Iron Dextran Injection Research Articles

Potential Mechanisms Underlying the Hepatic-Protective Effects of Danshensu on Iron Overload Mice.

The purpose of the present study was to investigate the protective effects and the underlying mechanisms of Danshensu on liver injury induced by iron overload. The mouse model was induced by injection of iron dextran intraperitoneally for 14 d. Danshensu significantly ameliorated liver injury by decreasing iron accumulation in the liver, possibly by down-regulating the expression of iron uptake-related proteins: divalent metal ion transporters-1 (DMT-1), transferrin receptor (TfR), and L-type calcium channel α1C subunit. Furthermore, Danshensu alleviated oxidative stress injury through potentiating glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities; Immunohistochemistry results demonstrated that Danshensu reduced the expression of inflammatory cytokines: interleukin-6 (IL-6) and transforming growth factor-beta (TGF-β). Moreover, Danshensu prominently inhibited hepatocyte apoptosis through decreasing Bax and Caspase-3 and increasing Bcl-2 expression levels. The present results suggest that Danshensu possess significant hepatic-protection at least partly through inhibition of iron uptake, oxidative stress, inflammatory, and apoptosis. Therefore, we believe that Danshensu could be used as a promising therapeutic agent for preventing and treating iron overload diseases.

Effects of Iron Deficiency Anemia and Its Rapid Correction on the Serum Metabolomic Profile of Rhesus Infants.

To determine whether rapid correction of iron deficiency using intramuscular iron dextran normalizes serum metabolomic changes in a nonhuman primate model of iron deficiency anemia (IDA). Blood was collected from naturally iron-sufficient (IS; n=10) and IDA (n=12) male and female infant rhesus monkeys (Macaca mulatta) at 6 months of age. IDA infants were treated with intramuscular injections of iron dextran, 10mg/weekly for 4-8 weeks. Iron status was reevaluated following treatment using hematological measurements and sera were metabolically profiled using HPLC/MS with isobaric standards for identification and quantification. Early-life iron deficiency anemia negatively affects many cellular metabolic processes, including energy production, electron transport, and oxidative degradation of toxins. Slow iron repletion with dietary supplementation restores iron deficient monkeys from a hematological perspective, but the serum metabolomic profile remains differed from monkeys that had been iron sufficient their entire life. Whether rapid iron restoration through intramuscular injections of iron dextran normalizes serum metabolomic profile is not known. A total of 654 metabolites were measured with differences in 53 metabolites identified between IS and IDA monkeys at 6 months (P0.05). Pathway analyses provided evidence of altered liver function, hypometabolic state, differential essential fatty acid production, irregular inosine and guanosine metabolism, and atypical bile acid production in IDA infants. After treatment, iron-related hematological parameters had recovered, but the formerly IDA infants remained metabolically distinct from the IS infants, with 225 metabolites differentially expressed between the groups. As with slow iron repletion, rapid iron repletion does not normalize the altered serum metabolomic profile in rhesus infants with IDA, suggesting the need for iron supplementation in the pre-anemic stage. National Institutes of Health.

The Effect of Iron Dextran Injection on Daily Weight Gain and Haemoglobin Values in Whole Milk Fed Calves.

Simple SummaryWhole milk contains low levels of iron, as such this trial examined iron deficiency anaemia in dairy calves fed whole milk. Our trial evaluated the effect of iron supplementation on growth rate and haemoglobin (Hb) levels of these calves. We enrolled 237 calves across six farms, each farm had half of its calves injected with iron and half without. Calves were weighed three times throughout the study and had haemoglobin levels measured at one and six weeks old. Iron caused an average increase in growth rate of 78 g/d (Standard Deviation (SD) 18 g/d) in injected calves compared with control calves. Iron caused a significant increase of haemoglobin levels by six weeks, and haemoglobin levels in the calves that had not received the iron, the iron dropped by an average of 12.1 g/L (SD 15.1). Calves with a higher growth rate in the first six weeks were also more likely to have low Hb levels at six weeks. There was variation in the growth rate differences and haemoglobin levels on each farm. However, overall across all farms, iron makes a difference to daily weight gain (DG) in the first six weeks but the magnitude of effect seems to be farm-specific, as there is a notable difference between farm DG variations. Anaemia caused by iron deficiency has long been reported in dairy calves. This study investigated iron deficiency anaemia on UK dairy farms feeding whole milk and evaluated the effect of iron supplementation on the daily weight gain (DG) and haemoglobin (Hb) levels of these calves. Two-hundred-and-thirty-seven calves were enrolled across six farms. At enrolment, calves were randomly allocated to either receive treatment with iron injection (INJ; n = 120) consisting of 5 mL (1 g iron) of iron dextran (Uniferon 20% Injection, Pharmacosmos) or no injection, control (CON; n = 117). Calves were blood-sampled for Hb and total proteins and weighed at weeks one, six and 12 of age. Iron had a significant effect on DG from one to six weeks, with an average 78 g/d (SD 18 g/d, n = 188, 95% Confidence interval: 44–112 g/d, p < 0.001) DG increase in the INJ calves. Iron had a significant effect on Hb concentration at six weeks between the INJ group and CON group (110.7 (SD 12.4) versus 94.9 g/L (SD 13.2), respectively). Calves with a higher growth rate from one to six weeks were more likely to have low Hb levels at six weeks. There was farm variation in both Hb levels and DG, however, despite this, there was an effect of iron across all farms.

