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

p21(WAF1/CIP1/SDI1), an inhibitor of cyclin-dependent kinases, is expressed at varying levels in human adrenal glands removed during surgery or organ recovery. In glands with p21 mRNA, nuclear p21 immunoreactivity, which was occasionally extensive, colocalized with p53 immunoreactivity and DNA damage, as evidenced by in situ end-labeling. Many cells showed morphological features of apoptosis when observed by fluorescent DNA dye staining and electron microscopy. This pattern was also associated with high levels of cytoplasmic heat shock protein 70. To address the question of the origin of p21 expression in some human adrenal glands, rat adrenal glands were subjected to 30 min of ischemia followed by 8 h of reperfusion. Cells with nuclear p21 and p53 appeared in the adrenal cortex together with DNA damage detected by in situ end-labeling. Nuclear p21 immunoreactivity was also produced in adrenal tissue fragments incubated at 37 degrees C in vitro. However, in this case, p21 expression was confined to the cut edge of the tissue. In contrast, p21 in human adrenal glands, as in ischemic rat glands, was within the inner regions of the cortex, supporting an origin of the protein in vivo rather than postmortem. The p53/p21 pathway of reaction to cellular injury, potentially leading to apoptosis, may play a role in tissue damage such as that resulting from ischemia/reperfusion. In the human adrenal cortex this process may be a precursor of adrenal failure.
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PMID:Expression of p21(WAF1/CIP1/SDI1) and p53 in apoptotic cells in the adrenal cortex and induction by ischemia/reperfusion injury. 860 38

In ischaemic porcine myocardium, the growth of collateral vessels by angiogenesis is observed in clusters in the vicinity of focal necroses. Because mitosis of endothelial cells is a prerequisite for angiogenesis, the purpose of this study has been to evaluate the time course of mitosis as an indicator of vascular growth in a porcine model of coronary microembolization. Ischaemia was induced by injection of 25-microm microspheres in the left circumflex artery, followed by tissue collection from non-ischaemic and ischaemic areas of the same heart after 24, 72 or 168 h microembolization. Tissue was studied by histone H3 in-situ hybridization, PCNA/cyclin immunohistochemistry and electron microscopy. The number of blood vessels in ischaemic myocardium was compared with that in normal control tissue. Capillary growth started as early as 24 h after microembolization, as indicated by increasing numbers of proliferating, histone H3- and PCNA/cyclin-positive cells in the necrotic inflammatory foci of the ischaemic area. At 72 h and 168 h, the number of blood vessels was significantly higher in ischaemic than in normal myocardium, whereas at 168 h, mitosis of cells was, as in normal myocardium, a rare event. Coronary microembolization of porcine myocardium thus leads to an increased cellular proliferation rate between 24 h and less than 7 days after the onset of microembolization, followed by enhanced capillary growth. In-situ hybridization with histone H3 and PCNA/cyclin immunohistochemistry seem to be reliable markers for proliferation and vascular growth in non-cancerogenic tissue.
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PMID:Time course of mitosis and collateral growth following coronary microembolization in the porcine heart. 902 87

Injury to the cardiovascular system causes an elevated expression of endothelin-1 (ET-1) and activation of several important signaling pathways including the mitogen-activated kinase (MAPK) cascade. The activation of these pathways has been implicated in the pathogenesis of cardiovascular disease caused by hypoxia, infections, and ischemia /reperfusion injury, cardiomyopathy and restenosis after balloon angioplasty. Important downstream targets of the MAPK and ET-1 pathways are the cell cycle regulatory molecules (cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors). Regulation of these molecules contributes to remodeling throughout the cardiovascular system. In addition, cell cycle molecules are important in the regulation of angiogenesis. These new data have led to the development of potential therapeutic modalities targeting these regulatory molecules in order to ameliorate various cardiovascular disease states.
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PMID:Cell cycle molecules and diseases of the cardiovascular system. 1076 98

Cell-cycle-related proteins, such as cyclins or cyclin-dependent kinases, are re-expressed in neurons committed to death in response to a variety of insults, including excitotoxins, hypoxia and ischemia, loss of trophic support, or beta-amyloid peptide. In some of these conditions events that are typical of the mid-G1 phase, such as cyclin-dependent kinase 4/6 activation, are required for the induction of neuronal death. In other cases, the cycle must proceed further and recruit steps that are typical of the G1/S transition for death to occur. Finally, there are conditions in which cell-cycle proteins might be re-expressed, but do not contribute to neuronal death. We hypothesize that cell-cycle signaling becomes a mandatory component of neuronal demise when other mechanisms are not enough for neurons to reach the threshold for death. Under this scheme, the death threshold is set by the extent of DNA damage. Whenever the extent of DNA damage is below this threshold, a cell-cycle signaling becomes crucial for the induction of neuronal death through p53-dependent or -independent pathways.
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PMID:Activation of cell-cycle-associated proteins in neuronal death: a mandatory or dispensable path? 1116 84

