Iron Dextran Injection Research Articles

Resveratrol ameliorates iron overload induced liver fibrosis in mice by regulating iron homeostasis.

This study is intended to explore the protective effects of resveratrol (RES) on iron overload-induced liver fibrosis and its mechanism. Iron dextran (50 mg/kg) was injected intraperitoneally in all groups except the control group. Mice in the L-RES, M-RES and H-RES groups were gavaged with RES solution at 25, 50 mg/kg and 100 mg/kg, respectively, 4 h before injection of iron dextran every day; mice in the deferoxamine (DFO) group were injected with DFO intraperitoneally (100 mg/kg); mice in the control group received isovolumetric saline. After seven weeks of RES administration, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) activities and liver hydroxyproline (Hyp) levels were reduced; the malondialdehyde (MDA) activities decreased and the levels of superoxide dismutase (SOD) and glutathione (GSH) were raised. Hematoxylin and eosin (H&E), Prussian, and Masson staining indicated that RES treatment could improve cell damage and reduce hepatic iron deposition and collagen deposition in iron-overload mice. The expression of Bcl-2 was increased, the expression levels of Bax and caspase-3 were decreased under RES treatment. Moreover, RES reduced the expression of hepcidin, ferritin (Ft), divalent metal transporter-1 (DMT-1), transferrin receptor-2 (TFR-2), and raised the expression of ferroprotein-1 (FPN-1). In conclusion, RES could ameliorate iron overload-induced liver fibrosis, and the potential mechanisms may be related to antioxidant, anti-inflammatory, anti-apoptotic, and more importantly, regulation of iron homeostasis by reducing iron uptake and increasing iron export.

Iron Supplementation Improves Skeletal Muscle Contractile Properties in Mice with CKD.

Patients with chronic kidney disease (CKD) frequently have compromised physical performance, which increases their mortality; however, their skeletal muscle dysfunction has not been characterized at the single-fiber and molecular levels. Notably, interventions to mitigate CKD myopathy are scarce. The effect of CKD in the absence and presence of iron supplementation on the contractile function of individual skeletal muscle fibers from the soleus and extensor digitorum longus muscles was evaluated in 16-week-old mice. CKD was induced by the adenine diet, and iron supplementation was by weekly iron dextran injections. Maximally activated and fatigued fiber force production was decreased 24%-52% in untreated CKD, independent of size, by reducing strongly bound myosin/actin cross-bridges and/or decreasing myofilament stiffness in myosin heavy chain (MHC) I, IIA, and IIB fibers. Additionally, myosin/actin interactions in untreated CKD were slower for MHC I and IIA fibers and unchanged or faster in MHC IIB fibers. Iron supplementation improved anemia and did not change overall muscle mass in CKD mice. Iron supplementation ameliorated CKD-induced myopathy by increasing strongly bound cross-bridges, leading to improved specific tension, and/or returning the rate of myosin/actin interactions toward or equivalent to control values in MHC IIA and IIB fibers. Skeletal muscle force production was significantly reduced in untreated CKD, independent of fiber size, indicating that compromised physical function in patients is not solely due to muscle mass loss. Iron supplementation improved multiple aspects of CKD-induced myopathy, suggesting that timely correction of iron imbalance may aid in ameliorating contractile deficits in CKD patients.

Comparative Effects of Nigella Sativa and Cassia Senna in Iron Overloaded Mice

Background: Iron overload-related complications are the main concern in patients who must often receive blood transfusions. The only way to treat iron overload in these patients is by chelating agents. Owing to the high cost and adverse effects of chelating agents use of naturally present chelators is under study. Aim: To compare the protective effects of two commonly used herbs Nigella Sativa and Cassia Senna in iron-overloaded mice. Study Design: Experimental randomized controlled trial. Setting: Zoology department of Govt College University Lahore during six months period. Method: A total of forty-eight mice were divided into four groups (n = 12). Group one was normal to control while group 2, 3, and 4 were overloaded with iron by intravenous injection of iron dextran (0.1 ml/kg body weight) daily for fifteen days. After 15 days iron overload was confirmed by blood testing. For additional 15 days, group three mice were provided with Cassia Senna (100 mg/Kg body weight) while group four mice were permitted to feed on Nigella sativa (200 mg/Kg body weight). Animals were sacrificed on day 32 and organs were preserved to check the iron levels. Blood sampling was done on days 0, 15, and 31 to analyze serum iron levels. Results: The protective effect of Nigella Sativa was more marked than cassia senna in iron 0verloaded mice. Conclusion: The addition of Nigella Sativa instead of cassia senna in iron-laden patients as an adjunct therapy can be more beneficial in preventing the damaging effects of iron overload. Keywords: iron overload, Nigella Sativa, Cassia Senna

Rhabdomyolysis after Intravenous Ferric Gluconate: A Case Report.

