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Pharmaceuticals, Volume 11, Issue 4 (December 2018) – 49 articles

Cover Story (view full-size image): Iron is an essential micronutrient that is necessary for critical cellular functions, including DNA synthesis and oxidative metabolism, yet is potentially toxic in excess. The brain is particularly susceptible to iron-induced oxidative damage, given its high metabolic demand, yet multiple processes in the brain such as myelination and neurotransmitter synthesis are iron-dependent. Therefore, proper regulation of iron uptake into the brain is essential for normal brain development and function. Ferritin has the potential to deliver not only a higher amount of iron than the transferrin-based system, but also several therapeutic agents encapsulated within the ferritin core. The study of ferritin-dependent uptake and delivery into the brain and other cells may lead to promising new therapeutic targets and delivery routes. View this paper.
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14 pages, 3963 KiB  
Article
Differential Scanning Calorimetry Analyses of Idebenone-Loaded Solid Lipid Nanoparticles Interactions with a Model of Bio-Membrane: A Comparison with In Vitro Skin Permeation Data
by Lucia Montenegro, Francesco Castelli and Maria Grazia Sarpietro
Pharmaceuticals 2018, 11(4), 138; https://doi.org/10.3390/ph11040138 - 16 Dec 2018
Cited by 23 | Viewed by 4755
Abstract
Differential scanning calorimetry (DSC) has emerged as a helpful technique both to characterize drug delivery systems and to study their interactions with bio-membranes. In this work, we compared idebenone (IDE)-loaded solid lipid nanoparticle (SLN) interactions with bio-membranes assessed by DSC with previous in [...] Read more.
Differential scanning calorimetry (DSC) has emerged as a helpful technique both to characterize drug delivery systems and to study their interactions with bio-membranes. In this work, we compared idebenone (IDE)-loaded solid lipid nanoparticle (SLN) interactions with bio-membranes assessed by DSC with previous in vitro skin penetration data to evaluate the feasibility of predicting IDE skin penetration using DSC analyses. In vitro interactions experiments were performed using multi-lamellar liposomes as a model of bio-membrane. Enthalpy changes (ΔH) and transition temperature (Tm) were assessed during nine repeated DSC scans to evaluate IDE-loaded SLN–bio-membrane interactions over time. Analyzing ΔH and Tm values for each scan, we observed that the difference of ΔH and Tm values between the first and the last scan seemed to be related to SLN ability to locate IDE in the epidermis and in the stratum corneum, respectively. Therefore, the results of this study suggest the possibility of qualitatively predicting in vitro IDE skin penetration from IDE-loaded SLN utilizing the calorimetric parameters obtained from interaction experiments between the carriers under investigation and a model of bio-membrane. Full article
(This article belongs to the Special Issue Nano Drug Carriers)
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20 pages, 33844 KiB  
Review
Iron Regulation: Macrophages in Control
by Nyamdelger Sukhbaatar and Thomas Weichhart
Pharmaceuticals 2018, 11(4), 137; https://doi.org/10.3390/ph11040137 - 14 Dec 2018
Cited by 143 | Viewed by 15534
Abstract
Macrophages are sentinel cells of the innate immune system and have important functions in development, tissue homeostasis, and immunity. These phylogenetically ancient cells also developed a variety of mechanisms to control erythropoiesis and the handling of iron. Red pulp macrophages in the spleen, [...] Read more.
Macrophages are sentinel cells of the innate immune system and have important functions in development, tissue homeostasis, and immunity. These phylogenetically ancient cells also developed a variety of mechanisms to control erythropoiesis and the handling of iron. Red pulp macrophages in the spleen, Kupffer cells in the liver, and central nurse macrophages in the bone marrow ensure a coordinated metabolism of iron to support erythropoiesis. Phagocytosis of senescent red blood cells by macrophages in the spleen and the liver provide a continuous delivery of recycled iron under steady-state conditions and during anemic stress. Central nurse macrophages in the bone marrow utilize this iron and provide a cellular scaffold and niche to promote differentiation of erythroblasts. This review focuses on the role of the distinct macrophage populations that contribute to efficient iron metabolism and highlight important cellular and systemic mechanisms involved in iron-regulating processes. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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14 pages, 2488 KiB  
Article
Synthesis and Initial In Vivo Evaluation of [11C]AZ683—A Novel PET Radiotracer for Colony Stimulating Factor 1 Receptor (CSF1R)
by Sean S. Tanzey, Xia Shao, Jenelle Stauff, Janna Arteaga, Phillip Sherman, Peter J. H. Scott and Andrew V. Mossine
Pharmaceuticals 2018, 11(4), 136; https://doi.org/10.3390/ph11040136 - 13 Dec 2018
Cited by 25 | Viewed by 4976
Abstract
Positron emission tomography (PET) imaging of Colony Stimulating Factor 1 Receptor (CSF1R) is a new strategy for quantifying both neuroinflammation and inflammation in the periphery since CSF1R is expressed on microglia and macrophages. AZ683 has high affinity for CSF1R (Ki = 8 [...] Read more.
Positron emission tomography (PET) imaging of Colony Stimulating Factor 1 Receptor (CSF1R) is a new strategy for quantifying both neuroinflammation and inflammation in the periphery since CSF1R is expressed on microglia and macrophages. AZ683 has high affinity for CSF1R (Ki = 8 nM; IC50 = 6 nM) and >250-fold selectivity over 95 other kinases. In this paper, we report the radiosynthesis of [11C]AZ683 and initial evaluation of its use in CSF1R PET. [11C]AZ683 was synthesized by 11C-methylation of the desmethyl precursor with [11C]MeOTf in 3.0% non-corrected activity yield (based upon [11C]MeOTf), >99% radiochemical purity and high molar activity. Preliminary PET imaging with [11C]AZ683 revealed low brain uptake in rodents and nonhuman primates, suggesting that imaging neuroinflammation could be challenging but that the radiopharmaceutical could still be useful for peripheral imaging of inflammation. Full article
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24 pages, 324 KiB  
Review
Established and Emerging Concepts to Treat Imbalances of Iron Homeostasis in Inflammatory Diseases
by Verena Petzer, Igor Theurl and Günter Weiss
Pharmaceuticals 2018, 11(4), 135; https://doi.org/10.3390/ph11040135 - 11 Dec 2018
Cited by 32 | Viewed by 5150
Abstract
Inflammation, being a hallmark of many chronic diseases, including cancer, inflammatory bowel disease, rheumatoid arthritis, and chronic kidney disease, negatively affects iron homeostasis, leading to iron retention in macrophages of the mononuclear phagocyte system. Functional iron deficiency is the consequence, leading to anemia [...] Read more.
