铁代谢蛋白在肾脏的表达与功能

最近的研究证实,肾小管细胞具有能力表达包括转铁蛋白受体1(transferrin receptor-1,TfR1)、二价金属离子转运蛋白1(divalent metal transporter-1,DMT1)、膜铁转运蛋白1(ferroportin-1,FPN1)、铁调节蛋白(iron regulatory protein,IRP)和铁调素(hepcidin,Hepc)在内的几乎所有铁代谢蛋白.这些蛋白质的存在以及相关研究显示肾脏可能具有排出多余铁的功能,因此对体铁平衡起有十分重要的作用.     

膜铁转运蛋白1，铁调素的靶分子？

膜铁转运蛋白1是重要的跨膜铁输出分子,主要分布于十二指肠和单核巨噬系统的细胞膜上,参与机体的肠铁吸收和巨噬细胞对铁的再循环等过程。铁调素是调节机体铁代谢平衡的激素,机体通过肝脏分泌的铁调素对铁转运相关蛋白的表达进行调控,从而实现机体自身的铁稳态。最新研究显示,铁调素的靶分子可能是膜铁转运蛋白1,它通过直接的作用引起膜铁转运蛋白1的内化(internalization)、降解,从而调节其在细胞膜上的表达量,进而控制肠铁吸收和巨噬细胞对铁的再循环过程,以维持机体的铁稳态。     

低氧诱导因子对铁代谢的调节（英文）

低氧诱导因子(hypoxia-inducible factors,HIFs)是一类介导细胞内低氧反应的核转录复合体。HIF-α和HIF-β形成有功能的异质二聚体。哺乳动物中有HIF-1α、HIF-2α和HIF-3α。HIFs在铁代谢中发挥重要作用。受HIFs调节的铁代谢相关蛋白主要有二价金属转运蛋白1(divalent metal transporter 1,DMT1)、铁转出蛋白(ferroportin 1,FPN1)、十二指肠铁细胞色素b(duodenal cytochrome b,Dcytb)和转铁蛋白受体(transferrin receptor,Tf R)。铁调素(hepcidin)和铁调节蛋白(iron regulatory proteins,IRPs)是调节机体与细胞内铁代谢、维持铁稳态的重要因子,同样受到HIFs的调节。本文综述了HIFs对上述铁代谢相关蛋白的调节作用,以期为治疗铁代谢相关疾病提供可能的靶点。     

Hepcidin的生物学特性及其研究进展

Hepcidin是一种由肝脏合成的富含半胱氨酸的小分子肽。近几年的研究证实hepcidin对于调节机体铁离子的代谢平衡发挥着重要的作用,其可抑制肠道铁吸收和单核巨噬细胞系统铁释放。此外,除了机体铁状况,感染、炎症、贫血和缺氧等原因也会改变hepcidin的表达水平。通过对hepcidin的分子生物学特点、表达调控及生物活性、医学及药用价值等方面研究进展的概述,对采用基因工程的方法生产hepcidin进行了评述及展望。     

肥胖对小鼠十二指肠 DMT1和 FPN1表达的影响

目的：观察肥胖对小鼠十二指肠二价金属离子转运体（divalent metal transporter 1,DMT1）mRNA、膜铁转运蛋白（ferroportin1,FPN1）mRNA及蛋白表达的变化,探讨肥胖影响铁吸收的机制。方法 C57BL／6J小鼠随机分为正常对照组和肥胖模型组,每组6只,通过喂养高脂饲料喂养建立肥胖模型,对照组采用普通饲料饲养,实验干预期14周。建模完成后,采用实时荧光定量PCR方法检测小鼠十二指肠DMT1、FPN1 mRNA 的表达,用Western blot检测小鼠十二指肠FPN1蛋白表达。结果与对照组小鼠相比,肥胖模型组小鼠十二指肠DMT1、FPN1 mRNA表达以及FPN1蛋白表达水平降低,差异具有统计学意义（ P ＜0.05）。结论肥胖会下调机体十二指肠DMT1、FPN1的表达,导致铁吸收不良,为进一步研究肥胖引起铁缺乏机制提供理论和实验依据。     

锰离子转运蛋白的发现及功能机制研究进展

锰是维持人体健康的必需微量元素。锰缺乏或过量均可促发系列重大疾病发生。机体或细胞锰离子的稳态维持受多个锰离子转运蛋白的调控。近年,三个关键的锰离子转运蛋白SLC39A8、SLC39A14和SLC30A10相继被发现,这些基因突变可直接导致锰代谢异常所致的人类遗传病;同时,相关基因敲除或转基因模式动物模型不仅能够模拟人类锰代谢异常的症状,而且可深入研究这些锰离子转运蛋白在器官和细胞内的功能及其分子调控机制,从而开启了锰稳态调控研究的崭新征程。此外,有研究提示二价金属转运蛋白1(DMT1)、膜铁转运蛋白(FPN)、转铁蛋白/转铁蛋白受体系统(TF/Tf R)、TMEM165、分泌型Ca2+通道1(SPCA1)及ATP13A2等膜蛋白也可能参与细胞锰离子转运,使得锰离子的稳态调控变得更为复杂。现就锰转运蛋白的发现及功能机制研究的国内外进展作系统性综述,为后续研究提供新思路。     

