Genetic deficiency of apolipoprotein D in the mouse is associated with nonfasting hypertriglyceridemia and hyperinsulinemia

Producción CientíficaApolipoprotein D (ApoD) is an atypical apolipoprotein with an incompletely understood function in the regulation of triglyceride and glucose metabolism. We have demonstrated that elevated ApoD production in mice results in improved postprandial triglyceride clearance. This work studies the role of ApoD deficiency in the regulation of triglyceride and glucose metabolism and its dependence on aging. We used ApoD knockout (ApoD-KO) mice of 3 and 21 months of age. Body weight and food intake were measured. Hepatic histology, triglyceride content, lipoprotein lipase levels, and plasma metabolites were studied. Phenotypic characterization of glucose metabolism was performed using glucose tolerance test. β-Cell mass, islet volume, and islet number were analyzed by histomorphometry. Apolipoprotein D deficiency results in nonfasting hypertriglyceridemia in young (P = .01) and aged mice (P = .002). In young ApoD-KO mice, hypertriglyceridemiawas associated with 30% to 50% increased food intake in nonfasting and fasting conditions, respectively, without changes in body weight. In addition, lipoprotein lipase levels were reduced by 35% in adipose tissue (P = .006). In aged ApoD-KO mice, hypertriglyceridemia was not associated with changes in food intake or body weight, whereas hepatic triglyceride levels were reduced by 35% (P = .02). Furthermore, nonfasting plasma insulin levels were elevated by 2-fold in young (P = .016) and aged (P = .004) ApoD-KO mice, without changes in blood glucose levels, glucose tolerance, β-cell mass, or islet number. These findings underscore the importance of ApoD in the regulation of plasma insulin levels and triglyceride metabolism, suggesting that ApoD plays an important role in the pathogenesis of dyslipidemia

REX-001, a BM-MNC Enriched Solution, Induces Revascularization of Ischemic Tissues in a Murine Model of Chronic Limb-Threatening Ischemia

Background: Bone Marrow Mononuclear Cells (BM-MNC) constitute a promising alternative for the treatment of Chronic Limb-Threatening ischemia (CLTI), a disease characterized by extensive blockade of peripheral arteries, clinically presenting as excruciating pain at rest and ischemic ulcers which may lead to gangrene and amputation. BM-MNC implantation has shown to be efficient in promoting angiogenesis and ameliorating ischemic symptoms in CLTI patients. However, the variability seen between clinical trials makes necessary a further understanding of the mechanisms of action of BM-MNC, and moreover, to improve trial characteristics such as endpoints, inclusion/exclusion criteria or drug product compositions, in order to implement their use as stem-cell therapy. Materials: Herein, the effect of REX-001, a human-BM derived cell suspension enriched for mononuclear cells, granulocytes and CD34+ cells, has been assessed in a murine model of CLTI. In addition, a REX-001 placebo solution containing BM-derived red blood cells (BM-RBCs) was also tested. Thus, 24 h after double ligation of the femoral artery, REX-001 and placebo were administrated intramuscularly to Balb-c nude mice (n:51) and follow-up of ischemic symptoms (blood flow perfusion, motility, ulceration and necrosis) was carried out for 21 days. The number of vessels and vascular diameter sizes were measured within the ischemic tissues to evaluate neovascularization and arteriogenesis. Finally, several cell-tracking assays were performed to evaluate potential biodistribution of these cells. Results: REX-001 induced a significant recovery of blood flow by increasing vascular density within the ischemic limbs, with no cell translocation to other organs. Moreover, cell tracking assays confirmed a decrease in the number of infused cells after 2 weeks post-injection despite on-going revascularization, suggesting a paracrine mechanism of action. Conclusion: Overall, our data supported the role of REX-001 product to improve revascularization and ischemic reperfusion in CLTI

Atherosclerotic Pre-Conditioning Affects the Paracrine Role of Circulating Angiogenic Cells Ex-Vivo

In atherosclerosis, circulating angiogenic cells (CAC), also known as early endothelial progenitor cells (eEPC), are thought to participate mainly in a paracrine fashion by promoting the recruitment of other cell populations such as late EPC, or endothelial colony-forming cells (ECFC), to the injured areas. There, ECFC replace the damaged endothelium, promoting neovascularization. However, despite their regenerative role, the number and function of EPC are severely affected under pathological conditions, being essential to further understand how these cells react to such environments in order to implement their use in regenerative cell therapies. Herein, we evaluated the effect of direct incubation ex vivo of healthy CAC with the secretome of atherosclerotic arteries. By using a quantitative proteomics approach, 194 altered proteins were identified in the secretome of pre-conditioned CAC, many of them related to inhibition of angiogenesis (e.g., endostatin, thrombospondin-1, fibulins) and cell migration. Functional assays corroborated that healthy CAC released factors enhanced ECFC angiogenesis, but, after atherosclerotic pre-conditioning, the secretome of pre-stimulated CAC negatively affected ECFC migration, as well as their ability to form tubules on a basement membrane matrix assay. Overall, we have shown here, for the first time, the effect of atherosclerotic factors over the paracrine role of CAC ex vivo. The increased release of angiogenic inhibitors by CAC in response to atherosclerotic factors induced an angiogenic switch, by blocking ECFC ability to form tubules in response to pre-conditioned CAC. Thus, we confirmed here that the angiogenic role of CAC is highly affected by the atherosclerotic environment