Inflammation, being a hallmark of many chronic diseases, including cancer, inflammatory bowel disease, rheumatoid arthritis, and chronic kidney disease, negatively affects iron homeostasis, leading to iron retention in macrophages of the mononuclear phagocyte system. Functional iron deficiency is the consequence, leading to anemia of inflammation (AI). Iron deficiency, regardless of anemia, has a detrimental impact on quality of life so that treatment is warranted. Therapeutic strategies include (1) resolution of the underlying disease, (2) iron supplementation, and (3) iron redistribution strategies. Deeper insights into the pathophysiology of AI has led to the development of new therapeutics targeting inflammatory cytokines and the introduction of new iron formulations. Moreover, the discovery that the hormone, hepcidin, plays a key regulatory role in AI has stimulated the development of several therapeutic approaches targeting the function of this peptide. Hence, inflammation-driven hepcidin elevation causes iron retention in cells and tissues. Besides pathophysiological concepts and diagnostic approaches for AI, this review discusses current guidelines for iron replacement therapies with special emphasis on benefits, limitations, and unresolved questions concerning oral versus parenteral iron supplementation in chronic inflammatory diseases. Furthermore, the review explores how therapies aiming at curing the disease underlying AI can also affect anemia and discusses emerging hepcidin antagonizing drugs, which are currently under preclinical or clinical investigation. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
19 pages, 5899 KiB  
Article
Dissipative Particle Dynamics Investigation of the Transport of Salicylic Acid through a Simulated In Vitro Skin Permeation Model
by Daniel P. Otto, Johann Combrinck, Anja Otto, Louwrens R. Tiedt and Melgardt M. De Villiers
Pharmaceuticals 2018, 11(4), 134; https://doi.org/10.3390/ph11040134 - 5 Dec 2018
Cited by 12 | Viewed by 5326
Abstract
Permeation models are often used to determine diffusion properties of a drug through a membrane as it is released from a delivery system. In order to circumvent problematic in vivo studies, diffusion studies can be performed in vitro, using (semi-)synthetic membranes. In this [...] Read more.
Permeation models are often used to determine diffusion properties of a drug through a membrane as it is released from a delivery system. In order to circumvent problematic in vivo studies, diffusion studies can be performed in vitro, using (semi-)synthetic membranes. In this study salicylic acid permeation was studied, employing a nitrocellulose membrane. Both saturated and unsaturated salicylic acid solutions were studied. Additionally, the transport of salicylic acid through the nitrocellulose membrane was simulated by computational modelling. Experimental observations could be explained by the transport mechanism that was revealed by dissipative particle dynamics (DPD) simulations. The DPD model was developed with the aid of atomistic scale molecular dynamics (AA-MD). The choice of a suitable model membrane can therefore, be predicted by AA-MD and DPD simulations. Additionally, the difference in the magnitude of release from saturated and unsaturated salicylic acid and solutions could also be observed with DPD. Moreover, computational studies can reveal hidden variables such as membrane-permeant interaction that cannot be measured experimentally. A recommendation is made for the development of future model permeation membranes is to incorporate computational modelling to aid the choice of model. Full article
(This article belongs to the Special Issue Molecular Dynamics in Drug Design)
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23 pages, 3018 KiB  
Review
Functional Polymer Nanocarriers for Photodynamic Therapy
by Tuanwei Li and Lifeng Yan
Pharmaceuticals 2018, 11(4), 133; https://doi.org/10.3390/ph11040133 - 30 Nov 2018
Cited by 34 | Viewed by 7941
Abstract
Photodynamic therapy (PDT) is an appealing therapeutic modality in management of some solid tumors and other diseases for its minimal invasion and non-systemic toxicity. However, the hydrophobicity and non-selectivity of the photosensitizers, inherent serious hypoxia of tumor tissues and limited penetration depth of [...] Read more.
Photodynamic therapy (PDT) is an appealing therapeutic modality in management of some solid tumors and other diseases for its minimal invasion and non-systemic toxicity. However, the hydrophobicity and non-selectivity of the photosensitizers, inherent serious hypoxia of tumor tissues and limited penetration depth of light restrict PDT further applications in clinic. Functional polymer nanoparticles can be used as a nanocarrier for accurate PDT. Here, we elucidate the mechanism and application of PDT in cancer treatments, and then review some strategies to administer the biodistribution and activation of photosensitizers (PSs) to ameliorate or utilize the tumor hypoxic microenvironment to enhance the photodynamic therapy effect. Full article
(This article belongs to the Special Issue Nano Drug Carriers)
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26 pages, 4009 KiB  
Article
Evaluation of Radiolabeled Girentuximab In Vitro and In Vivo
by Tais Basaco, Stefanie Pektor, Josue M. Bermudez, Niurka Meneses, Manfred Heller, José A. Galván, Kayluz F. Boligán, Stefan Schürch, Stephan Von Gunten, Andreas Türler and Matthias Miederer
Pharmaceuticals 2018, 11(4), 132; https://doi.org/10.3390/ph11040132 - 28 Nov 2018
Cited by 6 | Viewed by 5833
Abstract
Girentuximab (cG250) targets carbonic anhydrase IX (CAIX), a protein which is expressed on the surface of most renal cancer cells (RCCs). cG250 labeled with 177Lu has been used in clinical trials for radioimmunotherapy (RIT) of RCCs. In this work, an extensive characterization [...] Read more.
Girentuximab (cG250) targets carbonic anhydrase IX (CAIX), a protein which is expressed on the surface of most renal cancer cells (RCCs). cG250 labeled with 177Lu has been used in clinical trials for radioimmunotherapy (RIT) of RCCs. In this work, an extensive characterization of the immunoconjugates allowed optimization of the labeling conditions with 177Lu while maintaining immunoreactivity of cG250, which was then investigated in in vitro and in vivo experiments. cG250 was conjugated with S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (DOTA(SCN)) by using incubation times between 30 and 90 min and characterized by mass spectrometry. Immunoconjugates with five to ten DOTA(SCN) molecules per cG250 molecule were obtained. Conjugates with ratios less than six DOTA(SCN)/cG250 had higher in vitro antigen affinity, both pre- and postlabeling with 177Lu. Radiochemical stability increased, in the presence of sodium ascorbate, which prevents radiolysis. The immunoreactivity of the radiolabeled cG250 tested by specific binding to SK-RC-52 cells decreased when the DOTA content per conjugate increased. The in vivo tumor uptake was < 10% ID/g and independent of the total amount of protein in the range between 5 and 100 µg cG250 per animal. Low tumor uptake was found to be due to significant necrotic areas and heterogeneous CAIX expression. In addition, low vascularity indicated relatively poor accessibility of the CAIX target. Full article
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14 pages, 1119 KiB  
Review
Iron as a Therapeutic Target in HFE-Related Hemochromatosis: Usual and Novel Aspects
by Olivier Loréal, Thibault Cavey, François Robin, Moussa Kenawi, Pascal Guggenbuhl and Pierre Brissot
Pharmaceuticals 2018, 11(4), 131; https://doi.org/10.3390/ph11040131 - 26 Nov 2018
Cited by 11 | Viewed by 7162
Abstract
Genetic hemochromatosis is an iron overload disease that is mainly related to the C282Y mutation in the HFE gene. This gene controls the expression of hepcidin, a peptide secreted in plasma by the liver and regulates systemic iron distribution. Homozygous C282Y mutation induces [...] Read more.
