Zinc Supplementation Enhances the Hematopoietic Activity of Erythropoiesis-Stimulating Agents but Not Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitors.

Since zinc is involved in many aspects of the hematopoietic process, zinc supplementation can reduce erythropoiesis-stimulating agents (ESAs) in patients undergoing hemodialysis. However, it remains unclear whether hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) have similar reduction effects. HIF-PHI stabilizes HIF, which promotes hematopoiesis, although HIF-1α levels are downregulated by zinc. This study aimed to investigate the effect of zinc supplementation on the hematopoietic effect of HIF-PHI in patients undergoing hemodialysis. Thirty patients undergoing maintenance hemodialysis who underwent periods of treatment with roxadustat or darbepoetin alfa during the past 3 years were retrospectively observed. Participants who underwent periods with and without zinc supplementation were selected, with nine treated with darbepoetin alfa and nine treated with roxadustat. Similarly to the ESA responsiveness index (ERI), the hematopoietic effect of zinc supplementation was determined by the HIF-PHI responsiveness index (HRI), which was calculated by dividing the HIF-PHI dose (mg/week) by the patient's dry weight (kg) and hemoglobin level (g/L). Zinc supplementation significantly increased ERI (p < 0.05), but no significant change was observed (p = 0.931) in HRI. Although zinc supplementation did not significantly affect HRI, adequate zinc supplementation is required to alleviate concerns such as vascular calcification and increased serum copper during the use of HIF-PHI.

Effects of Zinc Acetate Hydrate Supplementation on Renal Anemia with Hypozincemia in Hemodialysis Patients.

INTRODUCTION AND AIMS: This study examined whether zinc supplementation with zinc acetate hydrate improved renal anemia with hypozincemia in patients undergoing hemodialysis. METHODS: The study participants included 21 patients undergoing hemodialysis who presented with a serum zinc level < 60 mg/dL and who were administered zinc acetate hydrate at 50 mg (reduced to 25 mg, as appropriate) for 6 months. Patients with a hemorrhagic lesion, acute-phase disease (pneumonia or cardiac failure), or hematologic disease and those whose treatment was switched from peritoneal dialysis to hemodialysis were excluded. The changes in the erythropoietin resistance index (ERI) before and after zinc acetate hydrate administration were examined. ERI was defined as the dose (IU) of erythropoiesis-stimulating agent (ESA)/week/body weight (kg)/hemoglobin content (g/dL). The differences between the two groups were analyzed using the Wilcoxon signed rank sum test, and p < 0.05 was considered statistically significant. RESULTS: The study participants included 19 men and 2 women aged 41-95 years (mean ± standard deviation (SD): 67.1 ± 13.6). The changes in the values of parameters measured before and after zinc acetate hydrate administration were as follows: Blood Hb did not change significantly, from 10.0-13.6 g/dL (11.5 ± 1.0 g/dL) to 10.2-12.4 g/dL (11.4 ± 0.7 g/dL); serum zinc concentration significantly increased, from 33.0-59.0 mg/dL µg/dL (52.4 ± 7.6 mg/dL µg/dL) to 57.0-124.0 mg/dL µg/dL (84.1 ± 16.3 mg/dL µg/dL; p < 0.01); the ESA dose significantly decreased, from 0-12,000 IU/week (5630 ± 3351 IU/week) to 0-9000 IU/week (4428 ± 2779; p = 0.04); and ERI significantly decreased, from 0.0-18.2 (8.1 ± 5.1) to 0.0-16.0 (6.3 ± 4.3; p = 0.04). CONCLUSIONS: Zinc supplementation increased the serum zinc concentration and significantly reduced the ESA dose and ERI, suggesting that a correction of hypozincemia contributes to lessening renal anemia in these patients.

Hypoxia-inducible factor-prolyl hydroxylase inhibitors for renal anemia in chronic kidney disease: Advantages and disadvantages.

