The Effect of Hydrogen Sulphide on TNF-α-induced Endothelial Dysfunction

Cardiovascular disease is the leading cause of morbidity and mortality globally. Endothelial dysfunction (ED) is implicated in the development and aggravation of cardiovascular complications. There is growing interest in understanding the pathophysiological mechanisms underlying ED and identifying therapeutic strategies that may prevent or reduce the risk of vascular complications and associated diseases. Hydrogen sulphide (H2S) is an endogenous gasotransmitter that can act as an essential biological mediator. In the vasculature, H2S can mediate beneficial effects through anti-inflammatory and redox-modulating regulatory mechanisms. Reduced H2S bioavailability is reported in chronic diseases such as atherosclerosis, diabetes, hypertension and preeclampsia, suggesting the possible value of investigating H2S as a therapeutic strategy for vascular-related conditions. The study aimed to examine the cytoprotective roles of H2S against TNF-α-mediated ED. Human umbilical vein endothelial cells (HUVECs) were stimulated with TNF-α (1 ng/ml) followed by a slow H2S-releasing donor, GYY4137, post-treatment (100 μM). TNF-α proved to be an efficient agent enabling ED as evidence enhanced oxidising redox state, inflammation and apoptosis via mitochondrial-dependent downstream signalling pathway. Confocal microscopy and gene-transcriptional expression analysis revealed that TNF-α affects mitochondrial dynamics, characterised as well by fragmentation of the organelle. GYY4137 post-treatment balances the redox state that alleviates endothelial inflammation, mitochondrial dysfunction, and pro-apoptotic signalling. In addition, GYY4137 enhanced protein S-sulfhydration of Keap1 and caspase 3, stimulating Nrf2-downstream response and inhibiting caspase 3/7 activity, respectively. In conclusion, the findings of this research contribute to expanding the understanding of the overall role H2S underlying mechanisms and indicate that the slow-releasing H2S donor may have putative therapeutic applications in inflammation-associated ED

Partial Mitigation of Oxidized Phospholipid-Mediated Mitochondrial Dysfunction in Neuronal Cells by Oxocarotenoids

Mitochondria are important (patho)physiological sources of reactive oxygen species (ROS) that mediate mitochondrial dysfunction and phospholipid oxidation; an increase in mitochondrial content of oxidized phospholipid (OxPL) associates with cell death. Previously we showed that the circulating OxPL 1-palmitoyl-2-(5’-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) increases in patients with Alzheimer’s disease (AD), and associates with lower plasma antioxidant oxocarotenoids, zeaxanthin, and lutein. Since oxocarotenoids are metabolized in mitochondria, we propose that during AD, lower concentrations of mitochondrial zeaxanthin and lutein may result in greater phospholipid oxidation and predispose to neurodegeneration. Here, we have investigated whether non-toxic POVPC concentrations impair mitochondrial metabolism in differentiated (d)SH-SY5Y neuronal cells and whether there is any protective role for oxocarotenoids against mitochondrial dysfunction. After 24 hours, glutathione (GSH) concentration was lower in neuronal cells exposed to POVPC (1–20μM) compared with vehicle control without loss of viability compared to control. However, mitochondrial ROS production (determined by MitoSOX oxidation) was increased by 50% only after 20μM POVPC. Following delivery of lutein (0.1-1μM) and zeaxanthin (0.5-5μM) over 24 hours in vitro, oxocarotenoid recovery from dSH-SY5Y cells was >  50%. Co-incubation with oxocarotenoids prevented loss of GSH after 1μM but not 20μM POVPC, whereas the increase in ROS production induced by 20μM POVPC was prevented by lutein and zeaxanthin. Mitochondrial uncoupling increases and ATP production is inhibited by 20μM but not 1μM POVPC; carotenoids protected against uncoupling although did not restore ATP production. In summary, 20μM POVPC induced loss of GSH and a mitochondrial bioenergetic deficit in neuronal cells that was not mitigated by oxocarotenoids

Propuesta estratégica de mejora en la implementación de los estándares mínimos del Sistema Gestión de la Seguridad y Salud en el Trabajo (SG-SST) en la empresa Oxymaster para el año 2020.

