Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular charge of the macromolecule, horseradish peroxidase (HRPase, 40 000 mol. wt), was modified to yield highly anionic (PI less than 3.68) and cationic (PI = 9.5-10.5) derivatives. The effects upon the interactions between HRPase and arterial endothelium were then studied in vitro. The net rate of uptake of HRPase into endocytic vesicles and vacuoles of confluent endothelium was influenced by its molecular charge, there being less internalization of the anionic HRPase than of the native (pI = 7.9-8.2) and cationic derivatives. The molecular diameter was not significantly different between the cationic (Ae = 28.8 A), anionic (Ae = 31.2 A) and native (Ae = 29.6 A) HRPase. The rate of uptake of [U-14C]sucrose, a tracer of bulk fluid endocytosis, was unaffected by the presence of the differently charged HRPase, indicating that the volume of vesicles formed per cell per hour remained constant. The intracellular fate of HRPase of different charge was investigated biochemically and morphologically. The rate of loss of internalized HRPase activity in the endothelial cells approximated first-order kinetics. The rate of disappearance of intracellular HRPase activity was much greater for cationic (t1/2 = 8 h) and native (t1/2 = I 8 h) than for anionic HRPase (t1/2 = 80-100 h). By electron microscopy, all 3 forms of HRPase were restricted to intracellular membrane-bounded vesicles and vacuoles consistent with a vesicle-lysosomal pathway. Studies with purified lysosomal cathepsin D indicated that the differences in the intracellular half-lives of HRPase may be attributable in small part to decreased and increased rates of lysosomal proteolysis of anionic and cationic HRPase, respectively, in comparison with native HRPase. Pre-labelling of endothelial secondary lysosomes by inhibitors of phagosome-lysosome fusion (dextran sulphate, polyglutamate) lengthened the intracellular half-life of native HRPase, while introduction of cationic ferritin to cells pulsed with anionic HRPase greatly decreased its half-life. Thus an influence of molecular charge upon endosome-lysosome fusion cannot be excluded. The studies indicate that the net charge carried by exogenous HRPase influences both its internalization in endocytic vesicles and its subsequent intracellular fate, which in turn may be modified by the introduction of other differently charged macromolecules. These results are discussed in relation to macromolecular transport by vascular endothelium in vivo.
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PMID:Influence of molecular charge upon the endocytosis and intracellular fate of peroxidase activity in cultured arterial endothelium. 730 13

The abnormal shape and poor deformability of the sickled erythrocyte (RBC) have generally been held responsible for the microvascular occlusions of sickle cell disease. However, there is no correlation between the clinical severity of this disease and the presence of sickled RBC. In searching for additional factors that might contribute to the pathophysiology of sickle cell disease, we have investigated the possibility that sickle RBC might be less than normally repulsive of the vascular endothelium. After RBC suspensions are allowed to settle onto plates of cultured human endothelial cells, normal RBC are completely removed by as few as six washes. In contrast, sickle RBC remain adherent despite multiple washes. On subconfluent culture plates, normal RBC are distributed randomly, whereas sickle RBC cluster around endothelial cells. Sickle RBC adherence is not enhanced by deoxygenation but does increase with increasing RBC density. The enzymatic removal of membrane sialic acid greatly diminishes the adherence of sickle RBC to endothelial cells, suggesting that sialic acid participates in this abnormal cell-cell interaction. Although net negative charge appears normal, sickle RBC mainfest an abnormal clumping of negative surface charge as demonstrated by localization of cationized ferritin. These abnormalities are reproduced in normal RBC loaded with nonechinocytogenic amounts of calcium. We conclude that sickle RBC adhere to vascular endothelial cells in vitro, perhaps caused by a calcium-induced aberration of membrane topography. This adherence may be a pathogenetic factor in the microvascular occlusions characteristic of sickle cell disease.
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PMID:Abnormal adherence of sickle erythrocytes to cultured vascular endothelium: possible mechanism for microvascular occlusion in sickle cell disease. 735 Jan 95