Anemia is a common feature and complication of chronic kidney disease (CKD). Erythropoiesis-stimulating agents (ESAs) and recombinant human erythropoietin have been used widely in renal anemia treatment. Recently, hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs) that may improve the treatment of renal anemia patients were launched. Previous studies indicated that HIF-PHIs may decrease hepcidin levels and modulate iron metabolism, thereby increasing total iron-binding capacity and reducing the need for iron supplementation. Furthermore, HIF-PHIs can reduce inflammation and oxidative stress in CKD. Recombinant erythropoietin has become a routine treatment for patients with CKD and end-stage renal disease with relatively few adverse effects. However, higher doses of recombinant erythropoietin have been demonstrated to be an independent predictor of mortality in patients under hemodialysis. Phase III clinical trials of HIF-PHIs in patients with anemia and dialysis-dependent CKD have shown their efficacy and safety in both non-dialysis and dialysis CKD patients. However, HIFα binds to specific hypoxia-response elements in the vascular endothelial growth factor or retinoic acid-related orphan receptor gamma t (RORγt) promoter, which may be involved in the progression of cancer, psoriasis, and rheumatoid arthritis. In this paper, we have summarized the mechanism, clinical application, and clinical trials of HIF-PHIs in the treatment of renal anemia and aimed to provide an overview of the new drugs in clinical practice, as well as reconsider the advantages and disadvantages of HIF-PHIs and ESAs. Presently, there are not enough clinical studies examining the effects of long-term administration of HIF-PHIs. Therefore, further studies will be needed.

Antioxidant and haematinic effects of methanolic and aqueous methanolic roots extracts of Rauwolfia serpentina Benth in type 2 diabetic mice.

Present investigation was carried out to evaluate the antioxidant and haematinic effects of methanolic (MREt) and aqueous methanolic (AqMREt) root extracts of R. serpentina in mice model of type 2 diabetes (T2D). Experimental mice were divided into nine groups (six per group) as: fructose-induced (T2D) diabetic group (distilled water 1ml/kg), negative control (0.05% DMSO 1ml/kg), positive control (pioglitazone 15mg/kg) and six test groups (MREt 10, 30 & 60mg/kg & AqMREt 50, 100 & 150mg/kg). Whereas tenth group was served as normal control (1ml/kg distilled water). All test doses of MREt & AqMREt significantly (p<0.05) decreases the percent inhibition of catalase (CAT) and superoxide dismutase (SOD) when compared with diabetic controls. Treatment with both extracts also improved the total hemoglobin (Hb), red blood cell (RBC), white blood cell (WBC) counts, packed cell volume (PCV), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) in test groups. Fourier transform infrared (FTIR) spectral analysis revealed the presence of phenols moiety in both extracts. Findings suggested that AqMREt possesses more antioxidant and haematinic potential while the MREt of R. serpentina moderately possesses the same activities, which might be due to the high content of phenols present in AqMREt.

Iron supplementation for patients undergoing cardiac surgery: a protocol for a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Iron administration has been evaluated in several randomized controlled trials for the potential of increasing baseline hemoglobin values and decreasing the incidence of red blood cell transfusion during cardiac surgery. We describe the protocol for a study aiming to evaluate the efficacy and safety of perioperative iron administration in patients undergoing cardiac surgery. METHODS: We will search MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and the Web of Science, from inception to Nov. 19, 2020, for randomized controlled trials in any language evaluating the perioperative administration of iron in adult patients undergoing cardiac surgery; we will also include the first 50 results from Google Scholar. The primary outcome will be the incidence of red blood cell transfusion from the study intervention time until 8 weeks postoperatively. The secondary outcomes will be the number of red blood cell units transfused; change in ferritin level, reticulocyte count and hemoglobin concentration after iron administration; and adverse events. We will assess the risk of bias with the Cochrane Collaboration Risk of Bias Tool, and will analyze the primary and secondary outcomes using a random-effects model. INTERPRETATION: This study will summarize the current evidence about perioperative iron administration in patients undergoing cardiac surgery, help determine whether this intervention should be included in enhanced-recovery protocols, and shape future research if needed. The final manuscript will be submitted to a peer-reviewed journal. TRIAL REGISTRATION: PROSPERO no. CRD42020161927.

