Short chain fatty acids stimulate insulin secretion and reduce apoptosis in mouse and human islets in vitro:Role of free fatty acid receptor 2

Aims: To evaluate the role of free fatty acid receptor 2 (FFAR2)/G-protein coupled receptor 43 in mediating the effects of the short chain fatty acids (SCFAs) sodium acetate (SA) and sodium propionate (SP) on islet function in vitro, and to identify the intracellular signalling pathways used in SCFA-induced potentiation of glucose-induced insulin secretion. Materials and methods: Islets of Langerhans were isolated from wild-type and FFAR2−/− mice and from human donors without diabetes. The effects of SA and SP on dynamic insulin secretion from perifused islets were quantified by radioimmunoassay, signalling downstream of SCFAs was profiled by single-cell calcium microfluorimetry, and measurement of cAMP was performed using a fluorescence assay. Islet apoptosis was induced by exposure to cytokines or sodium palmitate, and the effects of SA and SP in regulating islet apoptosis were assessed by quantification of caspase 3/7 activities. Results: Deletion of FFAR2 did not affect islet morphology or insulin content. SA and SP reversibly potentiated insulin secretion from mouse islets in a FFAR2-dependent manner. SCFA-induced potentiation of insulin secretion was coupled to Gq activation of phospholipase C and protein kinase C, with no evidence of Gi-mediated signalling. SA and SP protected human and mouse islets from apoptosis, and these pro-survival properties were dependent on islet expression of FFAR2. Conclusion: Our results indicate that FFAR2 directly mediates both the stimulatory effects of SA and SP on insulin secretion and their protection against islet apoptosis. We have also shown that SCFA coupling in islets occurs via Gq-coupled intracellular signalling.</p

(–)-Epicatechin and Anthocyanins Modulate GLP-1 Metabolism: Evidence from C57BL/6J Mice and GLUTag Cells

BackgroundGenerated in intestinal L cells through cleavage of proglucagon (Gcg), glucagon-like peptide 1 (GLP-1) is secreted and rapidly inactivated by dipeptidyl peptidase IV (DPP-IV). GLP-1 regulates insulin secretion and overall glucose homeostasis. The capacity of dietary bioactives to increase GLP-1 circulating levels, and therefore increase insulin secretion and glucose metabolism, has gained significant interest of late.ObjectivesWe evaluated the effects of (-)-epicatechin (EC) and different anthocyanins (ACs) and AC metabolites on GLP-1 metabolism in mice and on GLUTag cells.MethodsWe fed 6-week-old C57BL/6J&nbsp;male mice a control diet or a control diet supplemented with either 40&nbsp;mg AC or 20&nbsp;mg EC/kg body weight for 14 weeks (AC) or 15 weeks (EC). Intestinal mRNA levels of Gcg and Dpp-iv were measured. In vitro, GLUTag cells were incubated in the presence or absence of different ACs, the AC metabolite protocatechuic acid (PCA), and EC. GLP-1 secretion and the main pathways involved in its release were assessed.ResultsLong-term supplementation with EC or AC increased mouse GLP-1 plasma concentrations (55% and 98%, respectively; P&nbsp;&lt;&nbsp;0.05). In mice, 1) EC and AC increased Gcg mRNA levels in the ileum (91%) and colon (41%), respectively (P&nbsp;&lt;&nbsp;0.05); and 2) AC lowered ileum Dpp-iv mRNA levels (35%), while EC decreased plasma DPP-IV activity (15%; P&nbsp;&lt;&nbsp;0.05). In GLUTag cells, 1) cyanidin, delphinidin, PCA, and EC increased GLP-1 secretion (53%, 33%, 53%, and 68%, respectively; P&nbsp;&lt;&nbsp;0.05); and 2) cyanidin, delphinidin, EC, and PCA increased cyclin adenosine monophosphate levels (25-50%; P&nbsp;&lt;&nbsp;0.05) and activated protein kinase A (PKA; 100%, 50%, 80%, and 86%, respectively; P&nbsp;&lt;&nbsp;0.05).ConclusionsIn mice, EC and ACs regulated different steps in GLP-1 regulation, leading to increased plasma GLP-1. Cyanidin, delphinidin, PCA, and EC promoted GLP-1 secretion from GLUTag cells by activating the PKA-dependent pathway. These findings support the beneficial actions of these flavonoids in sustaining intestinal and glucose homeostasis through the modulation of the GLP-1 metabolism

