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1.
Aisen P Enns C Wessling-Resnick M 《The international journal of biochemistry & cell biology》2001,33(10):940-959
With rare exceptions, virtually all studied organisms from Archaea to man are dependent on iron for survival. Despite the ubiquitous distribution and abundance of iron in the biosphere, iron-dependent life must contend with the paradoxical hazards of iron deficiency and iron overload, each with its serious or fatal consequences. Homeostatic mechanisms regulating the absorption, transport, storage and mobilization of cellular iron are therefore of critical importance in iron metabolism, and a rich biology and chemistry underlie all of these mechanisms. A coherent understanding of that biology and chemistry is now rapidly emerging. In this review we will emphasize discoveries of the past decade, which have brought a revolution to the understanding of the molecular events in iron metabolism. Of central importance has been the discovery of new proteins carrying out functions previously suspected but not understood or, more interestingly, unsuspected and surprising. Parallel discoveries have delineated regulatory mechanisms controlling the expression of proteins long known--the transferrin receptor and ferritin--as well as proteins new to the scene of iron metabolism and its homeostatic control. These proteins include the iron regulatory proteins (IRPs 1 and 2), a variety of ferrireductases in yeast an mammalian cells, membrane transporters (DMT1 and ferroportin 1), a multicopper ferroxidase involved in iron export from cells (hephaestin), and regulators of mitochondrial iron balance (frataxin and MFT). Experimental models, making use of organisms from yeast through the zebrafish to rodents have asserted their power in elucidating normal iron metabolism, as well as its genetic disorders and their underlying molecular defects. Iron absorption, previously poorly understood, is now a fruitful subject for research and well on its way to detailed elucidation. The long-sought hemochromatosis gene has been found, and active research is underway to determine how its aberrant functioning results in disease that is easily controlled but lethal when untreated. A surprising connection between iron metabolism and Friedreich's ataxia has been uncovered. It is no exaggeration to say that the new understanding of iron metabolism in health and disease has been explosive, and that what is past is likely to be prologue to what is ahead. 相似文献
2.
3.
Murray G Michalak EE Levitt AJ Levitan RD Enns MW Morehouse R Lam RW 《Chronobiology international》2005,22(5):937-943
In the context of Lewy's phase delay hypothesis, the present study tested whether effective treatment of winter Seasonal Affective Disorder (SAD) is mediated by advancing of circadian phase. Following a baseline week, 78 outpatients with SAD were randomized into 8 weeks of treatment with either fluoxetine and placebo light treatment or light treatment and placebo pill. Depression levels were measured on the Ham17+7 and the BDI-II, and circadian phase was estimated on the basis of daily sleep logs and self-reported morningness-eveningness. Among the 61 outpatients with complete data, both treatments were associated with significant antidepressant effect and phase advance. However, pre- and post-treatment comparisons found that the degree of symptom change did not correlate with the degree of phase change associated with treatment. The study therefore provides no evidence that circadian phase advance mediates the therapeutic mechanism in patients with SAD. Findings are discussed in terms of the limitations of the circadian measures employed. 相似文献
4.
Pieter Stolk Harald E Heemstra Hubert GM Leufkens Brigitte Bloechl-Daum Eibert R Heerdink 《Orphanet journal of rare diseases》2009,4(1):1-7
Background
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, which rapidly leads to chronic respiratory failure requiring mechanical ventilation. Currently, forced vital capacity (FVC) < 50% is considered as physiologic marker for admitting patients to Noninvasive Positive Pressure Ventilation (NPPV) intervention, although it has been recently shown the median survival of patients with baseline FVC < 75% much shorter than median survival of patients with baseline FVC > 75%, independently by any treatment.Aim
To assess the role of NPPV in improving outcome of ALS, a retrospective analysis was performed to investigate 1 year survival of ALS patients with FVC < 75% and nocturnal respiratory insufficiency, treated with NPPV, compared to a well-matched population of ALS patients, who refused or was intolerant to NPPV.Methods
We investigated seventy-two consecutive ALS patients who underwent pulmonary function test. Forty-four presented a FVC > 75% and served as control group. Twenty-eight patients presented a FVC < 75% and showed, at polysomnography analysis, nocturnal respiratory insufficiency, requiring NPPV; sixteen were treated with NPPV, while twelve refused or were intolerant.Results
Increased survival rate at 1 year in patients with FVC < 75% treated with NPPV, as compared to those who refused or could not tolerate NPPV (p = 0.02), was observed. The median rate of decline in FVC% was slower in NPPV patients than in patients who did not use NPPV (95% CI: 0.72 to 1.85; p < 0.0001).Conclusion
This report demonstrates that early treatment with NPPV prolongs survival and reduces decline of FVC% in ALS. 相似文献5.