JTZ-951 (enarodustat), a hypoxia-inducible factor prolyl hydroxylase inhibitor, improves iron utilization and anemia of inflammation: Comparative study against recombinant erythropoietin in rat.

Anemia with inflammation-induced defective iron utilization is a pathological condition observed in patients suffering from chronic kidney disease (CKD) or chronic inflammatory disease. There is no reasonable treatment for these conditions, because the effects of erythropoiesis stimulating agents (ESAs) or iron supplementation in the treatment of anemia are insufficient. JTZ-951 (enarodustat) has been characterized as a novel, orally bioavailable inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH), and has been developed as a novel therapeutic agent for anemia with CKD. In this study, the effects of JTZ-951 on iron utilization during erythropoiesis and on anemia of inflammation were compared with those of recombinant human erythropoietin (rHuEPO) using normal rat and rat model of anemia of inflammation. In normal rats, under conditions in which JTZ-951 and rHuEPO showed similar erythropoietic effect, repeated doses of JTZ-951 induced erythropoiesis while retaining the hemoglobin content in red blood cells, while administration of rHuEPO resulted in decrease in some erythrocyte-related parameters. As for iron-related parameters during erythropoiesis, JTZ-951 exhibited more efficient iron utilization compared to rHuEPO. A single dose of JTZ-951 resulted in decrease in hepcidin expression observed within 24 h after administration, but a single dose of rHuEPO did not. In a rat model of anemia of inflammation (also known as a model with functional iron-deficiency), JTZ-951 showed erythropoietic effect, in contrast with rHuEPO. These results suggest that, unlike rHuEPO, JTZ-951 stimulates erythropoiesis by increasing iron utilization, and improves anemia of inflammation.

Polysaccharide-rich extract from Polygonatum sibiricum protects hematopoiesis in bone marrow suppressed by triple negative breast cancer.

Polysaccharide is one of main components in Polygonatum sibiricum (PS), which is an herbal medicine widely used in East Asia. Polysaccharides from Polygonatum sibiricum has been shown to exhibit multiple biological activities, such as anti-diabetes, anti-inflammation, antioxidant, immunity modulation, and anticancer. Since hematopoietic system is one of determinant factors in cancer control, we here explored the effect of polysaccharide-rich extract from Polygonatum sibiricum (PREPS) on hematopoiesis in the mice bearing triple negative breast cancer (TNBC). We found that the 4T1 TNBC tumor significantly increased myeloid cells in peripheral blood, bone marrow and spleen, while decreasing bone marrow hematopoietic stem and progenitor cells (HSPCs), indicative of an inhibition of medullary hematopoiesis. When 4T1 TNBC tumor-bearing mice were treated with PREPS, the percentage of myeloid cells within tumor-infiltrating immune cells was reduced. In addition, PREPS also inhibited hematopoietic cell expansion in the spleen, which was induced by TNBC tumors. Importantly, PREPS markedly increased HSPCs and common lymphoid progenitors in the bone marrow that had been suppressed by TNBC tumors. These findings suggest that PREPS protect hematopoiesis inhibited by TNBC tumors in the bone marrow. Although PREPS alone did not achieve statistical significance in the suppression of TNBC tumor growth, it may have a long-lasting anti-tumor effect to assist TNBC therapies by sustaining hematopoiesis and lymphoid regeneration in bone marrow.