Patients with severe iron deficiency, malabsorption or intolerance to oral iron are frequently treated with intravenous iron replacement. We report the case of a 42-year-old woman with non-erosive oligoarticular arthritis with antiparietal cell antibodies and iron deficiency anemia secondary to menorrhagia and unresponsive to oral iron preparations. She was treated with an intravenous infusion of ferric gluconate. After the first infusion of 125 mg (in 250 mL saline), she developed transient pain in her knee and wrist joints. When the dose was subsequently halved, the patient showed no adverse symptoms in the next four infusions and had normalized hemoglobin levels and iron indices. However, after a subsequent 125 mg ferric gluconate infusion she developed severe leg pain, muscular and joint stiffness, and functional impairment of her hands, right foot, and ankle. Laboratory tests showed a progressive increase in creatine kinase, transaminase, and C-reactive protein that normalized several days after the infusion. Although rhabdomyolysis is not reported among endovenous iron-induced adverse events, our findings suggest that intravenous iron infusions might have increased free iron generation promoting oxidative joint and muscular injury, which would explain the joint pain and stiffness, and rhabdomyolysis. Greater attention should be paid to the more frequent cases of myalgia occurring after iron infusion, which may underlie a rhabdomyolytic event requiring clinical observation.LEARNING POINTSRhabdomyolysis can occur not only after intramuscular injection of iron dextran but also after infusion of ferric gluconate.The generation of increased free iron following iron administration can promote oxidative joint and muscular injury.Leg cramps and myalgia, which are relatively common adverse events after iron infusions, might represent undiagnosed events of mild to moderate rhabdomyolysis requiring further investigation.

The effect of iron dextran injection on oral candidiasis symptoms in experimental iron deficiency anemia of laboratory rats

Iron deficiency anemia (IDA) is the most common type of anemia that causes various health problems and is commonly companied by oral symptoms, including oral thrush from Candida infection. The study assessed the role of iron status in the pathogenicity of oral candidiasis in an animal model. IDA in rats was produced by feeding on iron-free diet (five weeks), followed by inducing oral candidiasis by Candida albicans suspension. After the infection, animal subgroups were treated by intramuscular injection (IM) of iron dextran (ID) at 2 and 4 mg/kg once a week for three weeks and normal saline injection for comparison. Blood parameters test and tongue histopathological study were conducted. The IDA parameters and the oral thrush lesions were detected in experimental rats. IM of 2 mg ID diminished oral white patches and improved blood hemoglobin (14.533 g/dl), serum iron (109.177 μg/dl), and serum ferritin (5.276 ng/ml) and decreased total iron-binding capacity (377.000 μg/dl). Tongue sections showed normal tongue papillae, reduced inflammation and regular keratin deposition on papillae. At a 4 mg dose, despite the improvement in the blood parameters, a mild reduction was found in tongue thrush by less normal appearance of tongue papillae sections, mild inflammatory cells and hyperplasia of squamous epithelium. The study findings indicate that iron status plays a critical role in the treatment of oral thrush infection.