Hepcidin在哺乳类及鱼类中的表达和作用

Hepcidin也称为铁调素,是肝脏特异性表达的一种阳离子小分子抗菌肽,具有抑制多种细菌、真菌、病毒和原生动物生长繁殖的作用,是机体天然免疫的一种效应分子;同时也是一种信号分子,参与机体铁代谢,通过直接抑制肠上皮细胞铁吸收和单核巨噬细胞铁释放调节机体铁平衡,与炎症性贫血、遗传性血色素沉着病等铁代谢紊乱性疾病的发病机制密切相关。脂多糖（LPS）、铁超载和病原体可诱导hepcidin表达,而贫血和缺氧可下调其表达。目前,鱼类hepcidin的研究也成为热点,但主要集中在hepcidin的抗菌活性方面,有关其在鱼类铁代谢方面的功能仍需要进一步研究。     

铁代谢与铁调素hepcidin

铁是机体必需的营养元素。然而,铁过载则导致细胞的损伤。由于生物体缺少排泄铁的机制,因而,肠铁吸收的调控便成为维持机体铁稳态的关键。新近研究发现hepcidin对机体铁稳态的调节起着至关重要的作用,被人们称为铁调节激素。Hepcidin主要在肝细胞中合成,之后分泌至血液将体内铁需要的信号传至小肠,调控肠铁的吸收。这一过程主要通过调节小肠铁转运相关蛋白的表达而实现。任何影响hepcidin表达的因素都可能破坏体内的铁平衡,造成铁代谢相关疾病。     

Iron Oxide Nanoparticle-Micelles (ION-Micelles) for Sensitive (Molecular) Magnetic Particle Imaging and Magnetic Resonance Imaging

Background

Iron oxide nanoparticles (IONs) are a promising nanoplatform for contrast-enhanced MRI. Recently, magnetic particle imaging (MPI) was introduced as a new imaging modality, which is able to directly visualize magnetic particles and could serve as a more sensitive and quantitative alternative to MRI. However, MPI requires magnetic particles with specific magnetic properties for optimal use. Current commercially available iron oxide formulations perform suboptimal in MPI, which is triggering research into optimized synthesis strategies. Most synthesis procedures aim at size control of iron oxide nanoparticles rather than control over the magnetic properties. In this study, we report on the synthesis, characterization and application of a novel ION platform for sensitive MPI and MRI.

Methods and Results

IONs were synthesized using a thermal-decomposition method and subsequently phase-transferred by encapsulation into lipidic micelles (ION-Micelles). Next, the material and magnetic properties of the ION-Micelles were analyzed. Most notably, vibrating sample magnetometry measurements showed that the effective magnetic core size of the IONs is 16 nm. In addition, magnetic particle spectrometry (MPS) measurements were performed. MPS is essentially zero-dimensional MPI and therefore allows to probe the potential of iron oxide formulations for MPI. ION-Micelles induced up to 200 times higher signal in MPS measurements than commercially available iron oxide formulations (Endorem, Resovist and Sinerem) and thus likely allow for significantly more sensitive MPI. In addition, the potential of the ION-Micelle platform for molecular MPI and MRI was showcased by MPS and MRI measurements of fibrin-binding peptide functionalized ION-Micelles (FibPep-ION-Micelles) bound to blood clots.

Conclusions

The presented data underlines the potential of the ION-Micelle nanoplatform for sensitive (molecular) MPI and warrants further investigation of the FibPep-ION-Micelle platform for in vivo, non-invasive imaging of fibrin in preclinical disease models of thrombus-related pathologies and atherosclerosis.     

Monopolar Spindle 1 (MPS1) Kinase Promotes Production of Closed MAD2 (C-MAD2) Conformer and Assembly of the Mitotic Checkpoint Complex

MPS1 kinase is an essential component of the spindle assembly checkpoint (SAC), but its functioning mechanisms are not fully understood. We have shown recently that direct interaction between BUBR1 and MAD2 is critical for assembly and function of the human mitotic checkpoint complex (MCC), the SAC effector. Here we report that inhibition of MPS1 kinase activity by reversine disrupts BUBR1-MAD2 as well as CDC20-MAD2 interactions, causing premature activation of the anaphase-promoting complex/cyclosome. The effect of MPS1 inhibition is likely due to reduction of closed MAD2 (C-MAD2), as expressing a MAD2 mutant (MAD2^L13A) that is locked in the C conformation rescued the checkpoint defects. In the presence of reversine, exogenous C-MAD2 does not localize to unattached kinetochores but is still incorporated into the MCC. Contrary to a previous report, we found that sustained MPS1 activity is required for maintaining both the MAD1·C-MAD2 complex and open MAD2 (O-MAD2) at unattached kinetochores to facilitate C-MAD2 production. Additionally, mitotic phosphorylation of BUBR1 is also affected by MPS1 inhibition but seems dispensable for MCC assembly. Our results support the notion that MPS1 kinase promotes C-MAD2 production and subsequent MCC assembly to activate the SAC.     

