29 research outputs found
Iron chelating properties of Eltrombopag: Investigating its role in thalassemia-induced osteoporosis
Chronic blood transfusions are responsible to cause iron overload, which leads to several
complications to end organs and osteoporosis. Iron chelation is needed to remove iron
excess and to contain bone-mass loss. Deferasirox is the most recent oral iron chelator that
prevents transfusion related iron overload complications. Recently Eltrombopag (ELT) iron
chelating properties are emerging. ELT is an agonist at Thrombopoietin receptor, used in
treatment of thrombocytopenia. We tested ELT and Deferasirox in iron overloaded osteoclasts from thalassemic patients and donors measuring intracellular iron, TRAP expression
and osteoclast activity. We confirmed ELT iron chelation capacity also in bone tissue and a
synergic effect when used with Deferasirox. Moreover, having demonstrated its effects on
osteoclast activity, we suggest for the first time that ELT could ameliorate bone tissue’s
health reducing bone mass loss
Childhood Cancer Survivors: An Overview of the Management of Late Effects
The collection of papers in this Special Issue entitled “Frailty in Pediatric and Young Adult Cancer Survivors: from bench to bedside” includes six interesting articles (five reviews and one single-center retrospective longitudinal cohort study) presented by expert researchers in the fields of oncology and pediatrics [...
Cannabinoid Receptor Type 2: A Possible Target in SARS-CoV-2 (CoV-19) Infection?
In late December 2019, a novel coronavirus (SARS-CoV-2 or CoV-19) appeared in Wuhan, China, causing a global pandemic. SARS-CoV-2 causes mild to severe respiratory tract inflammation, often developing into lung fibrosis with thrombosis in pulmonary small vessels and causing even death. COronaVIrus Disease (COVID-19) patients manifest exacerbated inflammatory and immune responses, cytokine storm, prevalence of pro-inflammatory M1 macrophages and increased levels of resident and circulating immune cells. Men show higher susceptibility to SARS-CoV-2 infection than women, likely due to estrogens production. The protective role of estrogens, as well as an immune-suppressive activity that limits the excessive inflammation, can be mediated by cannabinoid receptor type 2 (CB2). The role of this receptor in modulating inflammation and immune response is well documented in fact in several settings. The stimulation of CB2 receptors is known to limit the release of pro-inflammatory cytokines, shift the macrophage phenotype towards the anti-inflammatory M2 type and enhance the immune-modulating properties of mesenchymal stromal cells. For these reasons, we hypothesize that CB2 receptor can be a therapeutic target in COVID-19 pandemic emergency
Emerging Roles of the Iron Chelators in Inflammation
Iron is a crucial element for mammalian cells, considering its intervention in several physiologic processes. Its homeostasis is finely regulated, and its alteration could be responsible for the onset of several disorders. Iron is closely related to inflammation; indeed, during inflammation high levels of interleukin-6 cause an increased production of hepcidin which induces a degradation of ferroportin. Ferroportin degradation leads to decreased iron efflux that culminates in elevated intracellular iron concentration and consequently iron toxicity in cells and tissues. Therefore, iron chelation could be considered a novel and useful therapeutic strategy in order to counteract the inflammation in several autoimmune and inflammatory diseases. Several iron chelators are already known to have anti-inflammatory effects, among them deferiprone, deferoxamine, deferasirox, and Dp44mT are noteworthy. Recently, eltrombopag has been reported to have an important role in reducing inflammation, acting both directly by chelating iron, and indirectly by modulating iron efflux. This review offers an overview of the possible novel biological effects of the iron chelators in inflammation, suggesting them as novel anti-inflammatory molecules
The Role of Cannabinoid Receptor Type 2 in the Bone Loss Associated with pediatric Celiac Disease
Effects of CB2 and TRPV1 Stimulation on Osteoclast Overactivity Induced by Iron in Pediatric Inflammatory Bowel Disease
Background: The reduction of bone mineral density and osteoporosis have high impacts on the health of patients with inflammatory bowel diseases (IBD). We have previously shown that a dysregulated iron metabolism occurs in IBD and leads to a decrease in circulating iron concentration and excessive intracellular sequestration of iron. Studies suggest that iron overload significantly affects the bone, accelerating osteoclast (OC) differentiation and activation, promoting bone resorption. Moreover, we demonstrated that iron overload causes OC overactivity. The cannabinoid receptor type 2 (CB2) and the transient receptor potential vanilloid type-1 (TRPV1) are potential therapeutic targets for bone diseases. The aim of this study was to evaluate the roles of CB2 and TRPV1 receptors and of iron in the development of osteoporosis in pediatric IBD. Methods: We differentiated OCs from peripheral blood mononuclear cells of patients with IBD and healthy donors and evaluated CB2 and TRPV1 receptor expression; OC activity, and iron metabolism by Western blot, TRAP assays, bone resorption assays, and iron assays. Moreover, we analyzed the effects of the pharmacological modulation of CB2 and TRPV1 receptors on OC activity and on the iron metabolism. Results: We confirmed the well-known roles of CB2 and TRPV1 receptors in bone metabolism and suggested that their stimulation can reduce the OC overactivity induced by iron, providing new insights into the pathogenesis of pediatric IBD-related bone resorption. Conclusions: Stimulation of CB2 and TRPV1 could reduce IBD-related osteoporosis due to their direct effects on OC activity and to modulating the iron metabolism
