scholarly journals Changes in Hepcidin Levels in an Animal Model of Anemia of Chronic Inflammation: Mechanistic Insights Related to Iron Supplementation and Hepcidin Regulation

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Hye-Bin Kim ◽  
Ji Hae Jun ◽  
Jae-Kwang Shim ◽  
Ju Eun Oh ◽  
Cheolhun Lee ◽  
...  
Keyword(s):  
Animal Model ◽  
Chronic Inflammation ◽  
Iron Supplementation ◽  
Sprague Dawley ◽  
Additional Increase ◽  
Regulatory Pathways ◽  
Iron Administration ◽  
Iron Treatment ◽  
Iv Iron ◽  
Anemia Of Chronic Inflammation

We examined changes in hepcidin (closely associated with anemia of chronic inflammation (ACI)) and upstream regulatory pathways after intravenous (IV) iron supplementation in an ACI animal model. ACI was induced in male Sprague-Dawley rats by intraperitoneally administering complete Freund’s adjuvant (CFA). Two weeks after starting CFA treatment, ACI rats received IV iron (CFA-iron) or vehicle (CFA-saline). Three days after IV iron treatment, iron profiles, hepcidin levels, and expression of proteins involved in the signaling pathways upstream of hepcidin transcription in the liver were measured. In CFA-treated rats, anemia with a concomitant increase in the levels of serum inflammatory cytokines and reactive oxygen species occurred. In CFA-iron rats, hemoglobin (Hb) concentration was still lower than that in control rats. In CFA-saline rats, hepatic hepcidin and ferritin levels increased compared with those in control rats and were further increased in CFA-iron rats. In CFA-saline rats, NADPH oxidase- (NOX-) 2, NOX-4, and superoxide dismutase levels in the liver were upregulated compared with those in control rats and their levels were further increased in CFA-iron rats. In CFA-saline rats, activities of the IL-6/STAT and BMP/SMAD pathways were enhanced in the liver compared with those in control rats and their levels were further increased in CFA-iron rats, whereas IL-6 expression remained unaffected after IV iron administration. In HepG2 cells, iron caused phosphorylation of STAT-3 and SMAD1/5 and knockdown of STAT-3 and SMAD1/5 using siRNAs reduced iron-induced hepcidin upregulation to levels similar to those in corresponding control cells. Renal erythropoietin expression and serum erythroferrone concentration were lower in CFA-iron rats than those in control rats. In ACI rats, IV iron supplementation did not recover Hb within three days despite an increase in hepatic ferritin levels, which might be attributable to an additional increase in hepcidin levels that was already upregulated under ACI conditions. Both STAT-3 phosphorylation and SMAD1/5 phosphorylation were associated with hepcidin upregulation after IV iron treatment, and this seems to be linked to iron-induced oxidative stress.

scholarly journals Intravenous Iron Infusion Administration Schedule and Hematologic Response; A Single-Center Retrospective Cohort Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 14-15
Author(s):  
Melissa T. Maltez ◽  
Johnathan P. Mack
Keyword(s):  
Logistic Regression ◽  
Retrospective Cohort ◽  
Iron Supplementation ◽  
Intravenous Iron ◽  
Iron Dextran ◽  
Single Center ◽  
Hematologic Response ◽  
Iron Administration ◽  
Iv Iron ◽  
Iron Replacement

