EPO Applications Research Articles

Recent Advances in Modified Brain‐Targeting Drug Delivery Systems for Erythropoietin

AbstractErythropoietin (EPO) is an excellent neuroprotective molecule that decreases the extent of injury caused by various pathologies of the brain, such as Alzheimer's disease, Parkinson's disease, and stroke. However, due to the low permeability of the blood‒brain barrier (BBB), a high dose or even an overdose of EPO injections is often administered to achieve a sufficient EPO concentration in the brain. This often leads to many serious adverse reactions. Several studies have presented promising strategies for overcoming the BBB to deliver EPO. These methods include the formation of EPO modified by receptor‐mediated transcytosis targeting fusion proteins, cell‐penetrating peptides, and nanomaterials. In this review, the clinical progress of modified brain‐targeting drug delivery systems of EPO is summarized to provide a scientific basis and new information on the application of EPO in treating diseases of the central nervous system. Here, the production, pharmacological effects, and mechanism of action of the modified EPO, as well as the limiting factors and countermeasures are discussed.

Diagnostic Imaging Studies on Local and Systemic Erythropoietin Application for Promoting Bone Regeneration in Rat Calvarial Defects.

Simple SummaryErythropoietin (ЕPО) is a glycoprotein hormone which, apart from its physiological function in the regulation of erythropoiesis, has additional functions in the animal and human body. In orthopaedic patients EPO treatment induces regeneration of bone defects, proliferation of osteoblasts and new blood vessel formation, improvement of early endochondral ossification and bone mechanical strength, thus resulting in enhanced bone healing. The purpose of this study was to compare the effects of local and systemic application of recombinant human erythropoietin (rhEPO) on the healing of rat calvarial defects. The systemic effect of EPO treatment was monitored by haematological analyses on days 0, 30 and 90. Bone healing was monitored via radiography and computed tomography on the same time intervals. The results demonstrated that intraperitoneally-injected rhEpo did not result in bone formation. Simultaneously, it affects the erythropoiesis by increasing the erythrocyte counts, haemoglobin and haematocrit. At the same time, single local dose rhEpo applied on collagen carrier could be used for enhancing bone healing without systemic effect.The purpose of this study was to compare the effects of local and systemic application of recombinant human erythropoietin (rhEPO) on the healing of rat calvarial defects. Twenty-four male skeletally-mature Wistar rats were used. Two bone 5 mm critical size defects were created in calvarial bones of each rat. In rats from experimental group I (n = 12), EPO was applied locally on a collagen cone in left defects, whereas a collagen cone soaked with physiological saline was placed in right defects. The rats from experimental group II were injected once intraperitoneally with 4900 IU/kg EPO; a collagen cone was only placed in left defects, whereas the right defects were left empty. The systemic effect of EPO treatment was monitored by haematological analyses on days 0, 30 and 90. Bone healing was monitored via radiography and computed tomography on the same time intervals. The results demonstrated that local EPO application had no significant effect on haemopoiesis, unlike the systemic application. At the same time, it resulted in new bone formation and therefore, could be successfully used as a means of promoting bone regeneration.

DESIGN AND BUILD A WEBSITE-BASED FOREIGNER SERVICE APPLICATION APPLICATION AT THE CLASS 1 IMMIGRATION OFFICE SPECIFICALLY FOR NON-TPI WEST JAKARTA

The use of information technology has now been widely applied in the process of immigration services and supervision carried out by the Directorate General of Immigration. One of them is return of immigration documents and transferring foreigner data using a Google form. However, in its implementation there are still some problems. This study aims to determine the current business process for document return services and foreigner data mutations at West Jakarta Immigration Office and to provide an overview of designing a web-based application for immigration services for foreigner. The design of this application uses the Waterfall Model System Development Life Cycle (SDLC) method. The results of this study are a website-based application prototype for foreign citizen services with various features provided such as checking application status, information on requirements for submitting requests for return of immigration documents and mutation of foreigner data, submission of ERP applications, submission of EPO applications, submission of transfer requests address, and submission of a passport mutation application which can later be used as a reference to be applied to immigration document return services and foreigner data mutations at the Special Class 1 Immigration Office for non-TPI West Jakarta.