El presente trabajo busca reconocer la importancia de realizar una propuesta estratégica de mejora en el Área de Talento Humano de la empresa Oxymaster y en el estado actual de su Sistema de Gestión de la Seguridad y Salud en el trabajo (SG-SST). Que se sintetizará y evaluará por medio de una auditoría al área anteriormente mencionada con el fin de generar y ejecutar un correcto desarrollo del plan SGSST, analizando aspectos importantes como la evolución integral de acciones y el plan de mejora. Teniendo en cuenta que el plan SGSST es según el Decreto 1072 de 2015 un proceso lógico que busca la mejora continua, vinculando las políticas de la organización, la planificación, la aplicación, la evaluación, la auditoría y las acciones de mejora con el objetivo de anticipar, reconocer, evaluar y controlar los riesgos de la seguridad y la salud en el trabajo. (Art. 2.2.4.7.4).The present work seeks to recognize the importance of making a strategic proposal for improvement in the Human Talent Area of the Oxymaster company and in the current state of its Occupational Safety and Health Management System (SG-SST). That it will be synthesized and evaluated by means of an audit to the aforementioned area in order to generate and execute a correct development of the SGSST plan, analyzing important aspects such as the integral evolution of actions and the improvement plan. Taking into account that the SGSST plan is according to Decree 1072 of 2015 a logical process that seeks continuous improvement, linking the organization's policies, planning, application, evaluation, auditing and improvement actions with the aim of anticipate, recognize, assess and control the risks of safety and health at work. (Art. 2.2.4.7.4)

TNF-α-Mediated Endothelial Cell Apoptosis Is Rescued by Hydrogen Sulfide

Endothelial dysfunction is implicated in the development and aggravation of cardiovascular complications. Among the endothelium-released vasoactive factors, hydrogen sulfide (H2S) has been investigated for its beneficial effects on the vasculature through anti-inflammatory and redox-modulating regulatory mechanisms. Reduced H2S bioavailability is reported in chronic diseases such as cardiovascular disease, diabetes, atherosclerosis and preeclampsia, suggesting the value of investigating mechanisms, by which H2S acts as a vasoprotective gasotransmitter. We explored whether the protective effects of H2S were linked to the mitochondrial health of endothelial cells and the mechanisms by which H2S rescues apoptosis. Here, we demonstrate that endothelial dysfunction induced by TNF-α increased endothelial oxidative stress and induced apoptosis via mitochondrial cytochrome c release and caspase activation over 24 h. TNF-α also affected mitochondrial morphology and altered the mitochondrial network. Post-treatment with the slow-releasing H2S donor, GYY4137, alleviated oxidising redox state, decreased pro-caspase 3 activity, and prevented endothelial apoptosis caused by TNF-α alone. In addition, exogenous GYY4137 enhanced S-sulfhydration of pro-caspase 3 and improved mitochondrial health in TNF-α exposed cells. These data provide new insights into molecular mechanisms for cytoprotective effects of H2S via the mitochondrial-driven pathway

Exploring mitochondrial hydrogen sulfide signalling for therapeutic interventions in vascular diseases

Hydrogen sulfide (H2S), a gaseous signalling molecule, is important in numerous physiological and pathophysiological processes. Despite its initial identification as an environmental toxin, H2S is now well described as an essential physiological molecule that is finely balanced to maintain cellular functions, especially in modulating mitochondrial activity. Mitochondria are responsible for the oxidation of H2S and its safe elimination while maintaining mitochondrial biogenesis. H2S oxidation in mitochondria generates various reactive sulfur species that could post-translationally modify proteins by sulfhydration. Sulfhydrated proteins participate in many regulatory activities either by direct interactions in the electron transport chain or indirect regulation by epigenetics. These investigations explain the importance of research of H2S as a therapeutic molecule beyond the traditional understanding as a protective role through its anti-inflammatory and antioxidant properties. This review focuses on highlighting the significant involvement of the H2S pathway in vascular diseases and current H2S donors for therapeutic use under development

Diseño de una estrategia lúdica desde el emocionear para motivar los aprendizajes holísticos en niños y niñas del grado jardín del Gimnasio Campestre la Sabana

