促红细胞生成素及其受体在直肠癌中表达及临床意义

目的:探讨促红细胞生成素(erythropoietin,EPO)及促红细胞生成素受体(erythropoietin receptor,EPOR)在直肠癌中的表达情况及临床意义。方法:应用免疫组织化学方法检测60份直肠癌组织标本及60份正常直肠组织标本EPO与EPOR的表达情况。结果:(1)EPO和EPOR在正常直肠组织中的高表达率均为0,在直肠癌组织中的高表达率分别为65.0%、80.0%,差异有统计学意义(P<0.05)。(2)高、中分化腺癌中EPO及EPOR高表达率分别为40.6%、65.6%,低分化腺癌及未分化癌中高表达率分别为92.8%、96.4%,差异均有统计学意义(P<0.05)。Dukes分期A期和B期中EPO及EPOR高表达率分别为35.7%、64.3%,C期高表达率分别为90.6%、93.8%,差异均有统计学意义(P<0.05)。(3)EPO与EPOR在直肠癌组织中表达的相关分析结果显示EPO与EPOR呈正相关(r=0.419,P=0.004)。结论:直肠癌组织中EPO和EPOR的高表达水平与预后不良有关;EPO和EPOR共同促进直肠癌的发展、侵袭和转移。     

Emerging technologies in the delivery of erythropoietin for therapeutics

Deciphering the function of proteins and their roles in signaling pathways is one of the main goals of biomedical research, especially from the perspective of uncovering pathways that may ultimately be exploited for therapeutic benefit. Over the last half century, a greatly expanded understanding of the biology of the glycoprotein hormone erythropoietin (Epo) has emerged from regulator of the circulating erythrocyte mass to a widely used therapeutic agent. Originally viewed as the renal hormone responsible for erythropoiesis, recent in vivo studies in animal models and clinical trials demonstrate that many other tissues locally produce Epo independent of its effects on red blood cell mass. Thus, not only its hematopoietic activity but also the recently discovered nonerythropoietic actions in addition to new drug delivery systems are being thoroughly investigated in order to fulfill the specific Epo release requirements for each therapeutic approach. The present review focuses on updating the information previously provided by similar reviews and recent experimental approaches are presented to describe the advances in Epo drug delivery achieved in the last few years and future perspectives. © 2009 Wiley Periodicals, Inc. Med Res Rev, 31, No. 2, 284–309, 2011     

The role of erythropoietin in myocardial protection: potential mechanisms and applications

The glycoprotein erythropoietin was originally discovered as a principal regulator that promotes the survival, proliferation and differentiation of erythroid progenitor cells. Despite potentially detrimental effects, such as increased blood pressure and hyperviscosity, recombinant human erythropoietin has been demonstrated to be a safe drug, as millions of anemia sufferers have received it over the last decade as a form of treatment. Recently, erythropoietin receptors have been discovered in a variety of tissues, including the cardiovascular system, and erythropoietin has been demonstrated to have a beneficial effect in congestive heart failure patients with anemia. The purpose of this review is to summarize the pleiotropic cardioprotective effects of erythropoietin in the cardiovascular system and to evaluate its potential role as a biomarker in these disorders.     

Hepatic erythropoietin response in cirrhosis

Background Erythropoietin (EPO) is produced in the liver during fetal life, but after birth the production shifts to the kidneys. The liver maintains a production capacity of 10% of the total EPO-production, but can be up-regulated to 100%. Previous studies have demonstrated both elevated and reduced concentrations of EPO in cirrhosis. Increased EPO concentrations could be expected due to anemia, hypoxia, renal hypoperfusion, or EPO-mediated hepatoprotective mechanisms. In contrast, poor hepatic production capacity may cause reduced EPO concentrations in cirrhosis. In the present paper we aimed to study hepatic and renal venous concentrations of EPO in relation to the severity of the disease. Materials and methods We included 24 patients with alcoholic cirrhosis and eight age-matched healthy controls. All had a full catheterization performed with the determination of EPO concentrations in the hepatic, renal and femoral veins and artery. All patients were clinically, biochemically, and hemodynamically characterized. Results The median arterial EPO concentrations in the cirrhotic patients and controls were 7.1 mIU/mL (range 3.5–179) and 7.2?mIU/mL (range 3.8–15.3), respectively. In the patient group we found no significant correlations to stage of disease of hemodynamic derangement. Conclusion We found no significant differences in EPO concentrations across the liver, kidney, or peripheral circulation in the patient or control groups; and no significant correlations to clinical, biochemical, or hemodynamic characteristics. This suggests that hepatic EPO synthesis is not enhanced in cirrhosis, but larger scale studies are needed to clarify this question.     