The Endocannabinoid/Endovanilloid System in Bone: From Osteoporosis to Osteosarcoma
Bone is a dynamic tissue, whose homeostasis is maintained by a fine balance between osteoclast (OC) and osteoblast (OB) activity. The endocannabinoid/endovanilloid (EC/EV) system’s receptors are the cannabinoid receptor type 1 (CB1), the cannabinoid receptor type 2 (CB2), and the transient receptor potential cation channel subfamily V member 1 (TRPV1). Their stimulation modulates bone formation and bone resorption. Bone diseases are very common worldwide. Osteoporosis is the principal cause of bone loss and it can be caused by several factors such as postmenopausal estrogen decrease, glucocorticoid (GC) treatments, iron overload, and chemotherapies. Studies have demonstrated that CB1 and TRPV1 stimulation exerts osteoclastogenic effects, whereas CB2 stimulation has an anti-osteoclastogenic role. Moreover, the EC/EV system has been demonstrated to have a role in cancer, favoring apoptosis and inhibiting cell proliferation. In particular, in bone cancer, the modulation of the EC/EV system not only reduces cell growth and enhances apoptosis but it also reduces cell invasion and bone pain in mouse models. Therefore, EC/EV receptors may be a useful pharmacological target in the prevention and treatment of bone diseases. More studies to better investigate the biochemical mechanisms underlining the EC/EV system effects in bone are needed, but the synthesis of hybrid molecules, targeting these receptors and capable of oppositely regulating bone homeostasis, seems to be a promising and encouraging prospective in bone disease management
The Endocannabinoid System in Pediatric Inflammatory and Immune Diseases
Endocannabinoid system consists of cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors, their endogenous ligands, and the enzymes responsible for their synthesis and degradation. CB2, to a great extent, and CB1, to a lesser extent, are involved in regulating the immune response. They also regulate the inflammatory processes by inhibiting pro-inflammatory mediator release and immune cell proliferation. This review provides an overview on the role of the endocannabinoid system with a major focus on cannabinoid receptors in the pathogenesis and onset of inflammatory and autoimmune pediatric diseases, such as immune thrombocytopenia, juvenile idiopathic arthritis, inflammatory bowel disease, celiac disease, obesity, neuroinflammatory diseases, and type 1 diabetes mellitus. These disorders have a high social impact and represent a burden for the healthcare system, hence the importance of individuating more innovative and effective treatments. The endocannabinoid system could address this need, representing a possible new diagnostic marker and therapeutic target
Cb2 receptor stimulation and dexamethasone restore the anti-inflammatory and immune-regulatory properties of mesenchymal stromal cells of children with immune thrombocytopenia
Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by antibody-mediated platelet destruction, with a complex and unclear pathogenesis. The impaired immunosuppressive capacity of mesenchymal stromal cells in ITP patients (ITP-MSCs) might play a role in the development of the disease. Correcting the MSC defects could represent an alternative therapeutic approach for ITP. High-dose dexamethasone (HD-Dexa) is the mainstay of the ITP therapeutic regimen, although it has several side effects. We previously demonstrated a role for cannabinoid receptor 2 (CB2) as a mediator of anti-inflammatory and immunoregulatory properties of human MSCs. We analyzed the effects of CB2 stimulation, with the selective agonist JWH-133, and of Dexa alone and in combination on ITP-MSC survival and immunosuppressive capacity. We provided new insights into the pathogenesis of ITP, suggesting CB2 receptor involvement in the impairment of ITP-MSC function and confirming MSCs as responsive cellular targets of Dexa. Moreover, we demonstrated that CB2 stimulation and Dexa attenuate apoptosis, via Bcl2 signaling, and restore the immune-modulatory properties of MSCs derived from ITP patients. These data suggest the possibility of using Dexa in combination with JWH-133 in ITP, reducing its dose and side effects but maintaining its therapeutic benefits
Eltrombopag and its iron chelating properties in pediatric acute myeloid leukemia
Pediatric acute myeloid leukemia (AML) represents 20% of total childhood
leukemia diagnoses and is characterized by poor prognosis with a long-term survival
rate around the 50%, when patients are properly treated. The standard treatment
for pediatric AML currently consists in a combination of cytarabine (Ara-C) and
antracycline. Iron plays an important role in cancer development and progression.
Targeting iron and its metabolism mediators could be a novel therapeutic strategy
in cancer.Deferasirox (DFX) inhibits cancer cell proliferation and its use as an
antiblastic drug could be suggested. Eltrombopag (ELT), a thrombopoietin receptor
agonist used in immunethrombocytopenia, shows anticancer properties related to its
emerging iron chelating properties. We compare the anticancer effect of classically
used cytarabine with DFX and ELT effects in a pediatric AML cell line, THP-1, in order
to identify innovative and more effective therapeutic strategies. ELT and DFX reduce
intracellular iron concentration by inhibiting its uptake and by promoting its release.
In particular, even though further investigations are needed to better understand the
extact underlying action mechanisms, we demonstrated that ELT improves cytarabine
antineoplastic activity in pediatric AML cell line