El siguiente proyecto de investigación se enfatiza en las emociones y la motivación de los niños y niñas frente al aprendizaje holístico. De esta manera se diseña una estrategia lúdica y creativa, que permite reconocer e identificar las emociones, con el fin de ser aplicada en un salón de clase, teniendo en cuenta que dicha estrategia fortalece el desarrollo de la infancia y funciona también como guía no solo para los docentes, sino para la familia y la institución educativa. Se pretende entonces, que los niños y niñas durante el proceso de aprendizaje se sientan felices y emocionados, que disfruten y gocen cada instante durante la estadía en el Colegio, especialmente en la clase de Español, que es en donde se detectó la problemática del proyecto. vii Mediante la estrategia diseñada (juego), se busca que los niños y niñas desarrollen todas sus capacidades involucrando el cuerpo en su totalidad, que es lo que los hace únicos y especiales; así, tendrán la oportunidad de expresar sus emociones libremente y con espontaneidad, que es lo que se define como vida

Propuesta de intervención frente a la desnutrición infantil de 0 a 5 años del municipio de Puerto Carreño - Vichada

No aplicaLa población infantil de 0 a 5 años del municipio de Puerto Carreño – Vichada, continúa afrontando el grave problema de la desnutrición a pesar de los esfuerzos que las entidades estatales vienen realizando para mejorar esta situación. Uno de los vacíos que se han presentado al evaluar el impacto de las acciones de complementariedad alimentaria ha sido la carencia de un diagnóstico del estado nutricional que permita conocer la situación inicial de la intervención y facilite la determinación de un sistema de vigilancia nutricional. Una de las problemáticas más grandes que enfrenta el municipio de Puerto Carreño es el acceso a una alimentación adecuada, lo cual se ve reflejado en el consumo y el estado nutricional de su población en especial la que se encuentra entre 0 a 5 años, según los indicadores económicos y sociales, la tasa de pobreza del municipio es de 29,3% y la de pobreza extrema de 8,4% (DNP, 2016). Esta propuesta está orientada a disminuir las tasas desnutrición de la población infantil de 0 a 5 años en el municipio de Puerto Carreño, bajo un enfoque interinstitucional e intersectorial que implique los actores responsables de brindar una respuesta integral a la problemática de desnutrición en la población de 0 a 5 años del municipio. Desde el sector salud, las acciones orientadas deben ser transversales cuya base se encuentra en una atención sanitaria que permita la identificación de un diagnóstico y tratamiento temprano además de promover estrategias de promoción y prevención.The child population from 0 to 5 years of age in the municipality of Puerto Carreño - Vichada continues to face the serious problem of malnutrition despite the efforts that state entities have been making to improve this situation. One of the gaps that have arisen when evaluating the impact of food complementarity actions has been the lack of a nutritional status diagnosis that allows knowing the initial situation of the intervention and facilitates the determination of a nutritional surveillance system. One of the biggest problems facing the municipality of Puerto Carreño is access to adequate food, which is reflected in the consumption and nutritional status of its population, especially those between 0 to 5 years of age. According to economic and social indicators, the municipality's poverty rate is 29.3% and the extreme poverty rate is 8.4% (DNP, 2016). This proposal is aimed at reducing the malnutrition rates of the child population from 0 to 5 years of age in the municipality of Puerto Carreño, under an inter-institutional and intersectoral approach that involves the actors responsible for providing a comprehensive response to the problem of malnutrition in the population of 0 to 5 years of the municipality. From the health sector, the oriented actions must be transversal, based on health care that allows the identification of early diagnosis and treatment, as well as promoting promotion and prevention strategies

Cholesterol and oxysterol sulfates:Pathophysiological roles and analytical challenges

Cholesterol and oxysterol sulfates are important regulators of lipid metabolism, inflammation, cell apoptosis, and cell survival. Among the sulfate-based lipids, cholesterol sulfate (CS) is the most studied lipid both quantitatively and functionally. Despite the importance, very few studies have analysed and linked the actions of oxysterol sulfates to their physiological and pathophysiological roles. Overexpression of sulfotransferases confirmed the formation of a range of oxysterol sulfates and their antagonistic effects on liver X receptors (LXRs) prompting further investigations how are the changes to oxysterol/oxysterol sulfate homeostasis can contribute to LXR activity in the physiological milieu. Here, we aim to bring together for novel roles of oxysterol sulfates, the available techniques and the challenges associated with their analysis. Understanding the oxysterol/oxysterol sulfate levels and their pathophysiological mechanisms could lead to new therapeutic targets for metabolic diseases

