Contribution of superoxide to reduced antioxidant activity of glycoxidative serum albumin

Hyperglycemia increases oxidative stress in various tissues and leads to diabetic cardiovascular complication. Dyslipidemia, such as an increase in oxidized low-density lipoprotein (LDL), is well recognized in diabetic patients with hyperglycemia. However, the mechanism by which hyperglycemia causes the increased LDL oxidation remains unclear. Albumin is the most abundant protein in the circulation, and can function as an antioxidant. Therefore, we examined whether glycoxidative modification inhibits the antioxidant activity of albumin to LDL oxidation and clarified the mechanism by which this modification may suppress its antioxidant activity. Human serum albumin (HSA) was incubated in phosphate-buffered saline with and without glucose at 37°C for up to 8 weeks under aerobic conditions (referred to as glycoxidation (goHSA) and oxidation (oHSA), respectively). Metal chelator-treated, nonoxidative HSA (chHSA) and freshly prepared HSA (fHSA) were used as controls. N ^ε-(carboxymethyl)lysine (CML), a glycoxidative product, was determined by enzyme-linked immunosorbent assay. Oxidation was estimated by measuring the thiols of the HSA molecule. Copper-mediated oxidation of LDL was conducted in the presence or absence of modified HSAs at 37°C for 6 days. Malondialdehyde and negative charge of LDL were measured. To clarify the mechanism of reduced antioxidant activity of HSA, we examined firstly the binding activity of modified HSAs to copper, and secondly the effects of free radical scavengers on the formation of malondialdehyde. CML was formed in goHSA in a time- and concentration-dependent manner. Both goHSA and oHSA significantly decreased the contents of free thiol groups compared to ch- and fHSAs. The antioxidant activity of goHSA to LDL oxidation was the lowest among various modified HSAs. The oHSA showed a moderate decrease in antioxidant activity. The binding activity of go- and oHSAs to copper was lower than that of ch- and fHSAs. The formation of MDA from LDL oxidation in the presence of goHSA was completely inhibited by Tiron (1,2-dihydroxy-3,5-benzenedisulfonic acid) and superoxide dismutase. In contrast, catalase and mannitol had no effect. Our results indicate that in vitro glycoxidation of HSA induced a marked loss of antioxidant activity of this molecule to copper-mediated oxidation of LDL, which may be caused by the generation of superoxide. Received: December 17, 2001 / Accepted: June 28, 2002 Acknowledgments The authors thank Drs. Ryoji Nagai and Seikoh Horiuchi (Department of Biochemistry, Kumamoto University School of Medicine, Kumamoto, Japan) and Drs. Hiroyuki Itabe and Tatsuya Takano (Department of Microbiology and Molecular Pathology, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa, Japan) for kindly supplying antibodies. We also thank Associate Professor Takeo Yamaguchi (Department of Chemistry, Faculty of Science, Fukuoka University) for the ESR experiment and Miss Satoko Nagano for her excellent technical assistance. This work was supported by a Grant-in-Aid from the Ministry of Education, Science, Sports and Culture of Japan (No. 14570171) and in part by funds from the Central Research Institute of Fukuoka University (No. 016004). Correspondence to N. Sakata     

Emerging insights into the role of albumin with plasma exchange in Alzheimer’s disease management

Alzheimer’s disease (AD) is a neurodegenerative process that inexorably leads to progressive deterioration of cognition function and, ultimately, death. Central pathophysiologic features of AD include the accumulation of extracellular plaques comprised of amyloid-β peptide (Aβ) and the presence of intraneuronal neurofibrillary tangles. However, a large body of evidence suggests that oxidative stress and inflammation are major contributors to the pathogenesis and progression of AD. To date, available pharmacologic treatments are only symptomatic. Clinical trials focused on amyloid and non-amyloid-targeted treatments with small molecule pharmacotherapy and immunotherapies have accumulated a long list of failures. Considering that around 90 % of the circulating Aβ is bound to albumin, and that a dynamic equilibrium exists between peripheral and central Aβ, plasma exchange with albumin replacement has emerged as a new approach in a multitargeted AD therapeutic strategy (AMBAR Program). In plasma exchange, a patient’s plasma is removed by plasmapheresis to eliminate toxic endogenous substances, including Aβ and functionally impaired albumin. The fluid replacement used is therapeutic albumin, which acts not only as a plasma volume expander but also has numerous pleiotropic functions (e.g., circulating Aβ- binding capacity, transporter, detoxifier, antioxidant) that are clinically relevant for the treatment of AD. Positive results from the AMBAR Program (phase 1, 2, an 2b/3 trials), i.e., slower decline or stabilization of disease symptoms in the most relevant clinical efficacy and safety endpoints, offer a glimmer of hope to both AD patients and caregivers.     

