Cannabinoids induce functional Tregs by promoting tolerogenic DCs via autophagy and metabolic reprograming

The generation of functional regulatory T cells (Tregs) is essential to keep tissue homeostasis and restore healthy immune responses in many biological and inflammatory contexts. Cannabinoids have been pointed out as potential therapeutic tools for several diseases. Dendritic cells (DCs) express the endocannabinoid system, including the cannabinoid receptors CB1 and CB2. However, how cannabinoids might regulate functional properties of DCs is not completely understood. We uncover that the triggering of cannabinoid receptors promote human tolerogenic DCs that are able to prime functional FOXP3+ Tregs in the context of different inflammatory diseases. Mechanistically, cannabinoids imprint tolerogenicity in human DCs by inhibiting NF-κB, MAPK and mTOR signalling pathways while inducing AMPK and functional autophagy flux via CB1- and PPARα-mediated activation, which drives metabolic rewiring towards increased mitochondrial activity and oxidative phosphorylation. Cannabinoids exhibit in vivo protective and anti-inflammatory effects in LPS-induced sepsis and also promote the generation of FOXP3+ Tregs. In addition, immediate anaphylactic reactions are decreased in peanut allergic mice and the generation of allergen-specific FOXP3+ Tregs are promoted, demonstrating that these immunomodulatory effects take place in both type 1- and type 2-mediated inflammatory diseases. Our findings might open new avenues for novel cannabinoid-based interventions in different inflammatory and immune-mediated diseases

Municipal distribution of ovarian cancer mortality in Spain

<p>Abstract</p> <p>Background</p> <p>Spain was the country that registered the greatest increases in ovarian cancer mortality in Europe. This study describes the municipal distribution of ovarian cancer mortality in Spain using spatial models for small-area analysis.</p> <p>Methods</p> <p>Smoothed relative risks of ovarian cancer mortality were obtained, using the Besag, York and Molliè autoregressive spatial model. Standardised mortality ratios, smoothed relative risks, and distribution of the posterior probability of relative risks being greater than 1 were depicted on municipal maps.</p> <p>Results</p> <p>During the study period (1989–1998), 13,869 ovarian cancer deaths were registered in 2,718 Spanish towns, accounting for 4% of all cancer-related deaths among women. The highest relative risks were mainly concentrated in three areas, i.e., the interior of Barcelona and Gerona (north-east Spain), the north of Lugo and Asturias (north-west Spain) and along the Seville-Huelva boundary (in the south-west). Eivissa (Balearic Islands) and El Hierro (Canary Islands) also registered increased risks.</p> <p>Conclusion</p> <p>Well established ovarian cancer risk factors might not contribute significantly to the municipal distribution of ovarian cancer mortality. Environmental and occupational exposures possibly linked to this pattern and prevalent in specific regions, are discussed in this paper. Small-area geographical studies are effective instruments for detecting risk areas that may otherwise remain concealed on a more reduced scale.</p

The cannabinoid WIN55212-2 restores rhinovirus-induced epithelial barrier disruption

Carta al Editor. Received: 19 September 2020 | Revised: 20 November 2020 | Accepted: 5 December 2020Sección Deptal. de Química Orgánica (Óptica y Optometría)Fac. de Óptica y OptometríaTRUEMinisterio de Economía y Competitividad de España (MINECO)Swiss National Science FoundationChristine Kühne‐Center for Allergy Research and Education (CK‐CARE) (Suiza)Universidad Complutense de Madrid (España)inpres

Cannabinoids induce functional Tregs by promoting tolerogenic DCs via autophagy and metabolic reprograming