Genetic hemochromatosis is an iron overload disease that is mainly related to the C282Y mutation in the HFE gene. This gene controls the expression of hepcidin, a peptide secreted in plasma by the liver and regulates systemic iron distribution. Homozygous C282Y mutation induces hepcidin deficiency, leading to increased circulating transferrin saturation, and ultimately, iron accumulation in organs such as the liver, pancreas, heart, and bone. Iron in excess may induce or favor the development of complications such as cirrhosis, liver cancer, diabetes, heart failure, hypogonadism, but also complaints such as asthenia and disabling arthritis. Iron depletive treatment mainly consists of venesections that permit the removal of iron contained in red blood cells and the subsequent mobilization of stored iron in order to synthesize hemoglobin for new erythrocytes. It is highly efficient in removing excess iron and preventing most of the complications associated with excess iron in the body. However, this treatment does not target the biological mechanisms involved in the iron metabolism disturbance. New treatments based on the increase of hepcidin levels, by using hepcidin mimetics or inducers, or inhibitors of the iron export activity of ferroportin protein that is the target of hepcidin, if devoid of significant secondary effects, should be useful to better control iron parameters and symptoms, such as arthritis. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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18 pages, 728 KiB  
Article
Cereus jamacaru D.C. Hydroalcoholic Extract Promotes Anti-Cytotoxic and Antitumor Activity
by Jean Carlos Vencioneck Dutra, Jean Moisés Ferreira, Paula Roberta Costalonga Pereira, Judá Ben-Hur de Oliveira, Suiany Vitorino Gervásio, Mirieli Bernardes Xavier, Mainã Mantovanelli da Mota, Anny Carolyne da Luz, Irany Rodrigues Pretti, Hildegardo Seibert França, Claudia Masrouah Jamal and Maria do Carmo Pimentel Batitucci
Pharmaceuticals 2018, 11(4), 130; https://doi.org/10.3390/ph11040130 - 23 Nov 2018
Cited by 16 | Viewed by 5160
Abstract
Cereus jamacaru D.C. (mandacaru) is a cactus used as food and in the traditional medicine. In the present study, hydroalcoholic extract of C. jamacaru was evaluated for its chemical composition, antioxidant activity, cytotoxic and anti-cytotoxic effects in human lymphocytes and sarcoma 180 cells [...] Read more.
Cereus jamacaru D.C. (mandacaru) is a cactus used as food and in the traditional medicine. In the present study, hydroalcoholic extract of C. jamacaru was evaluated for its chemical composition, antioxidant activity, cytotoxic and anti-cytotoxic effects in human lymphocytes and sarcoma 180 cells in vitro by MTT assay and antitumoral, mutagenic and cytotoxic effects on mice sarcoma-induced in vivo. Phytochemical characterization showed positive reactions for coumarin, flavanol and tyramine and total flavonoid content of 0.51 µg/mL. C. jamacaru showed antioxidant activity following DPPH (EC50 = 427.74 µg/mL), ABTS (EC50 = 270.57 µg/mL) and Fe2+ chelating ions assays (EC50 = 41.18 µg/mL). C. jamacaru induced significant decrease of sarcoma 180 viability at 24 h and 48 h of treatment, did not induce cytotoxicity in human lymphocytes and inhibits the cytotoxicity of cisplatin in vitro. Following in vivo assays, C. jamacaru promoted tumor reduction (86.07% of tumor inhibition), without inducing mutagenic or cytotoxic damage on mice blood cells. We propose that phenolic and alkaloid compounds in the extract are related to antioxidant activity, increasing its ability in metal chelating activity and promoting anti-cytotoxic activity against cisplatin, as well as these compounds may act on the cell cycle of the tumor cells in vitro and in vivo, leading to anticancer effects and tumor reduction. Full article
(This article belongs to the Special Issue Plant Phytochemicals on Drug Development)
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14 pages, 951 KiB  
Review
Brain Iron Homeostasis: A Focus on Microglial Iron
by Israel C. Nnah and Marianne Wessling-Resnick
Pharmaceuticals 2018, 11(4), 129; https://doi.org/10.3390/ph11040129 - 23 Nov 2018
Cited by 76 | Viewed by 9268
Abstract
Iron is an essential trace element required for important brain functions including oxidative metabolism, synaptic plasticity, myelination, and the synthesis of neurotransmitters. Disruptions in brain iron homeostasis underlie many neurodegenerative diseases. Increasing evidence suggests that accumulation of brain iron and chronic neuroinflammation, characterized [...] Read more.
Iron is an essential trace element required for important brain functions including oxidative metabolism, synaptic plasticity, myelination, and the synthesis of neurotransmitters. Disruptions in brain iron homeostasis underlie many neurodegenerative diseases. Increasing evidence suggests that accumulation of brain iron and chronic neuroinflammation, characterized by microglia activation and secretion of proinflammatory cytokines, are hallmarks of neurodegenerative disorders including Alzheimer’ s disease. While substantial efforts have led to an increased understanding of iron metabolism and the role of microglial cells in neuroinflammation, important questions still remain unanswered. Whether or not increased brain iron augments the inflammatory responses of microglial cells, including the molecular cues that guide such responses, is still unclear. How these brain macrophages accumulate, store, and utilize intracellular iron to carry out their various functions under normal and disease conditions is incompletely understood. Here, we describe the known and emerging mechanisms involved in microglial cell iron transport and metabolism as well as inflammatory responses in the brain, with a focus on AD. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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13 pages, 1430 KiB  
Review
Iron Supplementation in Suckling Piglets: An Ostensibly Easy Therapy of Neonatal Iron Deficiency Anemia
by Mateusz Szudzik, Rafał R. Starzyński, Aneta Jończy, Rafał Mazgaj, Małgorzata Lenartowicz and Paweł Lipiński
Pharmaceuticals 2018, 11(4), 128; https://doi.org/10.3390/ph11040128 - 22 Nov 2018
Cited by 41 | Viewed by 8714 | Correction
Abstract
In pigs, iron deficiency anemia (IDA) is the most prevalent deficiency disorder during the early postnatal period, frequently developing into a serious illness. On the other hand, in humans, only low-birth-weight infants, including premature infants, are especially susceptible to developing IDA. In both [...] Read more.
In pigs, iron deficiency anemia (IDA) is the most prevalent deficiency disorder during the early postnatal period, frequently developing into a serious illness. On the other hand, in humans, only low-birth-weight infants, including premature infants, are especially susceptible to developing IDA. In both human and pig neonates, the initial cause of IDA is low birth iron stores. In piglets this shortage of stored iron results mainly from genetic selection over the past few decades for large litter sizes and high birth weights. As a consequence, pregnant sows cannot provide a sufficient amount of iron to the increasing number of developing fetuses. Supplementation with iron is a common practice for the treatment of IDA in piglets. For decades, the preferred procedure for delivering iron supplements during early life stages has been through the intramuscular injection of a large amount of iron dextran. However, this relatively simple therapy, which in general, efficiently corrects IDA, may generate toxic effects, and by inducing hepcidin expression, may decrease bioavailability of supplemental iron. New iron supplements are considered herein with the aim to combine the improvement of hematological status, blunting of hepcidin expression, and minimizing the toxicity of the administered iron. We propose that iron-deficient piglets constitute a convenient animal model for performing pre-clinical studies with iron supplements. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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30 pages, 1417 KiB  
Review
Hepcidin Therapeutics
by Angeliki Katsarou and Kostas Pantopoulos
Pharmaceuticals 2018, 11(4), 127; https://doi.org/10.3390/ph11040127 - 21 Nov 2018
Cited by 75 | Viewed by 11509
Abstract
Hepcidin is a key hormonal regulator of systemic iron homeostasis and its expression is induced by iron or inflammatory stimuli. Genetic defects in iron signaling to hepcidin lead to “hepcidinopathies” ranging from hereditary hemochromatosis to iron-refractory iron deficiency anemia, which are disorders caused [...] Read more.