Evolution of drug delivery systems: From 1950 to 2020 and beyond

Modern drug delivery technology began in 1952 with the advent of the Spansule® sustained-release capsule technology, which can deliver a drug for 12 h after oral administration through an initial immediate dose followed by the remaining released gradually. Until the 1980s, oral and transdermal formulations providing therapeutic durations up to 24 h for small molecules dominated the drug delivery field and the market. The introduction of Lupron Depot® in 1989 opened the door for long-acting injectables and implantables, extending the drug delivery duration from days to months and occasionally years. Notably, the new technologies allowed long-term delivery of peptide and protein drugs, although limited to parenteral administration. The introduction of the first PEGylated protein, Adagen®, in 1990 marked the new era of PEGylation, resulting in Doxil® (doxorubicin in PEGylated liposome) in 1995, Movantik® (PEGylated naloxone - naloxegol) in 2014, and Onpattro® (Patisiran - siRNA in PEGylated lipid nanoparticle) in 2018. Drug-polymer complexes were introduced, e.g., InFed® (iron-dextran complex injection) in 1974 and Abraxane® (paclitaxel-albumin complex) in 2005. In 2000, both Mylotarg™ (antibody-drug conjugate – gemtuzumab ozogamicin) and Rapamune® (sirolimus nanocrystal formulation) were introduced. The year 2000 also marked the launching of the National Nanotechnology Initiative by the U.S. government, which was soon followed by the rest of the world. Extensive work on nanomedicine, particularly formulations designed to escape from endosomes after being taken by tumor cells, along with PEGylation technology, ultimately resulted in the timely development of lipid nanoparticle formulations for COVID-19 vaccine delivery in 2020.While the advances in drug delivery technologies for the last seven decades are breathtaking, they are only the tip of an iceberg of technologies that have yet to be utilized in an approved formulation or even to be discovered. As life expectancy continues to increase, more people require long-term care for various diseases. Filling the current and future unmet needs requires innovative drug delivery technologies to overcome age-old familiar hurdles, e.g., improving water-solubility of poorly soluble drugs, overcoming biological barriers, and developing more efficient long-acting depot formulations. The lessons learned from the past are essential assets for developing future drug delivery technologies implemented into products. As the development of COVID-19 vaccines demonstrated, meeting the unforeseen crisis of the uncertain future requires continuous cumulation of failures (as learning experiences), knowledge, and technologies. Conscious efforts of supporting diversified research topics in the drug delivery field are urgently needed more than ever.

Abstract 9379: Ferroptosis Inhibitor Exerts Greater Efficacy Than Apoptosis and Necroptosis Inhibitors on Improving Cardiac Function via Restoring Cardiac Mitochondrial Function and Attenuating Cardiomyocyte Death in Rats With Iron-Overloaded Cardiomyopathy

Introduction: Iron overload cardiomyopathy (IOC) is a common cause of death in iron overload patients. Previous studies reported that iron overload led to cardiac mitochondrial dysfunction and cardiomyocyte death through multiple pathways including apoptosis, necroptosis and ferroptosis. However, the dominant cell death pathway in the iron-overloaded heart remains to be clarified. Hypothesis: We tested the hypothesis that apoptosis, necroptosis and ferroptosis play equally important roles in IOC; and inhibitors of the three cell death pathways have equal beneficial effect on improving cardiac function in iron-overloaded rats. Methods: Male Wistar rats received intraperitoneal injection of iron dextran, 5 days/week for 4 weeks. Then, the rats were divided into 5 groups (n=4/group) being treated with vehicle, apoptosis inhibitor (z-VAD-FMK), necroptosis inhibitor (necrostatin-1), ferroptosis inhibitor (ferrostatin-1) and iron chelator (deferoxamine) for 2 weeks. Cardiac function, mitochondrial function, mitophagy, apoptosis, necroptosis and ferroptosis were determined. Results: Iron-overloaded rats showed impaired cardiac and mitochondrial function associated with excessive mitophagy and increased expression of apoptosis- and ferroptosis-related proteins. All cell death inhibitors could decrease cardiac mitophagy, apoptosis and ferroptosis in iron overloaded rats. Ferrostatin-1 was more effective than the other drugs in diminishing mitochondrial depolarization and bax/bcl-2 ratio (Figure A). Therefore, ferrostatin-1 and deferoxamine reversed iron overload-induced cardiac dysfunction as indicated by the restored left ventricular ejection fraction (Figure B), whereas z-VAD-FMK and necrostatin-1 only partially improved this parameter. Conclusions: Ferroptosis might be the dominant type of cardiomyocyte death in IOC, and inhibition of ferroptosis is a potential therapeutic strategy against this condition.