Cindy N Roy Kenneth P Blemings Kathryn M Deck Paige S Davies Emily L Anderson Richard S Eisenstein Caroline A Enns 《Journal of cellular physiology》2002,190(2):218-226
Iron regulatory proteins (IRPs), the cytosolic proteins involved in the maintenance of cellular iron homeostasis, bind to stem loop structures found in the mRNA of key proteins involved iron uptake, storage, and metabolism and regulate the expression of these proteins in response to changes in cellular iron needs. We have shown previously that HFE-expressing fWTHFE/tTA HeLa cells have slightly increased transferrin receptor levels and dramatically reduced ferritin levels when compared to the same clonal cell line without HFE (Gross et al., 1998, J Biol Chem 273:22068-22074). While HFE does not alter transferrin receptor trafficking or non-transferrin mediated iron uptake, it does specifically reduce (55)Fe uptake from transferrin (Roy et al., 1999, J Biol Chem 274:9022-9028). In this report, we show that IRP RNA binding activity is increased by up to 5-fold in HFE-expressing cells through the activation of both IRP isoforms. Calcein measurements show a 45% decrease in the intracellular labile iron pool in HFE-expressing cells, which is in keeping with the IRP activation. These results all point to the direct effect of the interaction of HFE with transferrin receptor in lowering the intracellular labile iron pool and establishing a new set point for iron regulation within the cell. 相似文献
6.
Aspartate transcarbamoylase from Escherichia coli is composed of six catalytic (c) and six regulatory (r) polypeptides. We have studied the structure and function of this enzyme using chymotrypsin as a probe. The protease inactivates the isolated catalytic subunit (c3) but has not effects on the native enzyme (c6r6). Under identical conditions, the c3r6 complex is inactivated at a much slower rate than c3. The presence of the substrate analogue succinate together with carbamoyl phosphate reduces substantially the rate of inactivation. Extended exposure to chymotrypsin converts the catalytic subunit into a partially active derivative with a fourfold higher Michaelis constant. This derivative is indistinguishable from the unmodified catalytic subnit in gell electrophoresis under nondenaturing conditions. However, in the presence of sodium dodecyl sulfate, the major fragment in the electropherogram is smaller than that of the intact catalytic polypeptide. The results could be explained by postulating the presence of a chymotrypsin-sensitive peptide bond at or near the active site. Since X-ray crystallographic studies have indicated that the active sites are located in a central cavity, the resistance of the native enzyme towards inactivation may be due to the inability of chymotrypsin to enter this cavity. 相似文献
7.
Potassium uptake was studied in Down's syndrome (D.S.) platelets to determine if the Na+/K+ ATPase mediated movement of this ion was decreased compared to normal platelets. Total uptake of 42K was 1.58±0.16 μmoles/hr/109 normal platelets but was decreased to 1.06±0.06 μmoles/hr/109 D.S. platelets (p<.001). Na+/K+ ATPase mediated (ouabain sensitive) K+ uptake was 0.87±0.05 μmoles/hr/109 normal platelets but only 0.54±0.04 μmoles/hr/109 in D.S. platelets (p<.001). As the Na+/K+ ATPase mediated outward movement of Na+ is decreased in D.S. platelets, the present work demonstrates that bidirectional functional imparrment of the Na+/K+ ATPase pump is present in D.S. platelets. 相似文献
8.
