Effect Of Recombinant Human Erythropoietin Research Articles

Evaluation of recombinant human erythropoietin as a promoter of bone healing in cats with femoral fractures.

The bone regeneration potential of erythropoietin (EPO) is not yet fully investigated, but some previous experimental studies demonstrated that its application activated the differentiation of osteoblasts and promoted bone formation. The aim of the present study was to evaluate the effects of recombinant human erythropoietin (rhEpo) on bone healing in cats with fragmented long bone fractures. Twelve cats were divided into two groups-control (n = 6) in which physiological saline was applied at the fracture gap site and EPO (n = 6) with the application of 1,000 IU rhEpo. The effects of EPO on blood erythrocyte counts, hemoglobin content, and hematocrit were monitored by serial complete blood cell tests, whereas bone formation was evaluated by clinical and radiographic examinations on post-operative weeks 1, 2, 3, 4, 6, and 8. All tested blood parameters were within the reference range. A faster fracture healing and full limb weight-bearing were observed in the EPO group, with statistically significant differences with respect to the control group. The obtained results confirmed that the local application of rhEpo promoted bone healing in cats with fragmented femoral fractures and increased bone callus strength without having significant systemic effects.

Effect of recombinant human erythropoietin combined with iron sucrose on postoperative hemoglobin in patients undergoing artificial joint replacement

With the aging of the population, an increasing number of elderly patients are opting for artificial joint replacement, leading to the exploration of various rapid rehabilitation programs in the perioperative period. In this study, we aimed to investigate the effectiveness of combining recombinant human erythropoietin and iron sucrose in altering the range and trend of postoperative hemoglobin in patients undergoing arthroplasty. Specifically, we will examine whether this combination can effectively alter the rise and fall of postoperative haemoglobin, identify the inflection point of haemoglobin change or recovery after arthroplasty, and assess the effect of treatment on serum iron in postoperative blood. We conducted a retrospective study of 138 patients who underwent unilateral total joint arthroplasty by the same surgeon in the same hospital before July 2022. The results of this study may provide valuable insights for the development of effective rehabilitation programs for patients undergoing arthroplasty.

Spinal Stroke: Outcome Attenuation by Erythropoietin and Carbamylated Erythropoietin and Its Prediction by Sphingosine-1-Phosphate Serum Levels in Mice.

Spinal strokes may be associated with tremendous spinal cord injury. Erythropoietin (EPO) improves the neurological outcome of animals after spinal cord ischemia (SCI) and its effects on ischemia-induced endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are considered possible molecular mechanisms. Furthermore, sphingosin-1-phosphate (S1P) is suggested to correlate with SCI. In this study, the effect of recombinant human EPO (rhEPO) and carbamylated EPO (cEPO-Fc) on the outcome of mice after SCI and a prognostic value of S1P were investigated. SCI was induced in 12-month-old male mice by thoracic aortal cross-clamping after administration of rhEPO, cEPO-Fc, or a control. The locomotory behavior of mice was evaluated by the Basso mouse scale and S1P serum levels were measured by liquid chromatography-tandem mass spectrometry. The spinal cord was examined histologically and the expressions of key UPR proteins (ATF6, PERK, and IRE1a, caspase-12) were analyzed utilizing immunohistochemistry and real-time quantitative polymerase chain reaction. RhEPO and cEPO-Fc significantly improved outcomes after SCI. The expression of caspase-12 significantly increased in the control group within the first 24 h of reperfusion. Animals with better locomotory behavior had significantly higher serum levels of S1P. Our data indicate that rhEPO and cEPO-Fc have protective effects on the clinical outcome and neuronal tissue of mice after SCI and that the ER is involved in the molecular mechanisms. Moreover, serum S1P may predict the severity of impairment after SCI.

Further Evidence of Neuroprotective Effects of Recombinant Human Erythropoietin and Growth Hormone in Hypoxic Brain Injury in Neonatal Mice.