低氧预处理诱导促红细胞生成素对脑缺血后损伤及认知功能的保护作用

目的 观察低氧预处理(HPC)对全脑缺血/再灌注(I/R)5 d后大鼠认知功能(学习、记忆)障碍的改善作用及对促红细胞生成素(EPO)表达的调节作用,探讨HPC对I/R致海马区损伤的保护作用机制.方法 成年健康雄性SD大鼠120只被随机分为假手术组、I/R组、HPC 24 h组(脑缺血前24 h低氧)、HPC 48 h组(脑缺血前48 h低氧)4组.于术后5 d进行运动功能实验、被动躲避实验和水迷宫实验,测定大鼠的认知功能;用苏木素-伊红(HE)染色,检测脑海马区组织病理学变化;再灌注后1 h和4 h用免疫组化测定海马CA1和CA3区EPO蛋白含量.结果 运动功能实验、被动躲避实验和水迷宫实验测定显示,I/R能损害大鼠的认知功能;HPC组大鼠的认知功能均得到显著改善,且HPC 48 h组较HPC 24 h组改善更显著(P<0.05).HPC组神经细胞的坏死程度减轻,且在HPC 48 h组更显著.HPC组在全脑I/R后1 h和4 h海马CA1和CA3区的EPO蛋白表达均明显增加.HPC 48 h组作用更明显(P均<0.05);并且EPO蛋白含量与认知功能呈正相关(CA1区相关系数(r)=0.744,CA3区r=0.822,P均<0.013.结论 全脑I/R可导致神经细胞坏死并引发I/R后短期内(5 d)的认知功能障碍;HPC能减轻I/R损伤、改善缺血引起的认知功能障碍,且缺血前48 h的HPC保护作用更强.HPC可促进EPO在海马CA1和CA3区的表达,这也可能是HPC脑保护和改善认知功能障碍的机制之一.     

Effect of recombinant human erythropoietin on quality of life in cancer patients receiving chemotherapy: results of a randomized,controlled trial

The purpose of this study was to assess whether the administration of recombinant human erythropoietin (rHuEPO) would correct anemia and improve the quality of life (QOL) in cancer patients receiving chemotherapy. One hundred twenty-two patients with hemoglobin ≤11.0 g/dl were randomized to receive rHuEPO 10,000 U three times weekly (n = 61) or no additional treatment (n = 61). Response was assessed by measuring changes in hemoglobin level and QOL. QOL was evaluated before each cycle of chemotherapy at baseline, Week 4, and Week 12 using two separate self-report questionnaires. The analyses indicated that the rHuEPO-treated patients experienced significantly less fatigue (P < 0.05) than their control group counterparts, and reported significantly higher scores on energy level (P < 0.05), ability to perform daily activities (P < 0.01), and overall QOL (P< 0.05). The overall change in hemoglobin level was significantly greater in the rHuEPO group than in the control group (1.7 g/dl versus 0.3 g/dl, P < 0.001). rHuEPO effectively corrects anemia and significantly improves QOL in patients with solid tumors receiving chemotherapy.     

促红细胞生成素及其受体在非小细胞肺癌中的表达及临床意义

目的研究促红细胞生成素（EPO）及其受体（EPO-R）在非小细胞肺癌（NSCLC）中的表达及临床意义。方法应用免疫组织化学法检测唐山市协和医院、唐山市人民医院1999年1月至2003年12月手术切除的126例NSCLC EPO与EPO-R蛋白的表达,并分析其与临床病理参数的相关性。结果 NSCLC患者中EPO阳性率为59.5%（75/126）,高、中、低分化阳性率分别为27.7%,54.0%,74.1%,低分化者阳性率高于中、高分化者（P〈0.01）;Ⅰ~Ⅱ期阳性率为37.1%,Ⅲ~Ⅳ期为68.1%（P〈0.01）;淋巴结转移者（63.3%）明显高于淋巴结阴性者（35.3%）（P〈0.01）。EPO表达阴性者中位生存期为65个月,EPO表达弱阳性至中度阳性者中位生存期为26个月,EPO强阳性者为10个月（P〈0.01）。NSCLC患者中EPO-R阳性率为78.6%（99/126）。高、中、低分化阳性率分别为38.9%,74.0%,94.8%,低分化和中分化者阳性率明显高于高分化者（P〈0.01）;Ⅰ~Ⅱ期阳性率为40.0%,Ⅲ~Ⅳ期为93.4%（P〈0.01）;淋巴结转移者（80.7%）明显高于淋巴结阴性者（64.7%）（P〈0.01）。EPO-R表达阴性者中位生存期为69个月,EPO-R表达弱阳性至中度阳性者中位生存期为49个月,EPO-R强阳性者为11个月（P〈0.01）。COX回归分析显示,EPO表达（P〈0.01）、EPO-R表达（P〈0.01）均为独立的预后因素。结论 EPO和EPO-R高水平表达与NSCLC侵袭转移相关,EPO和EPO-R高表达与NSCLC预后不良相关。     

