Necrosis: Linking the Inflammasome to Inflammation

International audienceIn this issue of Cell Reports, Cullen et al. demonstrate that the release of mature interleukin-1β relies on necrotic plasma membrane permeabilization. Thus, caspases may have evolved to modulate the inflammatory potential of cell death, not to execute it

Targeting Autophagy to Counteract Obesity-Associated Oxidative Stress

Reactive oxygen species (ROS) operate as key regulators of cellular homeostasis within a physiological range of concentrations, yet they turn into cytotoxic entities when their levels exceed a threshold limit. Accordingly, ROS are an important etiological cue for obesity, which in turn represents a major risk factor for multiple diseases, including diabetes, cardiovascular disorders, non-alcoholic fatty liver disease, and cancer. Therefore, the implementation of novel therapeutic strategies to improve the obese phenotype by targeting oxidative stress is of great interest for the scientific community. To this end, it is of high importance to shed light on the mechanisms through which cells curtail ROS production or limit their toxic effects, in order to harness them in anti-obesity therapy. In this review, we specifically discuss the role of autophagy in redox biology, focusing on its implication in the pathogenesis of obesity. Because autophagy is specifically triggered in response to redox imbalance as a quintessential cytoprotective mechanism, maneuvers based on the activation of autophagy hold promises of efficacy for the prevention and treatment of obesity and obesity-related morbidities

Acetyl Coenzyme A: A Central Metabolite and Second Messenger

Acetyl-coenzyme A (acetyl-CoA) is a central metabolic intermediate. The abundance of acetyl-CoA in distinct subcellular compartments reflects the general energetic state of the cell. Moreover, acetyl-CoA concentrations influence the activity or specificity of multiple enzymes, either in an allosteric manner or by altering substrate availability. Finally, by influencing the acetylation profile of several proteins, including histones, acetyl-CoA controls key cellular processes, including energy metabolism, mitosis, and autophagy, both directly and via the epigenetic regulation of gene expression. Thus, acetyl-CoA determines the balance between cellular catabolism and anabolism by simultaneously operating as a metabolic intermediate and as a second messenger

Autophagy Alteration in ApoA‐I Related Systemic Amyloidosis

Amyloidoses are characterized by the accumulation and aggregation of misfolded proteins into fibrils in different organs, leading to cell death and consequent organ dysfunction. The specific substitution of Leu 75 for Pro in Apolipoprotein A-I protein sequence (ApoA-I; L75P-ApoA-I) results in late onset amyloidosis, where deposition of extracellular protein aggregates damages the normal functions of the liver. In this work, we describe that the autophagic process is inhibited in the presence of the L75P-ApoA-I amyloidogenic variant in stably transfected human hepatocyte carcinoma cells. The L75P-ApoA-I amyloidogenic variant alters the redox status of the cells, resulting into excessive mitochondrial stress and consequent cell death. Moreover, L75P-ApoA-I induces an impairment of the autophagic flux. Pharmacological induction of autophagy or transfection-enforced overexpression of the pro-autophagic transcription factor EB (TFEB) restores proficient proteostasis and reduces oxidative stress in these experimental settings, suggesting that pharmacological stimulation of autophagy could be a promising target to alleviate ApoA-I amyloidosis

Neuroprotective properties of queen bee acid by autophagy induction

Autophagy is a conserved intracellular catabolic pathway that removes cytoplasmic components to contribute to neuronal homeostasis. Accumulating evidence has increasingly shown that the induction of autophagy improves neuronal health and extends longevity in several animal models. Therefore, there is a great interest in the identification of effective autophagy enhancers with potential nutraceutical or pharmaceutical properties to ameliorate age-related diseases, such as neurodegenerative disorders, and/or promote longevity. Queen bee acid (QBA, 10-hydroxy-2-decenoic acid) is the major fatty acid component of, and is found exclusively in, royal jelly, which has beneficial properties for human health. It is reported that QBA has antitumor, anti-inflammatory, and antibacterial activities and promotes neurogenesis and neuronal health; however, the mechanism by which QBA exerts these effects has not been fully elucidated. The present study investigated the role of the autophagic process in the protective effect of QBA. We found that QBA is a novel autophagy inducer that triggers autophagy in various neuronal cell lines and mouse and fly models. The beclin-1 (BECN1) and mTOR pathways participate in the regulation of QBA-induced autophagy. Moreover, our results showed that QBA stimulates sirtuin 1 (SIRT1), which promotes autophagy by the deacetylation of critical ATG proteins. Finally, QBA-mediated autophagy promotes neuroprotection in Parkinson’s disease in vitro and in a mouse model and extends the lifespan of Drosophila melanogaster. This study provides detailed evidences showing that autophagy induction plays a critical role in the beneficial health effects of QBA.This research was supported by a grant (IB18048) from Junta de Extremadura, Spain, and a grant (RTI2018-099259-A-I00) from Ministerio de Ciencia e Innovación, Spain. This work was also partially supported by “Fondo Europeo de Desarrollo Regional” (FEDER) from the European Union. Part of the equipment employed in this work has been funded by Generalitat Valeciana and co-financed with ERDF funds (OP EDRF of Comunitat Valenciana 2014-2020). G.M-C is supported by University of Extremadura (ONCE Foundation). M.P-B is a recipient of a fellowship from the “Plan Propio de Iniciación a la Investigación, Desarrollo Tecnológico e Innovación (University of Extremadura).” S.M.S.Y-D is supported by CIBERNED. E.U-C was supported by an FPU predoctoral fellowship FPU16/00684 from Ministerio de Educación, Cultura y Deporte. A.B. was supported by a postdoctoral fellowship (APOSTD2017/077). M.S.A. was supported by a predoctoral fellowship (ACIF/2018/071) both from the Conselleria d’Educació, Investigació, Cultura i Esport (Generalitat Valenciana). E.A-C was supported by a grant (IB18048) from Junta de Extremadura, Spain. S.C-C was supported by an FPU predoctoral fellowship FPU19/04435 from Ministerio de Educación, Cultura y Deporte. J.M.B-S. P was funded by the “Ramón y Cajal” program (RYC-2018-025099). J.M.F. received research support from the Instituto de Salud Carlos III, CIBERNED (CB06/05/004). M.N-S was funded by the “Ramon y Cajal” Program (RYC-2016-20883) Spain