Two cases of brand-specific albumin sensitivity in patients receiving regular therapeutic plasma exchange

Therapeutic plasma exchange (PLEX) involves the removal of detrimental substances, commonly pathogenic antibodies or toxins, from a patient’s blood by exchanging their plasma with a replacement fluid. While a variety of replacement fluids are available, human albumin (4–5 %) is the most commonly used, as it is widely available, easily stored, and generally well tolerated. Despite its excellent safety profile, adverse reactions to albumin are well documented, ranging in severity from mild allergic symptoms to severe anaphylaxis. This report describes two cases of patients receiving frequent PLEX who developed sensitivities to human albumin. These patients differed substantially in the manifestations of their symptoms, the duration of their treatment, and their medical indication for PLEX. In both cases, symptom onset occurred shortly after completion of plasma exchange procedures and lasted for several hours. Symptoms disappeared when the patients were switched to albumin from a different manufacturer, suggesting that the reaction was specific to that formulation of albumin and not to the albumin itself. These cases highlight the possibility of manufacturer-specific acquired albumin sensitivities and provide a simple framework for the initial approach to the management of such reactions.     

二十碳五烯酸对白蛋白诱导肾小管上皮细胞转分化的影响

目的 探讨二十碳五烯酸(eicosapentaenoic acid,EPA)对人白蛋白诱导的人近端肾小管上皮细胞(HK-2)发生转分化的干预作用.方法 体外培养人HK-2细胞,随机分为6组:A组,空白对照组(未加任何刺激物);B组,单纯EPA组(加入30 μmol/L EPA);C组,血白蛋白(albumin,Alb)诱导组(加入5 mg/ml Alb);D组,低剂量EPA干预组(5mg/ml Alb+ 10 μmol/L EPA);E组,中剂量EPA干预组(5mg/ml Alb+ 30 μmol/L EPA);F组,高剂量EPA干预组(5 mg/ml Alb+ 50μmol/L EPA).细胞免疫荧光检测E钙黏蛋白(E-cadherin)、α平滑肌肌动蛋白(α-smooth muscle ac-tin,α-SMA)的表达;ELISA法检测纤维连接蛋白(fibronectin,FN)的水平;采用RT-PCR检测转化生长因子β1(transforming growth factor β1,TGF-β1)的mRNA表达.结果 与A组比较,B组TGF-β1mRNA、α-SMA、FN、E-cadherin表达均无统计学差异(P＞0.05);C组TGF-β1 mRNA、α-SMA、FN较其他各组表达明显增高(P＜0.05),而E-cadherin表达明显下降(P＜0.05).与C组比较,D组、E组、F组TGF-β1 mRNA、α-SMA、FN表达逐渐下降,两组间比较差异有统计学意义(P＜0.05);E-cadherin的表达逐渐增高,各组间比较差异有统计学意义(P＜0.05).提示EPA可显著抑制Alb刺激人肾小管上皮细胞表达E-cadherin、α-SMA,同时下调上清液中FN水平,且其抑制作用的强弱与EPA浓度密切相关.EPA还明显下调了Alb刺激后TGF-β1的表达.结论 一定浓度的人白蛋白可以诱导体外培养的HK-2细胞发生转分化;EPA可一定程度上抑制白蛋白诱导HK-2发生转分化过程,且呈剂量依赖性.     

Albumin administration prevents the onset of pressure ulcers in intensive care unit patients

Pressure ulcers (PUs) are a common problem in critically ill patients admitted to the intensive care units (ICUs) and they account for more than 70% of patients with low serum albumin at admission. The aim of this study was to test the efficacy of intravenous administration of albumin in patients with low serum albumin < 3·3 g/dl. In a 1‐year period, a total of 73 patients were admitted to the ICU (males 45, 61·64% and females 28, 38·36%); of these, 21 patients were admitted with hypoalbuminaemia (serum albumin < 3·3 g/dl) and randomised into two groups: 11 patients were treated with 25 g intravenous albumin for the first 3 days within the first week of ICU stay (group A) and 10 patients did not receive albumin (group B). Three patients (27·27%) showed the onset of PUs in group A, whereas seven patients (70%) showed the onset of PUs within the first 7 days of stay in group B. Moreover, ulcers of group B were more severe than those of group A. This study shows that intravenous administration of albumin reduces the onset of PUs in patients admitted to the ICU and in some cases it also reduces the risk of progression to advanced stages of PUs.     