Natural History of MYH7-Related Dilated Cardiomyopathy

BACKGROUND Variants in myosin heavy chain 7 (MYH7) are responsible for disease in 1% to 5% of patients with dilated cardiomyopathy (DCM); however, the clinical characteristics and natural history of MYH7-related DCM are poorly described. OBJECTIVES We sought to determine the phenotype and prognosis of MYH7-related DCM. We also evaluated the influence of variant location on phenotypic expression. METHODS We studied clinical data from 147 individuals with DCM-causing MYH7 variants (47.6% female; 35.6 +/- 19.2 years) recruited from 29 international centers. RESULTS At initial evaluation, 106 (72.1%) patients had DCM (left ventricular ejection fraction: 34.5% +/- 11.7%). Median follow-up was 4.5 years (IQR: 1.7-8.0 years), and 23.7% of carriers who were initially phenotype-negative developed DCM. Phenotypic expression by 40 and 60 years was 46% and 88%, respectively, with 18 patients (16%) first diagnosed at <18 years of age. Thirty-six percent of patients with DCM met imaging criteria for LV noncompaction. During follow-up, 28% showed left ventricular reverse remodeling. Incidence of adverse cardiac events among patients with DCM at 5 years was 11.6%, with 5 (4.6%) deaths caused by end-stage heart failure (ESHF) and 5 patients (4.6%) requiring heart transplantation. The major ventricular arrhythmia rate was low (1.0% and 2.1% at 5 years in patients with DCM and in those with LVEF of <= 35%, respectively). ESHF and major ventricular arrhythmia were significantly lower compared with LMNA-related DCM and similar to DCM caused by TTN truncating variants. CONCLUSIONS MYH7-related DCM is characterized by early age of onset, high phenotypic expression, low left ventricular reverse remodeling, and frequent progression to ESHF. Heart failure complications predominate over ventricular arrhythmias, which are rare. (C) 2022 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation

Correction : Chaparro et al. Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain: Large-Scale Epidemiological Study. J. Clin. Med. 2021, 10, 2885

The authors wish to make the following corrections to this paper [...]

Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain : Large-Scale Epidemiological Study

(1) Aims: To assess the incidence of inflammatory bowel disease (IBD) in Spain, to describe the main epidemiological and clinical characteristics at diagnosis and the evolution of the disease, and to explore the use of drug treatments. (2) Methods: Prospective, population-based nationwide registry. Adult patients diagnosed with IBD-Crohn's disease (CD), ulcerative colitis (UC) or IBD unclassified (IBD-U)-during 2017 in Spain were included and were followed-up for 1 year. (3) Results: We identified 3611 incident cases of IBD diagnosed during 2017 in 108 hospitals covering over 22 million inhabitants. The overall incidence (cases/100,000 person-years) was 16 for IBD, 7.5 for CD, 8 for UC, and 0.5 for IBD-U; 53% of patients were male and median age was 43 years (interquartile range = 31-56 years). During a median 12-month follow-up, 34% of patients were treated with systemic steroids, 25% with immunomodulators, 15% with biologics and 5.6% underwent surgery. The percentage of patients under these treatments was significantly higher in CD than UC and IBD-U. Use of systemic steroids and biologics was significantly higher in hospitals with high resources. In total, 28% of patients were hospitalized (35% CD and 22% UC patients, p < 0.01). (4) Conclusion: The incidence of IBD in Spain is rather high and similar to that reported in Northern Europe. IBD patients require substantial therapeutic resources, which are greater in CD and in hospitals with high resources, and much higher than previously reported. One third of patients are hospitalized in the first year after diagnosis and a relevant proportion undergo surgery

Adelante / Endavant

Séptimo desafío por la erradicación de la violencia contra las mujeres del Institut Universitari d’Estudis Feministes i de Gènere "Purificación Escribano" de la Universitat Jaume

Caracterización de tres modelos animales de resistencia insulínica

La diabetes mellitus es, sin duda, la pandemia de la era moderna. Según la Organización Mundial de la Salud (OMS) en el mundo hay más de 346 millones de personas con diabetes. Se estima que la prevalencia de diabetes en Europa es 7.8%, afectando a más de 48 millones de adultos en edades entre 20 y 79 años, lo que representa un aumento de la morbi-mortalidad asociada a esta patología al igual que un altísimo costo para el sistema sanitario en lo que respecta a atención médica y al tratamiento de las complicaciones asociadas a la diabetes. El 90% de las personas con diabetes padecen diabetes tipo 2, la cual se desarrolla a través de un proceso en varios pasos. Inicialmente el organismo es incapaz de usar la insulina eficientemente, una condición que se conoce como resistencia insulínica. En este momento, las células ß-pancreáticas tratan de compensar produciendo más insulina. Durante un tiempo, esta compensación ayuda a mantener normoglucemia, pero llega un momento en que la célula beta se queda exhausta y no puede secretar suficiente insulina para compensar la resistencia insulínica. En este punto, esta condición progresa frecuentemente a diabetes. La Resistencia insulínica es un síndrome caracterizado por una disminución en la capacidad de respuesta de los tejidos a la insulina (pérdida de sensibilidad), un defecto en la acción de la insulina que provoca un aumento en la insulina basal para mantener la glucemia en un rango normal. Esta respuesta anómala es una característica propia de diversas patologías, aunque principalmente se encuentra asociada con obesidad y diabetes tipo 2.Peer Reviewe