Effect of cyclophosphamide on hematopoietic stem cells in mice with iron overload

To explore the effect of cyclophosphamide on hematopoietic stem cells (HSCs) in mice with iron overload. Mouse models of iron overload were established in 30 male C57BL/6 mice by intraperitoneal injections of iron dextran at low (0.25 g/kg), moderate (0.5 g/kg), and high (1 g/kg) doses (n=10), with another 10 PBS-treated mice as the control group. The changes in body weight, liver, spleen and bone marrow of the mice were recorded, and serum level of ferritin was detected. The mice receiving a moderate dose of iron dextran were further divided into 8 groups for observation at different time points (D1, D2, D3, D4, D5, D6, D7, and D14 groups) and were given intraperitoneal injection of 50 mg/kg cyclophosphamide (Cy) for 2 consecutive days. Peripheral blood cells, bone marrow mononuclear cells (BMMNCs), and the frequencies of different HSCs (HPCs, HSCs, LT-HSCs) in the BMMNCs were monitored. The cell cycle distribution in the HSCs, level of reactive oxygen species and the microenvironment of the HSCs were analyzed using flow cytometry. Compared with the control mice, the mice with iron overload showed obvious weight loss with significantly increased serum ferritin level, enlargement of the liver and spleen, and iron deposition in the organs (P < 0.05). No significant changes were noted in the peripheral blood of the mice with iron overload. The cyclophosphamide-treated mice exhibited significantly decreased number of WBCs and lymphocyte ratio at days 1 to 4 (P < 0.05). The numbers of BMMNCs and HPCs in mice with iron overload did not show significant changes as compared with those in the control mice, but the numbers of HSCs and LTHSCs decreased significantly in the mice with iron overload (P < 0.05). In cyclophosphamide-treated mice, the number of HSCs increased since day 1 and reached the peak level on day 3 (P < 0.05). Compared with those in the control group, the HSCs did not exhibit significant changes in cell cycle distribution in mice with iron overload, but the proportion of G0/G1 cells decreased significantly in cyclophosphamide group since day 1 and reached the lowest level on day 3 (P < 0.05). Iron deposition in the bone marrow causes long- term damages of the HSCs in the bone marrow but does not induce obvious changes in the peripheral blood. In mice with iron overload, intraperitoneal injection of 50 mg/kg cyclophosphamide for two days promotes cell cycle changes of the resting HSCs to mobilize the HSCs, and this effect is the most obvious on day 4.

Iron Accumulates in Retinal Vascular Endothelial Cells But Has Minimal Retinal Penetration After IP Iron Dextran Injection in Mice.

PurposeIron supplementation therapy is used for iron-deficiency anemia but has been associated with macular degeneration in a 43-year-old patient. Iron entry into the neurosensory retina (NSR) can be toxic. It is important to determine conditions under which serum iron might cross the blood retinal barrier (BRB) into the NSR. Herein, an established mouse model of systemic iron overload using high-dose intraperitoneal iron dextran (IP FeDex) was studied. In addition, because the NSR expresses the iron regulatory hormone hepcidin, which could limit iron influx into the NSR, we gave retina-specific hepcidin knockout (RS-HepcKO) mice IP FeDex to test this possibility.MethodsWild-type (WT) and RS-HepcKO mice were given IP FeDex. In vivo retina imaging was performed. Blood and tissues were analyzed for iron levels. Quantitative PCR was used to measure levels of mRNAs encoding iron regulatory and photoreceptor-specific genes. Ferritin and albumin were localized in the retina by immunofluorescence.ResultsIP FeDex in both WT and RS-HepcKO mice induced high levels of iron in the liver, serum, retinal vascular endothelial cells (rVECs), and RPE, but not the NSR. The BRB remained intact. Retinal degeneration did not occur.ConclusionsFollowing injection of high-dose IP FeDex, iron accumulated in the BRB, but not the NSR. Thus, the BRB can shield the NSR from iron delivered in this manner. This ability is not dependent on NSR hepcidin production.