Experimental in vivo data have recently shown complementary neuroprotective actions of rhEPO and growth hormone (rhGH) in a neonatal murine model of hypoxic brain injury. Here, we hypothesized that rhGH and rhEPO mediate stabilization of the blood–brain barrier (BBB) and regenerative vascular effects in hypoxic injury to the developing brain. Using an established model of neonatal hypoxia, neonatal mice (P7) were treated i.p. with rhGH (4000 µg/kg) or rhEPO (5000 IU/kg) 0/12/24 h after hypoxic exposure. After a regeneration period of 48 h or 7 d, cerebral mRNA expression of Vegf-A, its receptors and co-receptors, and selected tight junction proteins were determined using qRT-PCR and ELISA. Vessel structures were assessed by Pecam-1 and occludin (Ocln) IHC. While Vegf-A expression increased significantly with rhGH treatment (p < 0.01), expression of the Vegfr and TEK receptor tyrosine kinase (Tie-2) system remained unchanged. RhEPO increased Vegf-A (p < 0.05) and Angpt-2 (p < 0.05) expression. While hypoxia reduced the mean vessel area in the parietal cortex compared to controls (p < 0.05), rhGH and rhEPO prevented this reduction after 48 h of regeneration. Hypoxia significantly reduced the Ocln+ fraction of cortical vascular endothelial cells. Ocln signal intensity increased in the cortex in response to rhGH (p < 0.05) and in the cortex and hippocampus in response to rhEPO (p < 0.05). Our data indicate that rhGH and rhEPO have protective effects on hypoxia-induced BBB disruption and regenerative vascular effects during the post-hypoxic period in the developing brain.

Effects of Recombinant Human Erythropoietin and 2-Mercaptoethane Sulfonate on Liver Ischemia-Reperfusion Injury in Rats.

The aim of this study was to determine the effects of recombinant human erythropoietin and 2-merkaptoethane sulfonate, administered in combination, on the biochemical and histopathological changes of ischemia-reperfusion injury. Fifty female Wistar Albino rats were used in this study. The animals were randomly divided into 5 groups: a sham group that underwent standard laparotomy only, an ischemia-reperfusion group that was subjected to 30 minutes of hepatic ischemia and 2 hours of reperfusion, a group that intraperitoneally received 1000 IU/kg recombinant human erythropoietin 5 minutes before ischemia- reperfusion, a group that intraperitoneally received 150 mg/kg 2-merkaptoethane sulfonate 15 minutes before ischemia-reperfusion, and a combined group that received both drugs intraperitoneally before ischemia-reperfusion. After the reperfusion period, serum aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and malon- dialdehyde levels were measured. We also evaluated histological changes in rat liver tissues samples. Serum aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and malondialdehyde levels were high in the control groups, but aspartate and alanine aminotransferase levels were within normal limits, especially in rats that only received recombinant human erythropoietin. In rats that received combined treatment, parenchymal alterations in liver tissue were less severe than in the other groups and necrosis did not occur. Recombinant human erythropoietin was clearly more effective than 2-merkaptoethane sulfonate for preventing oxidative injury. When the agents were combined, obvious biochemically and histologically protective effects occurred, providing significant tissue protection in ischemia-reperfusion injury.

Recombinant human erythropoietin and interferon-\u03b2-1b protect against 3-nitropropionic acid-induced neurotoxicity in rats: possible role of JAK/STAT signaling pathway

3-Nitropropionic acid (3-NP) model serves as a beneficial tool to evaluate the effect of novel treatments for Huntington’s disease (HD). The aim of the present study was to demonstrate the neuroprotective effect of recombinant human erythropoietin (rhEPO) and interferon-beta-1b (IFN-β-1b) in 3-NP-induced neurotoxicity in rats. Rats were injected with 3-NP (10 mg/kg/day, i.p) for 2 weeks and were divided into five subgroups; the first served as the HD group, the second received rhEPO (5000 IU/kg/every other day, i.p.) for 2 weeks, the third received rhEPO starting from the 5th day of 3-NP injection, the fourth received IFN-β-1b (300,000 units, every day other day, s.c) for 2 weeks, and the last received IFN-β-1b starting from the 5th day of 3-NP injection. All treatments significantly improved motor and behavior performance of rats. Moreover, all treatments markedly restored mitochondrial function as well as brain-derived neurotrophic factor level, and reduced oxidative stress biomarkers, pro-inflammatory mediators, nuclear factor kappa B expression, caspase-3, and Bax/Bcl2 ratio in the striatum. In conclusion, the present study demonstrates the neuroprotective potential of rhEPO or IFN-β-1b on 3-NP-induced neurotoxicity in rats. Furthermore, our study suggests that activation of JAK2/STAT3 or JAK1/STAT3 may contribute to the neuroprotective activity of rhEPO or IFN-β-1b, respectively. We also found that early treatment with rhEPO did not confer any benefits compared with late rhEPO treatment, while early IFN-β-1b showed a marked significant benefit compared with late IFN-β-1b.