Hepcidin is a key hormonal regulator of systemic iron homeostasis and its expression is induced by iron or inflammatory stimuli. Genetic defects in iron signaling to hepcidin lead to “hepcidinopathies” ranging from hereditary hemochromatosis to iron-refractory iron deficiency anemia, which are disorders caused by hepcidin deficiency or excess, respectively. Moreover, dysregulation of hepcidin is a pathogenic cofactor in iron-loading anemias with ineffective erythropoiesis and in anemia of inflammation. Experiments with preclinical animal models provided evidence that restoration of appropriate hepcidin levels can be used for the treatment of these conditions. This fueled the rapidly growing field of hepcidin therapeutics. Several hepcidin agonists and antagonists, as well as inducers and inhibitors of hepcidin expression have been identified to date. Some of them were further developed and are currently being evaluated in clinical trials. This review summarizes the state of the art. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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18 pages, 3399 KiB  
Article
Effects of Boswellia Serrata Roxb. and Curcuma longa L. in an In Vitro Intestinal Inflammation Model Using Immune Cells and Caco-2
by Paolo Governa, Maddalena Marchi, Veronica Cocetta, Bianca De Leo, Philippa T. K. Saunders, Daniela Catanzaro, Elisabetta Miraldi, Monica Montopoli and Marco Biagi
Pharmaceuticals 2018, 11(4), 126; https://doi.org/10.3390/ph11040126 - 20 Nov 2018
Cited by 33 | Viewed by 10576
Abstract
Inflammatory bowel diseases, which consist of chronic inflammatory conditions of the colon and the small intestine, are considered a global disease of our modern society. Recently, the interest toward the use of herbal therapies for the management of inflammatory bowel diseases has increased [...] Read more.
Inflammatory bowel diseases, which consist of chronic inflammatory conditions of the colon and the small intestine, are considered a global disease of our modern society. Recently, the interest toward the use of herbal therapies for the management of inflammatory bowel diseases has increased because of their effectiveness and favourable safety profile, compared to conventional drugs. Boswellia serrata Roxb. and Curcuma longa L. are amongst the most promising herbal drugs, however, their clinical use in inflammatory bowel diseases is limited and little is known on their mechanism of action. The aim of this work was to investigate the effects of two phytochemically characterized extracts of B. serrata and C. longa in an in vitro model of intestinal inflammation. Their impact on cytokine release and reactive oxygen species production, as well as the maintenance of the intestinal barrier function and on intestinal mucosa immune cells infiltration, has been evaluated. The extracts showed a good protective effect on the intestinal epithelium at 1 µg/mL, with TEER values increasing by approximately 1.5 fold, compared to LPS-stimulated cells. C. longa showed an anti-inflammatory mechanism of action, reducing IL-8, TNF-α and IL-6 production by approximately 30%, 25% and 40%, respectively, compared to the inflammatory stimuli. B. serrata action was linked to its antioxidant effect, with ROS production being reduced by 25%, compared to H2O2-stimulated Caco-2 cells. C. longa and B. serrata resulted to be promising agents for the management of inflammatory bowel diseases by modulating in vitro parameters which have been identified in the clinical conditions. Full article
(This article belongs to the Special Issue Plant Phytochemicals on Drug Development)
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7 pages, 882 KiB  
Review
TRPM8 Channels and Dry Eye
by Jee Myung Yang, Edward T. Wei, Seong Jin Kim and Kyung Chul Yoon
Pharmaceuticals 2018, 11(4), 125; https://doi.org/10.3390/ph11040125 - 15 Nov 2018
Cited by 30 | Viewed by 5881
Abstract
Transient receptor potential (TRP) channels transduce signals of chemical irritation and temperature change from the ocular surface to the brain. Dry eye disease (DED) is a multifactorial disorder wherein the eyes react to trivial stimuli with abnormal sensations, such as dryness, blurring, presence [...] Read more.
Transient receptor potential (TRP) channels transduce signals of chemical irritation and temperature change from the ocular surface to the brain. Dry eye disease (DED) is a multifactorial disorder wherein the eyes react to trivial stimuli with abnormal sensations, such as dryness, blurring, presence of foreign body, discomfort, irritation, and pain. There is increasing evidence of TRP channel dysfunction (i.e., TRPV1 and TRPM8) in DED pathophysiology. Here, we review some of this literature and discuss one strategy on how to manage DED using a TRPM8 agonist. Full article
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18 pages, 1460 KiB  
Review
Emerging and Dynamic Biomedical Uses of Ferritin
by Brian Chiou and James R. Connor
Pharmaceuticals 2018, 11(4), 124; https://doi.org/10.3390/ph11040124 - 13 Nov 2018
Cited by 72 | Viewed by 13955
Abstract
Ferritin, a ubiquitously expressed protein, has classically been considered the main iron cellular storage molecule in the body. Owing to the ferroxidase activity of the H-subunit and the nucleation ability of the L-subunit, ferritin can store a large amount of iron within its [...] Read more.
Ferritin, a ubiquitously expressed protein, has classically been considered the main iron cellular storage molecule in the body. Owing to the ferroxidase activity of the H-subunit and the nucleation ability of the L-subunit, ferritin can store a large amount of iron within its mineral core. However, recent evidence has demonstrated a range of abilities of ferritin that extends well beyond the scope of iron storage. This review aims to discuss novel functions and biomedical uses of ferritin in the processes of iron delivery, delivery of biologics such as chemotherapies and contrast agents, and the utility of ferritin as a biomarker in a number of neurological diseases. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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21 pages, 1536 KiB  
Review
TNBC Challenge: Oligonucleotide Aptamers for New Imaging and Therapy Modalities
by Simona Camorani, Monica Fedele, Antonella Zannetti and Laura Cerchia
Pharmaceuticals 2018, 11(4), 123; https://doi.org/10.3390/ph11040123 - 13 Nov 2018
Cited by 38 | Viewed by 7276
Abstract
Compared to other breast cancers, triple-negative breast cancer (TNBC) usually affects younger patients, is larger in size, of higher grade and is biologically more aggressive. To date, conventional cytotoxic chemotherapy remains the only available treatment for TNBC because it lacks expression of the [...] Read more.