Incidence of the mucopolysaccharidoses in Northern Ireland

An epidemiological study of the mucopolysaccharidoses (MPS) in Northern Ireland using multiple ascertainment sources was carried out and the incidence rate for the period 1958–1985 was estimated. An incidence of approximately 1 in 76 000 live births was obtained for MPS 1H (Hurler phenotype); 1 in 280 000 for MPS 1 H/S (Hurler/Scheie phenotype); 1 in 140 000 live births (1 in 72 000 male live births) for MPS II (Hunter syndrome); 1 in 280 000 for MPS III (Sanfilippo syndrome) and 1 in 76 000 for MPS IV A (Morquio syndrome type A). No cases of MPS IS (Scheie phenotype), MPS IV B (Morquio syndrome type B) or MPS VI (Maroteaux–Lamy syndrome) were ascertained during the study period. Three cases of non-immune hydrops fetalis born to consanguineous parents were thought to be due to β-glucuronidase deficiency (MPS VII) on the basis of placental histology and enzyme studies on both parents but no living cases of MPS VII were ascertained. The overall incidence for all types of mucopolysaccharidosis was approximately 1 in 25 000 live births. A comparison is made with incidence estimates obtained from other published studies. Received: 25 May 1997 / Accepted: 22 August 1997     

Effect of Kupffer cell blockade at different periods following partial hepatectomy on regeneration of hepatocytes

In male Wistar rats, weighing 140-160 g, the block of the liver mononuclear phagocyte system (MPS) was carried out by means of "carbonyl iron" (type R-100F, particle size 1-1.5 micron). It was induced 2 hours before or 3 and 18 hours after partial hepatectomy. Iron injection previously or at the early prereplicative regeneration period led to a significant delay of the hepatocyte nucleus labeling and mitotic indices peaks against the background of an overall depression of hepatocyte proliferation. The MPS block during the intensive DNA synthesis by regenerating liver hepatocytes was less effective. The facts testify to the importance of Kupffer's cells in the regulation of the reparative liver regeneration.     

Comparative studies of mucopolysaccharides from marine animals. II. Illex illecebrosvs (Lesueur) and various crustaceans

Various mucopolysaccharides (MPS) were extracted from the tentacles of the squid, Illex illecebrosus (Leseuer) and the viscera of crustaceans comprising the blue crab, Callinectes sapidus Rathbun, the green crab, Carcinus maenas (Linné), the red crab, Geryon quinquedens Smith, the rock crab, Cancer irroratus Say, the lobster (body and head), Homarus americana Milne Edwards, and the shrimp (head), Pandalus borealis (Kröyer). The MPS were analyzed for uronic acid, hexosamine, N-sulfate, protein, neutral sugar, and anticoagulant activity. Chemical analysis of the two fractions extracted from the squid tentacles, suggests that fraction F1 is similar to chondroitin sulfate and F2 is heparin-like. In the crustaceans, the MPS extracted appear to resemble chondroitin sulfate and heparin. The blood anticoagulant activity of the MPS from the red crab was ≈66 IU/mg, whereas those obtained from the other species ranged from 7 to 30 IU/mg. Based on these data and the chemical analysis, it appears that the MPS from the red crab is heparin-like, while the MPS from the other species are more like chondroitin sulfate.     

Assessment of Dysmyelination with RAFFn MRI: Application to Murine MPS I

Type I mucopolysaccharidosis (MPS I) is an autosomal recessive lysosomal storage disorder with neurological features. Humans and laboratory animals with MPS I exhibit various white matter abnormalities involving the corpus callosum and other regions. In this study, we first validated a novel MRI technique, entitled Relaxation Along a Fictitious Field in the rotating frame of rank n (RAFFn), as a measure of myelination and dysmyelination in mice. We then examined differences between MPS I mice and heterozygotes using RAFF5 and histology. RAFF5 (i.e., RAFFn with n = 5) relaxation time constants were highly correlated with histological myelin density (R2 = 0.68, P<0.001), and RAFF5 clearly distinguished between the hypomyelinated and dysmyelinated shiverer mouse and the wild-type mouse. Bloch-McConnell theoretical analysis revealed slower exchange correlation times and smaller exchange-induced relaxation rate constants for RAFF4 and RAFF5 compared to RAFF1-3, T_1ρ, and T_2ρ. These data suggest that RAFF5 may assess methylene protons in myelin lipids and proteins, though other mechanisms (e.g. detection of myelin-bound water) may also explain the sensitivity of RAFF5 to myelin. In MPS I mice, mean RAFF5 relaxation time constants were significantly larger for the striatum (P = 0.004) and internal capsule (P = 0.039), and marginally larger for the fornix (P = 0.15). Histological assessment revealed no differences between MPS I mice and heterozygotes in myelin density or corpus callosum thickness. Taken together, these findings support subtle dysmyelination in the brains of mice with MPS I. Dysmyelination may result from myelin lipid abnormalities caused by the absence of α-L-iduronidase. Our findings may help to explain locomotor and cognitive deficits seen in mice with MPS I.