Recombinant human erythropoietin attenuates hepatic dysfunction by suppressing hepatocellular apoptosis in lipopolysaccharide-induced disseminated intravascular coagulation in rats.

The aim of the present study was to clarify the effect of recombinant human erythropoietin (EPO) and low molecular weight heparin (LMWH) on a rat model of lipopolysaccharide (LPS)-induced disseminated intravascular coagulation (DIC). Experimental DIC was induced by sustained infusion of 5 mg/kg LPS for 4 h. EPO or LMWH was then administered to the LPS-induced DIC model. LPS-induced consumption coagulopathy, hemostatic activation and plasma TNF elevation remained unaltered in the LPS+EPO group, except for the D-dimer levels, and these abnormalities were significantly improved in the LPS+LMWH group. Plasma alanine aminotransferase (ALT) levels were markedly reduced in the LPS+EPO group, accompanied by a significant suppression of hepatocellular apoptosis. In the LPS+LMWH group, plasma creatinine levels and glomerular fibrin deposition were significantly attenuated, along with plasma ALT levels and hepatocellular apoptosis. Thus, a single administration of EPO may improve hepatic dysfunction by primarily exerting an anti-apoptotic, not anticoagulant, effect in the LPS-induced DIC model.

Efficacy and safety of high and low dose recombinant human erythropoietin on neurodevelopment of premature infants: A meta-analysis.

Background:To evaluate the effect of recombinant human erythropoietin (rhEPO) in nervous system of premature infants including different dosage.Methods:The multiple databases like Pubmed, Embase, Cochrane databases and China National Knowledge Database were used to search for the relevant studies, and full-text articles involved in the evaluation on effect of rhEPO for neurodevelopment among premature infants. Review Manager 5.2 was adopted to estimate the effects of the results among selected articles. Forest plots, sensitivity analysis and bias analysis for the articles included were also conducted.Results:Finally, 10 eligible studies were eventually satisfied the included criteria. The results showed that rhEPO was much higher than placebo group in composite cognitive score (MD = 5.89, 95% confidential interval {CI} [1.95, 9.82], P = .003; I2 = 89%), there was no significant difference between rhEPO and placebo groups (RR = 0.93, 95% CI [0.60, 1.43], P = .74; I2 = 51%) and no difference in neurodevelopmental impairment between rhEPO and placebo was insignificant (RR = 0.55 95% CI [0.30, 1.02], P = .06). Composite cognitive score in high dose rhEPO was much higher than placebo group (MD = 10.39, 95% CI [8.84, 11.93], P < .0001, I2 = 0%) and low dose rhEPO also had higher composite cognitive score than placebo group (MD = 2.58, 95% CI [0.80, 4.37], P = .004, I2 = 11%). Limited publication bias was observed in this study.Conclusion:Recombinant human erythropoietin might be a promotor for neurodevelopment among premature infants with limited adverse events.

An Abductive Inference Approach to Assess the Performance-Enhancing Effects of Drugs Included on the World Anti-Doping Agency Prohibited List.

