scholarly journals Selective Inhibition of ALK2 Signaling Suppresses Serum Hepcidin and Increases Serum Iron

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 14-14
Author(s):  
Thomas A Backus ◽  
Natalia Medeiros ◽  
Evan Lema ◽  
Ffolliott Fisher ◽  
Jasbir Seehra ◽  
...  
Keyword(s):  
Small Molecule ◽  
Serum Iron ◽  
Disease State ◽  
Deficiency Anemia ◽  
Publicly Traded ◽  
Multiple Modalities ◽  
Iron Mobilization ◽  
Bmp Receptors ◽  
Serum Hepcidin

Hepcidin is an endocrine regulator of iron metabolism that, when elevated, can decrease levels of iron available for erythropoiesis and, as a result, decrease red blood cell production. Signaling though activin-like kinase-2 (ALK2), a TGFβ type 1 receptor, has been implicated in regulation of hepcidin-mediated iron regulation and mobilization; however, to date, ALK2's specific degree of involvement has not been convincingly elucidated, mainly due to the redundant effects of the type 1 receptors ALK3 and ALK5. Activation of type 1 receptors including ALK2, ALK3, and ALK5 via ligand BMPs and co-receptor hemojuvelin (m-HJV), results in downstream SMAD phosphorylation, increased hepcidin, and decreased serum iron while suppression of the receptor signaling would have the opposite effects. In order to assess the specific effect of ALK2 inhibition on hepcidin and iron mobilization, we utilized multiple modalities of inhibition and tested inhibitors in both naive and diseased animals. KTI-2338, a small molecule ALK2 kinase inhibitor, has been characterized to inhibit ALK2 signaling potently and selectively in in-vitro assays. To further assess the specific contribution of ALK2 to hepcidin expression and iron mobilization, we evaluated the effect of the novel neutralizing antibody KTI-A2.0MAb. This fully human antibody is targeted against the extracellular domain of ALK2 with no affinity for the other type 1 receptors and provides a unique tool for understanding ALK2 involvement in this system. In wild-type animals, targeting ALK2 signaling with either a small molecule or biologic therapeutic leads to decreased serum hepcidin and increased serum iron. To assess the efficacy of ALK2 inhibition in a disease state, we utilized an siRNA-based model of Iron Refractory Iron Deficiency Anemia (IRIDA). In IRIDA, patients exhibit a loss of functional TMPRSS6, a gene that encodes the transmembrane type II serine protease Matriptase-2 (MT-2). MT-2 suppresses hepcidin secretion by cleaving m-HJV, interrupting ALK2 signaling and downstream SMAD activation. Failure to cleave m-HJV allows continued activation of BMPRs, increased hepcidin, and decreased serum iron. Phenocopying what is observed in IRIDA patients, intravenous dosing of TMPRSS6 targeted siRNA results in suppressed TMPRSS6 expression and functional MT-2, increases in serum hepcidin, and decreases in serum iron. Therapeutic dosing of either a small molecule or biologic ALK2 inhibitor in the siRNA based IRIDA model resulted in rescue of hemoglobin, hematocrit, serum hepcidin, and serum iron in the disease state. Following treatment, hemoglobin, hematocrit, and serum iron were increased and serum hepcidin was decreased in treated groups compared to control cohorts receiving vehicle. Herein, we have evaluated multiple modalities of ALK2 inhibition in both healthy and disease states. We have characterized that inhibition of ALK2 signaling via either modality in both naïve and anemic mice contributes to a decrease in serum hepcidin and increase in serum iron levels. Though the use of a selective ALK2 targeted biologic does not completely preclude involvement of other BMP receptors such as ALK3, these data support our assertion that ALK2 signaling is an integral part of hepcidin-mediated iron mobilization, and illustrate the potential therapeutic benefit of ALK2 inhibition (with a small molecule inhibitor or a neutralizing monoclonal antibody) in anemia of high hepcidin including IRIDA and anemia of inflammation. Disclosures Backus: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Medeiros:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lema:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Fisher:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Seehra:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lachey:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company.