Aportes de la biotecnología al diagnóstico y tratamiento de la enfermedad renal crónica y comorbilidades frecuentes / Biotechnology contribution to the diagnosis and treatment of chronic kidney disease and frequent comorbidities

Este trabajo tiene como objetivo revisar las contribuciones de la biotecnología, en relación con el tratamiento, diagnóstico y la monitorización de la enfermedad renal crónica (ERC) y sus comorbilidades más frecuentes, especialmente la anemia. En relación con los tratamientos, enfocamos el desarrollo de productos biofarmacéuticos como los agentes estimulantes de la eritropoyesis (ESA), que fueron los primeros biofármacos utilizados para el tratamiento de la anemia asociada a la ERC; analizamos sus características y utilización actual después de varios años de experiencia clínica, así como también otras alternativas en desarrollo. Revisamos distintos tipos de bioterapias, la utilización de las células estromales mesenquimales de médula ósea (MSC) y tratamientos alternativos con modificaciones dietarias, que se basan en la asociación entre la microbiota intestinal de los pacientes renales crónicos y sus condiciones fisiopatológicas. Finalmente, en relación con el diagnóstico y monitorización, nos referimos al estudio y validación de biomarcadores diagnósticos, predictivos y terapéuticos que han permitido optimizar los resultados clínicos en este tipo de pacientes. (AU)

The aim of this work is to review the contributions of biotechnology, in relation to the treatment, diagnosis and monitoring of chronic kidney disease (CKD) and its most frequent comorbidities, especially anemia. Regarding the treatment, we focus on the development of biopharmaceutical products such as erythropoiesis stimulating agents (ESA), which were the first biopharmaceuticals used to treat anemia associated with chronic kidney disease (CKD). We analyzed their characteristics and their current use after several years of clinical experience, as well as other alternatives in development. We also review different types of biotherapies, the use of bone marrow mesenchymal stromal cells (MSC) and alternative treatments with dietary modifications, which are based on the association between the intestinal microbiota of chronic kidney patients and their pathophysiological conditions. Finally, in relation to diagnosis and monitoring, we refer to the study and validation of diagnostic, predictive and therapeutic biomarkers that have made clinical results possible to be optimized in this type of patient. (AU)

Integration of organ metabolomics and proteomics in exploring the blood enriching mechanism of Danggui Buxue Decoction in hemorrhagic anemia rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Danggui Buxue Decoction (DBD), as a classical Chinese medicine prescription, is composed of Danggui (DG) and Huangqi (HQ) at a ratio of 1:5, and it has been used clinically in treating anemia for hundreds of years. AIM OF THE STUDY: The aim of this study was to explore the treatment mechanisms of DBD in anemia rats from the perspective of thymus and spleen. MATERIALS AND METHODS: In this study, a successful hemorrhagic anemia model was established, and metabolomics (UPLC-QTOF-MS/MS) and proteomics (label-free approach) together with bioinformatics (Gene Ontology analysis and Reactome pathway enrichment), correlation analysis (pearson correlation matrix) and joint pathway analysis (MetaboAnalyst) were employed to discover the underlying mechanisms of DBD. RESULTS: DBD had a significant blood enrichment effect on hemorrhagic anemia rats. Metabolomics and proteomics results showed that DBD regulated a total of 10 metabolites (lysophosphatidylcholines, etc.) and 41 proteins (myeloperoxidase, etc.) in thymus, and 9 metabolites (L-methionine, etc.) and 24 proteins (transferrin, etc.) in spleen. With GO analysis and Reactome pathway enrichment, DBD mainly improved anti-oxidative stress ability of thymocyte and accelerated oxidative phosphorylation to provide ATP for splenocyte. Phenotype key indexes were strongly and positively associated with most of the differential proteins and metabolites, especially nucleosides, amino acids, Fabp4, Decr1 and Ndufs3. 14 pathways in thymus and 9 pathways in spleen were obtained through joint pathway analysis, in addition, the most influential pathway in thymus was arachidonic acid metabolism, while in spleen was the biosynthesis of phenylalanine, tyrosine and tryptophan. Furthermore, DBD was validated to up-regulate Mpo, Hbb and Cp levels and down-regulate Ca2+ level in thymus, as well as up-regulate Fabp4, Ndufs3, Tf, Decr1 and ATP levels in spleen. CONCLUSION: DBD might enhance thymus function mainly by reducing excessive lipid metabolism and intracellular Ca2+ level, and promote ATP production in spleen to provide energy.