Some have questioned the evidence for performance-enhancing effects of several substances included on the World Anti-Doping Agency's Prohibited List due to the divergent or inconclusive findings in randomized controlled trials (RCTs). However, inductive statistical inference based on RCTs-only may result in biased conclusions because of the scarcity of studies, inter-study heterogeneity, too few outcome events, or insufficient power. An abductive inference approach, where the body of evidence is evaluated beyond considerations of statistical significance, may serve as a tool to assess the plausibility of performance-enhancing effects of substances by also considering observations and facts not solely obtained from RCTs. Herein, we explored the applicability of an abductive inference approach as a tool to assess the performance-enhancing effects of substances included on the Prohibited List. We applied an abductive inference approach to make inferences on debated issues pertaining to the ergogenic effects of recombinant human erythropoietin (rHuEPO), beta2-agonists and anabolic androgenic steroids (AAS), and extended the approach to more controversial drug classes where RCTs are limited. We report that an abductive inference approach is a useful tool to assess the ergogenic effect of substances included on the Prohibited List-particularly for substances where inductive inference is inconclusive. Specifically, a systematic abductive inference approach can aid researchers in assessing the effects of doping substances, either by leading to suggestions of causal relationships or identifying the need for additional research.

The effect of combination therapy with erythropoietin and methylprednisolone in patients with traumatic cervical spinal cord injury: a pilot randomized controlled trial.

Pilot double-blinded randomized controlled trial. To investigate the additive effect of recombinant human erythropoietin (rhEPO) on functional outcome and disability in patients with traumatic cervical spinal cord injury (TCSCI). University-affiliated hospital in Mashhad, Iran. Patients with acute TCSCI admitted within 8 h after injury were randomly assigned to receive only methylprednisolone (M group) or rhEPO 500 IU/mL plus methylprednisolone (M + E group). All the patients underwent surgery within the next several days. Neurological function was assessed on admission, and at 6th and 12th months after the injury according to the sphincter function and American spinal cord injury association (ASIA) scale. Overall, 54 patients (mean age: 39.7 ± 13.3 years) including 46 (85%) males were studied in two groups of 27. The likelihood of developing adverse neurological outcomes (ASIA impairment score of A compared to D or E) was not significantly different between the groups after 6 (OR = 0.39, 95% CI = 0.03-4.80, P = 0.46) and 12 months (OR = 0.83, 95% CI = 0.11-6.11, P = 0.86). The groups also showed no significant difference in 1-year mortality (OR = 0.83, 95% CI = 0.25-2.74, P = 0.76). It is not clear whether combination therapy with erythropoietin compared to methylprednisolone alone improves neurological functions of patients with TCSCI. Our study provides interim data to guide future larger definitive trials.

Effects of Recombinant Human Erythropoietin on Inflammatory Factors in Rats with Traumatic Brain Injury

To study the effects of recombinant human erythropoietin on inflammatory factors in rats with traumatic brain injury is the main objective. A total of 45 specific-pathogen-free grade male Sprague-Dawley rats were randomly assigned into sham operation group (sham group), model group and recombinant human erythropoietin intervention group (treatment group) (n=15). Model and treatment groups were prepared into traumatic brain injury model by hitting the head through the modified Feeney’s free-fall impact method, while the head of sham group was not hit. After modeling, treatment group was intraperitoneally injected with recombinant human erythropoietin at 5000 IU/kg daily and sham and model groups were intraperitoneally injected with the same dose of normal saline. The rats were killed after 7 d of continuous administration. The changes of brain mitochondrial membrane potential were detected through rhodamine 123 staining and immunocytochemistry and Western blotting were separately employed to measure the expressions of interleukin-1β, interleukin-6 and tumor necrosis factor-α in brain tissues and the expression levels of dynamin-related protein 1, fission 1, mitofusin 2 and optic atrophy 1, mitochondrial dynamics related proteins in brain tissues. Compared with sham group, model group exhibited significantly weakened rhodamine 123 fluorescence intensity, increased expressions of interleukin-1β, interleukin-6 and tumor necrosis factor-α, dynamin-related protein 1 and fission 1 and reduced expressions of mitofusin 2 and optic atrophy 1 in brain tissues (p<0.05). In comparison with model group, treatment group had significantly enhanced rhodamine 123 fluorescence intensity, reduced expressions of interleukin-1β, interleukin-6 and tumor necrosis factor-α, dynamin-related protein 1 and fission 1 and elevated expressions of mitofusin 2 and optic atrophy 1 in brain tissues (p<0.05). Recombinant human erythropoietin can protect the brain after traumatic brain injury by relieving the inflammatory response and mitochondrial injury after traumatic brain injury.