Does intraurethral erythropoietin administration effect wound healing after hypospadias correction? an experimental rat study.

To analyze effects of intraurethral EPO application on urethral wound healing by defining hystopathologic changes in a rat model of hypospadias. A hypospadias model was created in 30 rats and randomized into 3 groups of 10. For 14 days, the first group was administered 25 iu EPO instillation intraurethrally once a day, while group 2 was administered with 50 iu EPO in the same manner. The third group was assigned as control group. On the day 15, rats were sacrificed and penectomies were performed. One independent pathologist who is blinded to groups and treatments evaluated the penis samples. Histopathologic examinations yielded the mean fibrosis scores (± SD) as 1.9 ± 0.568, 1.1 ± 0.786 and 2.5 ± 0.535 in groups I, II and III, respectively. There was significant difference between the EPO groups and the control group (p = 0.04-I, p = 0.003-II). The mean inflammation scar scores (± SD) were determined as 1 ± 1.054, 2 ± 1.247, 2.63 ± 0.744 in groups I, II and III, respectively. There was a significant difference in terms of inflammation between control group and group I (p = 0.005). Mean congestion scores (± SD) were found 1.2 ± 0.789 in groups I-II and 0.75 ± 0.463 in group III (p = 0.310). Hyperemia was seen in 60% 70% and 37.5% in groups I, II and III, respectively (p = 0.387). Intraurethral EPO therapy effected urethral wound healing in a good way. Thus it could be feasible to treat the patients with after hypospadias surgeries and to improve success rates.

Building a smart city with dimensions of technology, people and institutions. By using WASPAS

The core infrastructure of a smart city Components means - Ensuring adequate water supply Including generated electricity, Solid waste management is sanitary, efficient urban Mobility and public transport, and affordable housing, especially for the poor, is a strong source of information Technological connectivity, digitalization, good management, Smart Cities Mission is an Indian Urban development of Govt Ministry-led rehabilitation and An urban renewal project. Smart cities are information for city management and Information Communication Technologies (ICT) Incorporating metros, them from traditional to digital, improving the efficiency of operations and with the aim of providing services. A smart city is an information and information Communication Ability to operate using technologies (ICT). Increase and share information with the public, Quality of government services, and welfare of citizens it is the municipality that promotes both. Smart Town Bhopal has been ranked first in the latest assessment Central housing by 2022 and by the Ministry of Concrete Affairs. It is the central Capital of the territory and population of 2.5 million contains the amount Key to Smart City The objective is to improve city functions, Improve economic growth, and smart Citizens through technologies and data improving the quality of life. Analytics. Alternative: Treatment, controls, differentiation and T-State. Evaluation Option: Total patent applications to the EPO, to the EPO High technology patent applications, to the EPO Smart for ICT patent applications, and City Patent Applications. EPO City Patent Applications. from the result it is seen that Total patent to EPO Applications and received first rank whereas is the Total patent to EPO Applications and received got is having the lowest rank. The value of the dataset for Range of smart city in WASPAS Method shows that it results in Total Patent applications EPO and top ranking.

A biomathematical model of human erythropoiesis and iron metabolism

Anaemia therapy or perisurgical support of erythropoiesis often require both, EPO and iron medication. However, excessive iron medication can result in iron overload and it is challenging to control haemoglobin levels in a desired range. To support this task, we develop a biomathematical model to simulate EPO- and iron medication in humans. We combine our previously established model of human erythropoiesis including comprehensive pharmacokinetic models of EPO applications with a newly developed model of iron metabolism including iron supplementation. Equations were derived by translating known biological mechanisms into ordinary differential equations. Qualitative model behaviour is studied in detail considering a variety of interventions such as bleeding, iron malnutrition and medication. The model can explain time courses of erythrocytes, reticulocytes, haemoglobin, haematocrit, red blood cells, EPO, serum iron, ferritin, transferrin saturation, and transferrin under a variety of scenarios including EPO and iron application into healthy volunteers or chemotherapy patients. Unknown model parameters were determined by fitting the predictions of the model to time series data from literature. We demonstrate how the model can be used to make predictions of untested therapy options such as cytotoxic chemotherapy supported by iron and EPO. Following our ultimate goal of establishing a model of anaemia treatment in chronic kidney disease, we aim at translating our model to this pathological condition in the near future.

