Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to determine whether the phenomenon of sickle erythrocyte adherence to cultured vascular endothelium exists under conditions of blood flow, we exposed monolayers of bovine aortic endothelial cells to flowing sickle cell blood under controlled conditions in a specially designed flow chamber. Individual red cells were imaged by means of epifluorescent videomicroscopy, five percent of the total number of red cells in an aliquot of blood having been labelled by the passive uptake of sodium fluorescein isothiocyanate. At a shear rate of 270 sec-1 at the blood-monolayer interface, red cells from sickle cell blood frequently adhered to the monolayer for periods ranging from 100's of m sec to greater than 30 sec. With adhesion defined as the average number of adherent red cells during the sixth minute of blood flow (corrected upward to account for unlabelled erythrocytes), adhesion with sickle cell blood was of the order of 10(4) erythrocytes/cm2 ECM and exceeded (p less than 0.001) that for normal blood by a factor of 5.6. Further studies utilizing in situ displacement of blood with culture medium followed by brightfield microscopy indicate that the adherent cells were predominantly discocytes having single points of tethering to unknown sites on the monolayer. Adhesion of sickle cell erythrocytes to endothelium, therefore, is a very real phenomenon under physiologic conditions of blood flow; this phenomenon may contribute to the pathophysiology of vaso-occlusive events seen in sickle cell disease.
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PMID:Sickle erythrocytes adhere to endothelial cell monolayers (ECM's) exposed to flowing blood. 361 85

Vascular endothelial cells are critical participants in maintaining blood flow, with the ability to respond rapidly to injury. We have outlined above how the regulated secretion of a variety of hemostatic and inflammatory mediators contributes to these nearly instantaneous responses. The WPB are the most prominent of these regulated secretory granules, and there is growing evidence of additional granules that release their contents under a variety of conditions. The mechanisms responsible for the targeting of proteins to regulated secretory granules, and of exocytosis of these granules are being elucidated. EC appear to share some characteristics with other secretory cell types, but also are likely to have unique properties related to the storage and secretion of large multimeric proteins such as VWF and multimerin. Understanding these mechanisms may lead to new strategies for treating coronary artery disease, stroke, sickle cell disease, and hemophilia through drugs that modulate sorting and secretion, or by gene transfer approaches that introduce therapeutic molecules into the WPB for regulated release.
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PMID:Regulated secretion in endothelial cells: biology and clinical implications. 1181 99

SCD stems from amutation in the beta globin gene. Upon deoxygenation, hemoglobin polymerizes and triggers RBC remodeling. This phenomenon is central to SCD pathogenesis as individuals suffering from the disease are plagued by painful vaso-occlusive crises episodes. These episodes are the result of a combination of processes including inflammation, thrombosis, and blood cell adhesion to the vascular wall which leads to blockages within the vasculature termed vaso-occlusions. Vaso-occlusive episodes deprive tissues of oxygen and are a major contributor to SCD-related complications; unfortunately, the complex mechanisms that contribute to vaso-occlusions are not well understood. Vaso-occlusions can occur in post-capillary venules; hence, the microvasculature is a prime target for SCD therapies. Traditional in vitro systems poorly recapitulate architectural and dynamic flow properties of in vivo systems. However, microfluidic devices can capture features of the native vasculature such as cellular composition, flow, geometry, and ECM presentation. This review, although not comprehensive, highlights microfluidic approaches that aim to improve our current understanding of the pathophysiological mechanisms surrounding SCD. Microfluidic platforms can aid in identifying factors that may contribute to disease severity and can serve as suitable test beds for novel treatment strategies which may improve patient outcomes.
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PMID:Microfluidics for investigating vaso-occlusions in sickle cell disease. 2837 86

Stem cells use mode of cell division, symmetric (SCD) versus asymmetric (ACD), to balance expansion with self-renewal and the generation of daughter cells with different cell fates. Studies in model organisms have identified intrinsic mechanisms that govern this process, which involves partitioning molecular components between daughter cells, frequently through the regulation of the mitotic spindle. Research performed in vertebrate tissues is revealing both conservation of these intrinsic mechanisms and crucial roles for extrinsic cues in regulating the frequency of these divisions. Morphogens and positional cues, including planar cell polarity proteins and guidance molecules, regulate key signaling pathways required to organize cell/ECM contacts and spindle pole dynamics. Noncanonical WNT7A/VANGL2 signaling governs asymmetric cell division and the acquisition of cell fates through spindle pole orientation in satellite stem cells of regenerating muscle fibers. During cortical neurogenesis, the same pathway regulates glial cell fate determination by regulating spindle size, independent of its orientation. Sonic hedgehog (SHH) stimulates the symmetric expansion of cortical stem and cerebellar progenitor cells and contributes to cell fate acquisition in collaboration with Notch and Wnt signaling pathways. SLIT2 also contributes to stem cell homeostasis by restricting ACD frequency through the regulation of spindle orientation. The capacity to influence stem cells makes these secreted factors excellent targets for therapeutic strategies designed to enhance cell populations in degenerative disease or restrict cell proliferation in different types of cancers.
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PMID:Extracellular Regulation of the Mitotic Spindle and Fate Determinants Driving Asymmetric Cell Division. 2840 13

The fate of transplanted kidneys is substantially influenced by graft quality, with transplantation of kidneys from elderly and expanded criteria donors (ECDs) associated with higher occurrence of delayed graft function, rejection, and inferior long-term outcomes. However, little is known about early molecular fingerprints of these events in different donor categories. Borderline changes represent the most frequent histological finding early after kidney transplantation. Therefore, we examined outcomes and transcriptomic profiles of early-case biopsies diagnosed as borderline changes in different donor categories. In this single-center, retrospective, observational study, we compared midterm outcomes of kidney transplant recipients with early borderline changes as a first pathology between ECD (n = 109), standard criteria donor (SCDs, n = 109), and living donor (LD, n = 51) cohorts. Intragraft gene expression profiling by microarray was performed in part of these ECD, SCD, and LD cohorts. Although 5 year graft survival in patients with borderline changes in early-case biopsies was not influenced by donor category (log-rank P = 0.293), impaired kidney graft function (estimated glomerular filtration rate by Chronic Kidney Disease Epidemiology Collaboration equation) at M3, 1, 2, and 3 years was observed in the ECD cohort (P < 0.001). Graft biopsies from ECD donors had higher vascular intimal fibrosis and arteriolar hyalinosis compared to SCD and LD (P < 0.001), suggesting chronic vascular changes. Increased transcripts typical for ECD, as compared to both LD and SCD, showed enrichment of the inflammatory, defense, and wounding responses and the ECM-receptor interaction pathway. Additionally, increased transcripts in ECD vs. LD showed activation of complement and coagulation and cytokine-cytokine receptor pathways along with platelet activation and cell cycle regulation. Comparative gene expression overlaps of ECD, SCD, and LD using Venn diagrams found 64 up- and 16 down-regulated genes in ECD compared to both LD and SCD. Shared increased transcripts in ECD vs. both SCD and LD included thrombospondin-2 (THBS2), angiopoietin-like 4 (ANGPTL4), collagens (COL6A3, COL1A1), chemokine CCL13, and interleukin IL11, and most significantly, down-regulated transcripts included proline-rich 35 (PRR35) and fibroblast growth factor 9. Early borderline changes in ECD kidney transplantation are characterized by increased regulation of inflammation, extracellular matrix remodeling, and acute kidney injury transcripts in comparison with both LD and SCD grafts.
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PMID:Molecular Fingerprints of Borderline Changes in Kidney Allografts Are Influenced by Donor Category. 3226 65