Erythropoietin Plays a Protective Role in Submandibular Gland Hypofunction Induced by Irradiation

This study aims to explore the radioprotective effects of recombinant human erythropoietin (rhEPO) on rats' submandibular gland hypofunction induced by irradiation (IR). Thirty rats were divided into 3 groups: 1) control group, 2) IR group, and 3) IR+rhEPO group. The IR group and IR+rhEPO group received a single dose of 15Grays (Gy) (0.98Gy/min), plus, the IR+rhEPO group also received subcutaneous administration of rhEPO at a dose of 3,000 IU/kg body weight 3days before irradiation and then repeated every 24hours for the first 2 weeks after irradiation. Immunohistochemistry analysis to erythropoietin receptor was performed to detect the levels of erythropoietin receptor in submandibular glands with or without radiation. Ninetydays after irradiation, the salivary flow rates were assessed, and the submandibular gland of every rat was subjected to hematoxylin and eosin staining and immunohistochemical staining with antiaquaporin 5 and anti-proliferating cell nuclear antigen antibodies. Apoptosis was examined by the terminal deoxynucleotidyl transferase biotin-dUDP nick end-labeling assay. In addition, to examine the protective role of rhEPO on human submandibular gland cells, the apoptotic and proliferation rate of cells under a radiation dose of 8Gy was detected. One-way analysis of variance was carried out to analyze the results of each group, and the P value was set at 0.05. Erythropoietin receptor was expressed in the submandibular glands at a low level under normal conditions but upregulated after irradiation. rhEPO administration remarkably alleviated gland atrophy, increased salivary flow rates with upregulation of aquaporin-5 compared with the IR group. In addition, fewer apoptotic cells and more proliferative cells were observed in the IR+rhEPO group compared with the IR group, both invivo and invitro. rhEPO administration may be a useful countermeasure to mitigate submandibular gland hypofunction after therapeutic radiation exposure.

Current Evidence on the Protective Effects of Recombinant Human Erythropoietin and Its Molecular Variants against Pathological Hallmarks of Alzheimer's Disease.

Substantial evidence in the literature demonstrates the pleiotropic effects of the administration of recombinant human erythropoietin (rhEPO) and its molecular variants in different tissues and organs, including the brain. Some of these reports suggest that the chemical properties of this molecule by itself or in combination with other agents (e.g., growth factors) could provide the necessary pharmacological characteristics to be considered a potential protective agent in neurological disorders such as Alzheimer’s disease (AD). AD is a degenerative disorder of the brain, characterized by an aberrant accumulation of amyloid β (Aβ) and hyperphosphorylated tau (tau-p) proteins in the extracellular and intracellular space, respectively, leading to inflammation, oxidative stress, excitotoxicity, and other neuronal alterations that compromise cell viability, causing neurodegeneration in the hippocampus and the cerebral cortex. Unfortunately, to date, it lacks an effective therapeutic strategy for its treatment. Therefore, in this review, we analyze the evidence regarding the effects of exogenous EPOs (rhEPO and its molecular variants) in several in vivo and in vitro Aβ and tau-p models of AD-type neurodegeneration, to be considered as an alternative protective treatment to this condition. Particularly, we focus on analyzing the differential effect of molecular variants of rhEPO when changes in doses, route of administration, duration of treatment or application times, are evaluated for the improved cellular alterations generated in this disease. This narrative review shows the evidence of the effectiveness of the exogenous EPOs as potential therapeutic molecules, focused on the mechanisms that establish cellular damage and clinical manifestation in the AD.

Effect of erythropoietin on mercury-induced nephrotoxicity: Role of membrane transporters.