The vesiculo-vacuolar organelle (VVO) is a recently described organelle found in the cytoplasm of endothelial cells that line tumor microvessels and normal venules. VVOs are grape-like clusters of interconnecting uncoated vesicles and vacuoles, bounded by trilaminar unit membranes, that span the entire thickness of vascular endothelium, thereby providing a potential trans-endothelial connection between the vascular lumen and the extravascular space. Macromolecular tracers preferentially cross hyperpermeable tumor microvessels through VVOs. The present investigation was undertaken to elucidate further the ultrastructure and function of VVOs in a murine ovarian carcinoma (MOT) and in normal venules. Morphometry revealed that VVOs were enormous cytoplasmic structures (median area, 0.12-0.14 microns2 in single electron micrographs). Moreover, the individual vesicles and vacuoles that comprised VVOs were on average substantially larger than capillary caveolae and followed a non-normal distribution that was skewed to the right. Specimen tilting provided conclusive evidence that individual VVO vesicles and vacuoles communicated with each other and with the endothelial cells' plasma membranes by stomata, some of which were closed by diaphragms composed of a single membrane. Studies with two tracers, ferritin (FE, diameter approximately 11 nm) and horseradish peroxidase (HRP, diameter approximately 5 nm), revealed that passage of macromolecules through VVOs was regulated at the level of stomatal diaphragms, thereby demonstrating a mechanism for controlling the passage of macromolecules across endothelial cells. Thus, compared with tumor microvessels, little circulating FE and HRP entered the VVOs of normal venular endothelium because stomata joining vesicles and vacuoles to each other and to the lumen and ablumen were closed. VVOs and their component vesicles/vacuoles were readily distinguished from endosomal organelles such as coated vesicles and multivesicular bodies, which also accumulated FE and HRP. Our findings indicate that VVOs provide a major pathway for the extravasation of circulating macromolecules across endothelia taller than capillary endothelium and suggest that upregulated VVO function accounts for the well-known hyperpermeability of tumor blood vessels.
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PMID:The vesiculo-vacuolar organelle (VVO): a distinct endothelial cell structure that provides a transcellular pathway for macromolecular extravasation. 855 58

In contrast to normal microvessels, those that supply tumors are strikingly hyperpermeable to circulating macromolecules such as plasma proteins. This leakiness is largely attributable to a tumor-secreted cytokine, vascular permeability factor (VPF). Tracer studies have shown that macromolecules cross tumor vascular endothelium by way of a recently described cytoplasmic organelle, the vesiculo-vacuolar organelle or VVO (VVOs are grapelike clusters of interconnected, uncoated vesicles and vacuoles). However, equivalent VVOs are also present in the cytoplasm of normal venules that do not leak substantial amounts of plasma protein. To explain these findings, we hypothesized that VPF increased the permeability of tumor blood vessels by increasing VVO function and that the VVOs of normal venules were relatively impermeable in the absence of VPF stimulation. To test this hypothesis, VPF was injected intradermally in normal animals after intravenous injection of a soluble macromolecular tracer, ferritin, whose extravasation could be followed by electron microscopy. VPF caused normal venules to leak ferritin, and, as predicted by our hypothesis, ferritin extravasated by way of VVOs, just as in hyperpermeable tumor microvessels. Ultrathin (14-nm) serial electron microscopic sections and computer-aided three-dimensional reconstructions better defined VVO structure. VVOs occupied 16-18% of endothelial cytoplasm in normal venules. Individual VVOs were clusters of numerous (median, 124) interconnected vesicles and vacuoles that formed complex pathways across venular endothelium with multiple openings to both luminal and abluminal surfaces. Like VPF, histamine and serotonin also stimulated ferritin extravasation across venules by way of VVOs. Together, these data establish VVOs as the major pathway by which soluble plasma proteins exit venules in response to several mediators that increase venular hyperpermeability. These same mediators also increased the extravasation of colloidal carbon, but this large particulate nonphysiological tracer exited venules primarily through endothelial gaps.
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PMID:Vesiculo-vacuolar organelles and the regulation of venule permeability to macromolecules by vascular permeability factor, histamine, and serotonin. 864 8

Increased concentration of serum alkaline phosphatase (ALP) is a common feature in rheumatoid arthritis (RA), although its origin remains unclear. The aim of this study is to analyze the origin and clinical significance of the elevated ALP value in RA. In 123 RA and 63 age- and sex-matched OA (osteoarthropathy) patients, concentrations of total ALP and its isozymes in serum and synovial fluid were studied. Serum CRP, Fe, ferritin, and Cu values were examined, respectively. The expression of ALP as protein was also investigated by using an enzymehistochemical and an immunohistochemical staining methods. Serum ALP values were elevated in 37.4% of RA (245.2 +/- 91.2 IU/L), and significantly higher than those of OA (192.3 +/- 45.2 IU/L: P < 0.01, RA v.s. OA). The serum CRP, and ferritin values each had a relation with the serum ALP activity. Fluid ALP concentration of RA was 110.3 +/- 40.1 IU/L, and that of OA, 83.6 +/- 15.0 IU/L (P < 0.05), respectively. In RA, a predominant isozyme was liver-type one both in the sera (91%) and the synovial fluid (59%). However, this result means that bone-type one was more abundant in the synovial fluids (41%) than those in the sera (9%). An enzymehistochemical and an immunohistochemical studies revealed that ALP was positive in a perivascular area, sublining cells, and a part of vascular endothelium in RA. In contrast, the synovial tissue from OA and a healthy patient exhibited only a weak staining. In RA, a positive correlation between the elevation of serum ALP and the disease activity was confirmed. Furthermore, we elucidated that ALP is produced in RA synovium.
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PMID:[Alkaline phosphatase (ALP) activity in rheumatoid arthritis (RA): its clinical significance and synthesis of ALP in RA synovium]. 978 85