Background: Clinical trials studying the efficacy of intravenous (IV) iron replacement have used a variety of dosing schedules, even for the same iron formulations and there isn't a clear standard for how IV iron replacement should be scheduled. Differences in iron absorption efficiency have been observed with different oral iron supplementation schedules but it is not known if the same is true for IV iron. The objective of this study was to evaluate the association between iron administration schedule and hemoglobin response in patients treated at a tertiary care center. Methods: Data was collected retrospectively using The Ottawa Hospital Data Warehouse (OHDW) capturing all iron infusions given at 3 local institutions between January 2007 and December 2018. Patients that received at least 2 intravenous iron infusions within 180 days of each other were included. A 'course' of iron replacement was defined as consecutive infusions with ≤180 days between doses. Patients transfused red blood cells within 90 days of the last iron infusion in each course were excluded. Patient age, sex, dose and formulation of administered, date of each iron infusion, and laboratory parameters from the period starting 3 months before the first infusion to 6 months after the last infusion were extracted for analysis. Patients were categorized into 4 groups based on the mean time between iron infusions in each course: 1-10 days, 11-20 days, 21-30 days, and >30 days. Achieving a maximum hemoglobin (Hb) 10 g/L or higher than the pre-infusion Hb was defined as a 'good' response. A logistic regression model was used to evaluate the association between interval between infusions and achieving a 'good' Hb response. The model was adjusted for sex, age, presence of chronic kidney disease (CKD), dose of iron per course, number of infusions per course, and number of courses. CKD was defined as having a serum creatinine >177 µmol/L. Iron sucrose, iron gluconate, and iron dextran were available for administration during the study period. Results: A total of 4350 patients were included in the analysis. These patients received a total of 6409 courses of iron replacement, with a median of 2 courses (interquartile range [IQR] 1-3) per patient, and 4 infusions (IQR 3-6) per replacement course. Infusions were given a median of 21.9 days (IQR 12-34) apart in each course, with a range of 1-179 days. Iron sucrose was given in most courses (81.6%), followed by iron gluconate (18.2%) and iron dextran (0.1%). Patient characteristics are summarized in Table 1 and laboratory values prior to the first infusion of each course are summarized in Table 2. The interval between iron infusions was associated with Hb response. Results of the logistic regression are summarized Table 3. Compared with patients receiving infusions every 10-20 days, patients receiving infusions more frequently or less frequently were less likely to achieve a good Hb response. Male sex was associated with increased odds of response, while increasing age, having CKD, and receiving more courses of iron were associated with decreased odds of response. Conclusions: In this single-center retrospective cohort analysis, an association between interval of iron infusions and hematologic response was observed. Patients given iron every 10-20 days more likely to achieve a good response compared with more, or less frequent dosing intervals. Strengths of this study include the large sample size, adjustment for sex, age, presence of CKD, and number of iron infusions and courses given. Transfused patients were excluded, so the hemoglobin response is attributable to iron replacement. The study has several important limitations. The clinical decision-making for the infusion schedule was not known and factors that went into this decision are a possible source of confounding (for example, ongoing bleeding). The suspected cause of iron deficiency was not known. Additionally, concomitant oral iron supplementation and iron infusions or transfusions occurring outside the study institution are unknowns and may influence to outcome. The hypothesis-generating findings suggest that the schedule of iron administration may play an important role in hematologic response to iron infusions. Disclosures No relevant conflicts of interest to declare.

Ultrastructural investigation of spontaneous pituitary gonadotroph cell adenomas in aging Sprague-Dawley rats

1983 ◽  
Vol 41 ◽  
pp. 702-703
Author(s):  
D. J. McComb ◽  
J. Beri ◽  
F. Zak ◽  
K. Kovacs
Keyword(s):  
Electron Microscopy ◽  
Animal Model ◽  
Epoxy Resin ◽  
Immunoelectron Microscopy ◽  
Tumor Type ◽  
Gonadal Function ◽  
Sprague Dawley ◽  
Male And Female ◽  
Reticulin Fibers ◽  
Sprague Dawley Rats

Gonadotroph cell adenomas of the pituitary are infrequent in human patients and are not invariably associated with altered gonadal function. To date, no animal model of this tumor type exists. Herein, we describe spontaneous gonadotroph cell adenomas in old male and female Sprague-Dawley rats by histology, immunocytology and electron microscopy.The material consisted of the pituitaries of 27 male and 38 female Sprague Dawley rats, all 26 months of age or older, removed at routine autopsy. Sections of formal in-fixed, paraffin-embedded tissue were stained with hematoxylin-phloxine-saffron (HPS), the PAS method and the Gordon-Sweet technique for the demonstration of reticulin fibers. For immunostaining, sections were exposed to anti-rat β-LH, anti-ratβ-TSH, anti-rat PRL, anti-rat GH and anti-rat ACTH 1-39. For electron microscopy, tissue was fixed in 2.5% glutaraldehyde, postfixed in 1% OsO4 and embedded in epoxy-resin. Tissue fixed in 10% formalin, embedded in epoxy resin without osmification, was used for immunoelectron microscopy.

scholarly journals The combination of Acalypha indica–Centella asiatica extracts decreases the neuronal damage in hypoxia-induced hippocampal injury animal model

2018 ◽  
Vol 27 (3) ◽  
pp. 137-44
Author(s):  
Siti Farida ◽  
Desak G.B. Krisnamurti ◽  
Ninik Mudjihartini ◽  
Erni H. Purwaningsih ◽  
Imelda M. Sianipar ◽  
...  
Keyword(s):  
Animal Model ◽  
Neuronal Damage ◽  
Cell Damage ◽  
Neuronal Cell ◽  
Centella Asiatica ◽  
Nerve Cells ◽  
Control Treatment ◽  
Control Group ◽  
Sprague Dawley ◽  
Acalypha Indica