Mercury is a widespread pollutant. Mercuric ions uptake into tubular cells is supported by the Organic anion transporter 1 (Oat1) and 3 (Oat3) and its elimination into urine is through the Multidrug resistance-associated protein 2 (Mrp2). We investigated the effect of recombinant human erythropoietin (Epo) on renal function and on renal expression of Oat1, Oat3, and Mrp2 in a model of mercuric chloride (HgCl2)-induced renal damage. Four experimental groups of adult male Wistar rats were used: Control, Epo, HgCl2, and Epo + HgCl2. Epo (3000 IU/kg, b.w., i.p.) was administered 24 h before HgCl2 (4 mg/kg, b.w., i.p.). Experiments were performed 18 h after the HgCl2 dose. Parameters of renal function and structure were evaluated. The protein expression of Oat1, Oat3 and Mrp2 in renal tissue was assessed by immunoblotting techniques. Mercury levels were determined by cold vapor atomic absorption spectrometry. Pretreatment with Epo ameliorated the HgCl2-induced tubular injury as assessed by histopathology and urinary biomarkers. Immunoblotting showed that pretreatment with Epo regulated the renal expression of mercury transporters in a way to decrease mercury content in the kidney. Epo pretreatment ameliorates HgCl2-induced renal tubular injury by modulation of mercury transporters expression in the kidneys.

Effects of rhEPO on Nrf2 and HO-1 expression in rats with acute kidney injury and its protective effects on kidney

If the kidney suddenly loses its ability to remove waste, acute kidney injury (AKI) will occur that dangerous levels of waste may accumulate, and the chemical composition of the blood may become unbalanced. AKI usually develops rapidly within a few days and is very common in hospitalized patients, especially those in urgent need of intensive care. AKI can be fatal and requires serious treatment. However, it can be reversible. The purpose of this research was to investigate the effects of recombinant human erythropoietin (rhEPO) on the expression of nuclear factor E2-related factor 2 (Nuclear factor E2, Nrf2) and Heme oxygenase (HO-1) in rats AKI and its protective effects on the kidney. For this purpose, 40 SD rats were averagely and randomly divided into 4 groups: control group, sham operation group, model group, and rhEPO group. The rhEPO group was injected with 5% glucose mixed with rhEPO to form 3000 IU/ (kg/d) rhEPO. Except for the rhEPO group, three groups were injected with 5% glucose at the same dose level as the rhEPO group respectively. Before the third administration, the renal pedicle was clamped for 60 min and then perfused for 24 hours. Changes of Serum creatinine (Scr) and Urea nitrogen (BUN) of rats in each group were detected before and after modeling. Twenty-four hours after modeling, renal tissues of rats in each group were taken, and expressions of Nrf2 and HO-1 in renal tissues were detected by qRT-PCR and Western blot methods. There were no significant differences in Scr and BUN contents in the four groups before modeling (p&gt; 0.05). There were no significant differences in Scr and BUN contents in the control group and sham operation group after modeling compared with those before modeling (p&gt; 0.05). Expressions of Nrf2 and HO-1 in the rhEPO group were higher than those in the model group, the sham operation group and the control group (p&lt; 0.05), while expressions of Nrf2 and HO-1 in model group were higher than those in sham operation group and control group (p&lt; 0.05). There were no significant differences in expressions of Nrf2 and HO-1 between the sham operation group and the control group (p&gt; 0.05). rhEPO can induce expressions of Nrf2 and HO-1 in AKI rats. RhEPO has a protective effect on the kidney, which may be related to expressions of Nrf2 and HO-1.

Recombinant Human Erythropoietin for Kidney Transplantation: A Systematic Review and Meta-Analysis.

The protective effect of recombinant human erythropoietin (rHuEPO) on kidney transplantation has not been established. Therefore, we conducted a systematic review and meta-analysis to evaluate the potential influence of rHuEPO on transplanted kidneys. To identify relevant studies, we searched electronic databases (PubMed, Medline, EMBASE, Ovid, the Cochrane Library, and major nephrology journals) from inception until June 15, 2018. Two independent reviewers assessed study quality. The systematic review and meta-analysis were performed with fixed- or random-effects models according to heterogeneity, and results are expressed as risk ratios (RR) or weighted mean differences. Six randomized controlled trials with a total of 435 patients met the inclusion criteria. rHuEPO, compared with placebo, had no statistically significant effect on delayed graft function (RR = 0.89, 95% confidence interval [CI] , 0.73 to 1.07; P = 0.22) and slow graft function (RR = 0.93, 95% CI, 0.60 to 1.43; P = 0.73). The rHuEPO and control groups did not differ in thromboembolic events, mortality, acute rejection, and blood transfusion. A significant difference was found in long-term estimated glomerular filtration rate (RR = 3.65, 95% CI, -4.45 to 11.75; P = 0.003). Our findings suggests that rHuEPO has a limited nephroprotective effect in patients undergoing kidney transplantation and does not increase the susceptibility to adverse events.

