DNA glycosylase Neil3 regulates vascular smooth muscle cell biology during atherosclerosis development.

BACKGROUND AND AIMS: Atherogenesis involves a complex interaction between immune cells and lipids, processes greatly influenced by the vascular smooth muscle cell (VSMC) phenotype. The DNA glycosylase NEIL3 has previously been shown to have a role in atherogenesis, though whether this is due to its ability to repair DNA damage or to other non-canonical functions is not yet clear. Hereby, we investigate the role of NEIL3 in atherogenesis, specifically in VSMC phenotypic modulation, which is critical in plaque formation and stability. METHODS: Chow diet-fed atherosclerosis-prone Apoe-/- mice deficient in Neil3, and NEIL3-abrogated human primary aortic VSMCs were characterized by qPCR, and immunohistochemical and enzymatic-based assays; moreover, single-cell RNA sequencing, mRNA sequencing, and proteomics were used to map the molecular effects of Neil3/NEIL3 deficiency in the aortic VSMC phenotype. Furthermore, BrdU-based proliferation assays and Western blot were performed to elucidate the involvement of the Akt signaling pathway in the transdifferentiation of aortic VSMCs lacking Neil3/NEIL3. RESULTS: We show that Neil3 deficiency increases atherosclerotic plaque development without affecting systemic lipids. This observation was associated with a shift in VSMC phenotype towards a proliferating, lipid-accumulating and secretory macrophage-like cell phenotype, without changes in DNA damage. VSMC transdifferentiation in Neil3-deficient mice encompassed increased activity of the Akt signaling pathway, supported by cell experiments showing Akt-dependent proliferation in NEIL3-abrogated human primary aortic VSMCs. CONCLUSIONS: Our findings show that Neil3 deficiency promotes atherosclerosis development through non-canonical mechanisms affecting VSMC phenotype involving activation of the Akt signaling pathway

Hyperkalemia in Heart Failure Patients in Spain and Its Impact on Guidelines and Recommendations: ESC-EORP-HFA Heart Failure Long-Term Registry

[Abstract] Introduction and objectives: Hyperkalemia is a growing concern in the treatment of patients with heart failure and reduced ejection fraction because it limits the use of effective drugs. We report estimates of the magnitude of this problem in routine clinical practice in Spain, as well as changes in potassium levels during follow-up and associated factors. Methods: This study included patients with acute (n=881) or chronic (n=3587) heart failure recruited in 28 Spanish hospitals of the European heart failure registry of the European Society of Cardiology and followed up for 1 year. Various outcomes were analyzed, including changes in serum potassium levels and their impact on treatment. Results: Hyperkalemia (K+> 5.4 mEq/L) was identified in 4.3% (95%CI, 3.7%-5.0%) and 8.2% (6.5%-10.2%) of patients with chronic and acute heart failure, respectively, and was responsible for 28.9% of all cases of contraindication to mineralocorticoid receptor antagonist use and for 10.8% of all cases of failure to reach the target dose. Serum potassium levels were not recorded in 291 (10.8%) of the 2693 chronic heart failure patients with reduced ejection fraction. During follow-up, potassium levels increased in 179 of 1431 patients (12.5%, 95%CI, 10.8%-14.3%). This increase was directly related to age, diabetes, and history of stroke and was inversely related to history of hyperkalemia. Conclusions: This study highlights the magnitude of the problem of hyperkalemia in patients with heart failure in everyday clinical practice and the need to improve monitoring of this factor in these patients due to its interference with the possibility of receiving optimal treatment.[Resumen] Introducción y objetivos. La hiperpotasemia es una preocupación creciente en el tratamiento de los pacientes con insuficiencia cardiaca y fracción de eyección reducida, pues limita el uso de fármacos eficaces. Este trabajo ofrece estimaciones de la magnitud de este problema en la práctica clínica habitual en España, los cambios en las concentraciones de potasio en el seguimiento y los factores asociados. Métodos. Pacientes con insuficiencia cardiaca aguda (n = 881) y crónica (n = 3.587) seleccionados en 28 hospitales españoles del registro europeo de insuficiencia cardiaca de la European Society of Cardiology y seguidos 1 año para diferentes desenlaces, incluidos cambios en las cifras de potasio y su impacto en el tratamiento. Resultados. La hiperpotasemia (K+ > 5,4 mEq/l) está presente en el 4,3% (IC95%, 3,7-5,0%) y el 8,2% (6,5-10,2%) de los pacientes con insuficiencia cardiaca crónica y aguda; causa el 28,9% de todos los casos en que se contraindica el uso de antagonistas del receptor de mineralocorticoides y el 10,8% de los que no alcanzan la dosis objetivo. Del total de 2.693 pacientes ambulatorios con fracción de eyección reducida, 291 (10,8%) no tenían registrada medición de potasio. Durante el seguimiento, 179 de 1.431 (12,5%, IC95%, 10,8-14,3%) aumentaron su concentración de potasio, aumento relacionado directamente con la edad, la diabetes mellitus y los antecedentes de ictus e inversamente con los antecedentes de hiperpotasemia. Conclusiones. Este trabajo destaca el problema de la hiperpotasemia en pacientes con insuficiencia cardiaca de la práctica clínica habitual y la necesidad de continuar y mejorar la vigilancia de este factor en estos pacientes por su interferencia en el tratamiento óptimo

