Exploring the genetic and genomic connection underlying neurodegeneration with brain iron accumulation and the risk for Parkinson's disease.

Neurodegeneration with brain iron accumulation (NBIA) represents a group of neurodegenerative disorders characterized by abnormal iron accumulation in the brain. In Parkinson's Disease (PD), iron accumulation is a cardinal feature of degenerating regions in the brain and seems to be a key player in mechanisms that precipitate cell death. The aim of this study was to explore the genetic and genomic connection between NBIA and PD. We screened for known and rare pathogenic mutations in autosomal dominant and recessive genes linked to NBIA in a total of 4481 PD cases and 10,253 controls from the Accelerating Medicines Partnership Parkinsons' Disease Program and the UKBiobank. We examined whether a genetic burden of NBIA variants contributes to PD risk through single-gene, gene-set, and single-variant association analyses. In addition, we assessed publicly available expression quantitative trait loci (eQTL) data through Summary-based Mendelian Randomization and conducted transcriptomic analyses in blood of 1886 PD cases and 1285 controls. Out of 29 previously reported NBIA screened coding variants, four were associated with PD risk at a nominal p value < 0.05. No enrichment of heterozygous variants in NBIA-related genes risk was identified in PD cases versus controls. Burden analyses did not reveal a cumulative effect of rare NBIA genetic variation on PD risk. Transcriptomic analyses suggested that DCAF17 is differentially expressed in blood from PD cases and controls. Due to low mutation occurrence in the datasets and lack of replication, our analyses suggest that NBIA and PD may be separate molecular entities.

Overexpression of alpha-synuclein promotes both cell proliferation and cell toxicity in human SH-SY5Y neuroblastoma cells.

Alpha-Synuclein (aSyn) is a chameleon-like protein. Its overexpression and intracellular deposition defines neurodegenerative α-synucleinopathies including Parkinson's disease. Whether aSyn up-regulation is the cause or the protective reaction to α-synucleinopathies remains unresolved. Remarkably, the accumulation of aSyn is involved in cancer. Here, the neuroblastoma SH-SY5Y cell line was genetically engineered to overexpress aSyn at low and at high levels. aSyn cytotoxicity was assessed by the MTT and vital-dye exclusion methods, observed at the beginning of the sub-culture of low-aSyn overexpressing neurons when cells can barely proliferate exponentially. Conversely, high-aSyn overexpressing cultures grew at high rates while showing enhanced colony formation compared to low-aSyn neurons. Cytotoxicity of aSyn overexpression was indirectly revealed by the addition of pro-oxidant rotenone. Pretreatment with partially reduced graphene oxide, an apoptotic agent, increased toxicity of rotenone in low-aSyn neurons, but, it did not in high-aSyn neurons. Consistent with their enhanced proliferation, high-aSyn neurons showed elevated levels of SMP30, a senescence-marker protein, and the mitosis Ki-67 marker. High-aSyn overexpression conferred to the carcinogenic neurons heightened tumorigenicity and resistance to senescence compared to low-aSyn cells, thus pointing to an inadequate level of aSyn stimulation, rather than the aSyn overload itself, as one of the factors contributing to α-synucleinopathy.

Serum levels of interleukin-2 predict the recurrence of atrial fibrillation after pulmonary vein ablation.

AIMS: Interleukin-2 has a significant antitumor activity in some types of cancer, and has been associated with the development of atrial fibrillation (AF). In addition, IL-2 serum levels in recent onset AF have been related with pharmaceutical cardioversion outcomes. We evaluated the hypothesis that a relationship exists between inflammation and the outcome of catheter ablation of AF. METHODS: We studied 44 patients with paroxysmal AF who underwent catheter ablation. Patients with structural heart disease, coronary artery or valve disease, active inflammatory disease, known or suspected neoplasm, endocrinopathies, or exposure to anti-inflammatory drugs were excluded. All study participants underwent evaluation with a standardized protocol, including echocardiography, and cytokine levels of interleukin-2, interleukin-4, interleukin-6, interleukin-10, tumour necrosis factor-alpha, and gamma-interferon determination before procedure. Clinical and electrocardiographic follow-up were performed with Holter-ECG at 3, 6 and 12months in order to know if sinus rhythm was maintained. RESULTS: After catheter ablation of the 44 patients included (53±10years, 27.3% female), all patients returned to sinus rhythm. During the first year of follow-up seven patients (15.9%) experienced recurrence of AF. The demographics, clinical and echocardiographic features, and pharmacological treatments of these patients were similar to those who maintained sinus rhythm. The only independent factor predictive of recurrence of AF was an elevated level of IL-2 (OR 1.18, 95% CI 1.12-1.38). CONCLUSIONS: High serum levels of interleukin-2, a pro-inflammatory non-vascular cytokine, are associated with the recurrence of AF in patients undergoing catheter ablation.