Ameliorating effects of white mulberry on iron-overload-induced oxidative stress and liver fibrosis in Swiss albino mice

Excess iron causes oxidative damage of biomolecules, leading to tissue injury primarily liver failure. In this study, we explored the remediating effects of Morus alba L. (MAME) on iron-overload-induced oxidative stress and liver injury in mice. The In vitro study revealed the antioxidant and free radical scavenging properties of MAME. Intraperitoneal injection of iron-dextran was administered in Swiss albino mice to induce iron-overload condition and the mice were further treated with MAME. MAME treatment significantly decreased liver iron, serum ferritin level, oxidative stress, and restored serum parameters and liver antioxidants. Moreover, biochemical and histopathological analyses confirmed the alleviated liver damage and fibrosis upon MAME treatment. The protective effect of MAME against iron-overload-induced apoptosis was confirmed by upregulation of protein levels of Bax, Caspase-3, and PARP. The treatment also affected the expression of MAPKs (ERK, JNK, and p38). GC-MS analysis revealed the presence of various bioactive phytochemicals in MAME that may be responsible for ameliorating effects of excess iron. Thus MAME can be envisaged as an effective iron chelator in the treatment of iron-overload-induced liver injury and fibrosis.

Iron chelation suppresses secondary bleeding after intracerebral hemorrhage in angiotensin II-infused mice.

AimsSecondary bleeding and further hematoma expansion (HE) aggravate brain injury after intracerebral hemorrhage (ICH). The majority of HE results from hypertensive ICH. Previous study reported higher iron content in the brains of hypertensive patients. Iron overload exacerbates the risk of hemorrhagic transformation in thromboembolic stroke mice. Whether iron overload during the process of hypertension participates in secondary bleeding of hypertensive ICH remains unclear.MethodsHypertension was induced by continuous infusion of angiotensin II (Ang II) with an osmotic pump into C57BL/6 mice. ICH was simulated by intrastriatal injection of the liquid polymer Onyx‐18. Iron chelation and iron overload was achieved by deferoxamine mesylate or iron dextran injection. Secondary bleeding was quantified by measuring the hemoglobin content in the ipsilateral brain hemisphere.ResultsAng II‐induced hypertensive mice showed increased iron accumulation in the brain and expanded secondary hemorrhage after ICH modeling. Moreover, iron chelation suppressed while iron overload aggravated secondary bleeding. Mechanistically, iron exacerbated the loss of contractile cerebral vascular smooth muscle cells (VSMCs), aggravated blood–brain barrier (BBB) leakage in Ang II‐induced hypertensive mice, and increased glial and MMP9 accumulation after ICH.ConclusionIron overload plays a key role in secondary bleeding after ICH in Ang II‐induced hypertensive mice. Iron chelation during the process of Ang II‐induced hypertension suppresses secondary bleeding after ICH.

Moderate-intensity aerobic training reduces cardiac damage attributable to experimental iron overload in rats.

What is the central question of this study? The current literature indicates that oxidative stress plays a major role in iron overload. Although exercise is a well-established approach to treat/prevent cardiovascular diseases, its effects on iron overload are not known. What is the main finding and its importance? Moderate-intensity aerobic training had benefits in a rodent model of iron-overload cardiomyopathy by improving the antioxidant capacity of the heart. After further confirmation by translational and clinical studies, we should consider using this non-pharmacological, highly accessible and easily executable adjuvant approach allied to other therapies to improve the quality of life of iron-overloaded patients. Iron is an essential micronutrient for several life processes, but its excess can damage organs owing to oxidative stress, with cardiomyopathy being the leading cause of death in iron-overloaded patients. Although exercise has long been considered as a cardioprotective tool, its effects on iron overload are not known. This study was designed to investigate the effects of moderate-intensity aerobic training in rats previously submitted to chronic iron overload. Wistar rats received i.p. injections of iron dextran (100mg/kg, 5days/week for 4weeks); thereafter, the rats were kept sedentary or exercised (60min/day, progressive aerobic training, 60-70% of maximal speed, 5days/week on a treadmill) for 8weeks. At the end of the experimental period, haemodynamics were recorded and blood samples, livers and hearts harvested. Myocardial mechanics of papillary muscles were assessed in vitro, and cardiac remodelling was evaluated by histology and immunoblotting. Iron overload led to liver iron deposition, liver fibrosis and increased serum alanine aminotransferase and aspartate aminotransferase. Moreover, cardiac iron accumulation was accompanied by impaired myocardial mechanics, increased cardiac collagen typeI and lipid peroxidation (TBARS), and release of creatine phosphokinase-MB to the serum. Although exercise did not influence iron levels, tissue injury markers were significantly reduced. Likewise, myocardial contractility and inotropic responsiveness were improved in exercised rats, in association with an increase in the endogenous antioxidant enzyme catalase. In conclusion, moderate-intensity aerobic exercise was associated with attenuated oxidative stress and cardiac damage in a rodent model of iron overload, thereby suggesting its potential role as a non-pharmacological adjuvant therapy for iron-overload cardiomyopathy.