Contemporary Clinical and Molecular Epidemiology of Vancomycin-Resistant Enterococcal Bacteremia: A Prospective Multicenter Cohort Study (VENOUS I)

Background Vancomycin-resistant enterococci (VRE) are major therapeutic challenges. Prospective contemporary data characterizing the clinical and molecular epidemiology of VRE bloodstream infections (BSIs) are lacking. Methods The Vancomycin-Resistant Enterococcal BSI Outcomes Study (VENOUS I) is a prospective observational cohort of adult patients with enterococcal BSI in 11 US hospitals. We included patients with Enterococcus faecalis or Enterococcus faecium BSI with >= 1 follow-up blood culture(s) within 7 days and availability of isolate(s) for further characterization. The primary study outcome was in-hospital mortality. Secondary outcomes were mortality at days 4, 7, 10, 12, and 15 after index blood culture. A desirability of outcome ranking was constructed to assess the association of vancomycin resistance with outcomes. All index isolates were subjected to whole genome sequencing. Results Forty-two of 232 (18%) patients died in hospital and 39 (17%) exhibited microbiological failure (lack of clearance in the first 4 days). Neutropenia (hazard ratio [HR], 3.13), microbiological failure (HR, 2.4), VRE BSI (HR, 2.13), use of urinary catheter (HR, 1.85), and Pitt BSI score >= 2 (HR, 1.83) were significant predictors of in-hospital mortality. Microbiological failure was the strongest predictor of in-hospital mortality in patients with E faecium bacteremia (HR, 5.03). The impact of vancomycin resistance on mortality in our cohort changed throughout the course of hospitalization. Enterococcus faecalis sequence type 6 was a predominant multidrug-resistant lineage, whereas a heterogeneous genomic population of E faecium was identified. Conclusions Failure of early eradication of VRE from the bloodstream is a major factor associated with poor outcomes. Failure to eradicate enterococci from the bloodstream in the first 4 days after the index blood culture was the most consistent factor associated with increased risk of mortality. The association of vancomycin resistance with mortality changed throughout the course of the hospitalization

Mature iPSC-derived astrocytes of an ALS/FTD patient carrying the TDP43A90V mutation display a mild reactive state and release polyP toxic to motoneurons

Astrocytes play a critical role in the maintenance of a healthy central nervous system and astrocyte dysfunction has been implicated in various neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). There is compelling evidence that mouse and human ALS and ALS/FTD astrocytes can reduce the number of healthy wild-type motoneurons (MNs) in co-cultures or after treatment with astrocyte conditioned media (ACM), independently of their genotype. A growing number of studies have shown that soluble toxic factor(s) in the ACM cause non-cell autonomous MN death, including our recent identification of inorganic polyphosphate (polyP) that is excessively released from mouse primary astrocytes (SOD1, TARDBP, and C9ORF72) and human induced pluripotent stem cells (iPSC)-derived astrocytes (TARDBP) to kill MNs. However, others have reported that astrocytes carrying mutant TDP43 do not produce detectable MN toxicity. This controversy is likely to arise from the findings that human iPSC-derived astrocytes exhibit a rather immature and/or reactive phenotype in a number of studies. Here, we have succeeded in generating a highly homogenous population of functional quiescent mature astrocytes from control subject iPSCs. Using identical conditions, we also generated mature astrocytes from an ALS/FTD patient carrying the TDP43A90V mutation. These mutant TDP43 patient-derived astrocytes exhibit key pathological hallmarks, including enhanced cytoplasmic TDP-43 and polyP levels. Additionally, mutant TDP43 astrocytes displayed a mild reactive signature and an aberrant function as they were unable to promote synaptogenesis of hippocampal neurons. The polyP-dependent neurotoxic nature of the TDP43A90V mutation was further confirmed as neutralization of polyP in ACM derived from mutant TDP43 astrocytes prevented MN death. Our results establish that human astrocytes carrying the TDP43A90V mutation exhibit a cell-autonomous pathological signature, hence providing an experimental model to decipher the molecular mechanisms underlying the generation of the neurotoxic phenotype