Dendritic cell deficiencies persist seven months after SARS-CoV-2 infection

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection induces an exacerbated inflammation driven by innate immunity components. Dendritic cells (DCs) play a key role in the defense against viral infections, for instance plasmacytoid DCs (pDCs), have the capacity to produce vast amounts of interferon-alpha (IFN-α). In COVID-19 there is a deficit in DC numbers and IFN-α production, which has been associated with disease severity. In this work, we described that in addition to the DC deficiency, several DC activation and homing markers were altered in acute COVID-19 patients, which were associated with multiple inflammatory markers. Remarkably, previously hospitalized and nonhospitalized patients remained with decreased numbers of CD1c+ myeloid DCs and pDCs seven months after SARS-CoV-2 infection. Moreover, the expression of DC markers such as CD86 and CD4 were only restored in previously nonhospitalized patients, while no restoration of integrin β7 and indoleamine 2,3-dyoxigenase (IDO) levels were observed. These findings contribute to a better understanding of the immunological sequelae of COVID-19

Bactericidal activity of caprylic acid entrapped in mesoporous silica nanoparticles

[EN] Development of nanotechnologies to improve the functionality of natural antimicrobials for food applications has received much attention in recent years. Mesoporous silica particles, such as MCM-41, have been recently proposed as smart delivery devices capable of loading and releasing large amounts of cargo. In this study, the antimicrobial activity of caprylic acid entrapped in MCM-41 nanoparticles against Escherichia coli, Salmonella enterica, Staphylococcus aureus and Listeria monocytogenes was tested and compared with the bactericidal effect of free caprylic acid using the macrodilution method. The minimum bactericidal concentration for free caprylic acid was established to be below 18.5 mM for S. aureus and L. monocytogenes and within the 18.5-20 mM range for E. coli and S. enterica. Moreover, caprylic acid loaded nanoparticles showed a total inhibition of the growth within the 18.5-20 mM range for the tested bacteria, and therefore the antimicrobial activity was preserved. Transmission electron microscopy images revealed that bacteria treatment with the caprylic acid-loaded nanoparticles generated disruption of cell envelope and leakage of cytoplasmic content, which resulted in cell death. We believe that caprylic acid encapsulation in nanoparticles MCM-41 can provide an effective system for potential applications in food safety in the food industry due to the possible controlled release of fatty acid and the masking of its unpleasant organoleptic properties. (C) 2015 Elsevier Ltd. All rights reservedRuiz Rico, M.; Fuentes López, C.; Pérez-Esteve, É.; Jiménez Belenguer, AI.; Quiles Chuliá, MD.; Marcos Martínez, MD.; Martínez-Máñez, R.... (2015). Bactericidal activity of caprylic acid entrapped in mesoporous silica nanoparticles. Food Control. 56:77-85. doi:10.1016/j.foodcont.2015.03.016S77855

¿Quién se ha sentido así? Fomentando la vulnerabilidad y la esperanza transformadora en el conocimiento activista del Grado de Estudios Ingleses

Memoria ID2022-112. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2022-2023

Molecular mechanisms of atherosclerotic disease: Studies on the role of the DNA glycosylase NEIL3 and the epitranscriptome in the development of atherosclerosis

Cardiovascular diseases are one of the top causes of mortality worldwide, and the main underlying cause is atherosclerosis. Atherosclerosis is a multifactorial and progressive arterial disease where lipid accumulation and a low-level inflammatory response are at play. This leads to the formation of a plaque, which upon rupture can trigger thrombosis and artery occlusion, causing myocardial infarction or stroke. Numerous studies have shown that cells within atherosclerotic plaques, like vascular smooth muscle cells (VSMCs), accumulate DNA damage. If left unrepaired, DNA damage can promote plaque instability leading to the fatal consequences of atherosclerosis. NEIL3 is a canonical DNA glycosylase involved in oxidative stress-damaged DNA base lesion repair, which seems to have functions beyond DNA repair, e.g., in cell proliferation. Yet, the role of NEIL3 in atherosclerosis is not well understood. The aim of this thesis was to examine the role of NEIL3 deficiency in atherosclerosis with a focus on VSMCs, using mouse- and cell-based models. Our results show that NEIL3 could be a new player in atherosclerosis affecting VSMC phenotypic identity. Moreover, epitranscriptomics has emerged as a novel research field investigating the role of post-transcriptional RNA modifications on gene expression. Epitranscriptomics is previously shown to function in diseases like cancer, but a possible role in atherosclerosis is not known. The aim of this thesis was also to explore the role of RNA modifications in human atherosclerosis. Our results show that the well-studied RNA modification N6-methyladenosine is decreased in human atherosclerotic lesions, with dysregulated levels of several RNA modification enzymes. Overall, this work intends to refine the understanding of the molecular mechanisms involved in atherosclerosis, where targeting NEIL3 or RNA modification-related proteins could help creating new prognosis tools and treatment strategies

It’s a Matter of Trust: How Thirty Years of History Prepared a Community-Based Organization to Respond to the COVID-19 Pandemic

The COVID-19 pandemic drew public attention to the essential work and vulnerability of low-income Latina immigrants. Less recognized were the ways immigrant community organizations mobilized under exceptional conditions to provide immediate support to their communities while continuing to work toward durable systematic change. This paper analyzes the approach of Mujeres Unidas y Activas (MUA) in the San Francisco Bay Area. Over three decades, MUA developed an organizing model that builds transformative relationships among peers and provides direct services and leadership development for civic engagement. MUA has a long history of research collaborations and self-study aligned with critical community-engaged research methods and values. In 2019, MUA formed a research team of its leaders and academics to analyze the impact of their model. Since data collection occurred between March 2020 and December 2022, the research also documented the organization’s response to COVID-19. This paper argues that specific organizational values and practices of liderazgo, apoyo, and confianza (leadership, support, and trust) proved to be particularly powerful resources for sustaining individuals and community work through the pandemic, enabling women who have experienced multiple forms of structural violence to perceive themselves as capable of healing themselves and their communities while working to address root causes of trauma and inequity