Volociximab in cancer

Importance of the field: Despite the advances in the cardiovascular field, cardiovascular diseases remain an important health problem with a high mortality rate. Novel therapeutic attempts that target myocardial ischemia and heart failure offer attractive adjuncts and/or alternatives to commonly employed regimens. The development of novel laboratory technologies over the last decade has led to substantial progress in bringing new therapies to the bedside.

Areas covered in this review: Current experimental and clinical trials in the use of erythropoietin (EPO) in cardiovascular diseases are reviewed.

What the reader will gain: This review will widen knowledge of the therapeutic potential of EPO's non-erythropoietic beneficial effects in a clinical cardiovascular setting.

Take home message: Results from preclinical trials regarding the non-erythropoietic effects of erythropoietin are really encouraging. Further clinical studies are warranted to define the beneficial role of EPO in the clinical setting of coronary artery disease, heart failure and peripheral artery disease.     

脑缺血耐受大鼠缺氧诱导因子-1α和促红细胞生成素的表达

目的：探讨脑缺血预处理诱导脑缺血耐受形成中促红细胞生成素（EPO）及缺氧诱导因子-1α（HIF-1α）mRNA及蛋白表达的变化。方法：将99只Wistar大鼠随机分成假手术对照组9只、假手术＋再缺血组45只、预缺血＋再缺血组45只,后两组再随机分成5个亚组。线栓法阻塞大脑中动脉建立局灶性缺血预处理模型（预缺血10min）,分别在预缺血后1d、3d、7d、14d、21d进行再次缺血2h再灌注22h,然后取脑检查。应用免疫组化方法检测HIF-lα与EPO蛋白的表达,应用反转录聚合酶链式反应技术检测EPOmRNA和HIF-1αmRNA的表达。结果：①与假手术组各对应亚组相比,缺血预处理组中的1d、3d、7d亚组HIF-lα蛋白表达增高,3d、7d亚组中EPO蛋白表达增高,差异有显著性意义（P〈0.05;P〈0.01）。②与假手术组各对应亚组相比,缺血预处理组3d、7d亚组中HIF-lαmRNA及EPOmRNA表达明显增高,差异有显著性意义（P〈0.05）。③EPOmRNA表达与HIF-1αmRNA表达呈显著正相关。结论：缺血预处理诱导了脑缺血耐受,预缺血诱导的内源性HIF-lα及EPO表达增加参与脑缺血耐受形成的机制。     

Priming of late endothelial progenitor cells with erythropoietin before transplantation requires the CD131 receptor subunit and enhances their angiogenic potential

Summary. Background: Endothelial colony‐forming cells (ECFCs) are promising candidates for cell therapy of ischemic diseases. Erythropoietin (EPO) is a cytokine that promotes angiogenesis after ischemic injury. EPO receptors (EPORs) classically include two EPOR subunits, but may also associate with the β‐common chain (CD131) in a newly identified receptor involved in EPO cytoprotective effects. Objective: The aim was to take advantage of the proangiogenic properties of EPO to enhance ECFC graft efficiency. We postulated that priming ECFCs by adding epoietin α in culture medium prior to experiments might increase their angiogenic properties. We also explored the role of the CD131 subunit in EPO priming of ECFCs. Methods and Results: By western blotting on cord blood ECFC lysates, we showed that EPOR and CD131 expression increased significantly after EPO priming. These proteins coimmunoprecipitated and colocalized, suggesting that they are covalently bound in ECFCs. EPO at 5 IU mL^?1 significantly stimulated proliferation, wound healing, migration and tube formation of ECFCs. EPO priming also increased ECFC resistance to H₂O₂‐induced apoptosis and survival in vivo. Similarly, in vivo studies showed that, as compared with non‐primed ECFC injection, 5 IU mL^?1 EPO‐primed ECFCs, injected intravenously 24 h after hindlimb ischemia in athymic nude mice, increased the ischemic/non‐ischemic ratios of hindlimb blood flow and capillary density. These effects were all prevented by CD131 small interfering RNA transfection, and involved the phosphoinositide 3‐kinase–Akt pathway. Conclusion: These results highlight the potential role of EPO‐primed ECFCs for cell‐based therapy in hindlimb ischemia, and underline the critical role of CD131 as an EPO coreceptor.     

