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)

The influence of the very limited potential for an increase of blood supply to the inner eye on the growth of intraocular retinoblastoma are listed, demonstrated, and discussed. It is typical for the most malignant retinoblastomas to present with the most massive ischemia and necrosis. The limited possibilities for vascular enlargement and neovascularization lead to cuff-like perivascular survival of neoplastic cells with necrosis in the interspaces. Indirect supply from retinal and ciliary sources explain layer-like neoplastic growth on surface and base of tumors as well as separation of living neoplastic cells, attraction towards exit areas, cyst formation, and seeding. These processes may contribute to extraocular extension. Recognition of the limits of intraocular nutrition also is important for prognosis and therapy in cases of retinoblastoma.
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PMID:The nutritional sources and limits of intraocular retinoblastoma growth. 358 89

A total of 85 eyes (75 patients) with pseudogliomas (i.e., certain conditions which simulate retinoblastoma, were examined histopathologically to determine the incidence of rubeosis iridis. Neovascularization of the anterior surface of the iris was found in 70 eyes (82%). The principal associated changes in these eyes were moderate to severe inflammation of the uveal tract and retinal detachment. These findings are interpreted as indicating that inflammation, retinal detachment, and/or ischemia are effective stimulants in producing iris neovascularization, and rubeosis is not a significant factor in differentiating eyes with retinoblastoma from those eyes with pseudogliomas.
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PMID:Rubeosis iridis in "pseudogliomas". 616 Jun 30

Apoptosis is a form of genetically programmed cell death that can be induced by a variety of different stimuli. It is often referred to as a form of cellular suicide. Typically, apoptosis is characterized by the condensation and shrinkage of the cellular nucleus and cytoplasm, followed by the complete fragmentation of the cell and subsequent phagocytosis of the debris by surrounding cells. Although important during development, and also for maintaining homeostasis in some adult tissues, apoptosis can also be associated with disease processes. Recent laboratory studies indicate that apoptosis is a mechanism of cell death in several important ocular diseases including glaucoma, retinitis pigmentosa, cataract formation, retinoblastoma, retinal ischemia, and diabetic retinopathy. This review summarizes the results of these studies and provides a brief description of some of the key molecules that are involved in the genetic regulation of apoptosis. It is possible that a complete understanding of how these molecules function may someday lead to new treatment options aimed at blocking the death of cells in a variety of ocular diseases.
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PMID:Apoptosis in ocular disease: a molecular overview. 901 Aug 66

Vascular endothelial growth factor (VEGF) is induced by hypoxia and it has been implicated in the development of iris and retinal neovascularization (NV) in ischemic retinopathies in which it has been suggested that Muller cells are responsible for increased VEGF production. VEGF, however, is also known to be a potent mediator of vascular permeability in other tissues and may perform this function in retina. Immunohistochemical staining for VEGF was performed on a variety of human and experimental ischemic and non-ischemic ocular disorders in which blood retinal barrier (BRB) breakdown is known to occur to determine if there is an upregulation of VEGF in these conditions. We found increased VEGF immunoreactivity in ganglion cells of rats with oxygen-induced ischemic retinopathy and in ganglion cells, the inner plexiform layer, and some cells in the inner nuclear layer of rats with experimental autoimmune uveoretinitis (EAU), in which there was no identifiable ischemia or NV. In rats with EAU, VEGF staining intensity increased from 8 to 11 days after immunization, coincident with BRB failure. These results were confirmed using two distinct anti-VEGF antibodies and by immunoblot and the immunohistochemical staining was eliminated by pre-incubating the antibodies with VEGF peptide. VEGF staining was also increased in the retina and iris of patients with ischemic retinopathies, such as diabetic retinopathy and retinal vascular occlusive disease, and in patients with disorders in which retinal ischemia does not play a major role, such as aphakic/ pseudophakic cystoid macular edema, retinoblastoma, ocular inflammatory disease or infection, and choroidal melanoma. VEGF was primarily localized within retinal neurons and retinal pigmented epithelial cells in these cases. In addition or in association with its role of inducing NV, VEGF may contribute to BRB breakdown in a variety of ocular disorders and blockage of VEGF signaling may help to reduce some types of macular edema.
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PMID:Upregulation of vascular endothelial growth factor in ischemic and non-ischemic human and experimental retinal disease. 904 48