Characterization of adult stem/progenitor cell populations from bone marrow in a three-dimensional collagen gel culture system.

Stem cell transplantation therapy using mesenchymal stem cells (MSCs) is considered a useful strategy. Although MSCs are commonly isolated by exploiting their plastic adherence, several studies have suggested that there are other populations of stem and/or osteoprogenitor cells that are removed from primary culture during media replacement. Therefore, we developed a three-dimensional (3D) culture system in which adherent and nonadherent stem cells are selected and expanded. Here, we described the characterization of 3D culture-derived cell populations in vitro and the capacity of these cells to differentiate into bone and/or cartilage tissue when placed inside of demineralized bone matrix (DBM) cylinders, implanted subcutaneously into the backs of rat for 2, 4, and 8 weeks. Our results demonstrates that 3D culture cells were a heterogeneous population of uncommitted cells that express pluripotent-, hematopoietic-, mesenchymal-, and endothelial-specific markers in vitro and can undergo osteogenic differentiation in vivo.

[Factors influencing mobilisation of endothelial progenitor cells and angiogenic cytokines after an extensive acute myocardial infarction]. / Factores que influyen en la liberación de células endoteliales progenitoras y citocinas angiogénicas tras un infarto de miocardio extenso.

BACKGROUND AND OBJECTIVES: Following an acute myocardial infarction (AMI), bone-marrow derived endothelial progenitor cells (EPC) are mobilised into the peripheral blood. Our aim was to examine the factors influencing this spontaneous cell mobilisation. PATIENTS AND METHODS: In this study we analysed 47 patients with extensive AMI (left ventricular ejection fraction [LVEF] <50% by echocardiography during the first week post-AMI); we studied the peripheral blood EPC populations expressing CD133(+), CD34(+), KDR(+), CXCR4(+), as well as the cytokines VEGF (vascular endothelial growth factor), SDF-1 (stromal cell-derived factor 1) and TSP-1 (thrombospondin 1), measured on day 5±2.5 after AMI. RESULTS: The extension of AMI (CPK peak) correlated with the number of CD133(+) mobilised cells: (r=0.40; P=.011). Patients who did not receive perfusion during the acute phase (34%) had more CD34(+)CXCR4(+) cells with a median (interquartile ranges) of 2,401 (498-7,004) vs. 999 (100-1,600), P=.048, and strong correlations between VEGF and CD133(+)CD34(+)KDR(+) (r=.84; P<.01) and SDF-1 and CD34(+)CXCR4(+) (r=.67; P<.01), and between these 2 cytokines (r=.57; P=.01). In the reperfused patients, the correlation between VEGF and CD133(+)CD34(+)KDR(+) was lower (r=.38; P=.03) and the correlation between SDF-1 and CD34(+)CXCR4(+) and VEGF disappeared. Multivariate analysis showed that a VEGF >7pg/mL (P<.01) predicted the mobilisation of CD133(+)CD34(+)KDR(+), whereas hypertension showed a trend (P=.055). Diabetes (P=.045) predicted the number of CD34(+)CXCR4(+), with reperfusion treatment showing a trend in this subpopulation (P=.054). CONCLUSIONS: Mobilisation of progenitor cells after AMI is influenced by factors such as diabetes and the cytokine VEGF. Hypertension and reperfusion therapy during the acute phase also tend to influence the cell response.

[Coronary disease extension determines mobilization of endothelial progenitor cells and cytokines after a first myocardial infarction with ST elevation]. / La extensión de la enfermedad coronaria determina la movilización de las células progenitoras endoteliales y las citocinas tras un primer infarto de miocardio con elevación del ST.