Serum Hepcidin: Its Correlation with Serum Ferritin, Serum Iron and Hemoglobin in Patients of Iron Deficiency Anemia

2015 ◽  
Vol 14 (2) ◽  
pp. 105-113
Author(s):  
Sajjad H. Naqvi ◽  
Syed Faizan-ul-Hassan Naqvi ◽  
Iftikhar H. Naqvi ◽  
Muhammad Farhan ◽  
Tanveer Abbas ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Serum Ferritin ◽  
Serum Iron ◽  
Deficiency Anemia ◽  
Serum Hepcidin

scholarly journals Characterization of INCB00928, a Potent and Selective ALK2 Inhibitor for the Treatment of Anemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 52-52
Author(s):  
Yaoyu Chen ◽  
Matthew C. Stubbs ◽  
Michelle Pusey ◽  
Xiaoming Wen ◽  
Robert J. Collins ◽  
...  
Keyword(s):  
Small Molecule ◽  
Human Liver ◽  
Small Molecule Inhibitor ◽  
Deficiency Anemia ◽  
Type I ◽  
Dependent Manner ◽  
Publicly Traded ◽  
Molecule Inhibitor ◽  
Dose Dependent

A significant population of patients with myelofibrosis (MF) develop anemia and either require red blood cell (RBC) transfusions or have an inadequate response to the currently available therapies and become transfusion-dependent. In patients with MF, elevated levels of serum hepcidin, a key iron regulatory hormone, is associated with increased dependence on RBC transfusions and reduced overall survival. Elevated hepcidin expression has also been observed to cause severe functional iron deficiency anemia and is central to the pathophysiology of anemia of chronic disease. Thus, to ensure proper maintenance of iron homeostasis, hepcidin levels are tightly regulated. Specifically, the production of hepcidin is controlled by the bone morphogenetic protein (BMP) type I receptor ACVR1, a gene that encodes the serine/threonine kinase ALK2. In preclinical models, knockdown or complete loss of ALK2 decreases hepcidin production resulting in elevated serum iron levels. In this study, we report characterization of INCB00928, a novel small molecule inhibitor of ALK2 for the treatment of anemia. INCB00928 was observed to have subnanomolar activity against ALK2 and selectivity over ALK1 and ALK3 in biochemical enzyme assays. In cell-based profiling studies, INCB00928 inhibited ALK2 potently and selectively over ALK1 and ALK3 as determined by the inhibition of ligand-induced SMAD pathway signaling. Importantly, in both an immortalized human liver cell line as well as primary human hepatocytes, INCB00928 inhibited BMP-induced production of hepcidin with nanomolar activity. INCB00928 was also observed to have suitable absorption, distribution, metabolism, and excretion properties to be dosed in in vivo rodent studies. In tumor- and inflammation-induced mouse models of anemia, INCB00928 improved RBC count, hemoglobin, and hematocrit levels while decreasing hepcidin levels in a dose-dependent manner. Additionally, consistent with the improved symptoms of anemia, pSMAD1/5 inhibition was observed in a dose-dependent manner in liver tissues collected from INCB00928-treated mice. In summary, INCB00928 is a potent, selective, and orally available small molecule inhibitor of ALK2, which significantly reduces the production of hepcidin in human liver cells, primary hepatocytes, and in rodent models of anemia. For the majority of patients with MF, the management of anemia remains an unmet need. The preclinical findings from this study suggest ALK2 kinase inhibition with INCB00928 may be a promising novel treatment to reduce the production of hepcidin and improve MF-related anemia in humans, thus warranting further investigation. Disclosures Chen: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Stubbs:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Pusey:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Wen:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Collins:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Kapilashrami:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Rupar:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Thekkat:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Lin:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Bowman:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Yang:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Diamond:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Yeleswaram:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Kim:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Koblish:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Chen:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Wee:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company.

scholarly journals Prognosis of iron deficiency anemia in pregnant women with different somatotypes

2021 ◽  
Vol 70 (2) ◽  
pp. 83-89
Author(s):  
Kristina G. Tomayeva ◽  
Sergey N. Gaidukov ◽  
Elena N. Komissarova ◽  
Leonid A. Kokoyev
Keyword(s):  
Iron Deficiency ◽  
Pregnant Women ◽  
Iron Deficiency Anemia ◽  
Serum Iron ◽  
Hematological Parameters ◽  
Colorimetric Method ◽  
First Trimester ◽  
Study Groups ◽  
Deficiency Anemia ◽  
Serum Hepcidin