Iron dysregulation in vascular dementia: Focused on the AMPK/autophagy pathway

Recent researches suggested that iron dysregulation play an important role in the pathogenesis of vascular dementia (VD). Iron deposition had been found in hippocampus in vascular dementia model in recent research. Nevertheless, the underlying mechanisms of iron deposition and its neurotoxicity in vascular dementia was still unclear. Thus, our research was aimed at whether the neurotoxicity of iron was associated with autophagy regulation. We established a chronic cerebral hypoperfusion model in the rat brain in order to mimic the vascular dementia using permanent bilateral common carotid artery occlusion (2VO). The preparation of iron overloaded rats model by intraperitoneal injection of iron dextran. Following, we tested the learning and memory function of each group using Morris Water Maze. Consequently, we analyzed the iron content and iron transport related molecules (TFR1, DMT1) in hippocampus. Furthermore, we examined the effect of iron deposition on autophagy-related molecules including AMPK, Beclin1 and LC3 and the number of autophagosomes in hippocampus. Last, we tested the apoptosis of neurons in hippocampus. We found that iron deposition in hippocampus in model groups which accompanied the decline of learning and memory function. And the expression of TFR1 and DMT1 were up-regulated in model groups. Moreover, iron deposition up-regulated the expression of AMPK, Beclin1 and LC3 and increase the number of autophagosomes in hippocampus. And the expression of Bax was up-regulated and Bcl-2 was down-regulated in iron deposition groups. To sum up, our data suggested that iron deposition increased AMPK/autophagy pathway associated molecules in the hippocampus and promoted neuronal apoptosis, which might be a new pathogenesis in vascular dementia.

Protective effects of grape seed proanthocyanidins against iron overload-induced renal oxidative damage in rats

BackgroundExcessive exposure to iron can cause kidney damage, and chelating drugs such as deferoxamine and deferiprone have limited usefulness in treating iron poisoning. This study was designed to investigate the protective effects of grape seed proanthocyanidins (GSPAs) against iron overload induced nephrotoxicity in rats. The roles of GSPAs in chelating iron, antioxidant activity, renal function, pathological section, and apoptosis-related gene expression were assessed. MethodsNewly weaned male Sprague–Dawley rats aged 21 days (weight, 65 ± 5 g) were randomly divided into four groups containing 10 rats each: normal control (negative) group, iron overload (positive) group, GSPAs group, and GSPAs + iron overload (test) group. Iron dextran injections (2.5 mg⋅ kg−1) and GSPAs (25 mg⋅ kg−1) were intraperitoneally and intragastrically administered to rats daily for 7 weeks, respectively. Measurements included red blood cell (RBC) count and hemoglobin (Hb) level, serum total iron-binding capacity (TIBC), renal iron content, glutathione peroxidase (GSH-Px) activity, superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, total antioxidant activity (T-AOC), creatinine (CR) and blood urea nitrogen (BUN) levels, pathological changes, and apoptotic Fas, Bax expressions in the kidney tissue. Differences among the dietary groups were determined using one-way analysis of variance with post-hoc Tukey’s test. P < 0.05 was considered statistically significant. ResultsRBC count, Hb level, renal iron content, MDA content, CR and BUN levels, and Fas, Bax expressions significantly increased in the positive group than in the negative group; contrarily, TIBC, GSH-Px activity, and T-AOC significantly decreased in the positive group than in the negative group (P < 0.05). Although not statistically significant, SOD activity was slightly reduced in the positive group than in the negative group. Inflammatory cell infiltration and fibrous tissue proliferation were observed in the kidney tissue of the rats in the positive group; in contrast, the rats exhibited better recovery when GSPAs were used instead of iron alone. Compared with the positive group, RBC counts, Hb levels, renal iron contents, the MDA content, CR and BUN levels, and Fas, Bax expressions significantly decreased, whereas the TIBC, the GSH-Px and SOD activities as well as T-AOC significantly increased in the test group rats (P < 0.05). There were no significant differences in the RBC counts, Hb levels, TIBC, renal iron contents, the SOD activity and MDA content, CR and BUN levels, and Fas expression between the GSPAs and negative groups. The GSH-Px activity and T-AOC were significantly increased whereas Bax expression was significantly decreased in the GSPAs group rats than in the negative group rats (P < 0.05). The rats in the GSPAs, test, and negative groups displayed glomeruli and tubules with a clear structure; further, the epithelial cells in the renal tubules were neatly arranged. ConclusionsGSPAs have protective effects on nephrotoxicity in rats with iron overload. Thus, further investigation of GSPAs as a new and natural phytochemo-preventive agent against iron overload is warranted.

