Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A vast amount of circumstantial evidence implicates oxygen-derived free radicals, especially superoxide and hydroxyl radical (and to lesser extent, hydrogen peroxide), as mediators of inflammation and/or tissue destruction in inflammatory and arthritic disorders. The substrates for radical generation, namely properly stimulated phagocytic cells, transition metal catalysts, and (to a limited extent) ischemia, are all amply present, although there is no particular rheumatic disease in which a consistent abnormality of radical generation has been identified. These radical species can clearly degrade hyaluronic acid, modify collagen and perhaps proteoglycan structure and/or synthesis, alter and interact with immunoglobulins, activate enzymes and inactivate their inhibitors, and possibly participate in chemotaxis. In most situations, however, there is ample scavenging ability to detoxify these radicals before they hit their target, and many rheumatic disease drugs can decrease their production and/or effects. Despite the apparent sufficiency of natural scavengers and the lack of direct evidence that oxygen radicals are pathogenetically important, substantial pharmaceutical effort is still being made to develop free radical scavengers as therapeutic agents. Although individual free radicals die out quickly, rheumatologic interest in them has been sustained for nearly two decades.
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PMID:Oxygen radicals, inflammation, and arthritis: pathophysiological considerations and implications for treatment. 204 55

Nonthrombotic occlusion or stenosis of the mesenteric veins is a rare cause of intestinal ischemia that usually occurs in association with systemic vasculitis. The current report includes four male patients with segmental ischemic colitis caused by idiopathic myointimal hyperplasia in the small mesenteric veins and their intramural branches; neither vasculitis nor arterial involvement were present. Three of the four patients were less than or equal to 38 years of age; the fourth was 67. All four patients were previously healthy and had no history of drug use of any kind. Clinical findings included abdominal pain, diarrhea, bloody stools, and colonic strictures discovered by barium enema. The intima of the mesenteric and intestinal mural veins was focally thickened by a marked increase in cells and matrix between the endothelium and internal elastic lamina, whereas the vessel walls external to the thickened intima appeared normal. Histochemistry and immunoreactivity with antibodies to muscle-specific actins (HHF-35) disclosed that the intimal thickening was caused by proliferation of smooth muscle cells in a proteoglycan matrix. All patients recovered completely after segmental resection of the ischemic portion of the colon and had no recurrence of intestinal symptoms on follow-up of up to 7 years. These unusual venous lesions do not appear to have been previously described; their etiology and pathogenesis remain unknown.
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PMID:Idiopathic myointimal hyperplasia of mesenteric veins. 206 29

Fusion of the spine while restoring stability of the spinal segment, fails to preserve spinal mobility. Long term complications of accelerated degeneration in the neighboring segments have been reported. The present study explores the possibility of intervertebral disc autografting in a bipedal animal model by isolating a lumbar disc together with the adjacent end plates and repositioning it with minimal internal fixation. Fourteen Rhesus monkeys were sacrificed at 2, 4, 6, and 12 months after surgery and the grafted discs were examined radiologically, biochemically, pathologically, and biomechanically. Healing of the bony end plate was seen between 2 to 4 months postoperatively. There was early loss of disc height at 2 and 4 months but there was a suggestion of some reconstitution up to 12 months. There was minimal evidence of gross degeneration at all stages. Gradual loss of water content was found in the annulus and the nucleus. The nucleus pulposus seemed to be able to reaccumulate proteoglycan after an initial drop in the first 4 months. There was significant increase in hydroxyproline content in the annulus fibrosus and the nucleus pulposus. Biomechanically, the grafted disc showed hypermobility in the first 4 months but gradually became stabilized with time. Results from this study suggested that a fresh intervertebral disc autograft could survive a period of ischemia. Although the physiology of the disc was deranged, it was able to preserve a certain degree of segmental mobility without sacrificing stability. Further studies are required to validate these results and the field of disc allografting should be explored.
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PMID:Intervertebral disc autografting in a bipedal animal model. 913 72