Genetic deficiency of apolipoprotein D in the mouse is associated with nonfasting hypertriglyceridemia and hyperinsulinemia

Apolipoprotein D (ApoD) is an atypical apolipoprotein with an incompletely understood function in the regulation of triglyceride and glucose metabolism. We have demonstrated that elevated ApoD production in mice results in improved postprandial triglyceride clearance. This work studies the role of ApoD deficiency in the regulation of triglyceride and glucose metabolism and its dependence on aging. We used ApoD knockout (ApoD-KO) mice of 3 and 21 months of age. Body weight and food intake were measured. Hepatic histology, triglyceride content, lipoprotein lipase levels, and plasma metabolites were studied. Phenotypic characterization of glucose metabolism was performed using glucose tolerance test. β-Cell mass, islet volume, and islet number were analyzed by histomorphometry. Apolipoprotein D deficiency results in nonfasting hypertriglyceridemia in young (P =.01) and aged mice (P =.002). In young ApoD-KO mice, hypertriglyceridemia was associated with 30% to 50% increased food intake in nonfasting and fasting conditions, respectively, without changes in body weight. In addition, lipoprotein lipase levels were reduced by 35% in adipose tissue (P =.006). In aged ApoD-KO mice, hypertriglyceridemia was not associated with changes in food intake or body weight, whereas hepatic triglyceride levels were reduced by 35% (P =.02). Furthermore, nonfasting plasma insulin levels were elevated by 2-fold in young (P =.016) and aged (P =.004) ApoD-KO mice, without changes in blood glucose levels, glucose tolerance, β-cell mass, or islet number. These findings underscore the importance of ApoD in the regulation of plasma insulin levels and triglyceride metabolism, suggesting that ApoD plays an important role in the pathogenesis of dyslipidemia. © 2011 Elsevier Inc. All rights reserved.This work was supported by grants from the Carlos III Health Institute (CP08/00106), the Spanish Ministry of Science and Innovation (SAF2009-11282), and the FP7-PEOPLE-2009-RG (PIRG06-GA-2009-256369) to GP; grant from the Spanish Ministry of Science and Innovation (BFU2008-01170) to MDG and DS; and grants from the Carlos III Health Institute (PS09/ 00671) and the FP7-PEOPLE-2009-RG (IRG247835) to IC. MJP was supported by the Carlos III Health Institute (Spain).Peer Reviewe

Epoxypukalide induces proliferation and protects against cytokine-mediated apoptosis in primary cultures of pancreatic β-cells

This is an open-access article distributed under the terms of the Creative Commons Attribution License.There is an urgency to find new treatments for the devastating epidemic of diabetes. Pancreatic b-cells viability and function are impaired in the two most common forms of diabetes, type 1 and type 2. Regeneration of pancreatic b-cells has been proposed as a potential therapy for diabetes. In a preliminary study, we screened a collection of marine products for b-cell proliferation. One unique compound (epoxypukalide) showed capability to induce b-cell replication in the cell line INS1 832/ 13 and in primary rat cell cultures. Epoxypukalide was used to study b-cell proliferation by [3H]thymidine incorporation and BrdU incorporation followed by BrdU/insulin staining in primary cultures of rat islets. AKT and ERK1/2 signalling pathways were analyzed. Cell cycle activators, cyclin D2 and cyclin E, were detected by western-blot. Apoptosis was studied by TUNEL and cleaved caspase 3. b-cell function was measured by glucose-stimulated insulin secretion. Epoxypukalide induced 2.5- fold increase in b-cell proliferation; this effect was mediated by activation of ERK1/2 signalling pathway and upregulation of the cell cycle activators, cyclin D2 and cyclin E. Interestingly, epoxypukalide showed protection from basal (40% lower versus control) and cytokine-induced apoptosis (80% lower versus control). Finally, epoxypukalide did not impair b-cell function when measured by glucose-stimulated insulin secretion. In conclusion, epoxypukalide induces b-cell proliferation and protects against basal and cytokine-mediated b-cell death in primary cultures of rat islets. These findings may be translated into new treatments for diabetes. © 2013 López-Acosta et al.This work was supported by ISCIII-Subdireccion Geeneral de Evaluacion y Fomento de la Investigacion, Spain (PS09/00671 and CP08/00094), Europe-FP7 Marie Curie grant (IRG-247835) and Servicio Andaluz de Salud (PI-0256/2009).Peer Reviewe