Comparison of Oral and Parenteral Iron Administration on Iron Homeostasis, Oxidative and Immune Status in Anemic Neonatal Pigs

The present study was to evaluate the consequences of iron status across oral and parenteral iron administrations in prevention of iron deficiency anemia. A total of 24 one-day-old male neonatal piglets were allocated into three groups given non-iron supplementation (NON), intramuscular iron dextran injection (FeDex), and oral administration of ferrous glycine chelate (FeGly), respectively. At day 8, no significant differences in final body weight, average weight gain, and tissue coefficients were observed among three groups (P > 0.05). Both oral FeGly and FeDex injection significantly increased serum iron, ferritin, hemoglobin, and tissue iron deposition (P < 0.05). However, FeDex-injected supplementation resulted in rapidly rising hepcidin levels and hepatic iron deposition (P < 0.05). In addition, compared to parenteral iron supplementation, greater serum IgA level, SOD, and GSH-Px activities, lower expressions of IL-1β and TNF-α in the liver, and lower expressions of IL-6 and TNF-α in the spleen were found in oral iron piglets (P < 0.05). According to our results, oral administration of ferrous glycine chelate improved iron homeostasis, and oxidative and immune status in anemic neonatal pigs.

Evaluation of liver iron content using synchrotron radiation CT in iron-overload mice

Evaluation of liver iron content (LIC) is crucial for the judgment of hepatic iron overload (HIO). Here, we evaluated the potential utility of synchrotron radiation (SR) CT for quantifying LIC in mice suffered from HIO. The mice models of HIO were made by the injection of iron dextran. A series of total iron injection doses of 0, 12.5, 25, 50 and 100 mg were used. SR CT imaging was performed using a detector with the pixel size of 6.5 μm × 6.5 μm at the energy level of 12 keV . The iron micro-depositions were pathologically confirmed using Prussian blue staining. The reconstructed transverse sections were obtained by applying the filtered back projection (FBP) algorithm with PITRE software. 3D visualization was performed using Amira 5.4. LIC was confirmed by an inductively coupled plasma (ICP) spectrometer. SR CT-derived LIC (LICCT) was defined as the volume ratio of iron depositions to the liver. The volume ratio was measured using ImageJ software. SR CT presented a high-spatial resolution to clearly display iron micro-depositions in the iron-overload liver. Additionally, iron micro-depositions were found to distribute unevenly on 3D images. The LICCTs were 0, (1.890 ± 0.172)%, (4.148± 0.282)%, (6.769± 0.201)%, and (12.912 ± 0.270)% for injection doses of 0 mg, 12.5 mg, 25 mg, 50 mg and 100 mg, respectively. LICCT had a strong linear correlation with injection dose (R02= 0.993, P< 0.0001) or ICP-derived LIC (LICICP) (R2 = 0.9644, P < 0.0001). The linear correlation between LICCT and LICICP could be expressed by an equation. Using this equation, LIC could be predicted by measuring LICCT. Therefore, SR CT imaging showed potential ability to quantify LIC. The imaging modality may be used for the evaluation of disease progression and therapeutic efficacy in mice models.

Functional and biochemical responses of skeletal muscle following a moderate degree of systemic iron loading in mice.