Despite a relatively low incidence of serious side effects, fluoroquinolones and the fluoroquinolone pefloxacin have been reported to occasionally promote tendinopathy that might result in the complication of spontaneous rupture of tendons. In the present study, we investigated in rodents the intrinsic deleterious effect of pefloxacin (400 mg/kg of body weight) on Achilles tendon proteoglycans and collagen. Proteoglycan synthesis was determined by measurement of in vivo and ex vivo radiosulfate incorporation in mice. Collagen oxidative modifications were measured by carbonyl derivative detection by Western blotting. An experimental model of tendinous ischemia (2 h) and reperfusion (3 days) was achieved in rats. Biphasic changes in proteoglycan synthesis were observed after a single administration of pefloxacin, consisting of an early inhibition followed by a repair-like phase. The depletion phase was accompanied by a marked decrease in the endogenous serum sulfate level and a concomitant increase in the level of sulfate excretion in urine. Studies of ex vivo proteoglycan synthesis confirmed the in vivo results that were obtained. The decrease in proteoglycan anabolism seemed to be a direct effect of pefloxacin on tissue metabolism rather than a consequence of the low concentration of sulfate. Pefloxacin treatment for several days induced oxidative damage of type I collagen, with the alterations being identical to those observed in the experimental tendinous ischemia and reperfusion model. Oxidative damage was prevented by coadministration of N-acetylcysteine (150 mg/kg) to the mice. These results provide the first experimental evidence of a pefloxacin-induced oxidative stress in the Achilles tendon that altered proteoglycan anabolism and oxidized collagen.
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PMID:Pefloxacin-induced achilles tendon toxicity in rodents: biochemical changes in proteoglycan synthesis and oxidative damage to collagen. 1072 83

This study examines the alteration of oligodendrocyte progenitor cells which express membrane NG2 chondroitin sulfate proteoglycan after focal ischemia in the rat brain. Adult male Sprague-Dawley rats were subjected to 90 min occlusion of the middle cerebral artery, followed by reperfusion time of up to 2 weeks. The distribution and morphological changes in NG2-positive oligodendrocyte progenitor cells were immunohistochemically examined. Stellate-shaped NG2-positive cells with multiple branched processes were detected in both the gray and white matter of normal brain. After 2 weeks of reperfusion, NG2-positive cells in the area surrounding the infarction site (peri-infarct area) clearly showed enlarged cell bodies with hypertrophied processes. These stained strongly for NG2. Although the number of NG2-positive cells was increased significantly in the peri-infarct area, it decreased markedly in the infarct core compared to controls. Double immunostaining revealed that these NG2-positive cells were neither astrocytes nor microglia, but NG2-positive oligodendrocyte progenitor cells. These progenitor cells are known to differentiate into oligodendrocytes. As such, this upregulation of NG2 expression may be an adaptive mechanism attempting to remyelinate rat brain tissue after ischemic insult. Only further study will elucidate this hypothesis.
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PMID:Activation of NG2-positive oligodendrocyte progenitor cells during post-ischemic reperfusion in the rat brain. 1144 28

Midkine (MK) and pleiotrophin (PTN) are low molecular weight proteins with closely related structures. They are mainly composed of two domains held by disulfide bridges, and there are three antiparallel beta-sheets in each domain. MK and PTN promote the growth, survival, and migration of various cells, and play roles in neurogenesis and epithelial mesenchymal interactions during organogenesis. A chondroitin sulfate proteoglycan, protein-tyrosine phosphatase zeta (PTPzeta), is a receptor for MK and PTN. The downstream signaling system includes ERK and PI3 kinase. MK binds to the chondroitin sulfate portion of PTPzeta with high affinity. Among the various chondroitin sulfate structures, the E unit, which has 4,6-disulfated N-acetylgalactosamine, provides the strongest binding site. The expression of MK and PTN is increased in various human tumors, making them promising as tumor markers and as targets for tumor therapy. MK and PTN expression also increases upon ischemic injury. MK enhances the migration of inflammatory cells, and is involved in neointima formation and renal injury following ischemia. MK is also interesting from the viewpoints of the treatment of neurodegenerative diseases, increasing the efficiency of in vitro development, and the prevention of HIV infection.
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PMID:Midkine and pleiotrophin: two related proteins involved in development, survival, inflammation and tumorigenesis. 1220 4