Numerous pathologies may involve toxic side effects of free heme and heme-derived iron. Deficiency of the heme-catabolizing enzyme, heme oxygenase-1 (HO-1), in both a human patient and transgenic knockout mice leads to an abundance of circulating heme and damage to vascular endothelium. Although heme can be directly cytotoxic, the present investigations examine the possibility that hemoglobin-derived heme and iron might be indirectly toxic through the generation of oxidized forms of low-density lipoprotein (LDL). In support, hemoglobin in plasma, when oxidized to methemoglobin by oxidants such as leukocyte-derived reactive oxygen, causes oxidative modification of LDL. Heme, released from methemoglobin, catalyzes the oxidation of LDL, which in turn induces endothelial cytolysis primarily caused by lipid hydroperoxides. Exposure of endothelium to sublethal concentrations of this oxidized LDL leads to induction of both HO-1 and ferritin. Similar endothelial cytotoxicity was caused by LDL isolated from plasma of an HO-1-deficient child. Spectral analysis of the child's plasma revealed a substantial oxidation of plasma hemoglobin to methemoglobin. Iron accumulated in the HO-1-deficient child's LDL and several independent assays revealed oxidative modification of the LDL. We conclude that hemoglobin, when oxidized in plasma, can be indirectly cytotoxic through the generation of oxidized LDL by released heme and that, in response, the intracellular defense-HO-1 and ferritin-is induced. These results may be relevant to a variety of disorders-such as renal failure associated with intravascular hemolysis, hemorrhagic injury to the central nervous system, and, perhaps, atherogenesis-in which hemoglobin-derived heme may promote the formation of fatty acid hydroperoxides.
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PMID:Pro-oxidant and cytotoxic effects of circulating heme. 1213 Apr 98

Iron-derived reactive oxygen species (ROS) are implicated in the pathogenesis of numerous vascular disorders including atherosclerosis, microangiopathic haemolytic anaemia, vasculitis and reperfusion injury. One abundant source of redox-active iron is haem, which is inherently dangerous when released from intracellular haem proteins. The present review concerns the likely involvement of haem in vascular endothelial cell damage and the strategies used by endothelium to minimize such damage. Exposure of endothelial cells to haem greatly potentiates cell killing mediated by polymorphonuclear leukocytes and other sources of ROS. Free haem also promotes the conversion of low-density lipoprotein to cytotoxic oxidized products. If only because of its abundance, haemoglobin probably represents the most important potential source of haem within the vascular endothelium; free haemoglobin in plasma, when oxidized, can transfer haem to endothelium, thereby enhancing cellular susceptibility to oxidant-mediated injury. As a defence against such toxicity, upon exposure to free haem, endothelial cells up-regulate haem oxygenase-1 and ferritin. Haem oxygenase is a haem-degrading enzyme that opens the porphyrin ring, producing biliverdin, carbon monoxide and a most dangerous product-free redox-active iron. The latter can be controlled effectively by sequestration within ferritin, a multimeric protein with a very high capacity for storing iron. These homeostatic adjustments have been shown to be effective in the protection of endothelium against the damaging effects of exogenous haem and oxidants. The central importance of this protective system was highlighted recently by the discovery of a child diagnosed with haem oxygenase-1 deficiency, who exhibited extensive endothelial damage.
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PMID:Haem, haem oxygenase and ferritin in vascular endothelial cell injury. 1281 58

