Histone Deacetylase 3-Directed PROTACs Have Anti-inflammatory Potential by Blocking Polarization of M0-like into M1-like Macrophages.

Macrophage polarization plays a crucial role in inflammatory processes. The histone deacetylase 3 (HDAC3) has a deacetylase-independent function that can activate pro-inflammatory gene expression in lipopolysaccharide-stimulated M1-like macrophages and cannot be blocked by traditional small-molecule HDAC3 inhibitors. Here we employed the proteolysis targeting chimera (PROTAC) technology to target the deacetylase-independent function of HDAC3. We developed a potent and selective HDAC3-directed PROTAC, P7, which induces nearly complete HDAC3 degradation at low micromolar concentrations in both THP-1 cells and human primary macrophages. P7 increases the anti-inflammatory cytokine secretion in THP-1-derived M1-like macrophages. Importantly, P7 decreases the secretion of pro-inflammatory cytokines in M1-like macrophages derived from human primary macrophages. This can be explained by the observed inhibition of macrophage polarization from M0-like into M1-like macrophage. In conclusion, we demonstrate that the HDAC3-directed PROTAC P7 has anti-inflammatory activity and blocks macrophage polarization, demonstrating that this molecular mechanism can be targeted with small molecule therapeutics.

Getting on the right track: Interactions between viruses and the cytoskeletal motor proteins.

The cytoskeleton is an essential component of the cell and it is involved in multiple physiological functions, including intracellular organization and transport. It is composed of three main families of proteinaceous filaments; microtubules, actin filaments and intermediate filaments and their accessory proteins. Motor proteins, which comprise the dynein, kinesin and myosin superfamilies, are a remarkable group of accessory proteins that mainly mediate the intracellular transport of cargoes along with the cytoskeleton. Like other cellular structures and pathways, viruses can exploit the cytoskeleton to promote different steps of their life cycle through associations with motor proteins. The complexity of the cytoskeleton and the differences among viruses, however, has led to a wide diversity of interactions, which in most cases remain poorly understood. Unveiling the details of these interactions is necessary not only for a better comprehension of specific infections, but may also reveal new potential drug targets to fight dreadful diseases such as rabies disease and acquired immunodeficiency syndrome (AIDS). In this review, we describe a few examples of the mechanisms that some human viruses, that is, rabies virus, adenovirus, herpes simplex virus, human immunodeficiency virus, influenza A virus and papillomavirus, have developed to hijack dyneins, kinesins and myosins.

[Social determinants of the incidence of Covid-19 in Barcelona: a preliminary ecological study using public data.] / Determinantes sociales de la incidencia de la Covid-19 en Barcelona: un estudio ecológico preliminar usando datos públicos.

OBJECTIVE: Social determinants and health inequalities have a huge impact on health of populations. It is important to study their role in the management of the Covid-19 epidemic, especially in cities, as certain variables like the number of tests and the access to health system cannot be assumed as equal. The aim of this work was to determine the relation of social determinants in the incidence of Covid-19 in the city of Barcelona. METHODS: An observational retrospective ecological study was performed, with the neighbourhood as the population unit, based on data of cumulative incidence published at May 14th, 2020 by the Public Health Agency of Barcelona. Covid-19 incidence disparities depending on the income of the neighbourhoods, the Pearson linear correlation of the variables selected (age, sex, net density, immigrants, comorbidities, smokers, Body Mass Index [BMI] and Available Income per Family Index [AIFI]) with the incidence and the correlation with a multivariant Generalized Linear Model (GLM) were estimated. RESULTS: It was found that neighbourhoods belonging to the lowest quintile of income had a 42% more incidence than those belonging to the highest quintile: 942 cases per 100,000 inhabitants versus 545 per 100,000 inhabitants of the highest quintile. The Pearson correlation was statistically significative between the incidence of Covid-19 and the percentage of population over 75 (r=0.487), the percentage of immigration of the neighbourhood and the origin of the immigrants (r=-0.257), the AIFI (r=-0.462), the percentage of smokers (r=0.243) and the percentage of people with BMI over 25 (r=0.483). The GLM showed that the most correlated variables with the incidence are the percentage of people over 75 (Z-score=0.258), the percentage of people from Maghreb (Z-score=-0.206) and Latin America (Z-score=0.19) and the percentage of people with BMI over 25 (Z-score=0.334). The results of the GLM were significative. CONCLUSIONS: Social determinants are correlated with the modification of the incidence of Covid-19 in the neighbourhoods of Barcelona, with special relevance of the prevalence of BMI over 25 and the percentage of immigrants and its origin.