Argentine Consensus of congenital toxoplasmosis

La transmisión vertical de la infección por Toxoplasma gondii ocurre cuando la madre se infecta por primera vez en el transcurso del embarazo. El diagnóstico de la infección materna y la del re cién nacido se logra con el conjunto de pruebas serológicas, hallazgos clínicos y ecográficos. El reconocimiento temprano de la infección materna permite un tratamiento que reduce la tasa de transmisión y el riesgo de daño en el producto de la concepción. El objetivo de este consenso de expertos fue revisar la literatura científica para actualizar las recomendaciones de práctica clínica respecto de la prevención, el diagnóstico y el tratamiento de la toxoplasmosis congénita en nuestro país.Mother-to-child transmission in Toxoplasma gondii infection occurs only when the infection is acquired for the first time during pregnancy. Diag nosis of maternal infection and the newborn is achieved by a combination of serological tests, clinical features and ultrasound images. An early diagnosis of maternal infection allows treatment that offers a reduction both in transmission rate and risk of congenital damage. The aim of this expert consensus was to review the scientific literature which would enable an update of the clinical practice guideline of prevention, diagnosis and treatment of congenital toxoplasmosis in our country.Fil: Durlach, Ricardo A.. Asociación Argentina de Zoonosis; ArgentinaFil: Freuler, Cristina. Hospital Aleman; ArgentinaFil: Messina, Matías. Hospital Aleman; Argentina. Asociación Argentina de Zoonosis; ArgentinaFil: Freilij, Hector León. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; ArgentinaFil: Gonzalez Ayala, Silvia Elena. Universidad Nacional de La Plata. Facultad de Ciencias Médicas; ArgentinaFil: Venturini, María Cecilia. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias. Departamento de Epizootiología y Salud Pública. Laboratorio de Inmunoparasitología; ArgentinaFil: Kaufer, Federico. Hospital Aleman; ArgentinaFil: García, Fabiana. Centro de Estudios Infectológicos Dr. Daniel Stamboulia; ArgentinaFil: Ceriotto, Mariana. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Pardini, Lais Luján. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias. Departamento de Epizootiología y Salud Pública. Laboratorio de Inmunoparasitología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Nadal, Mónica Zaida. Hospital Materno Infantil Ramon Sarda ; Gobierno de la Ciudad Autonoma de Buenos Aires;Fil: Ortiz de Zárate, Marcela. Hospital Materno Infantil Ramon Sarda ; Gobierno de la Ciudad Autonoma de Buenos Aires;Fil: Schneider, Vanessa. Hospital Aleman; ArgentinaFil: Mayer Wolf, Micaela. Hospital Aleman; ArgentinaFil: Jacob, Néstor. Gobierno de la Ciudad Autonoma de Buenos Aires. Hospital General de Agudos Doctor Cosme Argerich.; ArgentinaFil: Abuin, Juan Carlos. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Altcheh, Jaime Marcelo. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; ArgentinaFil: Fiameni, Facundo. Hospital Aleman; ArgentinaFil: Salomon, Cristina del Carmen. Universidad del Aconcagua. Facultad de Ciencias Médicas; ArgentinaFil: Ledesma, Bibiana. Dirección Nacional de Instituto de Investigación. Adm.nacional de Laboratorio E Instituto de Salud "dr.c.g.malbran". Instituto Nacional de Enfermedades Infecciosas. Departamento de Parasitología; ArgentinaFil: Guarnera, Eduardo. Asociación Argentina de Zoonosis; Argentin