BACKGROUND: Anemia during pregnancy, undiagnosed and untreated promptly, is the cause of various obstetric complications: spontaneous miscarriages, premature birth, placental insufficiency, obstetric bleeding, ante- and intrapartum fetal death. AIM: The aim of this study was to evaluate the incidence of iron deficiency anemia in pregnant women with different somatotypes and to develop a prognostic model for the pathology onset. MATERIALS AND METHODS: We examined 390 pregnant women. Somatometry was performed according to the method of R.N. Dorokhov in terms of pregnancy not exceeding 9-10 weeks. Of the examined pregnant women, 110 were of the macrosomatotype, 173 of the meso- and 107 of the microsomatotype. In a clinical blood test, the levels of hemoglobin and red blood cells were determined using well-known methods. Blood iron levels were evaluated by the colorimetric method with ferrozine using a Parma Iron Reagents Kit (Parma Diagnostics Ltd., Russia). Serum hepcidin levels were determined spectrophotometrically using ELISA methods. RESULTS: Iron deficiency anemia was most commonly detected in pregnant women of the macro- and microsomatotype, when compared to those of the mesosomatotype (p 0.05). There was no severe anemia in the study groups. The levels of hematological parameters (serum iron and serum hepcidin) were significantly higher in the group of pregnant women with latent anemia, compared to the study group without signs of anemia (p 0.05). In the second trimester, iron deficiency anemia occurred in the group of patients with latent anemia. Using multiple regression analysis, a formula was obtained for predicting the onset of iron deficiency anemia in pregnant women of different somatotypes. CONCLUSIONS: Hematological parameters (serum iron and serum hepcidin) should be attributed to markers of iron deficiency anemia and timely predict the onset of pathology. The mathematical formula obtained allows predicting with high accuracy the onset of iron deficiency anemia in pregnant women, taking into account the somatotype in the first trimester of pregnancy, and timely preventing the onset of pathology.

scholarly journals Iron Deficiency Anemia and Serum Hepcidin Level in Children with Typhoid Fever: A Case–Control Study

2020 ◽  
Vol 15 (06) ◽  
pp. 288-292
Author(s):  
Ghada Mohamed ◽  
Samir Aboelhassan ◽  
Maysaa El Sayed Zaki ◽  
Yahya Wahba
Keyword(s):  
Iron Deficiency ◽  
Typhoid Fever ◽  
Iron Deficiency Anemia ◽  
Serum Iron ◽  
Case Control Study ◽  
Case Control ◽  
Deficiency Anemia ◽  
Hepcidin Level ◽  
Serum Hepcidin ◽  
Control Study

Abstract Objective Typhoid fever is a common systemic bacterial infection in children with a complex interplay between serum hepcidin and iron. We investigated the relationship between iron deficiency anemia (IDA) and serum hepcidin level in children with acute typhoid fever. Methods We conducted a preliminary case–control study in Mansoura University Children's Hospital, Egypt from April 2017 to May 2019 including 30 children aged 5 to 15 years with confirmed acute typhoid fever. We recruited 15 healthy nonanemic children, of comparable ages and sex as controls from the same hospital while attending for nonfebrile complaints. Typhoid fever cases were subdivided according to IDA existence into 16 cases with IDA and 14 non-IDA cases. We excluded all children having diseases which may affect serum iron and hepcidin levels, for example, liver, blood, gastrointestinal, and kidney diseases, and patients receiving drugs interfering with iron metabolism. All participants were subjected to complete blood count, serum ferritin, iron, hepcidin levels, and total iron-binding capacity (TIBC). Results In non-IDA typhoid fever group, serum iron level was significantly low, while serum hepcidin level was significantly high when compared with controls (p < 0.001 and p = 0.02, respectively). In IDA typhoid fever group, no statistically significant difference existed as regards serum hepcidin level when compared with controls (p = 0.53). No significant correlations were detected between serum hepcidin levels and hemoglobin, serum iron, ferritin, and TIBC values in each group. Conclusion Preexisting iron status could affect serum hepcidin level in patients with acute typhoid fever. Coexistence of IDA might oppose the up-regulatory effect of acute typhoid fever on serum hepcidin level.