Gene transfer and antisense therapy offer novel approaches to the study and treatment of vascular diseases. The localized nature of vascular diseases like restenosis has made the application of genetic material an attractive therapeutic option. Viral and nonviral vectors have been developed to facilitate the entry of foreign DNA or RNA into cells. Vector improvement and production, demonstration of vector safety and demonstration of therapeutic efficacy are among the main present challenges. Various strategies have already been shown to be successful in preventing restenosis in animal models and include: the transfer of the herpes simplex virus thymidine kinase associated with ganciclovir: transfection of the cell cycle regulatory genes encoding for the active form of retinoblastoma gene product (Rb) or the cyclin-dependent kinase inhibitor p21, and antisense therapy. Therapeutic angiogenesis using gene transfer is a new strategy for the treatment of severe limb ischemia. Transfection of DNA encoding for the vascular endothelial growth factor has resulted in increasing collateral flow in animal models of peripheral ischemia. This approach is currently being investigated in a clinical trial in patients with distal ischemia. Other potential targets for genetic treatment in cardiovascular diseases include thrombosis, extracellular matrix synthesis and lipid metabolism.
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PMID:Gene and other biological therapies for vascular diseases. 910 54

Cyclin-dependent kinases (CDKs) are commonly known to regulate cell proliferation. However, previous reports suggest that in cultured postmitotic neurons, activation of CDKs is a signal for death rather than cell division. We determined whether CDK activation occurs in mature adult neurons during focal stroke in vivo and whether this signal was required for neuronal death after reperfusion injury. Cdk4/cyclin D1 levels and phosphorylation of its substrate retinoblastoma protein (pRb) increase after stroke. Deregulated levels of E2F1, a transcription factor regulated by pRb, are also observed. Administration of a CDK inhibitor blocks pRb phosphorylation and the increase in E2F1 levels and dramatically reduces neuronal death by 80%. These results indicate that CDKs are an important therapeutic target for the treatment of reperfusion injury after ischemia.
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PMID:Cyclin-dependent kinases as a therapeutic target for stroke. 1094 92

Cellular redox state has been increasingly recognized as a critical component of stress-induced cellular responses and disease. Inherent in these responses are reactive oxygen species (ROS), which inflict direct cellular damage in addition to acting as intracellular second messengers modulating signal transduction pathways. These intracellular highways of communication are critical in determining cell fates and whole-organ responses following environmental injury. Although gene therapy for inherited and acquired disorders has exploded in the last decade, the application of gene therapeutic approaches for transient pathologic conditions resulting from environmental stress is just beginning to be recognized. This review will summarize the theoretical and practical applications of gene therapy for the treatment of environmental injury by modulating redox-activated cellular responses. Several approaches can be utilized to achieve this goal. These include the application of gene targeting to modulate the cellular redox state directly by expressing recombinant genes capable of degrading ROS at pathophysiologic important subcellular sites. The use of mitochondrial superoxide dismutase (MnSOD), which degrades superoxides arising from ischemia/reperfusion injury, is one example of this approach. MnSOD serves as a "garbage disposal" for potentially toxic ROS prior to cellular injury and the activation of signal transduction cascades important in whole-organ pathology and inflammation. In contrast, some ROS have been suggested to have beneficial effects on cellular responses following environmental injury. Hence, expressing the nitrogen oxygen synthetase gene (NOS) to enhance the levels of nitric oxide (NO.) and augment the beneficial effects of this compound has also been suggested as a useful redox-modulating gene therapy approach. Lastly, indirect intervention in signal transduction pathways following environmental stress by expressing dominant inhibitory proteins of redox-activated signal transduction cascades has also been useful in modulating cellular responses to redox stress. Two such examples have utilized dominant inhibitory forms of the retinoblastoma gene product (Rb) and IkappaBalpha which prevent activation of cyclin-dependent protein kinases and NF-kappaB, respectively. Ultimately, the most efficacious therapeutic approach or combination of approaches that alter the redox responsiveness of cells and organs to environmental injury will be determined through a comprehensive understanding of the relevant pathophysiologic processes.
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PMID:Redox-mediated gene therapies for environmental injury: approaches and concepts. 1122 32

