Hepcidin antagonists for potential treatments of disorders with hepcidin excess

5noThe discovery of hepcidin clarified the basic mechanism of the control of systemic iron homeostasis. Hepcidin is mainly produced by the liver as a propeptide and processed by furin into the mature active peptide. Hepcidin binds ferroportin, the only cellular iron exporter, causing the internalization and degradation of both. Thus hepcidin blocks iron export from the key cells for dietary iron absorption (enterocytes), recycling of hemoglobin iron (the macrophages) and the release of storage iron from hepatocytes, resulting in the reduction of systemic iron availability. The BMP/HJV/SMAD pathway is the major regulator of hepcidin expression that responds to iron status. Also inflammation stimulates hepcidin via the IL6/STAT3 pathway with a support of an active BMP/HJV/SMAD pathway. In some pathological conditions hepcidin level is inadequately elevated and reduces iron availability in the body, resulting in anemia. These conditions occur in the genetic iron refractory iron deficiency anemia and the common anemia of chronic disease (ACD) or anemia of inflammation. Currently, there is no definite treatment for ACD. Erythropoiesis-stimulating agents and intravenous iron have been proposed in some cases but they are scarcely effective and may have adverse effects. Alternative approaches aimed to a pharmacological control of hepcidin expression have been attempted, targeting different regulatory steps. They include hepcidin sequestering agents (antibodies, anticalins, and aptamers), inhibitors of BMP/SMAD or of IL6/STAT3 pathway or of hepcidin transduction (siRNA/shRNA) or ferroportin stabilizers. In this review we summarized the biochemical interactions of the proteins involved in the BMP/HJV/SMAD pathway and its natural inhibitors, the murine and rat models with high hepcidin levels currently available and finally the progresses in the development of hepcidin antagonists, with particular attention to the role of heparins and heparin sulfate proteoglycans in hepcidin expression and modulation of the BMP6/SMAD pathway.openopenMaura, Poli; Michela, Asperti; Paola, Ruzzenenti; Maria, Regoni; Paolo, ArosioPoli, Maura; Asperti, Michela; Ruzzenenti, Paola; Regoni, Maria; Arosio, Paol

Mice lacking mitochondrial ferritin are more sensitive to doxorubicin-mediated cardiotoxicity

15noMitochondrial ferritin is a functional ferritin that localizes in themitochondria.Itisexpressedinthetestis, heart,brain,and cells with active respiratory activity. Its overexpression in culturedcellsprotectedagainstoxidativedamageandreduced cytosolic iron availability. However, no overt phenotype was describedinmicewithinactivationoftheFtMtgene.Here,we usedthe doxorubicin model ofcardiac injuryina novel strain of FtMt-null mice to investigate the antioxidant role of FtMt. These mice did not show any evident phenotype, but after acute treatment to doxorubicin, they showed enhanced mortalityandaltered heartmorphologywithfibrildisorganization and severe mitochondrial damage. Signs of mitochondrial damage were present also in mock-treated FtMt−/− mice. The hearts of saline- and doxorubicin-treated FtMt−/− mice had higher thiobarbituric acid reactive substance levels, heme oxygenase 1 expression, and protein oxidation, but did not differ from FtMt+/+ in the cardiac damage marker B-type natriureticpeptide(BNP),ATP levels, and apoptosis.However,the autophagy marker LC3 was activated. The results show that the absence of FtMt, which is highly expressed in the heart, increases the sensitivity of heart mitochondria to the toxicity of doxorubicin. This study represents the first in vivo evidence of the antioxidant role of FtMt.openopenMaccarinelli, Federica; Gammella, Elena; Asperti, Michela; Mariaregon, ; Donetti, Elena; Recalcati, Stefania; Poli, Maura; Finazzi, Dario; Arosio, Paolo; Biasiotto, Giorgio; Emiliaturco, ; Altruda, Fiorella; Lonardi, Silvia; Cornaghi, Laura; Cairo, GaetanoMaccarinelli, Federica; Gammella, Elena; Asperti, Michela; Mariaregon, ; Donetti, Elena; Recalcati, Stefania; Poli, Maura; Finazzi, Dario; Arosio, Paolo; Biasiotto, Giorgio; Emiliaturco, ; Altruda, Fiorella; Lonardi, Silvia; Cornaghi, Laura; Cairo, Gaetan

Photoacoustic molecular imaging for in vivo liver iron quantitation

Maccarinelli, F.; et al. Photoacoustic molecular imaging for in vivo liver iron quantitation. Journal of Biomedical Optics 21(5): 056008 (2016). (Mar 1, 2016). DOI: http://dx.doi.org/10.1117/1.JBO.21.5.056008Copyright 2017 Society of Photo Optical Instrumentation Engineers (SPIE). One print or electronic copy may be made for personal use only. Systematic reproduction and distribution, duplication of any material in this publication for a fee or for commercial purposes, or modification of the contents of the publication are prohibited.A recent study showed that ferritin is a suitable endogenous contrast agent for photoacoustic molecular imaging in cultured mammalian cells. We have therefore tested whether this imaging technique can be used for in vivo quantification of iron in mouse livers. To verify this hypothesis, we used multispectral optoacoustic tomography (MSOT) to image albino CD1 mice before and after experimental iron loading. Postmortem assays showed that the iron treatment caused a 15-fold increase in liver iron and a 40-fold increase in liver ferritin levels, while in vivo longitudinal analysis using MSOT revealed just a 1.6-fold increase in the ferritin/iron photoacoustic signal in the same animals. We conclude that MSOT can monitor changes in ferritin/iron levels in vivo, but its sensitivity is much lower than that of ex vivo iron assays.The work was partially supported by PRIN10-11 grant to P.A. F.M. was partially supported by a fellowship by Consorzio Interuniversitario Biotecnologie