Excessive iron loading may cause skeletal muscle atrophy and weakness because of its free radical generating properties. To determine whether a clinically relevant degree of iron loading impairs skeletal muscle function, young male mice received injections of iron dextran (4 mg iron/200 µl) or 2 mM d-glucose (control) 5 days/week for 2 weeks ( n = 10/group). Systemic iron loading induced an approximate fourfold increase in the skeletal muscle nonheme iron concentration. Soleus specific tension (1, 30-250 Hz) was lower among iron-loaded animals compared with controls despite similar body mass and muscle mass. Soleus lipid peroxidation (4-hydroxynonenal adducts) and protein oxidation (protein carbonyls) levels were similar between groups. In gastrocnemius muscle, reduced glutathione (GSH) and glutathione peroxidase activity were similar but glutathione disulfide (GSSG) and the GSSG/GSH ratio were greater in iron-loaded muscle. A greater protein expression level of endogenous thiol antioxidant thioredoxin (TRX) was observed among iron-loaded muscle whereas its endogenous inhibitor thioredoxin-interacting protein (TXNip) and the TRX/TXNip ratio were similar. Glutaredoxin2, a thiol-disulfide oxidoreductase activated by GSSG-induced destabilization of its iron-sulfur [2Fe-2S] cluster, was lower following iron loading. Additionally, protein levels of α-actinin and αII-spectrin at 240 kDa were lower in the iron-loaded group. Ryanodine receptor stabilizing subunit calstabin1 was also lower following iron loading. In summary, the contractile dysfunction that resulted from moderate iron loading may be mediated by a disturbance in the muscle redox balance and from changes arising from an increased proteolytic response and aberrant sarcoplasmic reticulum Ca2+ release. NEW & NOTEWORTHY Although severe iron loading is known to cause muscle oxidative stress and dysfunction, the effects of a moderate degree of systemic iron loading on muscle contractile function and biochemical responses remain unclear. This study demonstrates that a pathophysiological elevation in the skeletal muscle iron load leads to force deficits that coincide with impaired redox status, structural integrity, and lower ryanodine receptor-associated calstabin1 in the absence of muscle mass changes or oxidative damage.

Mangiferin and mangiferin-containing leaf extract from Mangifera foetida L for therapeutic attenuation of experimentally induced iron overload in a rat model

Introduction: Thalassemia is a hereditary anemia usually treated with regular blood transfusions, which can result in elevated levels of total iron in the body. As soon as the capacity of iron-regulating proteins (e.g., ferritin, transferrin) are used up, free plasma iron increases generating reactive oxygen species (ROS), leading to oxidative stress. Hence, blood transfusions should be accompanied by iron-chelating therapy, e.g., deferiprone (DFP). The purpose of this study was to evaluate the effect of mangiferin (M) and an aqueous leaf extract of Mangifera foetida L (EMF) as alternative iron-chelating antioxidants in an animal model. Methods: Thirty male Sprague Dawley rats were randomly divided into 5 equal groups: normal control, iron overload (IO), IO+DFP, IO+M, and IO+EMF. Iron overload was induced by intraperitoneal iron dextran injection with a total dose of 90 mg/mouse (15 mg Fe/mouse every 3-4 days for 3 weeks) followed by oral administration of DFP 462.5 mg/kg, mangiferin 75 mg/kg, or EMF 2.930 g/kg for 7 days. Results: Body weight (BW) increased in all groups during the 4 weeks of experiment, except for the IO group. As expected, DFP decreased significantly the total plasma iron and increased iron excretion via urine in iron-overloaded rats (positive control), mangiferin and EMF had similar – although slightly smaller – effects than DFP. The antioxidant activity of M and EMF were stronger compared to DFP as determined by plasma superoxide dismutase (SOD) activity. Conclusion: Mangiferin and EMF have iron-chelating and antioxidant effects and might be used for the treatment of iron overload in the body.

Acute Iron Dextran Injection Increases Liver Weight and Reduces Glycerol Kinase Expression in Liver