Co-administration of erythropoietin and iron complex improves late-phase liver regeneration

Erythropoietin and iron have individually shown beneficial effects on early-phase liver regeneration following partial hepatectomy (PHx); however, there are limited data on the combined effect on late-phase liver regeneration after PHx. Here we examined combined effects of recombinant human erythropoietin (rhEPO, 3,000 IU/kg) and iron isomaltoside (IIM, 40 mg/kg) on late-phase liver regeneration following PHx and investigated the possible underlying mechanism. Rats administrated with rhEPO showed significantly higher liver mass restoration, interleukin-6 (IL-6, a hepatocyte mitogen) levels, and Ki-67-positive hepatocytes on day 7 after PHx than saline-treated controls. These beneficial effects were further enhanced on days 7 and 14 by co-treatment with IIM. This combination also significantly improved liver function indices, such as increased albumin production and decreased bilirubin levels, but did not alter serum levels of toxic parameters, such as aspartate transaminase and alanine transaminase. This study demonstrates that the combination of rhEPO and IIM synergistically improves late-phase liver regeneration and function after PHx, probably by promoting IL-6-mediated hepatocyte proliferation without adverse effects. Thus, this combination treatment can be a potential therapeutic strategy for patients undergoing resection for hepatic malignancies.

Clinical study of recombinant human erythropoietin combined with iron to correct perioperative anemia in elderly patients with intertrochanteric fractures

To investigate the effectiveness of recombinant human erythropoietin (rHuEPO) combined with iron in treatment of anemia in elderly patients with intertrochanteric fractures during perioperative period. A clinical data of 71 patients with intertrochanteric fractures met the inclusion criteria between April 2016 and October 2017 was retrospectively analyzed. All patients were treated with closed reduction and proximal femoral intramedullary nail fixation. Thirty-one patients were treated with rHuEPO and iron before operation as trial group, and 40 patients were not treated with rHuEPO and iron as control group. There was no significant difference in gender, age, body mass index, cause of injury, fracture side and classification, American Society of Anesthesiologists (ASA) classification, combined medical diseases, time from fracture to admission, preoperative hospital stay, and operation time between the two groups ( P>0.05).The hemoglobin levels before operation and at 1, 3, and 7 days after operation, number of blood transfusion, blood transfusion rate, blood transfusion volume, postoperative hospital stay, complications were recorded and compared. After operation, 8 patients (25.8%) in trial group and 22 patients (55.0%) in control group received blood transfusion; the blood transfusion volume was (1.96±0.85) units in trial group and (3.19±1.61) units in control group. There were significant differences in blood transfusion rate and volume between the two groups ( P<0.05). There was no significant difference in preoperative hemoglobin level between the two groups ( P>0.05). The postoperative hemoglobin level was higher in trial group than in control group, and the difference between the two groups was significant at 7 days ( P<0.05). The postoperative hospital stay was (6.16±3.97) days in trial group and (9.25±4.47) days in control group, showing significant difference between the two groups ( P<0.05). There were 8 patients (25.8%) with pulmonary infection in trial group and 14 (35.0%) in control group after operation; 6 patients (19.4%) with deep venous thrombosis in trial group and 8 (20.0%) in control group. There was no significant difference in the incidences of complications between the two groups ( P>0.05). All patients were discharged from hospital normally, and no one died during hospitalization. The application of rHuEPO combined with iron before operation in elderly patients with intertrochanteric fractures can rapidly increase the hemoglobin level after operation, shorten the hospital stay, and do not increase the risk of deep venous thrombosis after operation.