NIGELLA SATIVA: ROLE IN IRON OVERLOAD

Background: In thalassemia patients, iron is overloaded because of multiple blood transfusions. This overloaded iron can damage the organs badly which is a major cause of death in these patients. Iron overload in thalassemia major can only be treated by removing the excessive iron through different chelating agents. Commercially available chelating agents are costly and associated with multiple adverse effects. Effectiveness of naturally present chelators is under study. This study was conducted to explore the chelating effect of one of commonly used herb Nigella sativa. Methods: This experimental, randomized controlled trial was conducted in Zoology Department, Government College University, Lahore in its multidisciplinary laboratory. A total of 36 male albino mice were divided into three groups, 12 in each group. Iron was overloaded in groups 2 and 3 by intravenous injections of iron dextran (0.1 ml/g body weight) for 15 days on daily basis. After 15 days, iron dextran injection was discontinued, and mice were allowed to feed on Nigella sativa (200 mg/Kg body weight) for further 15 days. Blood sampling was done at baseline, 15, and 30 days to analyse iron concentration in serum, heart, kidney, and liver. Data was analysed using Student’s t-test. Results: The artificially administered iron in mice increased the iron levels in serum, liver, heart and kidneys to a significant level while administration of N. sativa significantly decreased these levels. Conclusione propose clinical trials of Nigella sativa in thalassemia major patients as an adjunct therapy to explore its efficacy and safety. Pak J Physiol 2021;17(2):20–3

The protective mechanism of resveratrol against hepatic injury induced by iron overload in mice

Excessive iron deposition can produce toxicity. Liver, as the main storage site of iron, is more vulnerable to excessive iron than other organs. Many studies have found that Resveratrol (RES) can effectively eliminate oxygen free radicals and resist lipid peroxide damage. However, studies investigating the mechanism of how RES prevents liver injury induced by iron overload are few. This study aims to observe the protective effect of RES on liver injury induced by iron overload in mice. Mice, except for the control group, received an intraperitoneal injection of iron dextran (50 mg/kg) every morning. The L-RES and H-RES groups received intragastric administration of low- and high-concentration RES solutions (20 or 50 mg/kg). The deferoxamine (DFO) group was intraperitoneally injected with DFO (50 mg/kg), while the control and iron overload groups were intraperitoneally injected with the same amount of normal saline every afternoon. Two weeks after continuous administration, iron-overloaded mice treated with high and low doses of RES significantly improved liver injury (GOT and GPT) and decreased LDH activity and MDA content and increased SOD and GSH activities (P < 0.01). Morphological tests showed that RES treatment can reduce liver iron deposition and improve liver pathological changes in iron-overloaded mice. Furthermore, RES treatment caused a significant decrease in Ft expression (P < 0.01). In conclusion, RES can alleviate liver injury in iron-overloaded mice. The mechanism may be related to improve the antioxidant capacity and reduce excess iron in the liver.

The effects of secondary iron overload and iron chelation on a radiation-induced acute myeloid leukemia mouse model