scholarly journals A Monoclonal Antibody Targeting ALK2 As a Potential Therapeutic Agent for Anemia of Inflammation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2007-2007
Author(s):  
Natalia Medeiros ◽  
Thomas A Backus ◽  
Christopher Materna ◽  
Ffolliott Fisher ◽  
Jenn Lachey ◽  
...  
Keyword(s):  
Mouse Model ◽  
Serum Iron ◽  
Publicly Traded ◽  
Hemoglobin Content ◽  
Once Daily ◽  
Hepcidin Expression ◽  
Inflammatory Conditions ◽  
Serum Hepcidin ◽  
Anemia Of Inflammation ◽  
Daily Oral Administration

Abstract Background: Iron homeostasis is primarily regulated by hepcidin, a hormone predominantly expressed in the liver. Hepcidin activates the degradation of the transmembrane iron exporter ferroportin, thereby downregulating the release of iron from cells. Hepcidin expression is, at least partly, regulated in response to signaling of the type I TGF-β receptor ALK2, via SMAD2/3 phosphorylation. IL-6, which is commonly elevated in chronic kidney disease (CKD) and other inflammatory conditions, upregulates hepcidin expression and reduces serum iron bioavailability. As a result, chronic inflammatory conditions are often accompanied by secondary anemia of inflammation (AI). We have previously demonstrated that ALK2 inhibition suppressed hepcidin expression in rodents, monkeys and healthy humans. We further described that administration of a selective small molecule ALK2 kinase inhibitor (KTI-2338) reversed changes in hepcidin and iron in a mouse model of CKD, supporting the potential benefit of ALK2 inhibition in AI. Another approach to targeting ALK2 signaling is use of a neutralizing antibody. KTI-018 is a neutralizing ALK2 antibody with high affinity and selectivity for ALK2. This biologic has been demonstrated to reduce serum hepcidin and increase serum iron in healthy non-human primates. Aims: To further elucidate the specific contribution of ALK2 signaling as a driver in AI, and to determine the therapeutic potential of the antibody in this type of anemia, we assessed the effect of KTI-018 in the CKD mouse model. Methods: The study was conducted with 6-week-old male C57Bl/6 mice. Mice in the CKD cohort (CKD) were treated with once daily oral administration of adenine, a compound that metabolizes to 2,8-dihydroxyadenine, forming crystals in the proximal tubular epithelia and causing inflammation and fibrosis in the kidneys. Mice in the control cohort (healthy) received once daily oral administration of vehicle. Upon confirmation of disease, the CKD cohort was subdivided into two groups. The treatment group received twice weekly intraperitoneal treatment with KTI-018 (CKD-KTI-018), and the control group received tris-buffered saline (CKD-TBS). Healthy mice received TBS only. All mice were maintained on their assigned daily adenine or vehicle regimen. At day 53, the study was terminated and hematologic parameters, serum hepcidin, iron, and IL-6 levels were assessed. Results: After 42 days of adenine or vehicle administration, serum hepcidin, serum iron, and hematologic parameters were assessed in representative cohorts of CKD-TBS and healthy mice. The CKD-TBS cohort experienced changes associated with anemia of inflammation as compared to the healthy mice, including increased hepcidin, decreased serum iron, and decreased hematologic parameters. The differences between the healthy and CKD-TBS groups were maintained through the duration of the study. At study termination, CKD-TBS mice had increased serum IL-6 levels (218%), elevated serum hepcidin (149%), and reduced serum iron (-30%) as compared to the healthy mice. Laboratory findings characteristic of anemia were present in the CKD-TBS group, including decreased red blood cells (-6.1%), hemoglobin (-13.2%), and reticulocyte hemoglobin content (-9.3%) as compared to healthy mice. In contrast, CKD-KTI-018 mice had decreased serum hepcidin (-25%) and increased serum iron (59%) as compared to CKD-TBS mice. This restoration of serum iron corresponded to improvements in red blood cells, hemoglobin, and reticulocyte hemoglobin content, which were increased by 7.6%, 9.6%, and 6.7%, respectively, in the CKD-KTI-018 mice as compared to the CKD-TBS mice. These results demonstrate that, by decreasing serum hepcidin, KTI-018 increased the bioavailability of iron, which led to the restoration of hematologic parameters and appeared to reverse AI in mice. Discussion: In this study, a neutralizing ALK2 antibody decreased serum hepcidin, increased serum iron and consequently reversed AI in a mouse model of CKD. These results support the role of ALK2 signaling in AI and suggest that inhibition of ALK2 may be a potential treatment approach for anemia resulting from CKD and other chronic inflammatory diseases. Future studies will explore if ALK2 inhibition may prevent or treat progression of CKD itself, and the role that ALK2 inhibition may play in other chronic inflammatory conditions associated with elevated hepcidin. Disclosures Medeiros: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Backus: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Materna: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Fisher: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lachey: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Seehra: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company.

