Role of Stem Cell Factor in the Reactivation of Human Fetal Hemoglobin

In humans the switch from fetal to adult hemoglobin (HbF → HbA) takes place in the perinatal and postnatal period, determining the progressive replacement of HbF with HbA synthesis (i.e., the relative HbF content in red blood cells decreases from 80–90% to <1%). In spite of more than twenty years of intensive investigations on this classic model, the molecular mechanisms regulating the Hb switching, as well as HbF synthesis in adults, has been only in part elucidated. In adult life, the residual HbF, restricted to F cell compartment, may be reactivated up to 10–20% of total Hb synthesis in various conditions associated with “stress erythropoiesis”: this reactivation represented until now an interesting model of partial Hb switch reverse with important therapeutic implications in patients with hemoglobinopathies, and particularly in β-thalassemia. In vitro and in vivo models have led to the identification of several chemical compounds able to reactivate HbF synthesis in adult erythroid cells. Although the impact of these HbF inducers, including hypomethylating agents, histone deacetylase inhibitors and hydroxyurea, was clear on the natural history of sickle cell anemia, the benefit on the clinical course of β-thalassemia was only limited: particularly, the toxicity and the modest increase in γ-globin reactivation indicated the need for improved agents able to induce higher levels of HbF. In the present review we describe the biologic properties of Stem Cell Factor (SCF), a cytokine sustaining the survival and proliferation of erythroid cells, that at pharmacological doses acts as a potent stimulator of HbF synthesis in adult erythroid cells

Ferroportin and Erythroid Cells: An Update

In recent years there have been major advances in our knowledge of the regulation of iron metabolism that have had implications for understanding the pathophysiology of some human disorders like beta-thalassemia and other iron overload diseases. However, little is known about the relationship among ineffective erythropoiesis, the role of iron-regulatory genes, and tissue iron distribution in beta-thalassemia. The principal aim of this paper is an update about the role of Ferroportin during human normal and pathological erythroid differentiation. Particular attention will be given to beta-thalassemia and other diseases with iron overload. Recent discoveries indicate that there is a potential for therapeutic intervention in beta-thalassemia by means of manipulating iron metabolism

Irrigation Management in Coastal Zones to Prevent Soil and Groundwater Salinization

Soil salinization is one of the most widespread soil degradation processes on earth and, worldwide, one billion hectares are affected, mainly in the arid–semiarid regions of Asia, Australia and South America [1]. In Europe, soil salinity has effects on one million hectares mainly in the Mediterranean countries [1]. There are two types of salinization: primary salinization caused by natural events such as sea spray or rock weathering or seepage [2] and secondary salinization that is caused by human activities such as irrigation with salty water, groundwater overexploitation and excessive drainage [1]. Along the Adriatic coast of the Po Plain, freshwater resources are becoming increasingly scarce, because of irrigation and other intense water use, salinization and long periods of drought [3]. Custodio [4] underlines that, especially in southern Europe, the irrigation practices and the water requirements to sustain the coastal tourism industry exhort a strong pressure on water resources. The impact of groundwater salinization in coastal areas affects both natural vegetation biodiversity and agricultural production, through soil salinization and reduction of freshwater availability for irrigation. Salinization is closely associated with the process of desertification, because salinity may have direct negative effects on crop yields by reducing the ability of plant roots to take up water [5]. The most common salinity effect is a general stunting of plant growth, but not all plants respond in the same way. Grain and corn may reduce their seed production without appreciably plant dimensions reduction

htr2c gene variant and salivary cortisol levels after endurance physical activity a pilot study

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Hair Microelement Profile as a Prognostic Tool in Parkinson’s Disease

Abstract: Changes in the homeostasis of metals and microelements have been demonstrated in Parkinson’s disease, whose etiology includes both a genetic and environmental basis. We studied the difference of microelements in the hair of Parkinson’s disease subjects (n = 46) compared with healthy controls (n = 24). Hair was chosen as a representative matrix to measure microelements, since it is a vehicle of substance excretion from the human body and it allows for long-term evaluation of metal exposure. An inductively coupled plasma mass spectrometry (ICP-MS) analysis of hair collected from 24 Parkinson’s patients compared with their healthy relatives used as controls shows a significant decrease in Ca (U = 166, p = 0.012),), Mg (U = 187, p = 0.037), and Sr (U = 183, p = 0.030). Cd and Ca/Mg were decreased, and Cu was increased, in patients with respect to their healthy related controls at the limit of significance (p = 0.0501). Principal Component Analysis (PCA) of these microelements in hair shows a clustering into two groups according to gender, disease severity according to the Hoehn–Yahr scale, and pharmacological therapy. This pilot study represents a starting point for future investigations where a larger group of subjects will be involved to define other microelements useful when screening for early biomarkers of Parkinson’s disease

Effective erythropoiesis and HbF reactivation induced by kit ligand in β-thalassemia

In human β-thalassemia, the imbalance between α- and non–α-globin chains causes ineffective erythropoiesis, hemolysis, and anemia: this condition is effectively treated by an enhanced level of fetal hemoglobin (HbF). In spite of extensive studies on pharmacologic induction of HbF synthesis, clinical trials based on HbF reactivation in β-thalassemia produced inconsistent results. Here, we investigated the in vitro response of β-thalassemic erythroid progenitors to kit ligand (KL) in terms of HbF reactivation, stimulation of effective erythropoiesis, and inhibition of apoptosis. In unilineage erythroid cultures of 20 patients with intermedia or major β-thalassemia, addition of KL, alone or combined with dexamethasone (Dex), remarkably stimulated cell proliferation (3-4 logs more than control cultures), while decreasing the percentage of apoptotic and dyserythropoietic cells (<5%). More important, in both thalassemic groups, addition of KL or KL plus Dex induced a marked increase of γ-globin synthesis, thus reaching HbF levels 3-fold higher than in con-trol cultures (eg, from 27% to 75% or 81%, respectively, in β-thalassemia major). These studies indicate that in β-thalassemia, KL, alone or combined with Dex, induces an expansion of effective erythropoiesis and the reactivation of γ-globin genes up to fetal levels and may hence be considered as a potential therapeutic agent for this disease