Correlation of Glycated Albumin and Glycated Hemoglobin with Glycemic Control in Patients with Diabetic Chronic Kidney Disease on Hemodialysis

Background and aims. Diabetes mellitus (DM) is the most common cause of end-stage renal disease (ESRD) worldwide and is the primary etiology of ESRD in Indonesia. It is estimated that there are 10 million patients with DM in Indonesia and about 25-40% of diabetics develop diabetic nephropathy (DN) within 25 years. Poor glycemic control is associated with increased mortality in a large observational study among diabetics on hemodialysis. Glycated hemoglobin, or known as HbA1c, was the currently recommended biomarker to monitor long-term glycemic control in diabetes mellitus guideline. However, it becomes underestimated in patients with DN on hemodialysis (DN-HD), because of 20- 50% reduction of erythrocyte lifespan, clinical use of iron therapy, and effects of recombinant human erythropoietin. Glycated albumin (GA), ketoamine formed via a non-enzymatic glycation reaction of serum albumin, is free from interference by erythrocyte lifespan or erythropoietin therapy and subsequently can be used as an alternative biomarker to monitor glycemic control in DN-HD. As albumin has a half-life of only 14-21 days* compared to Hb 60-100 days in well ESKD patients, thus GA may provide a better reflection of recent diabetic control than HbA1c. The aim of this study was to analyze the correlation between GA and HbA1c with glycemic control in DN-HD. Methods The study was an analytical observational study with a cross-sectional design. The subjects were consecutive patients with DN-HD who visited Hemodialysis Unit at Mohammad Hoesin General Hospital Palembang during August-November 2014. The glycemic control index was determined by the average value of 2 times a week pre-HD random blood glucose for 4 weeks (aRBG). Results. The subjects were 25 patients with an average age of 56.16±7.49 years old. The average value of GA was 26.94±7.74%. GA was strongly correlated with aRBG with r=0.776; p=0.000. After correcting for age, sex, and BMI, the correlations became significantly very strong (r=0.809, p <0.001). The simple linear regression for the relationship between GA and aRBG was aRBG=4,62×GA+42.74 (R2=0.602, P<0.001), estimating that a 1% increase of GA was associated with 4.62mg/dL increase of aRBG. After correcting for age, sex, & BMI, the correlations between HbA1c and aRBG were significant (r=0.852, p<0.001). Conclusion. GA was strongly correlated with glycemic control in patients with DN-HD and HbA1c was correlated better.

Serum erythropoietin levels, breast cancer and breast cancer-initiating cells

BackgroundCancer is frequently associated with tumor-related anemia, and many chemotherapeutic agents impair hematopoiesis, leading to impaired quality of life for affected patients. The use of erythropoiesis-stimulating agents has come under scrutiny after prospective clinical trials using recombinant erythropoietin to correct anemia reported increased incidence of thromboembolic events and cancer-related deaths. Furthermore, previous preclinical reports indicated expansion of the pool of breast cancer-initiating cells when erythropoietin was combined with ionizing radiation.MethodsUsing four established breast cancer cell lines, we test the effects of recombinant human erythropoietin and the number of breast cancer-initiating cells in vitro and in vivo and study if recombinant human erythropoietin promotes the phenotype conversion of non-tumorigenic breast cancer cells into breast cancer-initiating cells. In a prospective study, we evaluate whether elevated endogenous serum erythropoietin levels correlate with increased numbers of tumor-initiating cells in a cohort of breast cancer patients who were scheduled to undergo radiation treatment.ResultsOur results indicate that recombinant erythropoietin increased the number of tumor-initiating cells in established breast cancer lines in vitro. Irradiation of breast cancer xenografts caused a phenotype conversion of non-stem breast cancer cells into induced breast cancer-initiating cells. This effect coincided with re-expression of the pluripotency factors c-Myc, Sox2, and Oct4 and was enhanced by recombinant erythropoietin. Hemoglobin levels were inversely correlated with serum erythropoietin levels, and the latter were correlated with disease stage. However, tumor sections revealed a negative correlation between serum erythropoietin levels and the number of ALDH1A3-positive cells, a marker for breast cancer-initiating cells.ConclusionsWe conclude that physiologically slow-rising serum erythropoietin levels in response to tumor-related or chemotherapy-induced anemia, as opposed to large doses of recombinant erythropoietin, do not increase the pool of breast cancer-initiating cells.