Spectrum-effect relationship between fingerprints and hemopoietic effects of small molecular fraction of Polygoni Multiflori radix praeparata.

Polygoni multiflori Radix Praeparata (PMRP) is a traditional medicine used for nourishing essence and blood in China. However, it is unclear which PMRP compounds are responsible for its hematopoietic effect. In this study, spectrum-effect relationship was used to discovery potential hematopoietic compounds. The fingerprints of 20 PMRP batches were established by HPLC and the hematopoietic effect was determined using red blood cell, hemoglobin, hematocrit, and platelet indexes in aplastic anemia model mice. The spectrum-effect relationship between common peaks and hematopoietic efficacy values was established using gray relational analysis and partial least squares analysis. Spectrum-effect relationship results showed that peaks 21 (emodin-8-O-(6´-O-acetyl)-ß-D-glucoside), 15 (2, 3, 5, 4'-tetrahydroxystilbene-2-O-di-glucoside), 16 (cis-2,3,5,4'-tetrahydroxy-stilbene-2-O-ß-D-glucoside), 11 (unknown), 20(unknown, 12 (epicatechin), 29 (carboxyl emodin), and 31 (emodin) in the fingerprints were closely related to the hematopoietic effect. This work successfully established the spectrum-effect relationship between PMRP hematopoietic effect and its fingerprints, which can be used to explain the material basis for the PMRP hematopoietic effect.

Screening of water distilled Rosa damascena Mill. flowers as hematopoietic agent in an animal model.

Pancytopenia is classified as low blood cell count. Low levels of hemoglobin, red blood cells, white blood cells and platelets are indicative of pancytopenic state. This pancytopenic state can be treatment (drug) or disease induced. Conventional approaches available to treat pancytopenia are usually associated with many undesirable adverse effects, are costly and parenterally administered. Interest in natural products has significantly increased due to their ability to stimulate cellular components of immune system. This study is designed to investigate the hematopoietic i.e. erythropoeitic, leucopoietic and thrombopoeitic potential of water distilled flowers of Rosa damascena Mill.

Acai Extract Transiently Upregulates Erythropoietin by Inducing a Renal Hypoxic Condition in Mice.

Acai (Euterpe oleracea Mart. Palmae, Arecaceae) is a palm plant native to the Brazilian Amazon. It contains many nutrients, such as polyphenols, iron, vitamin E, and unsaturated fatty acids, so in recent years, many of the antioxidant and anti-inflammatory effects of acai have been reported. However, the effects of acai on hematopoiesis have not been investigated yet. In the present study, we administered acai extract to mice and evaluated its hematopoietic effects. Acai treatment significantly increased the erythrocytes, hemoglobin, and hematocrit contents compared to controls for four days. Then, we examined the hematopoietic-related markers following a single injection. Acai administration significantly increased the levels of the hematopoietic-related hormone erythropoietin in blood compared to controls and also transiently upregulated the gene expression of Epo in the kidney. Furthermore, in the mice treated with acai extract, the kidneys were positively stained with the hypoxic probe pimonidazole in comparison to the controls. These results demonstrated that acai increases the erythropoietin expression via hypoxic action in the kidney. Acai can be expected to improve motility through hematopoiesis.

Oral Supplementation with Sucrosomial Ferric Pyrophosphate Plus L-Ascorbic Acid to Ameliorate the Martial Status: A Randomized Controlled Trial.

Altered martial indices before orthopedic surgery are associated with higher rates of complications and greatly affect the patient's functional ability. Oral supplements can optimize the preoperative martial status, with clinical efficacy and the patient's tolerability being highly dependent on the pharmaceutical formula. Patients undergoing elective hip/knee arthroplasty were randomized to be supplemented with a 30-day oral therapy of sucrosomial ferric pyrophosphate plus L-ascorbic acid. The tolerability was 2.7% among treated patients. Adjustments for confounding factors, such as iron absorption influencers, showed a relevant response limited to older patients (≥ 65 years old), whose uncharacterized Hb loss was averted upon treatment with iron formula. Older patients with no support lost -2.8 ± 5.1%, while the intervention group gained +0.7 ± 4.6% of circulating hemoglobin from baseline (p = 0.019). Gastrointestinal diseases, medications, and possible dietary factors could affect the efficacy of iron supplements. Future opportunities may consider to couple ferric pyrophosphate with other nutrients, to pay attention in avoiding absorption disruptors, or to implement interventions to obtain an earlier martial status optimization at the population level.