OBJETIVO: Los determinantes sociales tienen un gran impacto en la salud de las poblaciones. Es relevante estudiar su papel en la gestión de la epidemia de la Covid-19, especialmente en las ciudades, pues ciertas variables como el número de tests realizados o la disponibilidad de recursos sanitarios no se pueden asumir por igual. El objetivo de este trabajo fue estimar la relación de los determinantes sociales en la incidencia de la Covid-19 en Barcelona. METODOS: Se realizó un estudio ecológico, observacional retrospectivo, con el barrio como unidad de población, basado en los datos publicados a fecha de 14 de mayo de 2020 sobre incidencia acumulada de Covid-19 confirmada por PCR. Se estimó la diferencia de incidencia de la Covid-19 en función de la renta de los barrios, la correlación lineal de Pearson de las distintas variables seleccionadas (edad, sexo, densidad neta, inmigrantes, comorbilidades, tabaquismo, Índice de Masa Corporal [IMC] e Índice de Renta Familiar Disponible [IRFD]) con la incidencia acumulada y se llevó a cabo un análisis multivariante mediante un Modelo Lineal Generalizado (GLM). RESULTADOS: Los barrios del quintil de menor renta presentaban un 42% más de incidencia que aquellos del quintil con más renta: 942 casos por cada 100.000 habitantes frente a los 545 casos por cada 100.000 habitantes. La correlación de Pearson se mostró estadísticamente significativa entre la incidencia de la Covid-19 y el porcentaje de población mayor de 75 años (r=0,487), el porcentaje de inmigrantes (r=-0,257) y el origen de dichos inmigrantes, el IRFD (r=-0,462), el porcentaje de fumadores (r=0,243) y de personas con un IMC mayor de 25 (r=0,483). En GLM las variables que más correlación tenían con la incidencia entre barrios eran el porcentaje de población mayor de 75 años (Z-score=0,258), el porcentaje de inmigrantes latinoamericanos (Z-score=0,19) y magrebíes (Z-score=-0,206), y el porcentaje de personas con IMC>25 (Z-score=0,334). Los resultados del GLM fueron estadísticamente significativos. CONCLUSIONES: Los determinantes sociales se correlacionan con una modificación de la incidencia de la Covid-19 en los barrios de Barcelona, con especial relevancia de la prevalencia de IMC>25 y del porcentaje de inmigrantes y de su origen.

Determinantes sociales de la incidencia de la Covid-19 en Barcelona: un estudio ecológico preliminar usando datos públicos / Social determinants of the incidence of Covid-19 in Barcelona: a preliminary ecological study using public data

OBJETIVO: Los determinantes sociales tienen un gran impacto en la salud de las poblaciones. Es relevante estudiar su papel en la gestión de la epidemia de la Covid-19, especialmente en las ciudades, pues ciertas variables como el número de tests realizados o la disponibilidad de recursos sanitarios no se pueden asumir por igual. El objetivo de este trabajo fue estimar la relación de los determinantes sociales en la incidencia de la Covid-19 en Barcelona. MÉTODOS: Se realizó un estudio ecológico, observacional retrospectivo, con el barrio como unidad de población, basado en los datos publicados a fecha de 14 de mayo de 2020 sobre incidencia acumulada de Covid-19 confirmada por PCR. Se estimó la diferencia de incidencia de la Covid-19 en función de la renta de los barrios, la correlación lineal de Pearson de las distintas variables seleccionadas (edad, sexo, densidad neta, inmigrantes, comorbilidades, tabaquismo, Índice de Masa Corporal [IMC] e Índice de Renta Familiar Disponible [IRFD]) con la incidencia acumulada y se llevó a cabo un análisis multivariante mediante un Modelo Lineal Generalizado (GLM). RESULTADOS: Los barrios del quintil de menor renta presentaban un 42% más de incidencia que aquellos del quintil con más renta: 942 casos por cada 100.000 habitantes frente a los 545 casos por cada 100.000 habitantes. La correlación de Pearson se mostró estadísticamente significativa entre la incidencia de la Covid-19 y el porcentaje de población mayor de 75 años (r=0,487), el porcentaje de inmigrantes (r=-0,257) y el origen de dichos inmigrantes, el IRFD (r=-0,462), el porcentaje de fumadores (r=0,243) y de personas con un IMC mayor de 25 (r=0,483). En GLM las variables que más correlación tenían con la incidencia entre barrios eran el porcentaje de población mayor de 75 años (Z-score=0,258), el porcentaje de inmigrantes latinoamericanos (Z-score=0,19) y magrebíes (Z-score=-0,206), y el porcentaje de personas con IMC>25 (Z-score=0,334). Los resultados del GLM fueron estadísticamente significativos. CONCLUSIONES: Los determinantes sociales se correlacionan con una modificación de la incidencia de la Covid-19 en los barrios de Barcelona, con especial relevancia de la prevalencia de IMC>25 y del porcentaje de inmigrantes y de su origen

OBJECTIVE: Social determinants and health inequalities have a huge impact on health of populations. It is important to study their role in the management of the Covid-19 epidemic, especially in cities, as certain variables like the number of tests and the access to health system cannot be assumed as equal. The aim of this work was to determine the relation of social determinants in the incidence of Covid-19 in the city of Barcelona. METHODS: An observational retrospective ecological study was performed, with the neighbourhood as the population unit, based on data of cumulative incidence published at May 14th, 2020 by the Public Health Agency of Barcelona. Covid-19 incidence disparities depending on the income of the neighbourhoods, the Pearson linear correlation of the variables selected (age, sex, net density, immigrants, comorbidities, smokers, Body Mass Index [BMI] and Available Income per Family Index [AIFI]) with the incidence and the correlation with a multivariant Generalized Linear Model (GLM) were estimated. RESULTS: It was found that neighbourhoods belonging to the lowest quintile of income had a 42% more incidence than those belonging to the highest quintile: 942 cases per 100,000 inhabitants versus 545 per 100,000 inhabitants of the highest quintile. The Pearson correlation was statistically significative between the incidence of Covid-19 and the percentage of population over 75 (r=0.487), the percentage of immigration of the neighbourhood and the origin of the immigrants (r=-0.257), the AIFI (r=-0.462), the percentage of smokers (r=0.243) and the percentage of people with BMI over 25 (r=0.483). The GLM showed that the most correlated variables with the incidence are the percentage of people over 75 (Z-score=0.258), the percentage of people from Maghreb (Z-score=-0.206) and Latin America (Z-score=0.19) and the percentage of people with BMI over 25 (Z-score=0.334). The results of the GLM were significative. CONCLUSIONS: Social determinants are correlated with the modification of the incidence of Covid-19 in the neighbourhoods of Barcelona, with special relevance of the prevalence of BMI over 25 and the percentage of immigrants and its origin