BackgroundPatients with myelodysplastic syndrome (MDS) require chronic red blood cell (RBC) transfusion due to anemia. Multiple RBC transfusions cause secondary iron overload and subsequent excessive generation of reactive oxygen species (ROS), which leads to mutations, cell death, organ failure, and inferior disease outcomes. We hypothesize that iron loading promotes AML development by increasing oxidative stress and disrupting important signaling pathways in the bone marrow cells (BMCs). Conversely, iron chelation therapy (ICT) may reduce AML risk by lowering iron burden in the iron-loaded animals.MethodsWe utilized a radiation-induced acute myeloid leukemia (RI-AML) animal model. Iron overload was introduced via intraperitoneal injection of iron dextran, and iron chelation via oral gavage of deferasirox. A total of 86 irradiated B6D2F1 mice with various levels of iron burden were monitored for leukemia development over a period of 70 weeks. The Kaplan-Meier estimator was utilized to assess AML free survival. In addition, a second cohort of 30 mice was assigned for early analysis at 5 and 7 months post-irradiation. The BMCs of the early cohort were assessed for alterations of signaling pathways, DNA damage response and gene expression. Statistical significance was established using Student’s t-test or ANOVA.ResultsIron loading in irradiated B6D2F1 mice accelerated RI-AML development. However, there was a progressive decrease in AML risk for irradiated mice with increase in iron burden from 7.5 to 15 to 30 mg. In addition, ICT decreased AML incidence in the 7.5 mg iron-loaded irradiated mice, while AML onset was earlier for the 30 mg iron-loaded irradiated mice that received ICT. Furthermore, analysis of BMCs from irradiated mice at earlier intervals revealed accelerated dysregulation of signaling pathways upon iron loading, while ICT partially mitigated the effects.ConclusionsWe concluded that iron is a promoter of leukemogenesis in vivo up to a peak iron dose, but further iron loading decreases AML risk by increasing cell death. ICT can partially mitigate the adverse effects of iron overload, and to maximize its benefit this intervention should be undertaken prior to the development of extreme iron overload.

Correcting iron deficiency anemia with iron dextran alters the serum metabolomic profile of the infant Rhesus Monkey

The effects of infantile iron deficiency anemia (IDA) extend beyond hematological indices and include short- and long-term adverse effects on multiple cells and tissues. IDA is associated with an abnormal serum metabolomic profile, characterized by altered hepatic metabolism, lowered NAD flux, increased nucleoside levels, and a reduction in circulating dopamine levels. The objective of this study was to determine whether the serum metabolomic profile is normalized after rapid correction of IDA using iron dextran injections. Blood was collected from iron-sufficient (IS; n=10) and IDA (n=12) rhesus infants at 6 months of age. IDA infants were then administered iron dextran and vitamin B via intramuscular injections at weekly intervals for 2 to 8 weeks. Their hematological and metabolomic statuses were evaluated following treatment and compared with baseline and a separate group of age-matched IS infants (n=5). Serum metabolomic profiles assessed at baseline and after treatment via HPLC/MS using isobaric standards identified 654 quantifiable metabolites. At baseline, 53 metabolites differed between IS and IDA infants. Iron treatment restored traditional hematological indices, including hemoglobin and mean corpuscular volume, into the normal range, but the metabolite profile in the IDA group after iron treatment was markedly altered, with 323 metabolites differentially expressed when compared with an infant's own baseline profile. Rapid correction of IDA with iron dextran resulted in extensive metabolic changes across biochemical pathways indexing the liver function, bile acid release, essential fatty acid production, nucleoside release, and several neurologically important metabolites. The results highlight the importance of a cautious approach when developing a route and regimen of iron repletion to treat infantile IDA.

Chronic overload of concentration-dependent iron exerts different effects on ovarian function in C57BL/6J mice†.

Overloaded iron can deposit in the reproductive system and impair ovarian function. But few studies have identified the exact effect of overloaded iron on the endocrine function and fertility capacity in female mice. Here, we established iron-overloaded mouse models by intraperitoneal injection of iron dextran to adult female C57BL/6J mice at 0.1g/kg (LF group), 0.5g/kg (MF group), and 1.0g/kg (HF group) concentrations once a week for eight consecutive weeks. We found that overloaded iron resulted in smaller ovaries, as well as accumulated oxidative damages. The endocrine function and follicle development were also impeded in the MF and HF groups. The 10-month breeding trial indicated that (1) Low concentration of iron (0.1g/kg) wasn't detrimental to the ovary; (2) Middle concentration of iron (0.5g/kg) impeded the childbearing process, though it could be recovered following the iron excretion; and (3) High concentration of iron (1.0g/kg) damaged the fertility, even gave rise to sterility. Yet for those fertile mice, litter number and litter size were smaller and the ovarian reserve of their offspring was impaired. Transcriptome profiling results indicated that overloaded iron could compromise ovarian function by disrupting ovarian steroidogenesis, interfering with ovarian microenvironment, and inhibiting Wnt signaling. Taken together, we have demonstrated the effect that chronic concentration-dependent iron overload exerted on mouse ovarian function, which may act as a preliminary basis for further mechanism and intervention investigations.

Iatrogenic Iron Promotes Neurodegeneration and Activates Self-Protection of Neural Cells against Exogenous Iron Attacks.