Effect of Topical Erythropoietin (EPO) on palatal wound healing subsequent to Free Gingival Grafting (FGG)

Free gingival grafting, the most predictable technique to increase the keratinized gingiva, leaves an open wound on the palate and the resulting discomfort during the healing phase is a significant concern. This study was intended to evaluate the effect of topical erythropoietin on healing of the donor site. Twelve patients lacking an attached gingiva at two sites in the mandible were included. In the test group, 1 mL of gel containing erythropoietin at a concentration of 4,000 IU mL-1 was applied to the donor site, whereas the control group was treated with 2 mL of the gel alone. On the second day after surgery, the same procedure was repeated. H2O2 was used to evaluate the amount of epithelialization. Clinical healing was compared using photographs and direct examination. The EPO group showed significantly better keratinization only on day 21. Comparison of clinical healing based on direct examination revealed significantly better healing in the test group on day 28. Furthermore, inflammation in the test group was lower than in the control group on the same day. Topical application of EPO improves palatal wound healing during the third and fourth weeks after free gingival graft procedures.

Spatial and Cellular Expression Patterns of Erythropoietin-Receptor and Erythropoietin during a 42-Day Post-Lesional Time Course after Graded Thoracic Spinal Cord Impact Lesions in the Rat.

Erythropoietin (Epo) exhibits promising neuroregenerative potential for spinal cord injury (SCI), and might be involved in other long-term sequelae, such as neuropathic pain development. The current studies investigated the time courses and spatial and cellular patterns of Epo and erythropoietin receptor (EpoR) expression along the spinal axis after graded SCI. Male Long Evans rats received 100 kdyn, 150 kdyn, and 200 kdyn thoracic (T9) contusions from an Infinite Horizon impactor. Sham controls received laminectomies. Anatomical and quantitative immunohistochemical analyses of the EpoR/Epo expression along the whole spinal axis were performed 7, 15, and 42 postoperative days (DPO) after the lesioning. Cellular expression was investigated by double- and triple-labeling for EpoR/Epo with cellular markers and proliferating cells in subgroups of 5-bromo-2-deoxyuridine pre-treated animals. Prolonged EpoR/Epo-expression was confirmed by real-time reverse transcriptase polymerase chain reaction (RT-PCR). Quantified EpoR/Epo immunoreactivities in pain-related spinal cord regions and ventrolateral white matter (VLWM) were correlated with the mechanical sensitivity thresholds and locomotor function of the respective animals. EpoR and Epo were constitutively expressed in the ventral horn neurons and vascular and glial cells in the dorsal columns (DC) and the VLWM. After SCI, in addition to expression in the lesion core, EpoR/Epo immunoreactivities exhibited significant time- and lesion grade-dependent induction in the DC and VLWM along the spinal axis. EpoR and Epo immunoreactive cells were co-stained with markers for astroglial, neural precursor cell and vascular markers. In the VLWM, EpoR- and Epo-positive proliferating cells were co-stained with glial fibrillary acidic protein (GFAP) and nestin. The DC EpoR/Epo immunoreactivities exhibited linear relationships with the behavioral correlates of post-lesional chronic pain development at DPO 42. SCI leads to long-lasting multicellular EpoR/Epo induction beyond the lesion core in the spinal cord regions that are involved in central pain development and regenerative processes. Our studies provide a time frame to investigate the effects of Epo application on motor function or pain development, especially in the later time course after lesioning.