Erythroferrone as a sensitive biomarker to detect stimulation of erythropoiesis.

Erythroferrone (ERFE) is a glycoprotein hormone secreted by erythroblasts in response to erythropoietin stimulation. ERFE suppresses the hepatic synthesis of the master iron-regulatory hormone, hepcidin. The impact of erythropoiesis stimulation on ERFE secretion in humans is poorly understood. This paucity of information is due in part to the lack of available means for ERFE quantification in serum samples. The present study tested a new sensitive sandwich immunoassay for human ERFE. This assay was used to demonstrate that injection of various erythropoiesis stimulating agents (ESAs) increased the blood ERFE levels in healthy volunteers. After exogenous stimulation of erythropoiesis, ERFE increased up to 8-fold with a detection window of 13 days. The impact of one unit of blood withdrawal on erythropoiesis stimulation of ERFE was also tested. ERFE significantly increased after blood withdrawal in subjects injected with both iron and saline solution, suggesting that iron supplementation did not mask the ERFE increase after blood withdrawal. The effects of exercise-induced muscle damage on ERFE was assessed by comparing ERFE levels with creatine kinase levels in samples from subjects with heavy exercise loads, and determined that this was not a confounder. The ERFE assay is a sensitive means to investigate the connection between iron metabolism and erythropoiesis in humans, and to detect ESA abuse in the antidoping field.

In search of potential predictors of erythropoiesis-stimulating agents (ESAs) hyporesponsiveness: a population-based study.

BACKGROUND: Evidences show that around 20% of biosimilar or originator erythropoiesis-stimulating agents (ESAs) users are hyporesponsive. Controversial post-marketing data exist on the predictors of ESA hyporesponsiveness. The aim of this study was to identify predictors of ESA hyporesponsiveness in patients with chronic kidney disease (CKD) or cancer in clinical practice. METHODS: During the years 2009-2015, a multi-center, population-based, cohort study was conducted using claims databases of Treviso and Caserta Local Health Units (LHUs). All incident ESA users were characterized at baseline and the differences between the baseline hemoglobin (Hb) value, that is the Hb registered within 30 days prior to the first ESA dispensing (index date, ID) and each outcome Hb value (registered between 30 and 180 days after ID) were calculated and defined as delta Hb (ΔHb). Incident ESA users were defined as hyporesponsive if, during follow-up, they registered at least one ΔHb < 0 g/dL. Including all potential predictors of ESA hyporesponsiveness and stratifying by indication for use, univariate and multivariate binary logistic regression models and Receiver Operating Characteristic (ROC) curves were carried out. RESULTS: In general, 1080 incident ESA users (CKD: 57.0%; cancer: 43.0%) were identified. In CKD, predictors of ESA hyporesponsiveness were C-reactive protein (OR = 1.2, 95% CI: 1.0-1.5; P-value = 0.060) and high levels of baseline Hb (OR = 1.7, 95% CI: 1.2-2.2; P-value< 0,001), the latter being also predictor of ESA hyporesponsiveness in cancer (OR = 1.7, 95% CI: 1.1-2.4; P-value = 0.007). Both in CKD and in cancer, the type of ESA, biosimilar or originator, was not a predictor of ESA hyporesponsiveness. In CKD, concomitant use of iron preparations (OR = 0.3, 95% CI: 0.2-0.7; P-value = 0.002) and of high dosage of angiotensin-converting enzyme inhibitors/angiotensin II-receptor blockers (OR = 0.5, 95% CI: 0.3-0.9; P-value = 0.022) were protective factors against ESA hyporesponsiveness. CONCLUSIONS: The study confirmed traditional potential predictors of hyporesponsiveness to ESA. The use of biosimilar or originator ESA was not a predictor of hyporesponsiveness in an outpatient setting from two large Italian areas. A better knowledge of the predictors of ESA response would allow a better anemia management to improve patients' quality of life.