Metal implants are used worldwide, with millions of nails, plates, and fixtures grafted during orthopedic surgeries. Iron is the most common element of these metal implants. As time passes, implants can be corroded and iron can be released. Ionized iron permeates the surrounding tissues and enters circulation; importantly, iron ions pass through the blood–brain barrier. Can iron from implants represent a risk factor for neurological diseases? This remains an unanswered question. In this study, we discovered that patients with metal implants delivered through orthopedic surgeries have higher incidence of Parkinson’s disease or ischemic stroke compared to patients who underwent similar surgeries but did not have implants. Concentration of serum iron and ferritin was increased in subjects with metal implants. In experiments in vivo, we found that injection of iron dextran selectively decreased the presence of divalent metal transporter 1 (DMT1) in neurons through increasing the expression of Ndfip1, which degrades DMT1 and does not exist in glial cells. At the same time, excess of iron increased expression of DMT1 in astrocytes and microglial cells and triggered reactive astrogliosis and microgliosis. Facing the attack of excess iron, glial cells act as neuroprotectors to accumulate more extracellular iron by upregulating DMT1, whereas neurons limit iron uptake through increasing DMT1 degradation. Cerebral accumulation of iron in animals is associated with impaired cognition, locomotion, and mood. Excess iron from surgical implants thus can affect neural cells and may be regarded as a risk factor for neurodegeneration.

Case Report: Diagnosis and Treatment of Enteritis Caused by Bacterial in a Dog

Diagnosis of the cause of enteritis in dogs greatly influences the success of its treatment. This case report describes the management of a male dog, 5 months old, 4.8 kg body weight which reported diarrhea, fever and no appetite. The physical examination showed the dog had diarrhea, lethargy, anemic mucous membranes, body temperature of 39.6 °C and an increase in intestinal peristalsis. The results of blood tests showed normochromic microcytic anemia, decreased hemoglobin and PCV, lymphocytopenia, and eosinopenia. The results of the stool examination identified Escherichia coli, Aeromonas hydrophila and coliform. The dog is diagnosed with bacterial enteritis with a good prognosis. Treatment is given for 5 days with intramuscular injection of amoxicillin at a dose of 10 mg/kgBW bid, diphenhydramine HCl at a dose of 2 mg/kgBW bid, multivitamin syrup 0.1 ml/kgBW bid orally, and intramuscular injection of iron dextran at a dose of 10 mg/kgBW only on the fifth day. It was concluded that the dog had enteritis due to bacterial infection, and it recovered after 5 days of treatment.

Cotransplantation of Umbilical Cord Mesenchymal Stem Cells Promotes the Engraftment of Umbilical Cord Blood Stem Cells in Iron Overload NOD/SCID Mice

Iron overload aggravates the difficulty of umbilical cord blood (UCB) stem cell engraftment and reduces the survival of patients undergoing hematopoietic stem cell (HSC) transplantation. Mesenchymal stem cells (MSCs) have been suggested to have a significant role in HSC engraftment. This study aimed to determine the effect of intra-bone marrow (IBM) and i.v. cotransplantation of UBC mononuclear cells (MNCs) and umbilical cord (UC) MSCs on engraftment and hematopoietic recovery in an iron overload hematopoietic microenvironment. The iron overload model was established by dose-escalation intraperitoneal injection of iron dextran in NOD/SCID mice. Iron deposition in the bone marrow, heart, and liver was examined using hematoxylin and eosin (H&E) staining. Serum levels of ferritin and iron status in the liver were measured. The iron overload NOD/SCID mice were sublethally irradiated and divided into 5 groups for transplantation: (1) control group; (2) IBM+ group: IBM injection of combined UCB-MNCs/UC-MSCs; (3) IV+ group: i.v. injection of combined UCB-MNCs/UC-MSCs; (4) IBM group: IBM injection of only UCB-MNCs; and (5) IV group: i.v. injection of UCB-MNCs. At 6 weeks after transplantation, the human CD45+ cells in the bone marrow were analyzed by flow cytometry. The semiquantitative analysis of vascular endothelial growth factor (VEGF-A), osteopontin (OPN), and stromal cell-derived factor-1a (SDF-1a) were examined by immunohistochemical staining (IHC). Compared with the IBM and IV groups, the survival rate and the percentages of human CD45+ cells and CD34+ cells and colony-forming units (CFU) in bone marrow were elevated in the IBM+ and IV+ groups. In addition, the levels of VEGF-A, OPN, and SDF-1a in bone marrow were all higher in the IBM+ and IV+ groups. Our data show that IBM and i.v. cotransplantation of UC-MSCs can improve the engraftment and proliferation of UCB-MNCs in iron overload NOD/SCID mice. The increased expression of VEGF-A, OPN, and SDF-1a in the bone marrow may be involved in improving the hematopoietic microenvironment and promoting the implantation of human UCB stem cells in the bone marrow with iron overload.