INTRODUCTION AND OBJECTIVES: Multivessel coronary disease is still a postinfarction prognostic marker despite new forms of reperfusion, such as primary angioplasty. The aim of this study was to determine the time sequence of various sets of endothelial progenitor cells and angiogenic cytokines (vascular endothelial growth factor, hepatocyte growth factor) according to the degree of extension of the postinfarction coronary disease. METHODS: We studied the release kinetics in 32 patients admitted for a first myocardial infarction with ST elevation, grouped according to whether they had single or multivessel disease, and 26 controls. RESULTS: The patients had a higher number of endothelial progenitor cells and angiogenic cytokines than the controls at all 3 measurements (admission, day 3, and day 7) of the following subsets: CD34, CD34+CD133+, CD34+KDR+, and CD34+CD133+KDR+CD45+(weak); this latter was higher on day 7. The levels of these cell subsets were all higher in the patients with single-vessel disease and at all 3 measurements. The vascular endothelial growth factor levels were raised during the first week and the hepatocyte growth factor showed an early peak on admission for infarction. No significant differences were seen in the cytokines according to coronary disease extension. CONCLUSIONS: Although the release kinetics of different subsets of endothelial progenitor cells in patients with a first acute myocardial infarction with ST elevation was similar in those with single vessel disease to those with multivessel disease, the number of circulating endothelial progenitor cells was greater in the patients with single vessel disease. The vascular endothelial growth factor levels were raised during the first postinfarction week and the hepatocyte growth factor were higher on admission.

Influence of preinfarction angina on the release kinetics of endothelial progenitor cells and cytokines during the week after infarction.

BACKGROUND: Preinfarction angina, a possible form of ischaemic preconditioning, improves the prognosis in patients who experience a major ischaemic event; though the associated pathophysiology is not yet fully understood. The aim of this study was to determine the possible involvement of endothelial progenitor cells (EPC), the vascular endothelial growth factor (VEGF) and the hepatocyte growth factor (HGF) in the development of preinfarction angina. METHODS AND RESULTS: We studied 41 patients (60·5 ± 12 years; 34% women) and 14 healthy controls; 43·9% of the patients had preinfarction angina. No differences were found in the baseline characteristics of the two groups. Although the EPC, VEGF and HGF were raised as compared with the control group, no significant differences were found according to the presence or absence of preinfarction angina in the levels of EPC (baseline, P = 0·25; day 3, P = 0·11; day 7, P = 0·32), VEGF (baseline, P = 0·96; day 3, P = 0·06; day 7, P = 0·57) or HGF (baseline, P = 0·18; day 3, P = 1; day 7, P = 0·86). An association was seen in the patients who had preinfarction angina between the EPC levels at baseline and on days 3 and 7 and the HGF on admission with the time from the angina to the STEMI (ß = -0·070; ß = -0·066; ß = -0·081; ß = -80·16; P < 0·05), showing a reduction in the level of EPC cells for each hour passed since the event. CONCLUSIONS: No differences were found in the release kinetics of EPC, VEGF or HGF after a first infarction according to whether the patients had angina during the week before the infarction.

Resident and non-resident stem cells in acute myocardial infarction.

Cardiovascular disease is the leading cause of death in developed countries. Acute myocardial infarction (AMI) is the result of hypoxia leading to cardiomyocyte death. This causes loss of function of contractile tissue, which is replaced by non-contractile fibrous tissue affecting left ventricular ejection fraction (LVEF). One of the current approaches to recover LVEF after an AMI is focused on the search for functional cells to replace the dead tissue, via implantation in the heart of autologous progenitor cells with a regenerative capacity. This review classifies these cells into two types: a) non-resident cells and b) resident cells within the cardiac tissue. We provide an overall view of the various subpopulations and their markers, based, in animal and human models from the early pioneering work to the latest findings.

Stimulation of endothelial progenitor cells: a new putative effect of several cardiovascular drugs.

The role of vascular endothelium in cardiovascular disorders is well recognized. Mature endothelial cells contribute to the repair of endothelial injury, but they only have a limited capacity to do so. This has led to growing interest and further investigation into circulating endothelial progenitor cells (EPCs) and their role in vascular healing, repair, and postnatal neovascularization. The current perception of vascular health is that of a balance between ongoing injury and resultant vascular repair, mediated at least in part by circulating EPCs. Circulating EPCs play an important role in accelerating endothelialization at areas of vascular damage, and EPC enumeration is a viable strategy for assessing reparative capacity. Recent studies have shown that EPCs are affected both in number and function by several cardiovascular risk factors as well as various cardiovascular disease states, such as hypertension, hypercholesterolemia, and coronary artery disease. The present review summarizes the most relevant studies on the effects of cardiovascular drugs on vascular function and EPCs, focusing on their mechanisms of action.