An investigation of the role of solutes in the xylem sap and in the xylem parenchyma as the source of root pressure 总被引:7,自引:0,他引:7
Summary Solute osmotic potentials (x) in the vessels of hydroponically grown maize roots were measured to assess the osmotic-xylem-sap mechanism for generating root pressure (indicated by guttation). Solutes in vessels were measured in situ by X-ray microanalysis of plants frozen intact while guttating. Osmotic potentials outside the roots (o) were changed by adding polyethylene glycol to the nutrient solution. Guttation rate fell when o was decreased, but recovered towards the control value during 3–5 days when o was greater than or equal to –0.3 MPa, but not when o was equal to –0.4 MPa. In roots stressed to o = –0.3 MPa, x, was always more positive than o, and x changed only slightly (ca. 0.05 MPa). Thus the adjustment in the roots which increased root pressure cannot be ascribed to x, contradicting the osmotic-xylem-sap mechanism. An alternative driving force was sought in the osmotic potentials of the vacuoles of the living cells (v), which were analysed by microanalysis and estimated by plasmolysis. v showed larger responses to osmotic stress (0.1 MPa). Some plants were pretreated with abundant KNO3 in the nutrient solution. These plants showed very large adjustments in v (0.4 MPa) but little change in x (0.08 MPa). They guttated by 4 h after o was lowered to –0.4 MPa. It is argued that turgor pressure of the living cells is a likely alternative source of root pressure. Published evidence for high solute concentrations in the xylem sap is critically assessed.Abbreviations o
external water potential
- x
osmotic potential of xylem sap
- v
osmotic potential of vacuolar sap
- EDX
energy dispersive X-ray microanalysis
- CSEM
cryo-scanning electron microscope
- LN2
liquid nitrogen
- PEG
polyethylene glycol 相似文献
9.
Characterization of proteins that associate with an unglycosylated form of the transferrin receptor in A431 cells 总被引:1,自引:0,他引:1
B J Root C L Reckhow E M Clinton C A Enns 《The Journal of biological chemistry》1988,263(35):19071-19076
A protein doublet (Mr = 135,000/130,000) was found to coprecipitate with an unglycosylated form of the transferrin receptor in tunicamycin-treated A431 cells. This doublet is not detected with either a monoclonal or polyclonal antibody to the transferrin receptor on Western blots indicating that these proteins do not interact directly with transferrin receptor antibody. Proteolytic digestion patterns of the individual proteins of the Mr = 135,000/130,000 doublet suggest that they are related to one another and are distinct from the transferrin receptor. Further characterization of these proteins indicates that they form a high molecular weight complex with the unglycosylated but not the glycosylated form of the transferrin receptor. Pulse-chase experiments demonstrate that the proteins post-translationally associate with the receptor. 相似文献
10.
Juxing Chen Jinzhi Wang Kathrin R. Meyers Caroline A. Enns 《Traffic (Copenhagen, Denmark)》2009,10(10):1488-1501
Transferrin receptor 2 (TfR2) is a homologue of transferrin receptor 1 (TfR1) but has distinct functions from TfR1 in iron homeostasis. In keeping with its proposed role in iron sensing, previous studies showed that TfR2 has a short half-life and that holo-Tf stabilizes TfR2 by redirecting it from a degradative pathway to a recycling pathway. In this study, we characterized how the endocytosis, recycling and degradation of TfR2 relates to its function and differs from TfR1. TfR2 endocytosis was adaptor protein-2 (AP-2) dependent. Flow cytometry analysis showed that TfR1 and TfR2 utilized the same endocytic pathway only in the presence of holo-Tf, indicating that holo-Tf alters the interaction of TfR2 with the endocytic machinery. Unlike TfR1, phosphofurin acidic cluster sorting protein 1 (PACS-1) binds to the cytoplasmic domain of TfR2 and data suggest that PACS-1 is involved in the TfR2 recycling. Depletion of TSG101 by siRNA or expression of a dominant negative Vps4 inhibited TfR2 degradation, indicating that TfR2 degradation occurs through a multivesicular body (MVB) pathway. TfR2 degradation is not mediated through ubiquitination on the single lysine (K31) in the cytoplasmic domain or on the amino terminal residue. No ubiquitination of TfR2 by HA-ubiquitin was detected, indicating a lack of direct TfR2 ubiquitination involvement in its degradation. 相似文献