Effects of Iron Deficiency on Serum Metabolome, Hepatic Histology, and Function in Neonatal Piglets.

Simple SummaryIron deficiency is a serious nutrient deficiency in neonatal pigs during the suckling period in modern intensive farming systems and leads to impaired immune response, infection risks, and retardation of growth. The objective was to determine how iron deficiency in neonatal pigs alters the serum metabolomic profile using quantitative and qualitative analysis by ultra-performance liquid chromatography-tandem mass spectrometer (UPLCMS/MS). The current results revealed that iron deficiency led to a series of metabolic changes involved in tyrosine metabolism, phenylalanine metabolism, bile secretion, primary bile acid biosynthesis, steroid biosynthesis, and upregulated activities of the urea cycle enzymes in the liver of neonatal piglets. Few studies focused on the effects of iron on characterizing alterations of metabolic processes in neonatal piglets. In the present study, 16 neonatal piglets were randomly assigned to two groups. In the first group piglets were given an intramuscularly injection of iron dextran at 150 mg as a positive control (CON) and the second group were not supplemented with iron as a negative control for iron deficiency (ID). At day 8, iron status, serum biochemical parameters, serum metabolome, hepatic histology, and hepatic expression of genes for the metabolism were analyzed. Results indicated that piglets without iron supplementation had significantly reduced iron values and increased blood urea nitrogen concentrations at day 8 (p < 0.05). Analysis of serum metabolome revealed that concentrations of serum lysine, leucine, tyrosine, methionine, and cholesterol were significantly decreased while concentrations of 3-Methyldioxyindole, chenodeoxycholate acid, indoleacetic acid, icosadienoic acid, phenylpyruvic acid, pantothenic acid, ursocholic acid, and cholic acid were significantly increased in iron deficient piglets (p < 0.05). Furthermore, expressions of cyp7a1 and the urea cycle enzyme (ornithinetranscarbamoylase and argininosuccinate synthetase) were significantly increased in iron deficient pigs (p < 0.05). The present experimental results indicated that neonatal piglets without iron supplementation drop to borderline anemia within 8 days after birth. Iron deficiency led to a series of metabolic changes involved in tyrosine metabolism, phenylalanine metabolism, bile secretion, primary bile acid biosynthesis, steroid biosynthesis, and upregulated activities of the urea cycle enzymes in the liver of neonatal piglets, suggesting early effects on metabolic health of neonatal piglets.

Evaluation of Beneficial Effects of Melilotus officinalis on Blood Profiles in iron Overloaded Sprague Dawley Rats

Present study deals with the investigation of beneficial effects of different fraction of Melilotus officinalis (M. officinalis) on the toxic effects of iron on different blood parameters in iron overloaded sprague dawley rats. The six IP injections of iron dextran (12.5 mg/100g) were administered uniformly over a period of 30 days to induce iron overload. Different fractions of M. officinalis were given orally and Deferoxamine (DFO) subcutaneously for 30 days. The blood parameters were estimated on 15th and 30th day of treatment. Rats exposed to iron showed significant (p &lt; 0.01) decrease in RBC counts, Total and Differential WBC counts and Platelet counts. This indicates that excess of iron in iron overloaded disease can leads to bone marrow suppression. The animals treated with methanolic fraction of methanolic extract (MFME) and methanolic fraction of aqueous extract (MFAE) of M. officinalis shows significant (P&lt;0.01) improvement in haematological parameters as compared to disease control (DC) rats. Greater beneficial effects were observed on 30th day and at higher dose (300 mg/kg) as compared to 15th day and at lower dose (150 mg/kg). These results suggested that M. officinalis have beneficial effects on blood parameters in iron intoxicated rats.