Comparative liver function assessment of natural and available drug (Ferrous sulfate) for iron-deficiency anemia in rat model.

To assess the comparative effect of anti-anaemic drug (ferrous sulfate) with naturally occurring anti-anaemic compound (Illicium verum commonly called star anise) on liver in rat model. Model and both test groups were made anaemic. Ferrous sulfate was given to T1 group of rats as 30mg/kg body weight (b.w) and Illicium verum to T2 group of rats with dose of 80mg/kg b.w for six weeks. Illicium verum treated group (T2 rats) produced depression, decreased anxiety and enhanced short-term memory, whereas ferrous sulfate treated group (T1 rats) enhanced long term memory. The liver function test of T2 rats showed that the total bilirubin was in normal range, but direct bilirubin, SGPT, ALP and GGT were significantly decreased in T2 rats in comparison with T1 and also from model group of rats. It was concluded in this study that by comparing the effect of ferrous sulfate with naturally occurring Illicium verum on iron-defficiency anaemia, illicium verum produces same effects and can be used to treat iron-defficiency anaemia without affecting liver function.

Comparisons of antithrombosis, hematopoietic effects and chemical profiles of dried and rice wine-processed Rehmanniae Radix extracts.

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine (TCM), Rehmanniae Radix (RR, derived from the root of Rehmannia glutinosa (Gaertn.) DC.) is commonly used as natural medicine for thousands of years, two types including the dried and rice-wine processed RR were used for different clinical purposes respectively, which were the typical case that pharmaceutical effect changed by processing in TCM. AIM OF STUDY: The goal of this study was to investigate the differences in the antithrombosis and hematopoietic effects of extracts of dried and processed RR (DRR and PRR) in vivo, and to explore the chemical basis underlying changes of medicinal properties caused by processing. MATERIALS AND METHODS: The aqueous extracts of DRR and PRR were prepared. Protective effect of varying doses of different extracts were investigated in type-I carrageenan induced mice tail thrombosis and cyclophosphamide induced myelosuppression model. The chemical composition of DRR and PRR extracts were determined by High Performance Liquid Chromatography coupled with tandem quadrupole time-of-flight Mass Spectrometry (HPLC/Q-TOF-MS). RESULTS: In antithrombosis activity tests, PRR possessed less ameliorated effects than DRR in the model mouse on body temperature, tail thrombus length and blood flow. Both DRR and PRR had no significant influence on prothrombin time (PT) and activated partial thromboplastin time (APTT), only high dose DRR could decrease the content of fibrinogen (FIB) in plasma. Histological examination of lung tissue suggested that thrombosis was significantly improved in DRR-H group. For myelosuppression model, only PRR could improve peripheral hemogram, both DRR and PRR had hematopoietic effects as demonstrated by their abilities to ameliorate the bone marrow nucleated cells (BMNC) and pathology of bone marrow tissue. The hematopoietic effects of PRR were significantly more potent than that of DRR at the concentration of 9 g/kg. By comparing the chemical composition, we found that iridoid glycosides were decreased and furfural derivatives increased in DRR after processing which may be the chemical mechanism contribute to the differences in efficacy. CONCLUSIONS: According to the results of this research, processing with rice wine for nine cycles significantly reduced antithrombotic effects and enhanced the hematopoietic effects of DRR as demonstrated in model mice. It can scientifically explain the different effect among two types of RR in clinical through the diverse method of processing and usage. Meanwhile, the predicted activity compounds from two types of RR can be potential candidates for the treatment of thrombosis and anemia.

Laboratory evidence for the hematopoietic potential of Beta vulgaris leaf and stalk extract in a phenylhydrazine model of anemia.