scholarly journals A22 PREVALENCE OF IRON DEFICIENCY AND SUPPLEMENTATION PRACTICES FOR PATIENTS ON HOME PARENTERAL NUTRITION

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 289-291
Author(s):  
L Russell ◽  
R Mangat ◽  
J Plant ◽  
S Hansen ◽  
D Armstrong ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Parenteral Nutrition ◽  
Serum Iron ◽  
Iron Supplementation ◽  
Deficiency Anemia ◽  
Categorical Variables ◽  
Continuous Variables ◽  
Prescribing Practices ◽  
Sex Diagnosis ◽  
Funding Agencies

Abstract Background Iron deficiency (ID) is common in patients receiving parenteral nutrition (PN), likely due to a lack of iron in the PN formula. There is no clear consensus on how often serum iron should be tested or iron supplementation should be given, at which dose or route, in patients on long-term PN. Within the Hamilton Health Sciences (HHS) home PN (HPN) program, the prevalence of ID or iron deficiency anemia (IDA) is unknown. This knowledge will contribute to better iron prescribing practices with ultimate benefit on patient’s health. Aims To assess the prevalence of ID and IDA in patients enrolled in the HHS HPN Program. The secondary aim was to assess supplementation practices for patients enrolled in the HPN program according to gastrointestinal(GI) diagnosis and duration on PN. Methods We conducted a retrospective study including consecutive adult patients enrolled in the HHS-HPN program from January 2015 to November 2020. We collected data on demographics (age, sex, and GI diagnosis), iron supplementation (dose, duration, and route), and information related to iron-deficiency (hemoglobin, serum iron, ferritin, TIBC, and folate) at pre-set intervals (enrollment, 3, 6, 12, 18, 24, 30, 36, 48, 60 months) and last measured. ID was defined as ferritin ≤45μg/L or serum iron ≤9μmol/L. IDA was defined as hemoglobin &lt;130g/L in men or &lt;120g/L in women in the context of ID. Data were expressed as median (IQR) for continuous variables and n/N(%) for categorical variables. Chi2 was performed to assess differences between groups and logistic regression to assess predictors of ID and IDA. The analysis was conducted using SPSS software(v26). Results The analysis included 125 HPN patients (50 males, median age of 55 (40–65) years). Patients received PN for a median of 195 (83–521) days. The most common diagnoses were malignancy (36.8%) and inflammatory bowel disease (23.2%); the most common indications for HPN was short bowel (29.6%) and bowel obstruction (27.2%). Iron profiles were measured in 77% of patients. At enrollment, 42.2% of patients had ID and 38.9% had IDA. Only 13% of patients with ID and 22.8% with IDA had iron supplementation (Figure 1). A total of 38 patients received iron either oral or IV (oral=44.7% vs IV=55.3%; p=0.66). There was no correlation between low levels of serum iron or ferritin with iron supplementation (p=0.23, 0.45 respectively). Age, sex, diagnosis, or reason for PN did not correlate with ID or IDA at any time point. Conclusions Iron-deficiency and IDA are common in patients enrolled in the HHS HPN program independently of age, sex, diagnosis and reason for PN. Prospective studies are needed to implement the most effective way to ensure proper monitoring and treatment of iron deficiency in this population. Funding Agencies None

scholarly journals POS0567 HEPCIDIN IS POTENTIAL BIOMARKER TO DISTINGUISH BETWEEN IRON DEFICIENCY ANEMIA AND ANEMIA OF INFLAMMATION IN RHEUMATOID ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 518.2-518
Author(s):  
E. Galushko ◽  
A. Semashko ◽  
A. Gordeev ◽  
A. Lila
Keyword(s):  
Rheumatoid Arthritis ◽  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Complete Blood Count ◽  
Deficiency Anemia ◽  
Reactive Protein ◽  
Potential Biomarker ◽  
Serum Hepcidin ◽  
Proper Diagnosis ◽  
Anemia Of Inflammation