Compared to other breast cancers, triple-negative breast cancer (TNBC) usually affects younger patients, is larger in size, of higher grade and is biologically more aggressive. To date, conventional cytotoxic chemotherapy remains the only available treatment for TNBC because it lacks expression of the estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2), and no alternative targetable molecules have been identified so far. The high biological and clinical heterogeneity adds a further challenge to TNBC management and requires the identification of new biomarkers to improve detection by imaging, thus allowing the specific treatment of each individual TNBC subtype. The Systematic Evolution of Ligands by EXponential enrichment (SELEX) technique holds great promise to the search for novel targetable biomarkers, and aptamer-based molecular approaches have the potential to overcome obstacles of current imaging and therapy modalities. In this review, we highlight recent advances in oligonucleotide aptamers used as imaging and/or therapeutic agents in TNBC, discussing the potential options to discover, image and hit new actionable targets in TNBC. Full article
(This article belongs to the Special Issue Aptamer-Based Diagnostics and Therapeutics)
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7 pages, 202 KiB  
Article
Single-Blind Placebo-Controlled Response Test with Phenytoin 10% Cream in Neuropathic Pain Patients
by David J. Kopsky and Jan M. Keppel Hesselink
Pharmaceuticals 2018, 11(4), 122; https://doi.org/10.3390/ph11040122 - 12 Nov 2018
Cited by 13 | Viewed by 3489
Abstract
Background: Phenytoin cream applied topically has been explored in neuropathic pain conditions. In several case series, phenytoin 5% and 10% cream could reduce pain in a clinically relevant way with a fast onset of action within 30 min, and with positive effects on [...] Read more.
Background: Phenytoin cream applied topically has been explored in neuropathic pain conditions. In several case series, phenytoin 5% and 10% cream could reduce pain in a clinically relevant way with a fast onset of action within 30 min, and with positive effects on sleep. Objective: To evaluate a single-blind placebo-controlled response test (SIBRET) for use in clinical practice. Materials and Methods: Patients with localized neuropathic pain, having an equal pain intensity in at least 2 areas (e.g., both feet), and a pain intensity of at least 4 on the 11-point numerical rating scale (NRS), were selected to perform the SIBRET. In one area, placebo cream consisting of the base cream was applied, and on the other area, phenytoin 10% cream was applied with separate hands to avoid contamination. Responders were defined as patients who experienced within 30 min at least 2-points difference as scored on the NRS, between the phenytoin 10% and the placebo cream applied areas, in favor of the former. Responders were subsequently prescribed phenytoin 10% cream. Results: Of the 21 patients, 15 patients (71.45%) were classified as responders. The mean pain reduction after 30 min as measured with the NRS in the phenytoin 10% cream area was 3.3 (SD: 1.3) and in the placebo cream area 1.2 (SD: 1.1). The difference of the mean percentage pain reduction between phenytoin 10% cream and placebo cream was 33.2% (SD: 17.6, p < 0.001). Using a 50% reduction on the NRS as a full response criterion, we could identify 57.1% of responders on phenytoin 10% cream and only 9.5% responders on placebo cream. Conclusions: The SIBRET helps patients and clinicians to quickly identify the appropriate treatment and can thus be seen as an important contributor to the domain of personalized medicine in pain. These results can also be regarded as a proof of principle for the analgesic activity of 10% phenytoin cream. Full article
19 pages, 657 KiB  
Review
Antidiabetic Drugs in NAFLD: The Accomplishment of Two Goals at Once?
by Matteo Tacelli, Ciro Celsa, Bianca Magro, Aurora Giannetti, Grazia Pennisi, Federica Spatola and Salvatore Petta
Pharmaceuticals 2018, 11(4), 121; https://doi.org/10.3390/ph11040121 - 8 Nov 2018
Cited by 41 | Viewed by 6681
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common cause of chronic liver disease in Western countries, accounting for 20–30% of general population and reaching a prevalence of 55% in patients with type 2 diabetes mellitus (T2DM). Insulin resistance plays a key role [...] Read more.
Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common cause of chronic liver disease in Western countries, accounting for 20–30% of general population and reaching a prevalence of 55% in patients with type 2 diabetes mellitus (T2DM). Insulin resistance plays a key role in pathogenic mechanisms of NAFLD. Many drugs have been tested but no medications have yet been approved. Antidiabetic drugs could have a role in the progression reduction of the disease. The aim of this review is to summarize evidence on efficacy and safety of antidiabetic drugs in patients with NAFLD. Metformin, a biguanide, is the most frequently used drug in the treatment of T2DM. To date 15 randomized controlled trials (RCTs) and four meta-analysis on the use of metformin in NAFLD are available. No significant improvement in histological liver fibrosis was shown, but it can be useful in the treatment of co-factors of NAFLD, like body weight, transaminase or cholesterol levels, and HbA1c levels. A possible protective role in various types of cancer has been reported for Metformin. Thiazolidinediones modulate insulin sensitivity by the activation of PPAR-γ. The RCTs and the meta-analysis available about the role of these drugs in NAFLD show an improvement in ballooning, lobular inflammation, and perhaps fibrosis, but some side effects, in particular cardiovascular, were showed. GLP-1 analogues stimulate insulin secretion by pancreatic beta cell and inhibit glucagon release; Liraglutide is the most used drug in this class and significantly improves steatosis, hepatocyte ballooning and transaminase levels. Scanty data about the role of DPP-4 and SGLT inhibitors were published. No data about insulin effects on NAFLD are available but it was showed a possible association between insulin use and the development of solid neoplasms, in particular HCC. In conclusion, antidiabetic drugs seem to be promising drugs, because they are able to treat both NAFLD manifestations and diabetes, preventing worsening of hepatic damage, but data are still conflicting. All antidiabetic drugs can be safely used in patients with compensated cirrhosis, while insulin is the preferred drug in decompensated Child C cirrhosis. Full article
(This article belongs to the Special Issue New Advances in the Treatment of Nonalcoholic Fatty Liver Disease)
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14 pages, 3002 KiB  
Review
Reductive Mobilization of Iron from Intact Ferritin: Mechanisms and Physiological Implication
by Fadi Bou-Abdallah, John J. Paliakkara, Galina Melman and Artem Melman
Pharmaceuticals 2018, 11(4), 120; https://doi.org/10.3390/ph11040120 - 5 Nov 2018
Cited by 47 | Viewed by 6223
Abstract
Ferritins are highly conserved supramolecular protein nanostructures composed of two different subunit types, H (heavy) and L (light). The two subunits co-assemble into a 24-subunit heteropolymer, with tissue specific distributions, to form shell-like protein structures within which thousands of iron atoms are stored [...] Read more.