Erythropoietin exerts direct immunomodulatory effects on the cytokine production by activated human T-lymphocytes

The effect of erythropoietin-β (Epo-β) on the functional profile of activated human T-lymphocytes remains largely unknown, which hinders clinical application of Epo as an immunomodulatory agent. We studied the direct impact of Epo on the activation status of human T lymphocytes following activation by particles loaded with antibodies (Abs) against human CD2, CD3, and CD28. T cell activation was assessed by the surface expression of CD38 activation marker. Epo did not significantly affect activation status of both CD4+ and CD4− T cells, as well as of naive (CD45RA+CD197+), central memory (CD45RA−CD197+), effector memory (CD45RA−CD197−), and terminally-differentiated (CD45RA+CD197−) T cells. However, Epo markedly augmented production of IL-2, IL-4 and IL10 by activated T cells with concomitant reduction in IFN-γ secretion. Taken together, our data showed that Epo could directly down-regulate pro-inflammatory T cell responses without affecting T cell activation status.

Identifying author–inventors from Spain: methods and a first insight into results

The purpose of this paper is twofold: methodological and empirical. Methodologically, we describe a matching and disambiguation procedure for the identification of author–inventors (researchers who publish and patent) located in the same country. Our methodology aims to maximize precision and recall rates by taking into account national name writing customs and country-specific dictionaries for person and institution names (academic and non-academic) in the name matching stage and by including a recursive validation step in the person disambiguation stage. An application of this methodology to the identification of Spanish author–inventors is described in detail. Empirically, we present the first results of applying the described methodology to the matching of all SCOPUS 2003–2008 publications of Spanish authors to all 1978–2009 EPO applications with Spanish inventors. Using this data, we identify 4,194 Spanish author–inventors. A first look at their patenting and publication patterns reveals that they make quite a significant contribution to the country’s overall scientific and technological production in the time period considered: 27 % of all EPO patent applications invented in Spain and 15 % of all SCOPUS publications authored in Spain, excluding non-technological disciplines. To our knowledge, this is the first time that a large scale identification of author–inventors from Spain has been done, with no limitation in terms of fields, regions or types of institutions. We also make available online for scientific use an anonymized subset of the database (patent applications invented by authors affiliated to Spanish public universities).

Playing the ‘Name Game’ to identify academic patents in Germany

Identifying academic inventors is crucial for reliable assessments of academic patenting and for understanding patent-based university-to-industry technology transfer. It requires solving the "who is who" problem at the individual inventor level. This article describes data collection and matching techniques applied to identify academic inventors in Germany. To manage the large dataset, we adjust a matching technique applied in prior research by comparing the inventor and professor names in the first step after cleaning. We also suggest a new approach for determining the similarity score. To evaluate our methodology we apply it to the EP-INV-PatStat database and compare its results to alternative approaches. For our German data, results are less sensitive to the choice of name comparison algorithm than to the specific filtering criteria employed. Restricting the search to EPO applications or identifying inventors by professor title underestimates academic patenting in Germany.

Generation of RNA aptamer against rHuEPO-α by SELEX

IntroductionRecombinant human EPO-alpha (rHuEPO-α) is a 34 kDa EPO mimetic widely used as an illegal drug for enhancing stamina among athletes. In cancer biology, EPO interacts with EPO-Receptor to promote tumor growth. Thus, the availability of aptamer as an elegant class of molecular recognition element can be pragmatic for the development of aptamer-based diagnostic assay and towards therapeutic application of EPO. ObjectiveTo generate RNA aptamer against rHuEPO-α by using SELEX technology for the development of sandwich enzyme-linked aptamer assay (ELAA) and analyses of its therapeutic property. MethodsEleven cycles of SELEX was carried out using a randomized oligonucleotide pool. Subsequently, cloning and sequence analysis was performed to identify the potential aptamer candidate. The identified aptamer was adopted for sandwich ELAA. Characterization such as mapping analyses and truncation was executed towards therapeutic application. Results & DiscussionSequence analyses revealed the presence of a distinct major clone having the dissociation constant of 25±1 nM. Termed REPORA-6, this aptamer can act as 'universal probe' against all rHuEPOs. Together with anti-EPO monoclonal antibody, REPORA-6 aptamer facilitated the design of Sandwich ELAA. Detection limit achieved is 0.29 nM, substantiating the development of a potential aptamer-based diagnostic (aptanostic) of rHuEPO-α. Interestingly, REPORA-6 has the potential to block the interaction of EPO and EPO receptor (which mediates tumor growth/angiogenesis), thus suggesting it as a potential therapeutic agent towards alleviating tumor growth. REPORA-6 RNA aptamer is resistant against nuclease degradation action and can be truncated down to 58-nt. This miniaturized aptamer (termed REPORA-6b), can have better transfection efficiency and less susceptible to immune system, maintains its binding affinity against the target (22±2 nM). Conclusion: As one of the very few aptamers available in doping, REPORA-6 RNA aptamer can be potential agent in doping detection and also function as a promising therapeutic element in ameliorating cancer.