Background: Approximately 80–85% of strokes are ischemic and lead to alterations in neuronal cell morphology and cell death. There is a lack of studies on the effect of the combination of Acalypha indica L. (AI) and Centella asiatica L. (CA) in terms of its neurotherapy property. This study was conducted to investigate the neurotherapeutic effect of the combination of AI–CA extracts in improving rat’s hippocampal neuron injury post-hypoxia.Methods: A total of 36 Sprague-Dawley rats were categorized into six groups and placed in a hypoxia chamber for 7 consecutive days. Then, they were moved to normoxia cages and treated for 7 consecutive days as follows: control group without treatment as a negative control; treatment groups were administered citicoline 50 mg/kgBW as a positive control; three different dose combinations of AI150–CA150, AI200–CA150, and AI250–CA150 mg/kgBW, respectively. Histological analyses were performed to assess the improvement in nerve cell damage in the hippocampus.Results: Treatment with citicoline significantly decreased the damage of nerve cells (30.8%); the combination of the AI–CA extracts of AI150–CA150, AI200–CA150, and AI250–CA150 also significantly decreased the damage of nerve cells (36%, 36.4%, and 30.4%, respectively) compared to the control rats (15.4%).Conclusion: The combination of AI–CA extracts decreased the neuronal damage in the hypoxia-induced hippocampal injury animal model. The improvement effect of the combination of AI–CA extracts was not significantly different to citicoline.

scholarly journals Target Hemoglobin May Be Achieved with Intravenous Iron Alone in Anemic Patients with Cardiorenal Syndrome: An Observational Study

2015 ◽  
Vol 5 (4) ◽  
pp. 246-253 ◽  
Author(s):  
Eyal Ben-Assa ◽  
Yacov Shacham ◽  
Moshe Shashar ◽  
Eran Leshem-Rubinow ◽  
Amir Gal-Oz ◽  
...  
Keyword(s):  
Platelet Count ◽  
Adverse Effects ◽  
Observational Study ◽  
Treatment Strategy ◽  
Intravenous Iron ◽  
Cardiorenal Syndrome ◽  
Combination Group ◽  
Iron Treatment ◽  
Significant Difference ◽  
Iv Iron

Background: The treatment of anemia in patients with cardiorenal syndrome (CRS) is based mainly on intravenous (IV) iron therapy and/or erythropoiesis-stimulating agents (ESAs). There are concerns about the safety of ESAs due to a potentially higher risk for stroke and malignancy. Objective: We aimed to explore whether IV iron alone is sufficient to improve anemia in CRS patients and to define the predictors of treatment response. Methods: We retrospectively analyzed data of 81 CRS patient treated for anemia at our clinic. All patients received IV iron for 6 weeks. A subset of patients was additionally given subcutaneous ESAs. The end point was the improvement from baseline in hemoglobin (Hb) and ferritin levels at week 7. Results: We retrieved the files of 81 patients; 34 received IV iron alone and 47 were given IV iron and ESAs (the combination group). The Hb levels significantly increased in both groups (in the IV iron alone group: 10.6 ± 1.1 to 11.9 ±1.1 g/dl, p < 0.001; in the combination group: 10.2 ± 0.9 to 12.4 ± 1.3 g/dl, p < 0.001), but more pronouncedly in the combination group (2.17 vs. 1.24 g/dl; p = 0.001). The platelet count decreased significantly in the IV iron alone group but was unchanged in the combination group. Eighty percent of patients attained a Hb target of 11 g/dl, with no significant difference between the two groups (73.5 vs. 85.1%; p = 0.197). Low baseline Hb was the only predictor of a favorable outcome to treatment. Conclusion: Our observational study suggests that IV iron treatment without ESAs may substantially raise the Hb level to ≥11 g/dl in CRS patients. This treatment strategy may reduce the use of ESAs and hence its potential adverse effects.

scholarly journals Hypoxia-Inducible Factor Stabilizers in End Stage Kidney Disease: “Can the Promise Be Kept?”

2021 ◽  
Vol 22 (22) ◽  
pp. 12590
Author(s):  
Giuseppina Crugliano ◽  
Raffaele Serra ◽  
Nicola Ielapi ◽  
Yuri Battaglia ◽  
Giuseppe Coppolino ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Cardiovascular Events ◽  
Iron Supplementation ◽  
Hypoxia Inducible Factor ◽  
Current Treatment ◽  
Prolyl Hydroxylase ◽  
Individual Risk ◽  
Increased Risk ◽  
Gastrointestinal Side Effects ◽  
Iv Iron

Anemia is a common complication of chronic kidney disease (CKD). The prevalence of anemia in CKD strongly increases as the estimated Glomerular Filtration Rate (eGFR) decreases. The pathophysiology of anemia in CKD is complex. The main causes are erythropoietin (EPO) deficiency and functional iron deficiency (FID). The administration of injectable preparations of recombinant erythropoiesis-stimulating agents (ESAs), especially epoetin and darbepoetin, coupled with oral or intravenous(iv) iron supplementation, is the current treatment for anemia in CKD for both dialysis and non-dialysis patients. This approach reduces patients’ dependence on transfusion, ensuring the achievement of optimal hemoglobin target levels. However, there is still no evidence that treating anemia with ESAs can significantly reduce the risk of cardiovascular events. Meanwhile, iv iron supplementation causes an increased risk of allergic reactions, gastrointestinal side effects, infection, and cardiovascular events. Currently, there are no studies defining the best strategy for using ESAs to minimize possible risks. One class of agents under evaluation, known as prolyl hydroxylase inhibitors (PHIs), acts to stabilize hypoxia-inducible factor (HIF) by inhibiting prolyl hydroxylase (PH) enzymes. Several randomized controlled trials showed that HIF-PHIs are almost comparable to ESAs. In the era of personalized medicine, it is possible to envisage and investigate specific contexts of the application of HIF stabilizers based on the individual risk profile and mechanism of action.