HbF reactivation in sibling BFU-E colonies: synergistic interaction of kit ligand with low-dose dexamethasone

Mechanisms underlying fetal hemoglobin (HbF) reactivation in stress erythropoiesis have not been fully elucidated. We suggested that a key role is played by kit ligand (KL). Because glucocorticoids (GCs) mediate stress erythropoiesis, we explored their capacity to potentiate the stimulatory effect of KL on HbF reactivation, as evaluated in unilineage erythropoietic culture of purified adult progenitors (erythroid burst-forming units [BFU-Es]). The GC derivative dexamethasone (Dex) was tested in minibulk cultures at graded dosages within the therapeutical range (10−6 to 10−9M). Dex did not exert significant effects alone, but synergistically it potentiated the action of KL in a dose-dependent fashion. Specifically, Dex induced delayed erythroid maturation coupled with a 2-log increased number of generated erythroblasts and enhanced HbF synthesis up to 85% F cells and 55% γ-globin content at terminal maturation (ie, in more than 80%-90% mature erythroblasts). Equivalent results were obtained in unicellular erythroid cultures of sibling BFU-Es treated with KL alone or combined with graded amounts of Dex. These results indicate that the stimulatory effect of KL + Dex is related to the modulation of γ-globin expression rather than to recruitment of BFU-Es with elevated HbF synthetic potential. At the molecular level, Id2 expression is totally suppressed in control erythroid culture but is sustained in KL + Dex culture. Hypothetically, Id2 may mediate the expansion of early erythroid cells, which correlates with HbF reactivation. These studies indicate that GCs play an important role in HbF reactivation. Because Dex acts at dosages used in immunologic disease therapy, KL + Dex administration may be considered to develop preclinical models for β-hemoglobinopathy treatment

Hemorheological profiles and chronic inflammation markers in transfusion-dependent and non-transfusion- dependent thalassemia

: The rheological properties of blood play an important role in regulating blood flow in micro and macro circulation. In thalassemia syndromes red blood cells exhibit altered hemodynamic properties that facilitate microcirculatory diseases: increased aggregation and reduced deformability, as well as a marked increase in adherence to the vascular endothelial cells. A personalized approach to treating thalassemia patients (transfusions, iron chelation, and splenectomy), has increased patients' life expectancy, however they generally present many complications and several studies have demonstrated the presence of high incidence of thromboembolic events. In this study the hemorheological profiles of thalassemia patients have been characterized to point out new indices of vascular impairment in thalassemia. Plasma viscosity, blood viscosities at low and high shear rates (η1 and η200, respectively), erythrocyte aggregation index (η1/η200), and the erythrocyte viscoelastic profile (elastic modulus G', and viscous modulus G") have been studied in transfusion-dependent and non-transfusion-dependent thalassemia patients. Moreover, the levels of inflammation biomarkers in thalassemia have been evaluated to investigate a relationship between the biomarkers, the disease severity and the rheological parameters. The biomarkers studied are the main components of the immune and endothelial systems or are related to vascular inflammation: cytokines (IL-2, IL-6, IL-10, IL-17A, TNF-alpha), chemokines (IL-8, MIP-1alpha), adipocytokines (leptin and adiponectin), growth factors (VEGF, angiopoietin-1), adhesion molecules (ICAM-1, VCAM-1, E-selectin, L-selectin), and a monocyte/macrophage activation marker (CD163). This study shows that transfusion-dependent thalassemia patients, both major and intermedia, have blood viscosities comparable to those of healthy subjects. Non-transfusion-dependent thalassemia intermedia patients show high blood viscosities at low shear rates (η1), corresponding to the flow conditions of the microcirculation, an increase in erythrocyte aggregation, and high values of the elastic G' and viscous G" modules that reflect a reduced erythrocyte deformability and an increase in blood viscosity. Levels of cytokines, chemokines and adhesion molecules are different in transfusion- and non-transfusion dependent patients and positive correlations between η1 or η1/η200 and the cytokines IL-6 and IL-10 have been observed. The evaluation of the hemorheological profiles in thalassemia can provide new indicators of vascular impairment and disease severity in thalassemia in order to prevent the onset of thromboembolic events

RIGED-RA project - Restoration and management of Coastal Dunes in the Northern Adriatic Coast, Ravenna Area - Italy

Coastal dunes play an important role in protecting the coastline. Unfortunately, in the last decades dunes have been removed or damaged by human activities. In the Emilia- Romagna region significant residual dune systems are found only along Ravenna and Ferrara coasts. In this context, the RIGED-RA project "Restoration and management of coastal dunes along the Ravenna coast" (2013-2016) has been launched with the aims to identify dynamics, erosion and vulnerability of Northern Adriatic coast and associated residual dunes, and to define intervention strategies for dune protection and restoration. The methodology is based on a multidisciplinary approach that integrates the expertise of several researchers and investigates all aspects (biotic and abiotic), which drive the dune-beach system. All datasets were integrated to identify test sites for applying dune restoration. The intervention finished in April 2016; evolution and restoration efficiency will be assessed