Patent citation indicators: one size fits all?

The amount of citations that a patent receives is considered as an important indicator of the quality and impact of the patent. However, different methods and data sources are used to calculate this measure. This paper evaluates the similarities between citation indicators obtained when counting within different patent offices (USPTO, EPO and patent applications filed through the PCT). Additionally we discuss the effects of using indicators that correct for patent family and the effects of including citations from more than one source. Our findings reveal that the obtained citation indicators differ substantially. This is confirmed when comparing sets of highly cited patents identified by these different indicators. Correcting for patent families remedies this situation, at least if a broad definition (INPADOC) of families is being adopted. Our findings suggest that favoring one way of calculating a citation indicator over another, has non-trivial consequences and hence should be considered explicitly. If one aims to discard differences arising from source choices (both in terms of cited and citing documents), patent citation indicators based on INPADOC families present themselves as the preferred option.

Erythropoietin prevents delayed hemodynamic dysfunction after subarachnoid hemorrhage in a randomized controlled experimental setting

IntroductionErythropoietin (EPO) was proven as a promising approach for experimental subarachnoid hemorrhage (SAH). Clinical data are, however, inconclusive so far. A detailed characterization of specific EPO effects could facilitate the design of trials. The aim of the present investigation was, therefore, to characterize these effects on prevention of delayed proximal cerebral vasospasm (CVS), impaired microcirculation and cerebral blood flow (CBF) after experimental SAH. Methods27 male Sprague–Dawley rats were randomized in 3 groups: Sham, SAH control, and SAH EPO. SAH was induced by injection of 0.2ml autologous blood into the cisterna magna on days 1 and 2. Animals of the SAH EPO group received 5000iU rh EPO α 6h after the 2nd SAH intravenously. Surviving animals were examined on day 5 by MR perfusion weighted imaging (PWI). Cerebral blood flow (CBF) and volume (CBV) were determined by PWI, proximal CVS by basilar artery (BA) diameter, and neuroprotection by hippocampal cell count (CA1–CA4). ResultsBA diameter was significantly reduced in both SAH groups, but improved significantly after EPO (Sham: 144±3μm, SAH control: 79±6μm, SAH EPO 109±4μm). The rrCBV ratio was 8.78±0.72 Sham, 5.14±1.73 SAH control, and 6.80±0.44 SAH EPO. The improvement by EPO did not reach statistical significance. RrCBF ratio was also significantly reduced in both SAH groups, but was significantly improved by EPO (Sham: 8.78±0.34, SAH control: 4.26±1.05, SAH EPO 5.85±0.46). Surviving neuronal cells were significantly reduced in SAH controls in all areas, but in SAH EPO only in CA1. ConclusionThe present data suggest that an EPO application in a timely distance to the SAH is sufficient to prevent delayed proximal CVS, but that the doses were insufficient to improve microcirculation or to be directly neuroprotective.