Ferritins are highly conserved supramolecular protein nanostructures composed of two different subunit types, H (heavy) and L (light). The two subunits co-assemble into a 24-subunit heteropolymer, with tissue specific distributions, to form shell-like protein structures within which thousands of iron atoms are stored as a soluble inorganic ferric iron core. In-vitro (or in cell free systems), the mechanisms of iron(II) oxidation and formation of the mineral core have been extensively investigated, although it is still unclear how iron is loaded into the protein in-vivo. In contrast, there is a wide spread belief that the major pathway of iron mobilization from ferritin involves a lysosomal proteolytic degradation of ferritin, and the dissolution of the iron mineral core. However, it is still unclear whether other auxiliary iron mobilization mechanisms, involving physiological reducing agents and/or cellular reductases, contribute to the release of iron from ferritin. In vitro iron mobilization from ferritin can be achieved using different reducing agents, capable of easily reducing the ferritin iron core, to produce soluble ferrous ions that are subsequently chelated by strong iron(II)-chelating agents. Here, we review our current understanding of iron mobilization from ferritin by various reducing agents, and report on recent results from our laboratory, in support of a mechanism that involves a one-electron transfer through the protein shell to the iron mineral core. The physiological significance of the iron reductive mobilization from ferritin by the non-enzymatic FMN/NAD(P)H system is also discussed. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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14 pages, 3249 KiB  
Article
Design, Synthesis, Experimental and Theoretical Characterization of a New Multitarget 2-Thienyl-N-Acylhydrazone Derivative
by Isadora T. S. Bastos, Pedro de Sena M. Pinheiro, Fanny N. Costa, Miguel D. Rocha, Carlos Mauricio R. Sant’Anna, Delson Braz, Everton T. Souza, Marco A. Martins, Eliezer J. Barreiro, Fabio F. Ferreira, Regina C. Barroso and Carlos A. M. Fraga
Pharmaceuticals 2018, 11(4), 119; https://doi.org/10.3390/ph11040119 - 1 Nov 2018
Cited by 8 | Viewed by 4042
Abstract
Pulmonary arterial hypertension (PAH) is a chronic cardiovascular disease that displays inflammatory components, which contributes to the difficulty of adequate treatment with the available therapeutic arsenal. In this context, the N-acylhydrazone derivative LASSBio-1359 was previously described as a multitarget drug candidate able [...] Read more.
Pulmonary arterial hypertension (PAH) is a chronic cardiovascular disease that displays inflammatory components, which contributes to the difficulty of adequate treatment with the available therapeutic arsenal. In this context, the N-acylhydrazone derivative LASSBio-1359 was previously described as a multitarget drug candidate able to revert the events associated with the progression of PAH in animal models. However, in spite of having a dual profile as PDE4 inhibitor and adenosine A2A receptor agonist, LASSBio-1359 does not present balanced potencies in the modulation of these two targets, which difficult its therapeutic use. In this paper, we describe the design concept of LASSBio-1835, a novel structural analogue of LASSBio-1359, planned by exploiting ring bioisosterism. Using X-ray powder diffraction, calorimetric techniques, and molecular modeling, we clearly indicate the presence of a preferred synperiplanar conformation at the amide function, which is fixed by an intramolecular 1,5-N∙∙∙S σ-hole intramolecular interaction. Moreover, the evaluation of LASSBio-1835 (4) as a PDE4 inhibitor and as an A2A agonist confirms it presents a more balanced dual profile, being considered a promising prototype for the treatment of PAH. Full article
(This article belongs to the Special Issue Choices of the Journal)
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24 pages, 5276 KiB  
Review
Lipid Nanoparticles and Their Hydrogel Composites for Drug Delivery: A Review
by Claire Desfrançois, Rachel Auzély and Isabelle Texier
Pharmaceuticals 2018, 11(4), 118; https://doi.org/10.3390/ph11040118 - 1 Nov 2018
Cited by 75 | Viewed by 13507
Abstract
Several drug delivery systems already exist for the encapsulation and subsequent release of lipophilic drugs that are well described in the scientific literature. Among these, lipid nanoparticles (LNP) have specifically come up for dermal, transdermal, mucosal, intramuscular and ocular drug administration routes in [...] Read more.
Several drug delivery systems already exist for the encapsulation and subsequent release of lipophilic drugs that are well described in the scientific literature. Among these, lipid nanoparticles (LNP) have specifically come up for dermal, transdermal, mucosal, intramuscular and ocular drug administration routes in the last twenty years. However, for some of them (especially dermal, transdermal, mucosal), the LNP aqueous dispersions display unsuitable rheological properties. They therefore need to be processed as semi-solid formulations such as LNP-hydrogel composites to turn into versatile drug delivery systems able to provide precise spatial and temporal control of active ingredient release. In the present review, recent developments in the formulation of lipid nanoparticle-hydrogel composites are highlighted, including examples of successful encapsulation and release of lipophilic drugs through the skin, the eyes and by intramuscular injections. In relation to lipid nanoparticles, a specific emphasis has been put on the LNP key properties and how they influence their inclusion in the hydrogel. Polymer matrices include synthetic polymers such as poly(acrylic acid)-based materials, environment responsive (especially thermo-sensitive) polymers, and innovative polysaccharide-based hydrogels. The composite materials constitute smart, tunable drug delivery systems with a wide range of features, suitable for dermal, transdermal, and intramuscular controlled drug release. Full article
(This article belongs to the Special Issue Nano Drug Carriers)
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19 pages, 611 KiB  
Review
TRPA1 Antagonists for Pain Relief
by Ari Koivisto, Niina Jalava, Raymond Bratty and Antti Pertovaara
Pharmaceuticals 2018, 11(4), 117; https://doi.org/10.3390/ph11040117 - 1 Nov 2018
Cited by 87 | Viewed by 9703
Abstract
Here, we review the literature assessing the role of transient receptor potential ankyrin 1 (TRPA1), a calcium-permeable non-selective cation channel, in various types of pain conditions. In the nervous system, TRPA1 is expressed in a subpopulation of nociceptive primary sensory neurons, astroglia, oligodendrocytes [...] Read more.
Here, we review the literature assessing the role of transient receptor potential ankyrin 1 (TRPA1), a calcium-permeable non-selective cation channel, in various types of pain conditions. In the nervous system, TRPA1 is expressed in a subpopulation of nociceptive primary sensory neurons, astroglia, oligodendrocytes and Schwann cells. In peripheral terminals of nociceptive primary sensory neurons, it is involved in the transduction of potentially harmful stimuli and in their central terminals it is involved in amplification of nociceptive transmission. TRPA1 is a final common pathway for a large number of chemically diverse pronociceptive agonists generated in various pathophysiological pain conditions. Thereby, pain therapy using TRPA1 antagonists can be expected to be a superior approach when compared with many other drugs targeting single nociceptive signaling pathways. In experimental animal studies, pharmacological or genetic blocking of TRPA1 has effectively attenuated mechanical and cold pain hypersensitivity in various experimental models of pathophysiological pain, with only minor side effects, if any. TRPA1 antagonists acting peripherally are likely to be optimal for attenuating primary hyperalgesia (such as inflammation-induced sensitization of peripheral nerve terminals), while centrally acting TRPA1 antagonists are expected to be optimal for attenuating pain conditions in which central amplification of transmission plays a role (such as secondary hyperalgesia and tactile allodynia caused by various types of peripheral injuries). In an experimental model of peripheral diabetic neuropathy, prolonged blocking of TRPA1 has delayed the loss of nociceptive nerve endings and their function, thereby promising to provide a disease-modifying treatment. Full article
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13 pages, 1835 KiB  
Article
Variation in Prescription Opioid Dispensing across Neighborhoods of Diverse Socioeconomic Disadvantages in Victoria, Australia
by M Mofizul Islam and Dennis Wollersheim
Pharmaceuticals 2018, 11(4), 116; https://doi.org/10.3390/ph11040116 - 1 Nov 2018
Cited by 10 | Viewed by 4560
Abstract
The study examined the relationship between dispensing patterns of prescription opioids, neighborhood-disadvantage-index, and standardized doses dispensed. Three-year’s dispensing data drawn from 80 local government areas (LGAs) within Victoria, Australia’s second most populous state, was analyzed. Quantities dispensed in defined daily dose (DDD)/1000-people/day were [...] Read more.