Alterations in the composition of the glycocalyx of venular endothelium in postcapillary venules (rat mesentery) were explored in models of inflammation and ischemia-reperfusion injury. Lectins were covalently linked to fluorescently labeled microspheres (0.1-microm diameter) or directly labeled with FITC. Adhesion of lectins specific for glucose and galactose residues of glycosaminoglycans (GAGs) and other components of the endothelial glycocalyx decreased dramatically after superfusion of the mesentery with the chemoattractant N-formylmethionyl-leucyl-phenylalanine and during reperfusion after 60-min ischemia. These reductions were significantly attenuated by superfusion with pertussis toxin (PTX), suggesting that shedding of glycocalyx was mediated by G proteins. Adhesion of microspheres linked with antibody for syndecan-1, a major proteoglycan to which GAGs are bound, revealed increased labeling as GAGs were lost and permitted greater numbers of spheres to adhere to the protein core, which was not shed. Induction of ischemia by occluding proximal microvessels for 60 min resulted in a 40% increase in galactosaminoglycans and a 15% increase in glucosaminoglycans on the endothelium, which was not inhibited by PTX. Reperfusion of vessels led to a rapid loss of GAGs that was inhibited by pretreatment with PTX, with 40% of galactosaminoglycans and 25% of glucosaminoglycans accumulated being removed by G protein-mediated shedding and the remainder freely convected away by fluid shear. We conclude that the composition of the glycocalyx results from a balance of the rate of biosynthesis of GAGs by the endothelial cell and their shedding, which may be mediated by intracellular and/or membrane-bound proteases or lyases released or activated by G protein signaling.
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PMID:Inflammation- and ischemia-induced shedding of venular glycocalyx. 1470 29

The upregulation of extracellular matrix components, especially chondroitin sulfate proteoglycans, after brain injury and stroke is known to accompany the glial reaction, forming repellent scars that hinder axonal growth and the reorganization of the injured neuronal networks. The extracellular matrix associated with perineuronal nets (PNs) in the primarily injured and remote regions has not yet been systematically analyzed. We use the model of permanent middle cerebral artery occlusion (MCAO) to investigate the acute and long-lasting consequences of ischemia for PNs, related to the damage of neurons and reactions of glial cells, in spontaneously hypertensive rats. Extracellular matrix components associated with PNs around cortical interneurons and neurons in thalamic nuclei were characterized 1, 7, 14, and 35 days after MCAO, using Wisteria floribunda agglutinin (WFA) staining and immunocytochemistry. The degradation of PNs in the infarct core was initiated by loss of WFA-binding matrix components, indicating the cleavage of glycosaminoglycan chains of chondroitin sulfate proteoglycans. Immunostaining showed the subsequent removal of proteoglycan core proteins within the extending microglia/macrophage invasion zone lasting for 2 weeks after MCAO. In the cortical periinfarct region, delineated by an astrocytic scar against the infarct core, the number of WFA-stained and proteoglycan core protein-immunoreactive PNs was permanently reduced. In the homolateral ventroposterior thalamus, the delayed decrease in perineuronal matrix was related to the distribution pattern of activated microglia and massive neuronal degeneration. It can be concluded from these results that complementary to the known upregulation of matrix components in the glial scar, deficits in the expression of the neuron-associated extracellular matrix develop in the periinfarct and remote regions. These deficits may contribute to the long-lasting functional impairments after stroke.
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PMID:Decomposition and long-lasting downregulation of extracellular matrix in perineuronal nets induced by focal cerebral ischemia in rats. 1580 66