The role of erythropoietin in hemorrhagic shock-induced liver and renal injury in rats

Introduction  The aim of the present study was to evaluate the role of erythropoietin (EPO) in liver and renal injury following hemorrhagic shock (HS) after inhibition of tyrosine kinase activity in rats.. Methods  Forty-eight Sprague-Dawley rats were assigned to six groups: (I) HS alone; (II) HS followed by retransfusion; (III) EPO and genistein followed by HS; (IV) EPO and genistein followed by HS, followed by retransfusion; (V) HS followed by EPO and genistein; and (VI) HS followed by EPO and genistein, followed by retransfusion. HS was induced for 60 minutes after withdrawal of 30% of the calculated total blood volume of each rat from the left femoral artery. Blood and tissue samples (from the kidney and liver) were obtained 60 minutes after HS in Group I, III, and V; blood and tissue samples were obtained 60 minutes after retransfusion in Group II, IV, and VI. In Group III and IV, EPO was given 60 minutes before HS, and genistein 30 minutes before HS. In Group V and VI, EPO and genistein were given 30 minutes after HS. Results  Liver and renal injury were significantly attenuated with EPO and genistein administration. Conclusion  These results suggest that EPO is effective in attenuating liver and renal injury in HS, even with inhibition of tyrosine kinase activity with genistein.     

The dual role of thymidine phosphorylase in cancer development and chemotherapy

Thymidine phosphorylase (TP), also known as “platelet‐derived endothelial cell growth factor” (PD‐ECGF), is an enzyme, which is upregulated in a wide variety of solid tumors including breast and colorectal cancers. TP promotes tumor growth and metastasis by preventing apoptosis and inducing angiogenesis. Elevated levels of TP are associated with tumor aggressiveness and poor prognosis. Therefore, TP inhibitors are synthesized in an attempt to prevent tumor angiogenesis and metastasis. TP is also indispensable for the activation of the extensively used 5‐fluorouracil prodrug capecitabine, which is clinically used for the treatment of colon and breast cancer. Clinical trials that combine capecitabine with TP‐inducing therapies (such as taxanes or radiotherapy) suggest that increasing TP expression is an adequate strategy to enhance the antitumoral efficacy of capecitabine. Thus, TP plays a dual role in cancer development and therapy: on the one hand, TP inhibitors can abrogate the tumorigenic and metastatic properties of TP; on the other, TP activity is necessary for the activation of several chemotherapeutic drugs. This duality illustrates the complexity of the role of TP in tumor progression and in the clinical response to fluoropyrimidine‐based chemotherapy. © 2009 Wiley Periodicals, Inc. Med Res Rev, 29, No. 6, 903–953, 2009     

促红细胞生成素在多种贫血中的临床意义

促红细胞生成素(erythropoietin,EPO)在医学中应用范围极广,在贫血、组织断离、早产儿、癌症和血液学等方面均有良好的应用价值,尤其在多种贫血的鉴别方面更是如此。对EPO在缺铁性贫血、巨幼细胞性贫血和再生障碍性贫血等各种贫血中的临床应用情况进行分析与研究将为EPO在这些疾病中的临床应用提供理论依据。     

十全大补汤配方颗粒对骨髓抑制小鼠外周血及促红细胞生成素的影响

目的观察十全大补汤配方颗粒对骨髓抑制小鼠外周血及促红细胞生成素（EP0）的影响。方法采用60钴（60Co）照射、注射环磷酰胺、氯霉素复合处理建立小鼠骨髓抑制模型后,给予十全大补汤配方颗粒进行治疗,采用全自动血细胞分析仪检测其对外周血的影响;双抗体夹心生物素-亲和素复合物酶联免疫吸附试验（ABC-ELISA）法检测血清中EPO含量;逆转录-聚合酶链反应（RT-PCR）检测骨髓及肾脏EPOmRNA表达情况。结果与正常对照纽比较,模型组小鼠外周血血象、骨髓有核细胞数降低,血清EPO含量升高,肾脏、骨髓细胞EPOmRNA表达增强。经十全大补汤配方颗粒治疗后,外周血、骨髓有核细胞数升高,血清EPO含量升高,肾脏、骨髓有核细胞EPOmRNA的表达增强。结论十全大补汤配方颗粒可能通过在转录水平上促进肾脏、骨髓有核细胞EPOmRNA的表达,促进受损骨髓红系造血的恢复。     

