mice, in parallel with an almost complete reversal of the astroglial (GFAP) and microglial (CD68) reactivity occurring in this structure. Such neuroprotective effects attenuated the motor deficiencies shown by 6-OHDA-lesioned mice in the cylinder rearing test, but not in the pole test. Next, we explored the mechanism involved in the beneficial effect of VCE-004.8 in vivo, by analyzing cell survival in cultured SH-SY5Y cells exposed to 6-OHDA. We found an important cytoprotective effect of VCE-004.8 at a concentration of 10 µM, which was completely reversed by the addition of antagonists, T0070907 and SR144528, aimed at blocking PPAR-γ and CB2 receptors, respectively. The treatment with T0070907 alone only caused a partial reversal, whereas SR144528 alone had no effect, indicating a major contribution of PPAR-γ receptors in the cytoprotective effect of VCE-004.8 at 10 µM. In summary, our data confirmed the neuroprotective potential of VCE-004.8 in 6-OHDA-lesioned mice, and in vitro studies confirmed a greater relevance for PPAR-γ receptors rather than CB2 receptors in these effects.

Abstract Exaggerated inflammatory responses in microglia represent one of the major risk factors for various central nervous system’s (CNS) associated pathologies. Release of excessive inflammatory mediators such as prostaglandins and cytokines are the hallmark of hyper-activated microglia. Here we have investigated the hitherto unknown effects of capsaicin (cap) - a transient receptor potential vanilloid 1 (TRPV1) agonist- in murine primary microglia, organotypic hippocampal slice cultures (OHSCs) and human primary monocytes. Results demonstrate that cap (0.1–25 µM) significantly (p

A growing body of preclinical evidence indicates that certain cannabinoids, including cannabidiol (CBD) and synthetic derivatives, may play a role in the myelinating processes and are promising small molecules to be developed as drug candidates for management of demyelinating diseases such as multiple sclerosis (MS), stroke and traumatic brain injury (TBI), which are three of the most prevalent demyelinating disorders. Thanks to the properties described for CBD and its interesting profile in humans, both the phytocannabinoid and derivatives could be considered as potential candidates for clinical use. In this review we will summarize current advances in the use of CBD and other cannabinoids as future potential treatments. While new research is accelerating the process for the generation of novel drug candidates and identification of druggable targets, the collaboration of key players such as basic researchers, clinicians and pharmaceutical companies is required to bring novel therapies to the patients.

The Mayten tree (Maytenus boaria Mol.), a native plant of Chile that grows under environmentally limiting conditions, was historically harvested to extract an edible oil, and may represent an opportunity to expand current vegetable oil production. Seeds were collected from Mayten trees in north-central Chile, and seed oil was extracted by solvent extraction. The seed oil showed a reddish coloration, with quality parameters similar to those of other vegetable oils. The fatty acid composition revealed high levels of monounsaturated and polyunsaturated fatty acids. Oleic and linoleic acids, which are relevant to the human diet, were well represented in the extracted Mayten tree seed oil. The oil displayed an antioxidant capacity due to the high contents of antioxidant compounds (polyphenols and carotenoids) and may have potential health benefits for diseases associated with oxidative stress.

El relevante papel que está tomando la sustentabilidad en decisiones empresariales, por conciencia, responsabilidad o sensibilidad social, aunado al incremento del ecoconsumo, orienta el sondeo en empresas manufactureras exportadoras del estado de Hidalgo sobre la atención a iniciativas para transitar hacia una mercadotecnia ambiental, verde, sostenible o ecomarketing, desde la percepción de altos directivos y operativos. Las variables cuestionadas derivan de la gestión de riesgos ambientales y por ello la creación de valor para el consumidor y la sociedad. La investigación es cuantitativa, exploratoria, probabilística por área y cuotas, basada en dos constructos decisionales: ambiente y valor para la marca, significancia Chi2 en prueba de hipótesis y tablas de contingencia. Las percepciones entre directivos y operativos divergen en cuanto a instalación y uso de materiales ecológicos. Generalizando, 20% manifiesta realizar gestión ambiental, 45% lo intenta y 35% lo discrimina; y 35, 35 y 35% son los respectivos en creación de valor.