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

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

Aberrant mitosis occurs in many tauopathy-related neurodegenerative diseases and is believed to precede the formation of neurofibrillary tangles. In this study, we report for the first time that transient cerebral ischemia induces aberrant mitotic proteins and hyperphosphorylation of tau protein with neurofibrillary tangle-like conformational epitopes in adult female rat cortex. Following transient cerebral ischemia in rats, initiation of apoptosis precedes and is potentially integrated with subsequent aberrant mitosis and tau hyperphosphorylation. Furthermore, inhibition of mitosis-related cyclin-dependent kinases (Cdks) by roscovitine significantly reduced the hyperphosphorylation of tau. Administration of the female sex steroid and potent neuroprotective agent, 17beta-estradiol, reduced ischemia-reperfusion-induced cerebral damage and the subsequent aberrant mitosis and tauopathies. These results provide a neuropathological basis for the higher prevalence of dementia in stroke patients and support the hypothesis that apoptosis and aberrant mitosis are integrated pathological events in neurons that may play a critical role in the development of Alzheimer's disease and other tauopathy-related neuropathology.
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PMID:Transient cerebral ischemia induces aberrant neuronal cell cycle re-entry and Alzheimer's disease-like tauopathy in female rats. 1498 35

Cell cycle regulators such as cyclin-dependent kinases (Cdks) and their inhibitors (Ckis) have been reported to be involved in neuronal cell death (NCD) induced by a variety of insults such as ischemia, UV-irradiation, nerve growth factor (NGF)-withdrawal, and anticancer therapeutics. But their precise interactive regulation has still to be unveiled. In the present study, we focused on cell cycle regulators such as Cdk4, p21(WAF1) and p53 to clarify their regulatory mechanisms, using NCD induced by doxorubicin (D-NCD) in mouse cerebellar granule neurons as a model. Doxorubicin induced NCD in a dose-dependent manner, a typical feature of apoptosis as determined by TUNEL assay. Doxorubicin increased the protein expression of p53 in time- and dose-dependent manners. The protein expression of p21(WAF1), a Cki of Cdk4, was stimulated by doxorubicin at low concentrations, but it disappeared at high concentrations. Doxorubicin activated the kinase activity of Cdk4 without the enhancement of Cdk4 protein. 3-Amino-9-thio(10H)-acridone (3-ATA), the specific inhibitor of Cdk4, prevented D-NCD in a dose-dependent manner. Wortmannin, an inhibitor of ATM (ataxia telangiectasia, mutated) that has high homology with the phosphatidyl-inositol-3-kinase (PI3K) family and has protein kinase activity for the induction of p53 with specificity for serine and threonine residues, inhibited the activation of Cdk4 without the induction of p53 in D-NCD. These data suggest that (1) Cdk4 is one of the essential components for inducing NCD, that (2) p53 may prevent D-NCD through the induction of p21(WAF1) at low concentrations of doxorubicin, and that (3) Cdk4 might be activated by the same signal-molecules, like ATM, that are necessary for the activation of p53 in D-NCD.
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PMID:Roles of cyclin-dependent kinase 4 and p53 in neuronal cell death induced by doxorubicin on cerebellar granule neurons in mouse. 1524 44

The cyclin-dependent kinases (CDK) CDK1, CDK2, CDK4, and CDK6 are serine/threonine protein kinases targeted in cancer therapy due to their role in cell cycle progression. The postmitotic CDK5 is involved in biological pathways important for neuronal migration and differentiation. CDK5 represents an attractive pharmacological target as its deregulation is implicated in various neurodegenerative diseases such as Alzheimer's, Parkinson's, and Niemann-Pick type C diseases, ischemia, and amyotrophic lateral sclerosis. We have generated an improved crystal form of CDK5 in complex with p25, a segment of the p35 neuronal activator. The crystals were used to solve the structure of CDK5/p25 with (R)-roscovitine and aloisine at a resolution of 2.2 and 2.3 A, respectively. The structure of CDK5/p25/roscovitine provides a rationale for the preference of CDK5 for the R over the S stereoisomer. Furthermore, roscovitine stabilized an unusual collapsed conformation of the glycine-rich loop, an important site of CDK regulation, and we report an investigation of the effects of glycine-rich loop phosphorylation on roscovitine binding. The CDK5/p25 crystals represent a valuable new tool for the identification and optimization of selective CDK inhibitors.
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PMID:Mechanism of CDK5/p25 binding by CDK inhibitors. 1568 52

The mechanisms involving neuronal death after ischemic/hypoxic insult are complex, involving both rapid (excitotoxic) and delayed (apoptotic-like) processes. Recent evidence suggests that cell cycle regulators such as cyclin-dependent kinases are abnormally activated in neuropathological conditions, including stroke. However, the function of this activation is unclear. Here, we provide evidence that inhibition of the cell cycle regulator, Cdk4, and its activator, cyclinD1, plays critical roles in the delayed death component of ischemic/hypoxic stress by regulating the tumor suppressor retinoblastoma protein. In contrast, the excitotoxic component of ischemia/hypoxia is predominately regulated by Cdk5 and its activator p35, components of a cyclin-dependent kinase complex associated with neuronal development. Hence, our data both characterize the functional significance of the cell cycle Cdk4 and neuronal Cdk5 signals as well as define the pathways and circumstances by which they act to control ischemic/hypoxic damage.
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PMID:Multiple cyclin-dependent kinases signals are critical mediators of ischemia/hypoxic neuronal death in vitro and in vivo. 1616 66


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