Search

© 2021 by the authors., The discovery and application of antibiotics in the common clinical practice has undeniably been one of the major medical advances in our times. Their use meant a drastic drop in infectious diseases-related mortality and contributed to prolonging human life expectancy worldwide. Nevertheless, antibiotics are considered by many a double-edged sword. Their extensive use in the past few years has given rise to a global problem: antibiotic resistance. This factor and the increasing evidence that a wide range of antibiotics can damage mammalian mitochondria, have driven a significant sector of the medical and scientific communities to advise against the use of antibiotics for purposes other to treating severe infections. Notwithstanding, a notorious number of recent studies support the use of these drugs to treat very diverse conditions, ranging from cancer to neurodegenerative or mitochondrial diseases. In this context, there is great controversy on whether the risks associated to antibiotics outweigh their promising beneficial features. The aim of this review is to provide insight in the topic, purpose for which the most relevant findings regarding antibiotic therapies have been discussed., This work was supported by FIS PI16/00786 (2016) and FIS PI19/00377 (2019) grants, Ministerio de Sanidad, Spain and Fondo Europeo de Desarrollo Regional (FEDER Unión Europea), Spanish Ministry of Education, Culture and Sport. This activity has been co-financed by the European Regional Development Fund (ERDF) and by the Regional Ministry of Economic Transformation, Industry, Knowledge and Universities of the Junta de Andalucía, within the framework of the ERDF Andalusia operational program 2014–2020 Thematic objective “01—Reinforcement of research, technological develop-ment and innovation” through the reference research project CTS-5725 and PY18-850. We acknowledge the support of “Ayudas para la Formación de Profesorado Universitario” (FPU/MINECO), AEPMI (Asociación de Enfermos de Patología Mitocondrial), ENACH (Asociación de enfermos de Neurodegeneración con Acumulación Cerebral de Hierro), FEDER (Federación Española de Enfermedades Raras), Yo Nemálínica Association, KAT6A Association, Fundación MERCK Salud and Fundación MEHUER/Colegio Oficial de Farmacéuticos de Sevilla.

16 Páginas.-- 7 Figuras, Background: Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic neurological disorders frequently associated with iron accumulation in the basal nuclei of the brain characterized by progressive spasticity, dystonia, muscle rigidity, neuropsychiatric symptoms, and retinal degeneration or optic nerve atrophy. Pantothenate kinase-associated neurodegeneration (PKAN) is the most widespread NBIA disorder. It is caused by mutations in the gene of pantothenate kinase 2 (PANK2) which catalyzes the first reaction of coenzyme A (CoA) biosynthesis. Thus, altered PANK2 activity is expected to induce CoA deficiency as well as low levels of essential metabolic intermediates such as 4'-phosphopantetheine which is a necessary cofactor for critical proteins involved in cytosolic and mitochondrial pathways such as fatty acid biosynthesis, mitochondrial respiratory complex I assembly and lysine and tetrahydrofolate metabolism, among other metabolic processes. Methods: In this manuscript, we examined the effect of PANK2 mutations on the expression levels of proteins with phosphopantetheine cofactors in fibroblast derived from PKAN patients. These proteins include cytosolic acyl carrier protein (ACP), which is integrated within the multifunctional polypeptide chain of the fatty acid synthase involved in cytosolic fatty acid biosynthesis type I (FASI); mitochondrial ACP (mtACP) associated with mitocondrial fatty acid biosynthesis type II (FASII); mitochondrial alpha-aminoadipic semialdehyde synthase (AASS); and 10-formyltetrahydrofolate dehydrogenases (cytosolic, ALD1L1, and mitochondrial, ALD1L2). Results: In PKAN fibroblasts the expression levels of cytosolic FAS and ALD1L1 were not affected while the expression levels of mtACP, AASS and ALD1L2 were markedly reduced, suggesting that 4'-phosphopantetheinylation of mitochondrial but no cytosolic proteins were markedly affected in PKAN patients. Furthermore, the correction of PANK2 expression levels by treatment with pantothenate in selected mutations with residual enzyme content was able to correct the expression levels of mitochondrial phosphopantetheinyl-proteins and restore the affected pathways. The positive effects of pantothenate in particular mutations were also corroborated in induced neurons obtained by direct reprograming of mutant PANK2 fibroblasts. Conclusions: Our results suggest that the expression levels of mitochondrial phosphopantetheinyl-proteins are severely reduced in PKAN cells and that in selected mutations pantothenate increases the expression levels of both PANK2 and mitochondrial phosphopantetheinyl-proteins associated with remarkable improvement of cell pathophysiology., This work was supported by FIS PI16/00786 and PI19/00377 grants, Instituto de Salud Carlos III, Spain and Fondo Europeo de Desarrollo Regional (FEDER-Unión Europea), Proyectos de Investigación de Excelencia de la Junta de Andalucía CTS-5725 and PY18-850 and by ENACH (Asociación de Enfermos de Neurodegeneración con Acumulación Cerebral de Hierro), AEPMI (Asociación de Enfermos de Patología Mitocondrial), FEDER (Federación Española de Enfermedades Raras) and Fundación MERK Salud. S. Povea-Cabello is a recipient of a PhD fellowship from the Ministerio de Economía y Competitividad (MINECO).