This study was designed to provide laboratory evidence supporting the hematopoietic effect of Beta vulgaris (beet) leaf aqueous extract in phenylhydrazine-induced anemia model in albino rats. Extraction of the leaves/stalks was done by maceration in 30% hydro-ethanol for 48 h. An intraperitoneal injection of 20 mg/kg phenylhydrazine was applied for two consecutive days to develop hemolytic anemia on the 4th day after the 1st injection in 24 of 30 male albino rats. The animals were divided into 5 groups and received the following treatments: standard (ferrous ascorbate + folic acid; 13.5 + 0.135 mg/kg), B. vulgaris extract (100 and 200 mg/kg), or left untreated (normal and diseased controls). Blood samples were taken at 0, 4, 8, and 12 days of the experiment for hematological and clinico-chemical analysis. Beet leaf extract significantly restored the levels of red blood cells, white blood cells, hemoglobin, and hematocrit in dose- and time-dependent manners. Blood indices have been significantly corrected. Erythropoietin level was maintained at higher levels. Erythrocytic membrane oxidation biomarker (malondialdehyde) level was significantly reduced compared to the anemic untreated group. The extract exhibited potent, concentration (4-512 µg/mL)-dependent antioxidant activity indicated by the 2,2-diphenyl-1-picryl-hydrazyl (DPPH) assay, with IC50 value of 37.91 µg/mL. Beet leaf extract resulted in detection of flavonoid and phenolic compounds that may underlie its hematinic properties. These findings may indicate B. vulgaris as a good natural source for pharmaceutical preparations with hematopoietic effects and treatment of anemia and/or associated conditions.

Iron therapy for managing anaemia in chronic kidney disease.

PURPOSE OF REVIEW: Iron deficiency is a major contributory cause to the development of anaemia in chronic kidney disease (CKD), and thus, iron replacement therapy plays a critical role in the management of this condition. The two main routes for administering iron are oral and intravenous, and there have been a number of new publications relevant to both routes of administration. RECENT FINDINGS: Recent developments on the topic of iron management in CKD include the introduction of new oral iron preparations, as well as two recent meta-analyses on iron therapy in CKD (one on oral versus intravenous iron, and one on high- versus low-dose intravenous iron in haemodialysis patients). There is also increasing interest in other strategies to improve iron availability, such as intradialytic iron, hypoxia-inducible factor stabilization and antihepcidin strategies. SUMMARY: Even despite the latest publications in this field, we are still left with serious gaps in our evidence base on how best to provide supplemental iron to CKD patients. Most of the evidence suggests that intravenous iron is superior to oral iron in increasing haemoglobin and minimizing the use of erythropoiesis-stimulating agents, but the safety of intravenous iron remains a controversy. The PIVOTAL study will hopefully provide informative data to fill some of the gap in the evidence-base and inform best clinical practice.

Influence of Carnicor, Venofer, and Sevelamer on the levels of genotoxic damage in end-stage renal disease patients.

End-stage renal disease (ESRD) patients present high levels of phosphorus and calcium products in serum, which contribute to the development of vascular calcification and cardiovascular disease, and to low iron stores and carnitine deficiency. For these reasons, ESRD patients are generally supplemented with different medicines. Some of the most common treatments include the use of Carnicor, Venofer, and Sevelamer drugs. Carnicor is used as a source of L-carnitine, acting as antioxidant and neuroprotector. Venofer is used to reduce the deficit of iron. Sevelamer is used to treat hyperphosphatemia. To determine the potential harmful genotoxic effects of these drugs, a group of 214 patients included in a hemodialysis program with different intakes of Carnicor, Venofer, and Sevelamer were evaluated. The levels of basal and oxidative DNA damage, as well as chromosomal damage, were measured in all individuals using the comet and the micronucleus assays, respectively. Our results indicate that Carnicor administration was associated with low but significant increases in the frequency of basal DNA damage and micronuclei. Environ. Mol. Mutagen. 59:302-311, 2018. © 2018 Wiley Periodicals, Inc.