The erythropoietin and regenerative medicine: a lesson from fish

Background Erythropoietin (EPO), the main haematopoietic growth factor for the proliferation and differentiation of erythroid progenitor cells, is also known for its angiogenic and regenerative properties. Materials and methods In this study, we aimed to test the regenerative effects of EPO administration in an experimental model of Sea bass (Dicentrarchus labrax) subjected to amputation of the caudal fin. Results Erythropoietin‐treated fishes (3000 UI of human recombinant EPO‐alpha immediately after cutting and after 15 days) showed an increased growth rate of their fins compared with those untreated (anova variance: P: 0·01 vs. P: 0·04). By analysing fin length at established times (15 and 30 days after cut), EPO‐treated fishes always showed an increased length compared with untreated ones (T‐15: 1·1 ± 0·2 vs. 0·7 ± 0·2 cm, P: 0·03; T‐30: 1·9 ± 0·3 vs. 1·2 ± 0·2 cm, P: 0·01). Moreover, exogenous EPO administration induced an enormous increase in EPO‐blood levels at each observation time (T‐15: 2240 ± 210 vs. 16·7 ± 1·8 mU mL^?1, P < 0·001; T‐30: 2340 ± 190 vs. 17·1 ± 1·9 mU mL^?1, P < 0·001), whereas these levels remained quite unmodified in untreated fishes. Immunochemical analyses performed by confocal laser scanning microscopic observations showed an increased expression of EPO‐receptors and PECAM‐1 (an endothelial surface marker of vessels sprout) in the regenerating tissue, whereas no signs of inflammation or fibrosis were recognisable. Conclusions All these findings confirm EPO as a new factor involved in regenerative processes, also suggesting a potential, future utility for new therapeutical applications in the field of human regenerative medicine.     

早期使用促红细胞生成素对早产儿贫血防治的临床研究

目的探讨早期使用重组人类促红细胞生成素(rHuEPO)防治早产儿贫血的疗效。方法将57例早产儿按入院次序分为治疗组30例、对照组27例。治疗组出生第7天给予每周rHuEPO 750 IU/kg,隔日1次,皮下注射,用药5周;对照组未用rHuEPO。两组早产儿均每天口服铁剂,按元素铁6 mg/(kg.d)计算,口服维生素E 25 mg/d,维生素C0.2 g/d。必要时输血。共观察6周。结果①两组早产儿生后血红蛋白(Hb)均渐下降,但治疗组程度较轻,经t检验,两组之间差异有高度显著性意义(P<0.01);②对照组有5例输血,而预防组仅1例输血,经χ2检验差异有高度显著性意义(P<0.01);③治疗后治疗组网织红细胞(Ret)较对照组显著升高,两组差异有高度显著性意义(P<0.01);④血清铁蛋白水平(SF)在用药期间治疗组明显低于对照组,治疗结束后,治疗组血清SF上升,两组比较差异无显著性意义(P>0.05)。结论早期使用rHuEPO能有效防治早产儿贫血,体内充足的铁储备是确保rHuEPO疗效的重要因素。     

Economic analysis of erythropoietin use in orthopaedic surgery

The aim was to assess the cost-effectiveness of erythropoietin (EPO) to reduce patients' exposure to perioperative allogenic blood products in orthopaedic surgery. The use of EPO was assessed for EPO used alone and for EPO, to augment preoperative autologous donation (PAD). A decision analytical model was designed incorporating (i) the risk of receiving allogeneic blood, (ii) the costs of blood products, (iii) the likelihood of developing transfusion-related diseases, (iv) the costs of transfusion-related diseases, (v) the impact of transfusion-related diseases on patient morbidity and mortality and (vi) the effect of EPO upon the probability of transfusion. The efficacy of EPO was derived from data from a meta-analysis of published randomized trials. Estimates for the other parameters were obtained by a systematic review of the literature. EPO alone led to only modest incremental benefit compared to no intervention for orthopaedic surgery (0.000024 life-years gained per patient). As an augmentation to PAD, EPO also led to modest benefits (0.000006 life-years gained per patient). For EPO compared to no intervention, the incremental cost per life-year gained was $66 million (Canadian). For EPO to augment PAD, the incremental cost per life-year gained was $329 million (Canadian). Detailed sensitivity analysis did not reveal any circumstances in which the cost-effectiveness ratios reached a level generally considered attractive. On the basis of cost-effectiveness, the use of EPO to reduce perioperative allogeneic transfusions in orthopaedic surgery did not meet criteria conventionally considered acceptable.