scholarly journals Anemia of Chronic Inflammation

Anemia ◽  
2018 ◽  
pp. 150-155
Author(s):  
Satish P. Shanbhag ◽  
Cindy N. Roy
Keyword(s):  
Chronic Inflammation ◽  
Anemia Of Chronic Inflammation

Recombinant human regenerating gene 4 attenuates the severity of osteoarthritis by promoting the proliferation of articular chondrocyte in an animal model

2021 ◽  
Vol 14 ◽  
Author(s):  
Xue-jia Li ◽  
Fei Zhu ◽  
Bo Li ◽  
Dong Zhang ◽  
Cheng-Wei Liang
Keyword(s):  
Risk Factors ◽  
Animal Model ◽  
Sprague Dawley ◽  
Articular Chondrocyte ◽  
Chondrocyte Proliferation ◽  
Histological Changes ◽  
Proper Role ◽  
Sprague Dawley Rats ◽  
Gene 4

Introduction: Osteoarthritis (OA) is a dominant cause of morbidity and disability. As a chronic disease, its etiological risk factors and most therapies at present, are empirical and symptomatic. Regenerating gene 4 (Reg4) is involved in cell growth, survival, regeneration, adhesion, and resistance to apoptosis, which are partially thought to be the pathogenic mechanisms of OA. However, the proper role of Reg4 in OA is still unknown. Methods: In this study, a consecutive administration of rhReg4 was applied to normal Sprague-Dawley rats or rats after OA induction. Histological changes and chondrocyte proliferation in the articular cartilage were measured. Results: We found that RhReg4 promotes chondrocyte proliferation in normal rats, and RhReg4 attenuated the severity of OA in rats by promoting chondrocytes’ proliferation in OA rats. Conclusion: In conclusion, recombinant human regenerating gene 4 (rhReg4) attenuates the severity of osteoarthritis in OA animal models and may be used as a new method for the treatment of osteoarthritis.

scholarly journals Local Tissue Response to Subcutaneous Administration of Ceftriaxone in an Animal Model

2019 ◽  
Vol 64 (3) ◽  
Author(s):  
Vincent H. Tam ◽  
Daniel N. Cohen ◽  
Kimberly R. Ledesma ◽  
Bobby Guillory ◽  
Katrina Chan ◽  
...  
Keyword(s):  
Animal Model ◽  
Potassium Chloride ◽  
Subcutaneous Administration ◽  
Pharmaceutical Formulations ◽  
Tissue Response ◽  
Sprague Dawley ◽  
Local Tolerability ◽  
Local Inflammatory Response ◽  
Local Tissue ◽  
Thickness Skin

ABSTRACT Subcutaneous administration is a novel way to deliver antibiotics for an infection, but intolerability has been reported. Evaluating the local tolerability of subcutaneously administered antibiotics is not standardized. The goal of this study was to develop an animal model to assess the subcutaneous administration of ceftriaxone. Sprague-Dawley rats were given daily subcutaneous injections for 12 days. The back of each animal was divided into 4 quadrants, with injections rotating each day among the quadrants. Ceftriaxone (1,000 mg/kg of body weight daily) was given in different concentrations and durations. Normal saline and potassium chloride solutions (2 meq/2 ml) were used as negative and positive controls, respectively. After the treatment course, skin samples were biopsied, and the local inflammatory response was assessed histologically using a semiquantitative scoring system. The histopathology scores were compared using a Kruskal-Wallis test. Injections with potassium chloride resulted in full-thickness skin necrosis with subcutaneous atrophy that was not seen in the saline-injected animals; inflammation of the muscular panniculus was observed, with various degrees of myocyte injury. Serosanguinous cavity formation in the subcutaneous compartment was observed when ceftriaxone (125 mg/ml) was given as a bolus injection, but the extent of the local tissue response was remarkably reduced when the same ceftriaxone dose was given at a lower concentration (25 mg/ml) over 120 min (P = 0.63, compared to saline controls). At a low concentration, ceftriaxone infusion was found to be well tolerated in this animal tissue necrosis model. If validated, the model could be an instrumental platform to evaluate different pharmaceutical formulations for subcutaneous delivery.

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