Autophagy Alteration in ApoA-I Related Systemic Amyloidosis

Amyloidoses are characterized by the accumulation and aggregation of misfolded proteins into fibrils in different organs, leading to cell death and consequent organ dysfunction. The specific substitution of Leu 75 for Pro in Apolipoprotein A-I protein sequence (ApoA-I; L75P-ApoA-I) results in late onset amyloidosis, where deposition of extracellular protein aggregates damages the normal functions of the liver. In this work, we describe that the autophagic process is inhibited in the presence of the L75P-ApoA-I amyloidogenic variant in stably transfected human hepatocyte carcinoma cells. The L75P-ApoA-I amyloidogenic variant alters the redox status of the cells, resulting into excessive mitochondrial stress and consequent cell death. Moreover, L75P-ApoA-I induces an impairment of the autophagic flux. Pharmacological induction of autophagy or transfection-enforced overexpression of the pro-autophagic transcription factor EB (TFEB) restores proficient proteostasis and reduces oxidative stress in these experimental settings, suggesting that pharmacological stimulation of autophagy could be a promising target to alleviate ApoA-I amyloidosis

An obesogenic feedforward loop involving PPARγ, acyl-CoA binding protein and GABAA receptor

Acyl-coenzyme-A-binding protein (ACBP), also known as a diazepam-binding inhibitor (DBI), is a potent stimulator of appetite and lipogenesis. Bioinformatic analyses combined with systematic screens revealed that peroxisome proliferator-activated receptor gamma (PPARγ) is the transcription factor that best explains the ACBP/DBI upregulation in metabolically active organs including the liver and adipose tissue. The PPARγ agonist rosiglitazone-induced ACBP/DBI upregulation, as well as weight gain, that could be prevented by knockout of Acbp/Dbi in mice. Moreover, liver-specific knockdown of Pparg prevented the high-fat diet (HFD)-induced upregulation of circulating ACBP/DBI levels and reduced body weight gain. Conversely, knockout of Acbp/Dbi prevented the HFD-induced upregulation of PPARγ. Notably, a single amino acid substitution (F77I) in the γ2 subunit of gamma-aminobutyric acid A receptor (GABAAR), which abolishes ACBP/DBI binding to this receptor, prevented the HFD-induced weight gain, as well as the HFD-induced upregulation of ACBP/DBI, GABAAR γ2, and PPARγ. Based on these results, we postulate the existence of an obesogenic feedforward loop relying on ACBP/DBI, GABAAR, and PPARγ. Interruption of this vicious cycle, at any level, indistinguishably mitigates HFD-induced weight gain, hepatosteatosis, and hyperglycemia

Instagram y gamificación para incorporar los procesos fisiológicos al día a día de los estudiantes de Fisiología

El presente proyecto de innovación docente se basa en la utilización de la red social Instagram para incentivar el estudio diario y el aprendizaje cooperativo de una forma lúdica, autónoma y divertida. Se aplicó en la docencia de la Fisiología Humana en distintos grados en los que participa el Departamento de Fisiología. La metodología consiste en que los alumnos, trabajando en grupo, publiquen contenidos en Instagram, para repasar, sintetizar y compartir información de la asignatura. Los objetivos alcanzados fueron: motivación en el estudio continuado, implicación en el proceso de aprendizaje, trabajo en equipo y adquisición de competencias transversales como creatividad, liderazgo y compromiso. La participación en el proyecto fue muy alta (94%), así como la satisfacción de los alumnos, sobre todo en aspectos motivacionales (interés y curiosidad por la asignatura) y de integración, gracias al trabajo en equipo. En conclusión, la red Instagram es una herramienta útil como complemento de las clases, con objeto de incentivar el estudio diario, sintetizar la información y transmitirla mediante trabajo cooperativo