Oligodendrocyte (OL) progenitor cells are particularly susceptible to perinatal hypoxia/ischemia (H-I) resulting in decreased myelination and attenuated development of white matter fiber tracts. Brevican is an aggregating chondroitin sulfate proteoglycan (CSPG) secreted by OLs and their progenitors prior to and during active developmental myelination whereas neuron-glia antigen 2 (NG2) is a transmembrane CSPG produced by early OL progenitors. Although both proteoglycans are associated with maturation of OLs, it is not known if they are altered by H-I brain injury in the neonate. We have therefore examined the time course of changes in brevican and NG2 abundance and proteolysis in the neonatal rat hippocampus after H-I. In a standard H-I model of unilateral carotid artery ligation and exposure to hypoxia, a cavitary infarct involving the ipsilateral parietal and temporal regions of cerebral cortex, hippocampus, and striatum of most rat pups was clearly evident 4 days after H-I. The abundance of total extractable brevican was markedly reduced in the ipsilateral hippocampus at 1 and 14 days after H-I (relative to the contralateral side). At these times, the total G1 proteolytic fragment of brevican was lower in the ipsilateral hippocampus and the level of a protease-generated brevican fragment was significantly diminished in the OL-rich hippocampal fimbria. Hippocampal NG2 levels were also lower at 1 and 4 days after H-I, but were not different from the contralateral side at 14 days. Since brevican, brevican G1 fragment, and NG2 loss occur around the time of progressive cell death and the appearance of the infarct, it may be that H-I rapidly induces a cellular response that actively depletes these proteoglycans from the hippocampal matrix. While the mechanism of this loss is unclear, it would appear to be an early event in the process that could be involved in apoptotic cell death and/or tissue injury.
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PMID:The effect of hypoxic-ischemic brain injury in perinatal rats on the abundance and proteolysis of brevican and NG2. 1581 74

Apart from tumor-driven neovascularization, a less-appreciated consequence of neurofibromatosis type 1 (NF1) is the hyperproliferation of vascular mural cells (pericytes). This study aims at establishing a role for pericytes in NF1, and determining whether interference with the function of a key pericyte component (NG2 proteoglycan) inhibits NF1 tumor neovascularization. Neovascularization in NF1 was studied in Nf+/+(control), Nf1+/-, and Nf1-/-embryos at E-10, ischemia-induced retinal angiogenesis model in 24 eyes of Nf1+/-, Nf1+/+mice, and in malignant peripheral nerve sheath tumors (MPNSTs) derived from NF1 patients (ST88-14, NMS-2PC) orthotopically grown in nude mice (Crl: nu/nu). The anti-angiogenic effect of intracorneal polymer pellets containing anti-NG2 neutralizing antibody was quantified in the nude-mouse corneal angiogenesis model in which angiogenesis was induced by xenografting NMS-2PC tumor into the corneal stroma of 22 eyes. By using confocal microscopy, immunohistochemistry, and BrdU proliferation assay, the pericyte/endothelium ratios and proliferation rates were measured. Activated pericytes were present at the leading tip of the angiogenic sprouts. Pericytes showed continuous investment of endothelium in both NMS-2PC and ST88-14 MPNST tumor xenografts. Mean corneal angiogenesis induced by NMS-2PC tumor grafts in NG2-antibody treated eyes was 1.491 and 3.186 mm2 in isotype-matched non-immunoglobulin treated eyes (control) (P=0.0002). A total of 193.8 vascular nuclei (a measure of ischemia-induced retinal angiogenesis) was present in angiogenic retinal tufts in Nf1+/- mice compared to 89.23 in Nf1+/+ mice (control) (P<0.0001). Mean pericyte/endothelium investment ratios were 1.015, 1.380, and 2.084 in control, Nf1+/-, and Nf1-/-embryos, respectively. Pericytes were 23% (control), 49% (Nf1+/-), and 69% (Nf1-/-) BrdU-positive. Endothelial cells from the same embryos were 29% (control), 47% (Nf1+/-), and 62% (Nf1-/-) BrdU-positive. Angiogenesis is accelerated in NF1 due to hyperproliferation of pericytes and endothelial cells. Mitotically activated NG2-positive pericytes, and endothelial cells may serve as potential therapeutic targets in NF1.
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PMID:Targeting neovascular pericytes in neurofibromatosis type 1. 1588 74


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