Mitochondrial ferritin deficiency reduces male fertility in mice

Mitochondrial ferritin (FtMt) is a functional ferritin targeted to mitochondria that is highly expressed in the testis. To investigate the role of FtMt in the testis we set up a series of controlled matings between FtMt gene-deletion mice (FtMt–/–) with FtMt+/+ mice. We found that the number of newborns per litter and the fertility rate were strongly reduced for the FtMt–/– males, but not for the females, indicating that FtMt has an important role for male fertility. The morphology of the testis and of the spermatozoa of FtMt–/– mice was normal and we did not detect alterations in sperm parameters or in oxidative stress indices. In contrast, we observed that the cauda epididymides of FtMt–/– mice were significantly lighter and contained a lower number of spermatozoa compared with the controls. Also, the ATP content of FtMt–/– spermatozoa was found to be lower than that of FtMt+/+ spermatozoa. These data show that FtMt contributes to sperm epididymis maturation and to male fertility.The work was partially supported by MIUR grant PRIN10–11 to P. A. and by Telethon grant GGP1099 to P. A

Cardiologist and Diabetologist crosstalk in the era of cardiovascular outcome trials of novel glucose-lowering drugs

The prevalence of type 2 diabetes continues to increase and cardiovascular (CV) diseases remain the leading cause of death in diabetic patients. Diabetologists and Cardiologists have to work together in order to provide the best management to these patients. After years of disappointing studies showing no reduction of CV events with strict glycaemic control, some of the novel glucose-lowering drugs (GLDs) seem to offer a new approach to tackle the problem, since the CV outcome trials (CVOTs-D) of liraglutide, semaglutide, empagliflozin and canagliflozin have demonstrated not only their CV safety but also their efficacy in the reduction of CV morbidity and mortality. Along with the initial enthusiasm, concerns have been raised about the economical sustainability of long-term therapies considering higher costs of new molecules relative to the traditional ones. As expenses in the medical field are on the rise, healthcare systems need to balance the positive impact of an intervention and its overall cost. This review is meant to offer the Cardiologists a different point of view on the positive influence of GLDs, in the light of the main trials in the CV fields they are familiar with. The purpose of this article is to critically review the magnitude of the CVOTs-D results by the analysis of their statistical determinants, to establish the extent of the GLDs positive impact on patients with both diabetes and CV disease. The analysis has been performed taking into account models and statistical determinants used in the main landmark cardiology trials. It is fundamental to translate the result of CVOTs-D in clinical practice: the interdisciplinary crosstalk between the Cardiologist and Diabetologist is of paramount importance in order to fully exploit the power of the new available pharmacological strategies. Keywords: Cardiovascular outcome trials, Glucose-lowering drugs, Type 2 diabetes, Crosstalk, Cardiovascular ris

Presynaptic AMPA Receptors in Health and Disease

AMPA receptors (AMPARs) are ionotropic glutamate receptors that play a major role in excitatory neurotransmission. AMPARs are located at both presynaptic and postsynaptic plasma membranes. A huge number of studies investigated the role of postsynaptic AMPARs in the normal and abnormal functioning of the mammalian central nervous system (CNS). These studies highlighted that changes in the functional properties or abundance of postsynaptic AMPARs are major mechanisms underlying synaptic plasticity phenomena, providing molecular explanations for the processes of learning and memory. Conversely, the role of AMPARs at presynaptic terminals is as yet poorly clarified. Accruing evidence demonstrates that presynaptic AMPARs can modulate the release of various neurotransmitters. Recent studies also suggest that presynaptic AMPARs may possess double ionotropic-metabotropic features and that they are involved in the local regulation of actin dynamics in both dendritic and axonal compartments. In addition, evidence suggests a key role of presynaptic AMPARs in axonal pathology, in regulation of pain transmission and in the physiology of the auditory system. Thus, it appears that presynaptic AMPARs play an important modulatory role in nerve terminal activity, making them attractive as novel pharmacological targets for a variety of pathological conditions

Presynaptic AMPA Receptors in Health and Disease

AMPA receptors (AMPARs) are ionotropic glutamate receptors that play a major role in excitatory neurotransmission. AMPARs are located at both presynaptic and postsynaptic plasma membranes. A huge number of studies investigated the role of postsynaptic AMPARs in the normal and abnormal functioning of the mammalian central nervous system (CNS). These studies highlighted that changes in the functional properties or abundance of postsynaptic AMPARs are major mechanisms underlying synaptic plasticity phenomena, providing molecular explanations for the processes of learning and memory. Conversely, the role of AMPARs at presynaptic terminals is as yet poorly clarified. Accruing evidence demonstrates that presynaptic AMPARs can modulate the release of various neurotransmitters. Recent studies also suggest that presynaptic AMPARs may possess double ionotropic-metabotropic features and that they are involved in the local regulation of actin dynamics in both dendritic and axonal compartments. In addition, evidence suggests a key role of presynaptic AMPARs in axonal pathology, in regulation of pain transmission and in the physiology of the auditory system. Thus, it appears that presynaptic AMPARs play an important modulatory role in nerve terminal activity, making them attractive as novel pharmacological targets for a variety of pathological conditions.</jats:p