Iron is essential and needed in a very small amount. When iron exceeds normal need, metabolic alteration occurs, causing hepatosteatosis. The mechanism of iron inducing hepatosteatosis remains unclear. Glycerol kinase, the enzyme responsible in triglyceride synthesis initiation, is assumed to have a role in the pathomechanism of hepatosteatosis. This study aimed to investigate the gene expression of glycerol kinase in an acute iron overload condition. This study was conducted in Animal Laboratory Faculty of Medicine and Central Laboratory Universitas Padjadjaran from May to June 2017. Three groups of mice were divided by the dose of iron dextran injection (0, 0.1, 0.3 mg/day/mice). After 19 days, mice were terminated, liver weight was measured and glycerol kinase gene expression in the liver was determined by semi-qualitative PCR. Quantification of PCR result was calculated by ImageJ software. There was a significant change in liver weight of the mice in a dose-dependent manner of iron injection. The expression of glycerol kinase tended to decrease, but statistically insignificant. Acute iron dextran injection increases liver weight and tends to reduce glycerol kinase gene expression in mice liver.Keywords: Glycerol kinase, hepatosteatosis, iron overload Efek Zat Besi Dosis Tinggi Akut dalam Meningkatkan Berat Organ dan Menurunkan Ekspresi Gliserol Kinase HeparAbstrakZat besi merupakan nutrien esensial dan diperlukan dalam jumlah yang sangat kecil. Ketika kadar zat besi melebihi kadar normal dalam tubuh, terjadi perubahan metabolisme yang menyebabkan hepatosteatosis. Mekanisme zat besi dalam menyebabkan hepatosteatosis masih belum diketahui secara pasti. Gliserol kinase, enzim yang menginisiasi sintesis trigliserida, diduga berperan dalam patomekanisme hepatosteatosis. Penelitian ini bertujuan untuk meneliti ekspresi gen gliserol kinase pada hepar pada kondisi tinggi zat besi akut. Penelitian ini dilakukan di Laboratorium Hewan Fakultas Kedokteran dan Laboratorium Sentral Universitas Padjadjaran dari bulan Mei sampai dengan Juni 2017. Tiga kelompok mencit dibagi berdasarkan dosis injeksi iron dextran intraperitoneal (0, 0,1, 0,3 mg/hari/ekor). Setelah 19 hari, mencit diterminasi, berat hepar ditimbang dan ekspresi gen gliserol kinase diukur dengan metode semi-kualitatif PCR. Kuantifikasi hasil PCR dilakukan dengan menggunakan aplikasi ImageJ. Terdapat peningkatan berat hepar secara signifikan yang sejalan dengan dosis ijeksi zat besi. Ekspresi gen gliserol kinase cenderung menurun, meskipun secara statistik tidak signifikan. Keadaan tinggi kadar zat besi yang akut meningkatkan berat hepar dan cenderung menurunkan ekspresi gen gliserol kinase pada hepar mencit.Kata kunci: Gliserol kinase, hepatosteatosis, zat besi berlebih

Co-Transplantation of Ucbmn with UC-MSC Enhances Engraftment of Ucbmn in Iron Overload NOD/SCID Mice

Background: Umbilical cord blood (UCB)-derived hematopoietic stem cells (HSC) are ideal for allogeneic HSCT when a compatible donor is unavailable. However, the insufficient number of HSCs per UCB unit delays engraftment and may lead to graft failure and/or mortality. Besides, transfusion-induced iron overload has been reported to be involved in the delayed engraftment of HSC. Previously mesenchymal stem cells (MSC) have been implicated in playing a significant role in HSC engraftment. This study aimed to determine the effect of co-transplantation of umbilical cord mesenchymal stem cells (UC-MSC) on engraftment and hematopoietic recovery.Methods: The iron overload NOD/SCID mice were induced by dose-escalation injection of iron dextran. And the sublethally irradiated iron overload NOD/SCID mice were divided into four groups: (1) intravenous injection of normal saline (control group, n=8), (2) intravenous injection of umbilical cord mesenchymal MN) alone (n=10), (3) intravenous injection of UCBMN and UC-MSC (n=10), and (4) intrafemoral injection of UCBMN and UC-MSC (n=12). Six weeks after injection of UC, the bone marrow (BM) was harvested and analyzed. The semi-quantitative analysis of cytokines including SDF-1a, OPN, and VEGF-α were examined by immunohistochemistry.Results: As a result, iron deposits in bone liver, BM and spleen. In the BM of control group, no human CD45+ cells were found. Via the intra-bone marrow (iBM) injection, the percentage of human CD45+ cells was 9.86% ±1.86% (n=10) in the presence and 3.18% ±0.98% (n=6) in the absence of MSC, respectively, via the tail vein, the percentage of human CD45+ cells was 3.5%±0.94%. In additional, the levels of SDF-1a, OPN, and VEGF-a were all significantly higher in The mice that received MSC showed significantly enhanced engraftment in all three experiments (P=0.000).Conclusion: Co-transplantation of UC-MSC is effective for improving engraftment in iron overload NOD/SCID mice. The point underlying the positive outcome may relate to cytokines including SDF-1a, OPN, and VEGF-a secreted by UC-MSC, which has been indicated to play a crucial part in homing and engraftment. DisclosuresNo relevant conflicts of interest to declare.