Background:Anemia of inflammation (AI) and iron deficiency anemia (IDA) are the two most prevalent forms of anemia in patients with rheumatoid arthritis (RA). Diagnosis becomes challenging if AI is associated with true ID (AI/ID), as there is still a lack of a gold standard for differentiation between AI and AI/ID. However, as therapies to overcome anemia differ, proper diagnosis and understanding of underlying pathophysiological regulations are necessary.Objectives:The aim of the study was to evaluate the clinical efficiency of hepcidin, a key regulator of iron metabolism, in the diagnosis of IDA, as well as the differential diagnosis of AI/ID and AI in patients with RA.Methods:The study was undertaken 96 patients with RA, 67 of them were diagnosed anemia according to WHO criteria (104,3±21,4 g/l). Anemic patients and anemia-free patients with RA (n=29) were comparable (p>0.05) in age (44.4±14.8 and 49.8±9.3 years), disease duration (73.5±65.4 and 59.8±48.3 months) and DAS28 (6.3±1.6 and 5.9±1.9). All cases were subjected to following tests: complete blood count with peripheral smear, serum C-reactive protein, serum interleukin-6, iron studies, serum soluble transferrin receptor (sTfR), and serum hepcidin. Patients with RA and anemia were divided two groups: 25 patients with IDA and 42 - with AI. The AI cases were subdivided into pure AI and AI with coexistent ID (n=15).Results:The mean serum hepcidin concentration was significantly increased in pure AI patients (123.85±25.8 ng/mL) as compared to those in IDA patients (63.9±22.8 ng/mL, P < 0.05) and anemia-free patients with RA (88.1±39.09 ng/mL). Also, compared to pure AI patients [normal sTfR levels (<3 µg/mL)], the serum hepcidin concentration was reduced significantly in AI patients with ID [high sTfR levels (≥3 µg/mL)] with a mean of 79.0±23.97 ng/mL.Conclusion:Hepcidin measurement can provide a useful tool for differentiating AI from IDA and also help to identify an iron deficiency in AI patients. This might aid in the appropriate selection of therapy for these patients.Disclosure of Interests:None declared

scholarly journals Orexin A Enhances Pro-Opiomelanocortin Transcription Regulated by BMP-4 in Mouse Corticotrope AtT20 Cells

2021 ◽  
Vol 22 (9) ◽  
pp. 4553
Author(s):  
Satoshi Fujisawa ◽  
Motoshi Komatsubara ◽  
Naoko Tsukamoto-Yamauchi ◽  
Nahoko Iwata ◽  
Takahiro Nada ◽  
...  
Keyword(s):  
Stress Responses ◽  
Endocrine Function ◽  
Type I ◽  
Orexin A ◽  
Protein Levels ◽  
Bmp Receptors ◽  
Morphogenetic Protein ◽  
Crh Receptor Type 1

Orexin is expressed mainly in the hypothalamus and is known to activate the hypothalamic–pituitary–adrenal (HPA) axis that is involved in various stress responses and its resilience. However, the effects of orexin on the endocrine function of pituitary corticotrope cells remain unclear. In this study, we investigated the roles of orexin A in pro-opiomelanocortin (POMC) transcription using mouse corticotrope AtT20 cells, focusing on the bone morphogenetic protein (BMP) system expressed in the pituitary. Regarding the receptors for orexin, type 2 (OXR2) rather than type 1 (OX1R) receptor mRNA was predominantly expressed in AtT20 cells. It was found that orexin A treatment enhanced POMC expression, induced by corticotropin-releasing hormone (CRH) stimulation through upregulation of CRH receptor type-1 (CRHR1). Orexin A had no direct effect on the POMC transcription suppressed by BMP-4 treatment, whereas it suppressed Smad1/5/9 phosphorylation and Id-1 mRNA expression induced by BMP-4. It was further revealed that orexin A had no significant effect on the expression levels of type I and II BMP receptors but upregulated inhibitory Smad6/7 mRNA and protein levels in AtT20 cells. The results demonstrated that orexin A upregulated CRHR signaling and downregulated BMP-Smad signaling, leading to an enhancement of POMC transcription by corticotrope cells.