Argentine Consensus of congenital toxoplasmosis

La transmisión vertical de la infección por Toxoplasma gondii ocurre cuando la madre se infecta por primera vez en el transcurso del embarazo. El diagnóstico de la infección materna y la del re cién nacido se logra con el conjunto de pruebas serológicas, hallazgos clínicos y ecográficos. El reconocimiento temprano de la infección materna permite un tratamiento que reduce la tasa de transmisión y el riesgo de daño en el producto de la concepción. El objetivo de este consenso de expertos fue revisar la literatura científica para actualizar las recomendaciones de práctica clínica respecto de la prevención, el diagnóstico y el tratamiento de la toxoplasmosis congénita en nuestro país.Mother-to-child transmission in Toxoplasma gondii infection occurs only when the infection is acquired for the first time during pregnancy. Diag nosis of maternal infection and the newborn is achieved by a combination of serological tests, clinical features and ultrasound images. An early diagnosis of maternal infection allows treatment that offers a reduction both in transmission rate and risk of congenital damage. The aim of this expert consensus was to review the scientific literature which would enable an update of the clinical practice guideline of prevention, diagnosis and treatment of congenital toxoplasmosis in our country.Fil: Durlach, Ricardo A.. Asociación Argentina de Zoonosis; ArgentinaFil: Freuler, Cristina. Hospital Aleman; ArgentinaFil: Messina, Matías. Hospital Aleman; Argentina. Asociación Argentina de Zoonosis; ArgentinaFil: Freilij, Hector León. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; ArgentinaFil: Gonzalez Ayala, Silvia Elena. Universidad Nacional de La Plata. Facultad de Ciencias Médicas; ArgentinaFil: Venturini, María Cecilia. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias. Departamento de Epizootiología y Salud Pública. Laboratorio de Inmunoparasitología; ArgentinaFil: Kaufer, Federico. Hospital Aleman; ArgentinaFil: García, Fabiana. Centro de Estudios Infectológicos Dr. Daniel Stamboulia; ArgentinaFil: Ceriotto, Mariana. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Pardini, Lais Luján. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias. Departamento de Epizootiología y Salud Pública. Laboratorio de Inmunoparasitología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Nadal, Mónica Zaida. Hospital Materno Infantil Ramon Sarda ; Gobierno de la Ciudad Autonoma de Buenos Aires;Fil: Ortiz de Zárate, Marcela. Hospital Materno Infantil Ramon Sarda ; Gobierno de la Ciudad Autonoma de Buenos Aires;Fil: Schneider, Vanessa. Hospital Aleman; ArgentinaFil: Mayer Wolf, Micaela. Hospital Aleman; ArgentinaFil: Jacob, Néstor. Gobierno de la Ciudad Autonoma de Buenos Aires. Hospital General de Agudos Doctor Cosme Argerich.; ArgentinaFil: Abuin, Juan Carlos. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Altcheh, Jaime Marcelo. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; ArgentinaFil: Fiameni, Facundo. Hospital Aleman; ArgentinaFil: Salomon, Cristina del Carmen. Universidad del Aconcagua. Facultad de Ciencias Médicas; ArgentinaFil: Ledesma, Bibiana. Dirección Nacional de Instituto de Investigación. Adm.nacional de Laboratorio E Instituto de Salud "dr.c.g.malbran". Instituto Nacional de Enfermedades Infecciosas. Departamento de Parasitología; ArgentinaFil: Guarnera, Eduardo. Asociación Argentina de Zoonosis; Argentin

Novel genes and sex differences in COVID-19 severity

[EN] Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.S

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Regulatory elements involved in the post-transcriptional control of stage-specific gene expression in Trypanosoma cruzi: a review

Trypanosoma cruzi, a protozoan parasite that causes Chagas disease, exhibits unique mechanisms for gene expression such as constitutive polycistronic transcription of protein-coding genes, RNA editing and trans-splicing. In the absence of mechanism controlling transcription initiation, organized subsets of T. cruzi genes must be post-transcriptionally co-regulated in response to extracellular signals. The mechanisms that regulate stage-specific gene expression in this parasite have become much clearer through sequencing its whole genome as well as performing various proteomic and microarray analyses, which have demonstrated that at least half of the T. cruzi genes are differentially regulated during its life cycle. In this review, we attempt to highlight the recent advances in characterising cis and trans-acting elements in the T. cruzi genome that are involved in its post-transcriptional regulatory machinery