Orchestrated regulation of iron trafficking proteins in the kidney during iron overload facilitates systemic iron retention.

The exact route of iron through the kidney and its regulation during iron overload are not completely elucidated. Under physiologic conditions, non-transferrin and transferrin bound iron passes the glomerular filter and is reabsorbed through kidney epithelial cells, so that hardly any iron is found in the urine. To study the route of iron reabsorption through the kidney, we analyzed the location and regulation of iron metabolism related proteins in kidneys of mice with iron overload, elicited by iron dextran injections. Transferrin Receptor 1 was decreased as expected, following iron overload. In contrast, the multi-ligand hetero-dimeric receptor-complex megalin/cubilin, which also mediates the internalization of transferrin, was highly up-regulated. Moreover, with increasing iron, intracellular ferritin distribution shifted in renal epithelium from an apical location to a punctate distribution throughout the epithelial cells. In addition, in contrast to many other tissues, the iron exporter ferroportin was not reduced by iron overload in the kidney. Iron accumulated mainly in interstitial macrophages, and more prominently in the medulla than in the cortex. This suggests that despite the reduction of Transferrin Receptor 1, alternative pathways may effectively mediate re-absorption of iron that cycles through the kidney during parenterally induced iron-overload. The most iron consuming process of the body, erythropoiesis, is regulated by the renal erythropoietin producing cells in kidney interstitium. We propose, that the efficient re-absorption of iron by the kidney, also during iron overload enables these cells to sense systemic iron and regulate its usage based on the systemic iron state.

Iron storage disease (hemochromatosis) and hepcidin response to iron load in two species of pteropodid fruit bats relative to the common vampire bat.

Hepcidin is the key regulator of iron homeostasis in the body. Iron storage disease (hemochromatosis) is a frequent cause of liver disease and mortality in captive Egyptian fruit bats (Rousettus aegyptiacus), but reasons underlying this condition are unknown. Hereditary hemochromatosis in humans is due to deficiency of hepcidin or resistance to the action of hepcidin. Here, we investigated the role of hepcidin in iron metabolism in one species of pteropodid bat that is prone to iron storage disease [Egyptian fruit bat (with and without hemochromatosis)], one species of pteropodid bat where iron storage disease is rare [straw-colored fruit bat (Eidolon helvum)], and one species of bat with a natural diet very high in iron, in which iron storage disease is not reported [common vampire bat (Desmodus rotundus)]. Iron challenge via intramuscular injection of iron dextran resulted in significantly increased liver iron content and histologic iron scores in all three species, and increased plasma iron in Egyptian fruit bats and straw-colored fruit bats. Hepcidin mRNA expression increased in response to iron administration in healthy Egyptian fruit bats and common vampire bats, but not in straw-colored fruit bats or Egyptian fruit bats with hemochromatosis. Hepcidin gene expression significantly correlated with liver iron content in Egyptian fruit bats and common vampire bats, and with transferrin saturation and plasma ferritin concentration in Egyptian fruit bats. Induction of hepcidin gene expression in response to iron challenge is absent in straw-colored fruit bats and in Egyptian fruit bats with hemochromatosis and, relative to common vampire bats and healthy humans, is low in Egyptain fruit bats without hemochromatosis. Limited hepcidin response to iron challenge may contribute to the increased susceptibility of Egyptian fruit bats to iron storage disease.

A composite mouse model of aplastic anemia complicated with iron overload.

Iron overload is commonly encountered during the course of aplastic anemia (AA), but no composite animal model has been developed yet, which hinders drug research. In the present study, the optimal dosage and duration of intraperitoneal iron dextran injection for the development of an iron overload model in mice were explored. A composite model of AA was successfully established on the principle of immune-mediated bone marrow failure. Liver volume, peripheral hemogram, bone marrow pathology, serum iron, serum ferritin, pathological iron deposition in multiple organs (liver, bone marrow, spleen), liver hepcidin, and bone morphogenetic protein 6 (BMP6), SMAD family member 4 (SMAD4) and transferrin receptor 2 (TfR2) mRNA expression levels were compared among the normal control, AA, iron overload and composite model groups to validate the composite model, and explore the pathogenesis and features of iron overload in this model. The results indicated marked increases in iron deposits, with significantly increased liver/body weight ratios as well as serum iron and ferritin in the iron overload and composite model groups as compared with the normal control and AA groups (P<0.05). There were marked abnormalities in iron regulation gene expression between the AA and composite model groups, as seen by the significant decrease of hepcidin expression in the liver (P<0.01) that paralleled the changes in BMP6, SMAD4, and TfR2. In summary, a composite mouse model with iron overload and AA was successfully established, and AA was indicated to possibly have a critical role in abnormal iron metabolism, which promoted the development of iron deposits.