scholarly journals Lactoferrin Efficacy versus Ferrous Sulfate in Treatment of Children with Iron Deficiency Anemia

2021 ◽  
Vol 11 (01) ◽  
pp. e199-e204
Author(s):  
Osama Mahmoud El-Asheer ◽  
Ahmed Gaber Ahmed ◽  
Zainab AbdelAal Abdel Hafez ◽  
Marwa AbdelHafiz Dahpy ◽  
Amal AbdElSalam Soliman
Keyword(s):  
Side Effects ◽  
Iron Deficiency ◽  
Patient Compliance ◽  
Iron Deficiency Anemia ◽  
Ferrous Sulfate ◽  
Serum Iron ◽  
Deficiency Anemia ◽  
Serum Transferrin ◽  
Iron Binding ◽  
Clinical Benefits

AbstractLactoferrin (LF) is an iron-binding globular glycoprotein that is structurally and chemically similar to serum transferrin. Many studies have been done to evaluate the effect of oral LF administration on iron deficiency anemia (IDA) with controversial results. This study was designed to compare the efficacy of LF versus oral ferrous sulfate (OFS) therapy in the treatment of children with IDA. A significant increase in mean hemoglobin and serum iron concentrations was noted in the group that received oral bovine LF (11.06 ± 0.96 and 42.79 ± 6.14, respectively) versus the group that received OFS (10.24 ± 0.57 and 28.94 ± 5.05, respectively, with p < 0.001 for each) after 30 days of the treatment with fewer side effects (9.3 vs. 33.3% with p = 0.043). Oral bovine LF is a more effective and safer alternative in treating iron deficiency and IDA compared with OFS with clinical benefits of fewer side effects and better patient compliance.

scholarly journals Induced Disruption of the Iron-Regulatory Hormone Hepcidin Inhibits Acute Inflammatory Hypoferraemia

2016 ◽  
Vol 8 (5) ◽  
pp. 517-528 ◽  
Author(s):  
Andrew E. Armitage ◽  
Pei Jin Lim ◽  
Joe N. Frost ◽  
Sant-Rayn Pasricha ◽  
Elizabeth J. Soilleux ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mouse ◽  
Brucella Abortus ◽  
Serum Iron ◽  
Vibrio Vulnificus ◽  
Iron Status ◽  
Transgenic Mouse Model ◽  
Innate Immune ◽  
Serum Hepcidin

Withdrawal of iron from serum (hypoferraemia) is a conserved innate immune antimicrobial strategy that can withhold this critical nutrient from invading pathogens, impairing their growth. Hepcidin (Hamp1) is the master regulator of iron and its expression is induced by inflammation. Mice lacking Hamp1 from birth rapidly accumulate iron and are susceptible to infection by blood-dwelling siderophilic bacteria such as Vibrio vulnificus. In order to study the innate immune role of hepcidin against a background of normal iron status, we developed a transgenic mouse model of tamoxifen-sensitive conditional Hamp1 deletion (termed iHamp1-KO mice). These mice attain adulthood with an iron status indistinguishable from littermate controls. Hamp1 disruption and the consequent decline of serum hepcidin concentrations occurred within hours of a single tamoxifen dose. We found that the TLR ligands LPS and Pam3CSK4 and heat-killed Brucella abortus caused an equivalent induction of inflammation in control and iHamp1-KO mice. Pam3CSK4 and B. abortus only caused a drop in serum iron in control mice, while hypoferraemia due to LPS was evident but substantially blunted in iHamp1-KO mice. Our results characterise a powerful new model of rapidly inducible hepcidin disruption, and demonstrate the critical contribution of hepcidin to the hypoferraemia of inflammation.

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