© 2020 Martınez-Rey, Carmona-Rodríguez, Fernández-Aceñero, Mira and Santos Mañes., Tumor-infiltrating lymphocytes (TILs) are major players in the immune-mediated control of cancer and the response to immunotherapy. In primary cancers, however, TILs are commonly absent, suggesting T-cell entry into the tumor microenvironment (TME) to be selectively restricted. Blood and lymph vessels are the first barriers that circulating T-cells must cross to reach the tumor parenchyma. Certainly, the crossing of the endothelial cell (EC) basement membrane (EC-BM)—an extracellular matrix underlying EC—is a limiting step in T-cell diapedesis. This review highlights new data suggesting the antioxidant enzyme superoxide dismutase-3 (SOD3) to be a regulator of EC-BM composition in the tumor vasculature. In the EC, SOD3 induces vascular normalization and endows the EC-BM with the capacity for the extravasation of effector T-cells into the TME, which it achieves via the WNT signaling pathway. However, when activated in tumor cells, this same pathway is reported to exclude TILs. SOD3 also regulates TIL density in primary human colorectal cancers (CRC), thus affecting the relapse rate and patient survival., This work was funded by the Spanish Ministry of Science, Innovation and Universities (SAF2017-83732-R; AEI/FEDER, EU), the Comunidad de Madrid (B2017/BMD-3733; InmunothercanCM), and the Fundación Domingo Martínez and the Fundacioń Merck-Salud. DM-R was supported by a predoctoral fellowship from the Spanish Ministry of Science, Innovation and Universities and the EU European Social Fund (PRE2018-084023).

[Background] Binding of the programmed death-1 (PD-1) receptor to its ligands (PD-L1/2) transduces inhibitory signals that promote exhaustion of activated T cells. Blockade of the PD-1 pathway is widely used for cancer treatment, yet the inhibitory signals transduced by PD-1 in T cells remain elusive., [Methods] Expression profiles of human CD8+ T cells in resting, activated (CD3 + CD28) and PD-1-stimulated cells (CD3 + CD28 + PD-L1-Fc) conditions were evaluated by RNA-seq. Bioinformatic analyses were used to identify signaling pathways differentially regulated in PD-1-stimulated cells. Metabolic analyses were performed with SeaHorse technology, and mitochondrial ultrastructure was determined by transmission electron microscopy. PD-1-regulated mitochondrial genes were silenced using short-hairpin RNA in primary cells. Blue native gel electrophoresis was used to determine respiratory supercomplex assembly., [Results] PD-1 engagement in human CD8+ T cells triggers a specific, progressive genetic program different from that found in resting cells. Gene ontology identified metabolic processes, including glycolysis and oxidative phosphorylation (OXPHOS), as the main pathways targeted by PD-1. We observed severe functional and structural alterations in the mitochondria of PD-1-stimulated cells, including a reduction in the number and length of mitochondrial cristae. These cristae alterations were associated with reduced expression of CHCHD3 and CHCHD10, two proteins that form part of the mitochondrial contact site and cristae organizing system (MICOS). Although PD-1-stimulated cells showed severe cristae alterations, assembly of respiratory supercomplexes was unexpectedly greater in these cells than in activated T cells. CHCHD3 silencing in primary CD8+ T cells recapitulated some effects induced by PD-1 stimulation, including reduced mitochondrial polarization and interferon-γ production following T cell activation with anti-CD3 and -CD28 activating antibodies., [Conclusions] Our results suggest that mitochondria are the main targets of PD-1 inhibitory activity. PD-1 reprograms CD8+ T cell metabolism for efficient use of fatty acid oxidation; this mitochondrial phenotype might explain the long-lived phenotype of PD-1-engaged T cells., This work was funded by grants from the Spanish Ministerio de Economía y Competitividad (MINECO) (SAF2014–54475-R and SAF2017–83732-R to SM; SAF2016–75916-R to JMC; AEI/FEDER, EU), the Instituto de Salud Carlos III (PT17 PT17/0009/0019, AEI/FEDER, EU), the Comunidad de Madrid (B2017/BMD-3733; Inmunothercan-CM, to SM), and the Merck-Salud Foundation (to SM). JO, JS and CN-T are supported by predoctoral fellowships from the MINECO and the EU European Social Fund.

Using in vitro, in vivo and patient-based approaches, we investigated the potential of circulating microRNAs (miRNAs) as surrogate biomarkers of myocardial steatosis, a hallmark of diabetic cardiomyopathy. We analysed the cardiomyocyte-enriched miRNA signature in serum from patients with well-controlled type 2 diabetes and with verified absence of structural heart disease or inducible ischemia, and control volunteers of the same age range and BMI (N = 86), in serum from a high-fat diet-fed murine model, and in exosomes from lipid-loaded HL-1 cardiomyocytes. Circulating miR-1 and miR-133a levels were robustly associated with myocardial steatosis in type 2 diabetes patients, independently of confounding factors in both linear and logistic regression analyses (P, This work was supported by the Spanish Atherosclerosis Foundation/Spanish Atherosclerosis Society (Basic Research Award 2013), Fundación Merck Salud (Merck Serono Research Award in Cardiometabolism 2014), FIS PI14/01729 from the Instituto Salud Carlos III, co-financed by the European Fund for Regional Development (E.F.R.D.) and Fundació Marató TV3 (201521 10). CIBER Cardiovascular (CB16/11/00403) and CIBER de Diabetes y Enfermedades Metabólicas Asociadas are Instituto de Salud Carlos III Projects. DdG-C was a recipient of a Sara Borrell grant from the Instituto de Salud Carlos III (CD14/00109). PIRAMID study was supported by Eli Lilly, the Netherlands, which has a partnership with Takeda, the manufacturer of pioglitazone.