Matching of PATSTAT Applications to AIDA Firms: Discussion of the Methodology and Results

This paper is a brief methodological note on the matching of Italian firms in the AIDA database with applicants at the European Patent Office from the PATSTAT database. The need to match data on patent applications with balance-sheet information stems from the importance of patent statistics as a source of information on the innovative performance of firms. Starting from recent efforts to match applicants in PATSTAT with firms in the Bureau van Dijk databases (ORBIS, AMADEUS, FAME), we added an improved cleaning routine to maximize exact matches, followed by an approximate matching based on multiple combination of similarity scores. Starting with 272,475 firms, we matched 49,369 EPO applications in the period 1977-2009. The matching covers 68 percent of EPO applications by Italian firms for the entire period and 89 percent for 2000-2009. Finally, we describe the time, sector, size, geographical location and technology distribution of the matched applications.

The effect of erythropoietin application on erythrocyte Na,K- ATPase activities in patients with diabetic polyneuropathy

Objectives: In this study we aimed to investigate the effects of erythropoietin administration on Na,K-ATPase enzyme activity in diabetic patients with polyneuropathy. Methods: The study was carried out at Meram Education and Research Hospital department of Nephrology and Selcuk University Meram School of Medicine Hospital department of Biochemistry, Turkey. Eleven diabetic patients with diabetic polyneuropathy and on erythropoietin therapy and ten healthy control were contributed to this study. Diabetic group was formed from the patients with polyneuropathy and on erythropoietin therapy. Erythropoietin was administered with a dose of 150 U/kg/ week to the patients. Heparinized blood samples were taken from the control group for once and from the patients for twice before and one month after the erythropoietin therapy. Erythrocyte membranes were isolated and erythrocyte membrane Na,K-ATPase enzyme activities were measured. Na,K-ATPase activities were given as mmolPi.mg.protein –1.10 min-1. Results: Na,K-ATPase enzyme activities were 2.91±0.38 μmolPi.mg.prt-1.10min-1, 1.93±0.38 μmolPi.mg.prt-1.10min-1 and 2.40±0.63 μmolPi.mg.prt-1.10min-1 in control group, and patient group before and after therapy, respectively. Na,K-ATPase enzyme activities decreased in patient group before the therapy compared to the control group and significantly increased in patient group after erythropoietin therapy compared to the basal levels of the patients. We determined 24% increase in erythrocyte Na,K-ATPase activities after one month EPO application compared to the basal levels. Conclusion: It was concluded that erythropoietin therapy could improve neuropathy and this improvement was supported with the increase in Na,K-ATPase activities which could be used as a marker.

Erythropoietin and its antagonist regulate the hypoxic fictive breathing in newborn mice

Erythropoietin (Epo) in adult mouse interacts with the major brainstem centers associated with respiration to enhance the ventilatory response to acute and chronic conditions of physiological hypoxia (e.g. as occuring at high altitude). However, whether Epo is as well implicated in the regulation of breathing in newborns remains unknown. To answer this question en bloc brainstem‐spinal cord preparations were obtained from mice at postnatal day 4 (P4). After time‐ (30, 60 or 90 min) and dose‐dependent (0, 25 or 250 U) incubation with or without Epo, en bloc preparations were superfused with artificial cerebrospinal fluid (aCSF) bubbled with normoxic or hypoxic gas mixtures. Subsequently, the electrophysiological fictive breathing produced by axons at the C4 ventral root was recorded. Our results show that upon hypoxic conditions Epo stimulates the neural hypoxic respiratory activity and improves the post hypoxic recovery. In addition, proof‐of‐concept experiments showed that soluble Epo receptor (sEpoR), the endogenous antagonist of Epo, dramatically decreases the neural hypoxic respiratory activity. These results imply that Epo and its endogenous antagonist in P4 mice are implicated in the modulation and maintenance of respiratory motor output during hypoxic and post‐hypoxic challenges. As Epo is a highly promising protective therapeutic agent for several brain diseases, these results suggest that Epo applications may be also relevant for neuronal‐related respiratory disorders in term and preterm neonates.