Radioembolization with yttrium-90 microspheres work up: Practical approach and literature review

Radioembolization (RE) is a selective internal radiotherapy technique in which yttrium-90 blended microspheres are infused through the hepatic arteries. It is based on the fact that primary and secondary hepatic tumors are vascularized mostly by arterial blood flow whereas healthy hepatocytes obtain their blood supply mostly from the portal network. This enables high radiation doses to be delivered, sparing the surrounding non-malignant liver parenchyma. Most of the complications are caused by unexpected particles passing into the gastrointestinal tract through branches originating from the main hepatic arterial supply. Knowledge of this hepatic arterial network and of its variations and the technical considerations this raises are required in preparation for treatment. This work describes the specific anatomical features and techniques for this anatomy through recent literature illustrated by cases from our own experience.     

评估应用术前PLR、NLR及AGR预测乳腺癌患者预后的价值

目的探究术前血小板淋巴细胞比值（PLR）、中性粒细胞淋巴细胞比值（NLR）及白蛋白球蛋白比值（AGR）在评估乳腺癌患者预后中的价值。 方法选取2013年1月至2017年12月收治的1184例浸润性乳腺癌女性患者为浸润性乳腺癌组,随机选取仅患乳腺纤维腺瘤的患者279例为乳腺纤维腺瘤组。收集患者一般资料、术后病理资料、血型、术前外周血血小板、中性粒细胞、淋巴细胞数量以及血清白蛋白和球蛋白水平,并计算得出PLR、NLR及AGR。应用受试者功能特征曲线下面积来评估三者预测乳腺癌患者预后的能力。本研究使用SPSS 20.0及MedCalc软件进行统计学分析和绘图,P<0.05代表差异具有统计学意义。 结果浸润性乳腺癌患者的术前PLR及NLR均值显著高于乳腺纤维腺瘤患者（P<0.05）,而AGR低于乳腺纤维腺瘤患者（P<0.05）。Cox比例回归风险分析显示,患者的诊断年龄、PLR、NLR、AGR、肿瘤直径、组织学分级、阳性淋巴结个数和分子分型均为乳腺癌的预后危险因素（P<0.05）。ROC曲线分析结果得出,PLR、NLR及AGR的最佳诊断临界值分别为147.4、2.9及1.7。应用术前PLR（AUC=0.796,P<0.001）、NLR（AUC=0.716,P<0.001）及AGR（AUC=0.748,P<0.001）预测乳腺癌患者预后均有价值,且PLR价值更高。 结论术前PLR、NLR及AGR对乳腺癌患者预后的判断均具价值,三者相比,PLR价值更高,有望成为判断乳腺癌患者预后的补充指标。     

术前营养状况对脊柱手术术后并发症的影响

脊柱手术作为治疗脊柱病变的主要手段,其术后并发症的发生率逐步升高。如何防治脊柱手术术后并发症受到更多临床医师的重视。研究表明术前营养不良与许多术后并发症如手术部位伤口感染、出血、血栓形成、肺炎等的发生有关,且患者的术前个体营养状态是脊柱手术术后并发症的独立危险因素。本文主要就患者术前营养状态与脊柱手术术后并发症的关系作一综述。     

Non-oncotic properties of albumin. A multidisciplinary vision about the implications for critically ill patients

Introduction: Effective resuscitation with human albumin solutions is achieved with less fluid than with crystalloid solutions. However, the role of albumin in today’s critical care unit is also linked to its multiple pharmacological effects.

Areas covered: The potential clinical benefits of albumin in select populations of critically ill patients like sepsis seem related to immunomodulatory and anti-inflammatory effects, antibiotic transportation and endothelial stabilization. Albumin transports many drugs used in critically ill patients. Such binding to albumin is frequently lessened in critically ill patients with hypoalbuminemia. These changes could result in sub-optimal treatment. Albumin has immunomodulatory capacity by binding several bacterial products. Albumin also influences vascular integrity, contributing to the maintenance of the normal capillary permeability. Moreover, the albumin molecule encompasses several antioxidant properties, thereby significantly reducing re-oxygenation injury, which is especially important in sepsis. In fact, most studies of albumin administration are a combination of a degree of resuscitation with a degree of maintenance or supplementation of albumin.

Expert commentary: The potential clinical benefits of the use of albumin in selected critically ill patients such as sepsis seem related to its immunomodulatory and anti-inflammatory effects, antioxidant properties, antibiotic transportation and endothelial stabilization. Additional studies are warranted to further elucidate the underlying physiologic and molecular rationale.