Background and aim: Capsule endoscopy and double-balloon enteroscopy are well-recognized procedures in obscure gastrointestinal bleeding, with many factors that may influence their diagnosis yield. The aim of the present study was to characterize the degree of agreement between both techniques with focus on the type of lesion in a large cohort of patients at a referral center. Material and method: One thousand two hundred and nine capsules were administered in 1,078 patients and 381 enteroscopies were performed in 361 patients with obscure-gastrointestinal bleeding from 2004 to 2014. Results: Both procedures were carried out in 332 patients (mean age: 65.22 ± 15.41, 183 men) and they have a similar diagnosis yield (70.5% vs. 69.6%, p = 0.9). Overall enteroscopy diagnosis yield was higher within patients with a previous positive capsule endoscopy (79.3% vs. 27.9%, p < 0.001). The degree of agreement was very good for polyps (0.89 [95% CI: 0.78-0.99]), good for vascular lesions (0.66 [95% CI: 0.55-0.77]) and tumors (0.66 [95% CI: 0.55-0.76]) and moderate for ulcers (0.56 [95% CI: 0.46-0.67]). Diverticula (0.39 [95% CI: 0.29-0.5]) achieved a fair agreement. The results of CE and DBE differed in 73 patients (22%). Conclusions: The present study confirms that although overall diagnostic yield by capsule endoscopy and double-balloon enteroscopy is similar, there are many factors which can modify these values, mainly the type of lesion.

Objetivo: Analizar los conocimientos, las actitudes y las normas subjetivas como predictores de la intención de realizar comportamientos preventivos en hijos de personas con diabetes mellitus tipo 2, en dos ciudades del estado de Hidalgo, México. Métodos: Se trata de um estudio cuantitativo, no experimental, de naturaleza analítica y transversal. A través de uma muestra probabilística de dos etapas, 246 hijos (entre 15 y 59 años de edad) de pacientes apuntados en un programa de diabetes en el servicio de seguridad social fueron encuestados de manera personal. Resultados: Se observó que la reducción del riesgo de contraer diabetes afecta la intención de desarrollar comportamientos preventivos mediada por la actitud hacia la prevención (p=0,000) que es el predictor más importante de tal intención (p=0,000). Las normas subjetivas también tienen un impacto significativo en la intención del comportamiento preventivo (p=0,000), aunque la actitud hacia la prevención no es afectada por las creencias sobre la obtención (p=0,095) y la gravedad de la enfermedad (p=0,056). Conclusión: La aplicación del modelo permitió identificar aspectos relevantes para apoyar la promoción de la salud orientada a influir en los procesos de cambio de comportamiento social en uma población con el riesgo de contraer diabetes mellitus tipo 2 en México.

Objective: To analyze beliefs, attitudes and subjective norms as predictors of preventive behavioral intention in offspring of parents with type 2 diabetes mellitus in two cities in the state of Hidaldo, Mexico. Methods: This is a quantitative, nonexperimental, explanatory and cross-sectional study. Through a two-stage probabilistic sample, 246 subjects (between 15 and 59 years old) whose parents were enrolled in a diabetes program in the social security service were interviewed in a personal manner. Results: It was observed that the reduction in the risk of developing diabetes affects the intent of developing preventive behaviors mediated by attitude toward prevention (p=0.000), which is the most important predictor of that intention (p=0.000). Subjective norms also have a significant impact on the preventive behavioral intention (p=0.000), although the preventive attitude is not affected by beliefs regarding the development (p=0.095) and severity of the disease (p=0.056). Conclusion: The application of the model allowed the identification of relevant aspects to support health promotion, oriented to influence the processes of change in social behavior, in a population at risk of developing type 2 diabetes mellitus in Mexico. doi:10.5020/18061230.2014.p43