The study examined the relationship between dispensing patterns of prescription opioids, neighborhood-disadvantage-index, and standardized doses dispensed. Three-year’s dispensing data drawn from 80 local government areas (LGAs) within Victoria, Australia’s second most populous state, was analyzed. Quantities dispensed in defined daily dose (DDD)/1000-people/day were computed for LGAs of low, moderate, high, and very high socio-economic disadvantage. LGAs with various levels of dispensing, and neighborhood disadvantage were identified and mapped. A multivariable regression model examined the effect of neighborhood level disadvantage and identified other factors that are associated with standardized doses dispensed. More women were dispensed opioids than men. Dispensing increased with increasing age. Most of the LGAs with relatively high dispensing were socioeconomically disadvantaged and located outside the major cities. Dispensing gradually increased from low disadvantage to very high disadvantage areas. Dispensing of standardized doses were consistently higher in rural areas than in urban areas. Neighborhood level disadvantage, age, sex, and urbanization were significant factors in the standardized doses dispensed. As inappropriate dispensing of opioids is a major public health problem, research should facilitate understanding of utilization in small areas to enable tailored public health programs. Nationwide and consistent introduction of real-time prescription drug-monitoring programs, and structural interventions to reduce the fundamental causes of socioeconomic disadvantage and isolation are recommended. Full article
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20 pages, 2749 KiB  
Review
The Functional Versatility of Transferrin Receptor 2 and Its Therapeutic Value
by Antonella Roetto, Mariarosa Mezzanotte and Rosa Maria Pellegrino
Pharmaceuticals 2018, 11(4), 115; https://doi.org/10.3390/ph11040115 - 23 Oct 2018
Cited by 19 | Viewed by 5972
Abstract
Iron homeostasis is a tightly regulated process in all living organisms because this metal is essential for cellular metabolism, but could be extremely toxic when present in excess. In mammals, there is a complex pathway devoted to iron regulation, whose key protein is [...] Read more.
Iron homeostasis is a tightly regulated process in all living organisms because this metal is essential for cellular metabolism, but could be extremely toxic when present in excess. In mammals, there is a complex pathway devoted to iron regulation, whose key protein is hepcidin (Hepc), which is a powerful iron absorption inhibitor mainly produced by the liver. Transferrin receptor 2 (Tfr2) is one of the hepcidin regulators, and mutations in TFR2 gene are responsible for type 3 hereditary hemochromatosis (HFE3), a genetically heterogeneous disease characterized by systemic iron overload. It has been recently pointed out that Hepc production and iron regulation could be exerted also in tissues other than liver, and that Tfr2 has an extrahepatic role in iron metabolism as well. This review summarizes all the most recent data on Tfr2 extrahepatic role, taking into account the putative distinct roles of the two main Tfr2 isoforms, Tfr2α and Tfr2β. Representing Hepc modulation an effective approach to correct iron balance impairment in common human diseases, and with Tfr2 being one of its regulators, it would be worthwhile to envisage Tfr2 as a therapeutic target. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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16 pages, 1085 KiB  
Review
The Role of NCOA4-Mediated Ferritinophagy in Health and Disease
by Naiara Santana-Codina and Joseph D. Mancias
Pharmaceuticals 2018, 11(4), 114; https://doi.org/10.3390/ph11040114 - 23 Oct 2018
Cited by 213 | Viewed by 17069
Abstract
Nuclear receptor coactivator 4 (NCOA4) is a selective cargo receptor that mediates the autophagic degradation of ferritin (“ferritinophagy”), the cytosolic iron storage complex. NCOA4-mediated ferritinophagy maintains intracellular iron homeostasis by facilitating ferritin iron storage or release according to demand. Ferritinophagy is involved in [...] Read more.
Nuclear receptor coactivator 4 (NCOA4) is a selective cargo receptor that mediates the autophagic degradation of ferritin (“ferritinophagy”), the cytosolic iron storage complex. NCOA4-mediated ferritinophagy maintains intracellular iron homeostasis by facilitating ferritin iron storage or release according to demand. Ferritinophagy is involved in iron-dependent physiological processes such as erythropoiesis, where NCOA4 mediates ferritin iron release for mitochondrial heme synthesis. Recently, ferritinophagy has been shown to regulate ferroptosis, a newly described form of iron-dependent cell death mediated by excess lipid peroxidation. Dysregulation of iron metabolism and ferroptosis have been described in neurodegeneration, cancer, and infection, but little is known about the role of ferritinophagy in the pathogenesis of these diseases. Here, we will review the biochemical regulation of NCOA4, its contribution to physiological processes and its role in disease. Finally, we will discuss the potential of activating or inhibiting ferritinophagy and ferroptosis for therapeutic purposes. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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14 pages, 783 KiB  
Review
Links Between Iron and Lipids: Implications in Some Major Human Diseases
by Stephanie Rockfield, Ravneet Chhabra, Michelle Robertson, Nabila Rehman, Richa Bisht and Meera Nanjundan
Pharmaceuticals 2018, 11(4), 113; https://doi.org/10.3390/ph11040113 - 22 Oct 2018
Cited by 53 | Viewed by 5438
Abstract
Maintenance of iron homeostasis is critical to cellular health as both its excess and insufficiency are detrimental. Likewise, lipids, which are essential components of cellular membranes and signaling mediators, must also be tightly regulated to hinder disease progression. Recent research, using a myriad [...] Read more.
Maintenance of iron homeostasis is critical to cellular health as both its excess and insufficiency are detrimental. Likewise, lipids, which are essential components of cellular membranes and signaling mediators, must also be tightly regulated to hinder disease progression. Recent research, using a myriad of model organisms, as well as data from clinical studies, has revealed links between these two metabolic pathways, but the mechanisms behind these interactions and the role these have in the progression of human diseases remains unclear. In this review, we summarize literature describing cross-talk between iron and lipid pathways, including alterations in cholesterol, sphingolipid, and lipid droplet metabolism in response to changes in iron levels. We discuss human diseases correlating with both iron and lipid alterations, including neurodegenerative disorders, and the available evidence regarding the potential mechanisms underlying how iron may promote disease pathogenesis. Finally, we review research regarding iron reduction techniques and their therapeutic potential in treating patients with these debilitating conditions. We propose that iron-mediated alterations in lipid metabolic pathways are involved in the progression of these diseases, but further research is direly needed to elucidate the mechanisms involved. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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14 pages, 648 KiB  
Review
Potential Treatment of Retinal Diseases with Iron Chelators
by Wanting Shu and Joshua L. Dunaief
Pharmaceuticals 2018, 11(4), 112; https://doi.org/10.3390/ph11040112 - 22 Oct 2018
Cited by 35 | Viewed by 6079
Abstract
Iron is essential for life, while excess iron can be toxic. Iron generates hydroxyl radical, which is the most reactive free radical, causing oxidative stress. Since iron is absorbed through the diet but not excreted from the body, it accumulates with age in [...] Read more.