The adhesion of monocytes to vascular endothelium increases in the presence of high levels of low density lipoprotein (LDL). LDL changes oxidative status of endothelial cells leading to an increased expression of cell adhesion molecules. Acetylsalicylic acid (ASA) has been shown to exert antioxidant effects in high and very high concentrations. This study was designed to demonstrate the influence of acetylsalicylic acid and its major metabolite, salicylic acid (SA), on the adhesion of monocytes to LDL-stimulated endothelial cells. Monocyte adhesion to endothelial cells was concentration-dependently inhibited by both salicylates upon stimulation of endothelial cells with TNF-alpha, oxidized LDL (oxLDL), and native LDL (nLDL). The inhibitory effect of ASA was more potent than that of SA, whereas the cyclooxygenase inhibitor ibuprofen had no effect. F2-isoprostane release from LDL-stimulated endothelial cells was reduced by simultaneous incubation with ASA or SA, whereas ibuprofen had no effect. LDL-induced activation of the transcription factor NF-kappaB was inhibited by ASA, and ferritin protein was increased when endothelial cells were incubated with this drug. These results show that acetylsalicylic acid and-less potently-salicylic acid inhibit monocyte adhesion to LDL-stimulated endothelial cells by antioxidative effects. For ASA, the observed inhibition of monocyte adhesion was accomplished with concentrations that can be reached after single oral doses of 500 mg of ASA.
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PMID:Acetylsalicylic acid inhibits monocyte adhesion to endothelial cells by an antioxidative mechanism. 1508 62

Iron-derived reactive oxygen species are implicated in the pathogenesis of numerous vascular disorders including atherosclerosis, microangiopathic hemolytic anemia, vasculitis, and reperfusion injury. One abundant source of redox active iron is heme, which is inherently dangerous when released from intracellular heme proteins. The present review concerns the involvement of heme in vascular endothelial cell damage and the strategies used by endothelium to minimize such damage. Exposure of endothelium to heme greatly potentiates cell killing mediated by polymorphonuclear leukocytes and other sources of reactive oxygen. Free heme also promotes the conversion of low-density lipoprotein (LDL) into cytotoxic oxidized products. Only because of its abundance, hemoglobin probably represents the most important potential source of heme within the vascular endothelium; hemoglobin in plasma, when oxidized, transfers heme to endothelium and LDL, thereby enhancing cellular susceptibility to oxidant-mediated injury. As a defense against such toxicity, upon exposure to heme or hemoglobin, endothelial cells up-regulate heme oxygenase-1 and ferritin. Heme oxygenase-1 is a heme-degrading enzyme that opens the porphyrin ring, producing biliverdin, carbon monoxide, and the most dangerous product - free redox active iron. The latter can be effectively controlled by ferritin via sequestration and ferroxidase activity. Ferritin serves as a protective gene by virtue of antioxidant, antiapoptotic, and antiproliferative actions. These homeostatic adjustments have been shown effective in the protection of endothelium against the damaging effects of exogenous heme and oxidants. The central importance of this protective system was recently highlighted by a child diagnosed with heme oxygenase-1 deficiency, who exhibited extensive endothelial damage.
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PMID:Heme, heme oxygenase and ferritin in vascular endothelial cell injury. 1620 35

White matter lesions (WML) or leukoaraiosis is a major feature in cerebral imaging of older people, and their prevalence increases with age. The clinical effects of WML vary with the main impairment being detected in the cognitive functions, increased risk of severe depression and motor impairment. Although vascular comorbidities have been found to be the main changes in these brains, increased production of reactive oxygen species (ROS) could represent a risk factor for these lesions with elemental iron being a potential factor for ROS production. This study focuses on changes in iron, iron-regulating proteins and RNA expression of iron metabolism genes. Three groups of samples were used: WML, normal areas from lesional WM [NAWM (L)] as disease control and normal WM from control brains [NAWM(C)]. Ferric iron staining was undertaken using known Perl's reaction. Immunohistochemistry (IHC) of white matter for ceruloplasmin (Cp), haemochromatosis (HFE) and transferrin receptor (TfR) was done. Cellular localization of HFE and Cp was performed using dual-antibody IHC. Whole-genome RNA was extracted from WML, NAWM (L) and NAWM(C), and QPCR for HFE, TF, TfR, ceruloplasmin, ferritin and ferroportin was performed. Ferric iron staining shows increased diffuse iron staining among WML, followed by NAWM (L) and the least group being NAWM(C). IHC shows increased HFE and CP expression in lesional WM, while TfR shows no changes among the groups. HFE colocalized with vascular endothelium and microglia in WML and control samples, while Cp colocalized with microglia and some expression was shown by astrocytes. The mRNA expression using QPCR suggests a pattern that favours decreased intracellular iron influx, increased ferrous oxidation and increased iron export from the cells. Iron metabolism seems to be changed in brains with WML, increased elemental iron in these brains and in turn increased production of free oxidative radicals could represent a potentiating factor for the development of ageing WML.
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PMID:Brain iron dysregulation and the risk of ageing white matter lesions. 2197 76


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