Retinal neovascularization is a major cause of blindness and requires the activities of several signaling pathways and multiple cytokines. Activation of protein kinase C (PKC) enhances the angiogenic process and is involved in the signaling of vascular endothelial growth factor (VEGF). We have demonstrated a dramatic increase in the angiogenic response to oxygen-induced retinal ischemia in transgenic mice overexpressing PKC beta 2 isoform and a significant decrease in retinal neovascularization in PKC beta isoform null mice. The mitogenic action of VEGF, a potent hypoxia-induced angiogenic factor, was increased by 2-fold in retinal endothelial cells by the overexpression of PKC beta 1 or beta 2 isoforms and inhibited significantly by the overexpression of a dominant-negative PKC beta 2 isoform but not by the expression of PKC alpha, delta, and zeta isoforms. Association of PKC beta 2 isoform with retinoblastoma protein was discovered in retinal endothelial cells, and PKC beta 2 isoform increased retinoblastoma phosphorylation under basal and VEGF-stimulated conditions. The potential functional consequences of PKC beta-induced retinoblastoma phosphorylation could include enhanced E2 promoter binding factor transcriptional activity and increased VEGF-induced endothelial cell proliferation.
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PMID:Characterization of protein kinase C beta isoform's action on retinoblastoma protein phosphorylation, vascular endothelial growth factor-induced endothelial cell proliferation, and retinal neovascularization. 1180 27

Increasing evidence suggests that cyclin-dependent kinases participate in neuronal death induced by multiple stresses in vitro. However, their role in cell death paradigms in vivo is not well characterized. Accordingly, the authors examined whether cyclin-dependent kinase inhibition resulted in functionally relevant and sustained neuroprotection in a model of global ischemia. Intracerebroventricular administration of the cyclin-dependent kinase inhibitor flavopiridol, immediately or at 4 hours postreperfusion after a global insult, reduced injury in the CA1 of the hippocampus when examined 7 days after reperfusion. No significant protection was observed when flavopiridol was administered 8 hours after reperfusion. The tumor-suppressor retinoblastoma protein, a substrate of cyclin-dependent kinase, was phosphorylated on a cyclin-dependent kinase consensus site after the global insult; this phosphorylation was inhibited by flavopiridol administration. Importantly, flavopiridol had no effect on core body temperature, suggesting that the mechanism of neuroprotection was through cyclin-dependent kinase inhibition but not through hypothermia. Furthermore, inhibition of cyclin-dependent kinases improved spatial learning behavior as assessed by the Morris water maze 7 to 9 days after reperfusion. However, the histologic protection observed at day 7 was absent 28 days after reperfusion. These results indicate that cyclin-dependent kinase inhibition provides an extended period of morphologic and functional neuroprotection that may allow time for other neuroprotective modalities to be introduced.
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PMID:Inhibition of cyclin-dependent kinases improves CA1 neuronal survival and behavioral performance after global ischemia in the rat. 1182 15

Recent studies suggest that postmitotic neurons can reenter the cell cycle as a prelude to apoptosis after brain injury. However, most dying neurons do not pass the G1/S-phase checkpoint to resume DNA synthesis. The specific factors that trigger abortive DNA synthesis are not characterized. Here we show that the combination of hypoxia and ischemia induces adult rodent neurons to resume DNA synthesis as indicated by incorporation of bromodeoxyuridine (BrdU) and expression of G1/S-phase cell cycle transition markers. After hypoxia-ischemia, the majority of BrdU- and neuronal nuclei (NeuN)-immunoreactive cells are also terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL)-stained, suggesting that they undergo apoptosis. BrdU+ neurons, labeled shortly after hypoxia-ischemia, persist for >5 d but eventually disappear by 28 d. Before disappearing, these BrdU+/NeuN+/TUNEL+ neurons express the proliferating cell marker Ki67, lose the G1-phase cyclin-dependent kinase (CDK) inhibitors p16INK4 and p27Kip1 and show induction of the late G1/S-phase CDK2 activity and phosphorylation of the retinoblastoma protein. This contrasts to kainic acid excitotoxicity and traumatic brain injury, which produce TUNEL-positive neurons without evidence of DNA synthesis or G1/S-phase cell cycle transition. These findings suggest that hypoxia-ischemia triggers neurons to reenter the cell cycle and resume apoptosis-associated DNA synthesis in brain. Our data also suggest that the demonstration of neurogenesis after brain injury requires not only BrdU uptake and mature neuronal markers but also evidence showing absence of apoptotic markers. Manipulating the aberrant apoptosis-associated DNA synthesis that occurs with hypoxia-ischemia and perhaps neurodegenerative diseases could promote neuronal survival and neurogenesis.
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PMID:Hypoxia-ischemia induces DNA synthesis without cell proliferation in dying neurons in adult rodent brain. 1556 94


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