Iron is essential for life, while excess iron can be toxic. Iron generates hydroxyl radical, which is the most reactive free radical, causing oxidative stress. Since iron is absorbed through the diet but not excreted from the body, it accumulates with age in tissues, including the retina, consequently leading to age-related toxicity. This accumulation is further promoted by inflammation. Hereditary diseases such as aceruloplasminemia, Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration, and posterior column ataxia with retinitis pigmentosa involve retinal degeneration associated with iron dysregulation. In addition to hereditary causes, dietary or parenteral iron supplementation has been recently reported to elevate iron levels in the retinal pigment epithelium (RPE) and promote retinal degeneration. Ocular siderosis from intraocular foreign bodies or subretinal hemorrhage can also lead to retinopathy. Evidence from mice and humans suggests that iron toxicity may contribute to age-related macular degeneration pathogenesis. Iron chelators can protect photoreceptors and RPE in various mouse models. The therapeutic potential for iron chelators is under investigation. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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15 pages, 2064 KiB  
Review
Protective Role of Histidine Supplementation Against Oxidative Stress Damage in the Management of Anemia of Chronic Kidney Disease
by Mayra Vera-Aviles, Eleni Vantana, Emmy Kardinasari, Ngat L. Koh and Gladys O. Latunde-Dada
Pharmaceuticals 2018, 11(4), 111; https://doi.org/10.3390/ph11040111 - 21 Oct 2018
Cited by 62 | Viewed by 9775
Abstract
Anemia is a major health condition associated with chronic kidney disease (CKD). A key underlying cause of this disorder is iron deficiency. Although intravenous iron treatment can be beneficial in correcting CKD-associated anemia, surplus iron can be detrimental and cause complications. Excessive generation [...] Read more.
Anemia is a major health condition associated with chronic kidney disease (CKD). A key underlying cause of this disorder is iron deficiency. Although intravenous iron treatment can be beneficial in correcting CKD-associated anemia, surplus iron can be detrimental and cause complications. Excessive generation of reactive oxygen species (ROS), particularly by mitochondria, leads to tissue oxidation and damage to DNA, proteins, and lipids. Oxidative stress increase in CKD has been further implicated in the pathogenesis of vascular calcification. Iron supplementation leads to the availability of excess free iron that is toxic and generates ROS that is linked, in turn, to inflammation, endothelial dysfunction, and cardiovascular disease. Histidine is indispensable to uremic patients because of the tendency toward negative plasma histidine levels. Histidine-deficient diets predispose healthy subjects to anemia and accentuate anemia in chronic uremic patients. Histidine is essential in globin synthesis and erythropoiesis and has also been implicated in the enhancement of iron absorption from human diets. Studies have found that L-histidine exhibits antioxidant capabilities, such as scavenging free radicals and chelating divalent metal ions, hence the advocacy for its use in improving oxidative stress in CKD. The current review advances and discusses evidence for iron-induced toxicity in CKD and the mechanisms by which histidine exerts cytoprotective functions. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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24 pages, 7176 KiB  
Review
Tuning the Anti(myco)bacterial Activity of 3-Hydroxy-4-pyridinone Chelators through Fluorophores
by Maria Rangel, Tânia Moniz, André M. N. Silva and Andreia Leite
Pharmaceuticals 2018, 11(4), 110; https://doi.org/10.3390/ph11040110 - 20 Oct 2018
Cited by 9 | Viewed by 4907
Abstract
Controlling the sources of Fe available to pathogens is one of the possible strategies that can be successfully used by novel antibacterial drugs. We focused our interest on the design of chelators to address Mycobacterium avium infections. Taking into account the molecular structure [...] Read more.
Controlling the sources of Fe available to pathogens is one of the possible strategies that can be successfully used by novel antibacterial drugs. We focused our interest on the design of chelators to address Mycobacterium avium infections. Taking into account the molecular structure of mycobacterial siderophores and considering that new chelators must be able to compete for Fe(III), we selected ligands of the 3-hydroxy-4-pyridinone class to achieve our purpose. After choosing the type of chelating unit it was also our objective to design chelators that could be monitored inside the cell and for that reason we designed chelators that could be functionalized with fluorophores. We didn’t realize at the time that the incorporation a fluorophore, to allow spectroscopic detection, would be so relevant for the antimycobacterial effect or to determine the affinity of the chelators towards biological membranes. From a biophysical perspective, this is a fascinating illustration of the fact that functionalization of a molecule with a particular label may lead to a change in its membrane permeation properties and result in a dramatic change in biological activity. For that reason we believe it is interesting to give a critical account of our entire work in this area and justify the statement “to label means to change”. New perspectives regarding combined therapeutic approaches and the use of rhodamine B conjugates to target closely related problems such as bacterial resistance and biofilm production are also discussed. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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22 pages, 635 KiB  
Review
New Perspectives in Iron Chelation Therapy for the Treatment of Neurodegenerative Diseases
by Marco T. Nuñez and Pedro Chana-Cuevas
Pharmaceuticals 2018, 11(4), 109; https://doi.org/10.3390/ph11040109 - 19 Oct 2018
Cited by 102 | Viewed by 10041
Abstract
Iron chelation has been introduced as a new therapeutic concept for the treatment of neurodegenerative diseases with features of iron overload. At difference with iron chelators used in systemic diseases, effective chelators for the treatment of neurodegenerative diseases must cross the blood–brain barrier. [...] Read more.
Iron chelation has been introduced as a new therapeutic concept for the treatment of neurodegenerative diseases with features of iron overload. At difference with iron chelators used in systemic diseases, effective chelators for the treatment of neurodegenerative diseases must cross the blood–brain barrier. Given the promissory but still inconclusive results obtained in clinical trials of iron chelation therapy, it is reasonable to postulate that new compounds with properties that extend beyond chelation should significantly improve these results. Desirable properties of a new generation of chelators include mitochondrial destination, the center of iron-reactive oxygen species interaction, and the ability to quench free radicals produced by the Fenton reaction. In addition, these chelators should have moderate iron binding affinity, sufficient to chelate excessive increments of the labile iron pool, estimated in the micromolar range, but not high enough to disrupt physiological iron homeostasis. Moreover, candidate chelators should have selectivity for the targeted neuronal type, to lessen unwanted secondary effects during long-term treatment. Here, on the basis of a number of clinical trials, we discuss critically the current situation of iron chelation therapy for the treatment of neurodegenerative diseases with an iron accumulation component. The list includes Parkinson’s disease, Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration, Huntington disease and Alzheimer’s disease. We also review the upsurge of new multifunctional iron chelators that in the future may replace the conventional types as therapeutic agents for the treatment of neurodegenerative diseases. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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