Supplemental iron dextran injections: Influence on hemoglobin concentrations and piglet growth

This case study assessed effectiveness of protocols for iron dextran administration on hemoglobin (Hb) concentrations in pigs and evaluated the effect of supplemental iron dextran injections prior to weaning on subsequent body weights (BW). Whole blood samples and body weights were collected from piglets at 14 days of age in four farms and at 27 days of age in the fifth farm. For Farms 1 to 3, six piglets per litter were matched by BW to provide a pair of heavy weight (HW) piglets, medium weight (MW) piglets, and light weight (LW) piglets in each litter. For Farms 4 and 5, MW piglets were not included. One piglet from each pair was injected intramuscularly with 200 mg iron dextran immediately after blood collection (treatment pigs). The other piglet in each pair served as the control. At 3 weeks after weaning, pigs were weighed and whole blood samples were collected to determine Hb concentrations. At 14 days of age and after weaning, the results were inconsistent among the farms. Prior to recommending supplemental iron injections for pigs, one must evaluate the existing on-farm protocol for iron administration.

The hepatocyte-specific HNF4α/miR-122 pathway contributes to iron overload–mediated hepatic inflammation

AbstractHepatic iron overload (IO) is a major complication of transfusional therapy. It was generally thought that IO triggers substantial inflammatory responses by producing reactive oxygen species in hepatic macrophages. Recently, a decrease in microRNA-122 (miR-122) expression was observed in a genetic knockout (Hfe−/−) mouse model of IO. Because hepatocyte-enriched miR-122 is a key regulator of multiple hepatic pathways, including inflammation, it is of interest whether hepatocyte directly contributes to IO-mediated hepatic inflammation. Here, we report that IO induced similar inflammatory responses in human primary hepatocytes and Thp-1–derived macrophages. In the mouse liver, IO resulted in altered expression of not only inflammatory genes but also >230 genes that are known targets of miR-122. In addition, both iron-dextran injection and a 3% carbonyl iron–containing diet led to upregulation of hepatic inflammation, which was associated with a significant reduction in HNF4α expression and its downstream target, miR-122. Interestingly, the same signaling pathway was changed in macrophage-deficient mice, suggesting that macrophages are not the only target of IO. Most importantly, hepatocyte-specific overexpression of miR-122 rescued IO-mediated hepatic inflammation. Our findings indicate the direct involvement of hepatocytes in IO-induced hepatic inflammation and are informative for developing new molecular targets and preventative therapies for patients with major hemoglobinopathy.

Effect of iron dextran injections on some synovia markers of Iraqi sport horses

Effect of iron dextran injections on some synovia markers of Iraqi sport horses

Effects of Moderate Iron Loading on Skeletal Muscle Function and Oxidative Injury

Skeletal muscle iron overload is known to increase oxidative injury and impair contractile function. However, the impact of a moderate, physiologically‐relevant degree of muscle iron loading on contractile function has not been investigated. Thus, this study examined effects of moderate iron loading on skeletal muscle function and oxidative injury induced by subcutaneous injections of iron dextran. Young‐adult male mice received injections of iron dextran (4 mg iron/200μL) or vehicle (dextrose) 5 days per week for a period of two weeks (n=10/group). One day following the last injection the soleus muscle was harvested to assess levels of non‐heme iron (NHI), oxidative injury, and contractile properties. Liver and soleus NHI was approximately 4‐fold greater in mice that received injections of iron compared to vehicle (p&lt;0.05). No difference in animal body mass or soleus muscle mass was observed (p&gt;0.05). Maximal specific tension of the soleus was lower among iron loaded animals (22.4±0.1 N/cm2) compared to controls (26.2±0.9 N/cm2; p&lt;0.05). However, soleus lipid peroxidation (4‐hydroxynoneal) and protein oxidation (protein carbonyls) levels were not different between the groups (p&gt;0.05). In summary, a moderate elevation in muscle iron reduced contractile function by a mechanism that does not appear to involve oxidative stress. Additional experiments are being conducted to reveal a possible mechanism behind the iron‐mediated reduction in muscle force production.Support or Funding InformationSupported by the Syracuse University SOE