The generation of functional regulatory T cells (Tregs) is essential to keep tissue homeostasis and restore healthy immune responses in many biological and inflammatory contexts. Cannabinoids have been pointed out as potential therapeutic tools for several diseases. Dendritic cells (DCs) express the endocannabinoid system, including the cannabinoid receptors CB1 and CB2. However, how cannabinoids might regulate functional properties of DCs is not completely understood. We uncover that the triggering of cannabinoid receptors promote human tolerogenic DCs that are able to prime functional FOXP3+ Tregs in the context of different inflammatory diseases. Mechanistically, cannabinoids imprint tolerogenicity in human DCs by inhibiting NF-κB, MAPK and mTOR signalling pathways while inducing AMPK and functional autophagy flux via CB1- and PPARα-mediated activation, which drives metabolic rewiring towards increased mitochondrial activity and oxidative phosphorylation. Cannabinoids exhibit in vivo protective and anti-inflammatory effects in LPS-induced sepsis and also promote the generation of FOXP3+ Tregs. In addition, immediate anaphylactic reactions are decreased in peanut allergic mice and the generation of allergen-specific FOXP3+ Tregs are promoted, demonstrating that these immunomodulatory effects take place in both type 1- and type 2-mediated inflammatory diseases. Our findings might open new avenues for novel cannabinoid-based interventions in different inflammatory and immune-mediated diseases

Municipal mortality due to thyroid cancer in Spain

BACKGROUND: Thyroid cancer is a tumor with a low but growing incidence in Spain. This study sought to depict its spatial municipal mortality pattern, using the classic model proposed by Besag, York and Mollié. METHODS: It was possible to compile and ascertain the posterior distribution of relative risk on the basis of a single Bayesian spatial model covering all of Spain's 8077 municipal areas. Maps were plotted depicting standardized mortality ratios, smoothed relative risk (RR) estimates, and the posterior probability that RR > 1. RESULTS: From 1989 to 1998 a total of 2,538 thyroid cancer deaths were registered in 1,041 municipalities. The highest relative risks were mostly situated in the Canary Islands, the province of Lugo, the east of La Coruña (Corunna) and western areas of Asturias and Orense. CONCLUSION: The observed mortality pattern coincides with areas in Spain where goiter has been declared endemic. The higher frequency in these same areas of undifferentiated, more aggressive carcinomas could be reflected in the mortality figures. Other unknown genetic or environmental factors could also play a role in the etiology of this tumor

Stateness and quality of democracy in Paraguay Estatalidad y calidad de la democracia en Paraguay

Taking into account the fact that in all existing indices of the quality of democracy Paraguay fares rather poorly, the author explores how «stateness» accounts for that poor performance. He argues that together with a pattern of truncated modernization that produced an invertebrate society conducive to generalized clientelism and the constitutional and institutional framework that reinforces and perpetuates it, the weakness of the State imposes additional severe constraints. These constraints manifest themselves in two dimensions: the weakness of the state apparatus and its narrow social base in terms of «state-for-the nation or the people».Partiendo de los índices existentes que sitúan al Paraguay entre las democracias de más baja calidad en América Latina, se explora el impacto de la estatalidad en esa baja calidad de la democracia. Se sostiene que, además de la modernización truncada que resultó en una sociedad invertebrada proclive a la proliferación de un clientelismo generalizado y la arquitectura constitucional e institucional que la refuerza y perpetúa, la debilidad del Estado impone limitaciones adicionales muy severas al desarrollo de una democracia de calidad. Estas limitaciones se manifiestan en dos dimensiones: la debilidad del Estado como aparato y su estrecha base social en términos de «Estado-para-la Nación o pueblo»

Stateness and quality of democracy in Paraguay

Taking into account the fact that in all existing indices of the quality of democracy Paraguay fares rather poorly, the author explores how «stateness» accounts for that poor performance. He argues that together with a pattern of truncated modernization that produced an invertebrate society conducive to generalized clientelism and the constitutional and institutional framework that reinforces and perpetuates it, the weakness of the State imposes additional severe constraints. These constraints manifest themselves in two dimensions: the weakness of the state apparatus and its narrow social base in terms of «state-for-the nation or the people».Partiendo de los índices existentes que sitúan al Paraguay entre las democracias de más baja calidad en América Latina, se explora el impacto de la estatalidad en esa baja calidad de la democracia. Se sostiene que, además de la modernización truncada que resultó en una sociedad invertebrada proclive a la proliferación de un clientelismo generalizado y la arquitectura constitucional e institucional que la refuerza y perpetúa, la debilidad del Estado impone limitaciones adicionales muy severas al desarrollo de una democracia de calidad. Estas limitaciones se manifiestan en dos dimensiones: la debilidad del Estado como aparato y su estrecha base social en términos de «Estado-para-la Nación o pueblo»