Erythropoietin prevents PC12 cells from beta-amyloid-induced apoptosis via PI3K⁄Akt pathway

BackgroundSeveral studies indicated that Erythropoietin (Epo) may provide remarkable neuroprotection in some neurological diseases. It also showed the significant decrease of Epo immunoreactivity in the cerebral cortex and hippocampus in aged rats, suggesting the role of Epo in the pathogenesis of age-related neurodegenerative diseases such as AD.MethodsThe protective effect of Epo was studied in differentiated PC12 cells treated with Abeta. The viability of the cells, the apoptosis of the cells and the level of Bax, Bcl-2, cleaved caspase-3 and cleaved PARP expression were detected by MTT, Hoechst 33258 staining and Western blotting respectively.Results20 μM Abeta (25-35) could induce a decreased viability and a increased apoptosis in PC12 cell in a time-dependent manner. However, 20 μM Abeta (35-25) had no effect on cell viability and apoptosis. Western blot analysis also showed that Abeta(25-35) treatment could decrease the expression of Bcl-2 (P < 0.05) and increase the expression of Bax (P < 0.05), Cleaved casapase-3 (P < 0.05), and Cleaved PARP (P < 0.05). The pretreatment of Epo could effectively reverse all the above changes induced by Abeta(25-35) (P < 0.05). Furthermore, the protective effect of Epo could be blocked by PI3K inhibitor LY294002 (P < 0.05).ConclusionsEpo prevented cell injuries in PC12 cells exposed to the Abeta(25-35) and this effect may depend on the PI3K⁄Akt pathway. Our study provided an important evidence for the potential application of Epo in the therapy of Alzheimer's disease.

Erythropoietin couples erythropoiesis, B-lymphopoiesis, and bone homeostasis within the bone marrow microenvironment

AbstractErythropoietin (Epo) has been used in the treatment of anemia resulting from numerous etiologies, including renal disease and cancer. However, its effects are controversial and the expression pattern of the Epo receptor (Epo-R) is debated. Using in vivo lineage tracing, we document that within the hematopoietic and mesenchymal lineage, expression of Epo-R is essentially restricted to erythroid lineage cells. As expected, adult mice treated with a clinically relevant dose of Epo had expanded erythropoiesis because of amplification of committed erythroid precursors. Surprisingly, we also found that Epo induced a rapid 26% loss of the trabecular bone volume and impaired B-lymphopoiesis within the bone marrow microenvironment. Despite the loss of trabecular bone, hematopoietic stem cell populations were unaffected. Inhibition of the osteoclast activity with bisphosphonate therapy blocked the Epo-induced bone loss. Intriguingly, bisphosphonate treatment also reduced the magnitude of the erythroid response to Epo. These data demonstrate a previously unrecognized in vivo regulatory network coordinating erythropoiesis, B-lymphopoiesis, and skeletal homeostasis. Importantly, these findings may be relevant to the clinical application of Epo.

Renoprotective effect of erythropoietin against ischaemia-reperfusion injury in a non-human primate model

The renoprotective effect of erythropoietin (Epo) against ischaemia-reperfusion injury (IR/I) was evaluated in a non-human primate model. Crab-eating macaques were divided into two groups: Control (n = 10), treated with saline, and EPO (n = 10), treated with Epo. Epo was injected intravenously at a dose of 12,000 units, 5 min before clamping the renal pedicle and 5 min before declamping. Renal IR/I was created by clamping the left renal artery for 90 min following right nephrectomy. Haemoglobin (Hb), haematocrit (Ht), creatinine (Cr), blood urea nitrogen (BUN), cystatin C and interleukin-6 (IL-6) were measured before (Pre) and after (Day 0) the operation, and on post-operative days: Day 1, Day 3, Day 5 and Day 7. Apoptotic cells were counted on Day 1. There were no differences in Hb and Ht between the two groups. Cr, BUN, cystatin C and IL-6 levels in the EPO group were lower than those in the Control group at most of the observation points. The number of apoptotic cells in the Control was significantly higher than that of and EPO group. Epo significantly ameliorates renal IR/I in this non-human primate model. Our findings justify the clinical application of Epo, not only for acute renal failure, but also in transplantation.