Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 adaptation of animals to oxygen availability is mediated by a transcription factor termed hypoxia-inducible factor (HIF). HIF is an alpha (alpha)/beta (beta) heterodimer that binds hypoxia response elements (HREs) of target genes, including some of medicinal importance, such as erythropoietin (EPO) and vascular endothelial growth factor (VEGF). While the concentration of the HIF-beta subunit, a constitutive nuclear protein, does not vary with oxygen availability, the abundance and activity of the HIF-alpha subunits are tightly regulated via oxygen-dependent modification of specific residues. Hydroxylation of prolyl residues (Pro402 and Pro564 in HIF-1alpha) promotes interaction with the von Hippel-Lindau E3 ubiquitin ligase and, consequently, proteolytic destruction by the ubiquitin-proteasome pathway. This prolyl hydroxylation is catalyzed by the prolyl-hydroxylase domain (PHD) containing enzymes for which three isozymes have been identified in humans (1-3). Additionally, asparaginyl hydroxylation (Asn803 in HIF-1alpha) by factor-inhibiting HIF (FIH) ablates interaction of the HIF-alpha subunit with the coactivator p300, providing an alternative mechanism for down-regulation of HIF-dependent genes. Under hypoxic conditions, when oxygen-mediated regulation of the alpha-subunits is curtailed or minimized, dimerization of the alpha- and beta-subunits occurs with subsequent target gene upregulation. Therapeutic activation of HIF signaling has been suggested as a potential treatment for numerous conditions, including ischemia, stroke, heart attack, inflammation, and wounding. One possible route to achieve this is via inhibition of the HIF hydroxylases. This chapter details methods for the purification and assaying of PHD2, the most abundant PHD and the most important in setting steady-state levels of HIF-alpha. Assays are described that measure the activity of PHD2 via direct and indirect means. Furthermore, conditions for the screening of small molecules against PHD2 are described.
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PMID:Hypoxia-inducible factor prolyl-hydroxylase: purification and assays of PHD2. 1799 47

The nuclear protein high-mobility group box 1 (HMGB-1) promotes inflammation in sepsis, but little is known about its role in brain ischemia-induced inflammation. We report that HMGB-1 and its receptors, receptor for advanced glycation end products (RAGE), Toll-like receptor 2 (TLR2), and TLR4, were expressed in normal brain and in cultured neurons, endothelia, and glial cells. During middle cerebral artery occlusion (MCAO), in mice, HMGB-1 immunostaining rapidly disappeared from all cells within the striatal ischemic core from 1 h after onset of occlusion. High-mobility group box 1 translocation from nucleus to cytoplasm was observed within the cortical periinfarct regions 2 h after ischemic reperfusion (2 h MCAO). High-mobility group box 1 predominantly translocated to the cytoplasm or disappeared in cells that colabeled with the neuronal marker NeuN. Furthermore, RAGE was robustly expressed in the periinfarct region after MCAO. Cellular release of HMGB-1 was detected by immunoblotting of cerebrospinal fluid as early as 2 h after ischemic reperfusion (2 h MCAO). High-mobility group box 1 released from neurons, in vitro, after glutamate excitotoxicity, maintained biologic activity and induced glial expression of tumor necrosis factor alpha (TNFalpha). Anti-HMGB-1 antibody suppressed TNFalpha upregulation in astrocytes exposed to conditioned media from glutamate-treated neurons. Moreover, TNFalpha and the cytokine intercellular adhesion molecule-1 increased in cultured glia and endothelial cells, respectively, after adding recombinant HMGB-1. In conclusion, HMGB-1 is released early after ischemic injury from neurons and may contribute to the initial stages of the inflammatory response.
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PMID:Early release of HMGB-1 from neurons after the onset of brain ischemia. 1800 May 11

Transglutaminase 2 (TG2) is a multifunctional enzyme that has been implicated in the pathogenesis of neurodegenerative diseases, ischemia, and stroke. The mechanism by which TG2 modulates disease progression have not been elucidated. In this study we investigate the role of TG2 in the cellular response to ischemia and hypoxia. TG2 is up-regulated in neurons exposed to oxygen and glucose deprivation (OGD), and increased TG2 expression protects neurons against OGD-induced cell death independent of its transamidating activity. We identified hypoxia inducible factor 1beta (HIF1beta) as a TG2 binding partner. HIF1beta and HIF1alpha together form the heterodimeric transcription factor hypoxia inducible factor 1 (HIF1). TG2 and the transaminase-inactive mutant C277S-TG2 inhibited a HIF-dependent transcription reporter assay under hypoxic conditions without affecting nuclear protein levels for HIF1alpha or HIF1beta, their ability to form the HIF1 heterodimeric transcription factor, or HIF1 binding to its DNA response element. Interestingly, TG2 attenuates the up-regulation of the HIF-dependent proapoptotic gene Bnip3 in response to OGD but had no effect on the expression of VEGF, which has been linked to prosurvival processes. This study demonstrates for the first time that TG2 protects against OGD, interacts with HIF1beta, and attenuates the HIF1 hypoxic response pathway. These results indicate that TG2 may play an important role in protecting against the delayed neuronal cell death in ischemia and stroke.
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PMID:Transglutaminase 2 protects against ischemic insult, interacts with HIF1beta, and attenuates HIF1 signaling. 1837 43

While foreign pathogens and their products have long been known to activate the innate immune system, the recent recognition of a group of endogenous molecules that serve a similar function has provided a framework for understanding the overlap between the inflammatory responses activated by pathogens and injury. These endogenous molecules, termed alarmins, are normal cell constituents that can be released into the extracellular milieu during states of cellular stress or damage and subsequently activate the immune system. One nuclear protein, High mobility group box-1 (HMGB1), has received particular attention as fulfilling the functions of an alarmin by being involved in both infectious and non-infectious inflammatory conditions. Once released, HMGB1 signals through various receptors to activate immune cells involved in the immune process. Although initial studies demonstrated HMGB1 as a late mediator of sepsis, recent findings indicate HMGB1 to have an important role in models of non-infectious inflammation, such as autoimmunity, cancer, trauma, and ischemia reperfusion injury. Furthermore, in contrast to its pro-inflammatory functions, there is evidence that HMGB1 also has restorative effects leading to tissue repair and regeneration. The complex functions of HMGB1 as an archetypical alarmin are outlined here to review our current understanding of a molecule that holds the potential for treatment in many important human conditions.
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PMID:HMGB1: endogenous danger signaling. 1843 61

Peripheral stimulation and physical therapy can promote neurovascular plasticity and functional recovery after CNS disorders such as ischemic stroke. Using a rodent model of whisker-barrel cortex stroke, we have previously demonstrated that whisker activity promotes angiogenesis in the penumbra of the ischemic barrel cortex. This study explored the potential of increased peripheral activity to promote neurogenesis and neural progenitor migration toward the ischemic barrel cortex. Three days after focal barrel cortex ischemia in adult mice, whiskers were manually stimulated (15 min x 3 times/day) to enhance afferent signals to the ischemic barrel cortex. 5-Bromo-2'-deoxyuridine (BrdU, i.p.) was administered once daily to label newborn cells. At 14 days after stroke, whisker stimulation significantly increased vascular endothelial growth factor and stromal-derived factor-1 expression in the penumbra. The whisker stimulation animals showed increased doublecortin (DCX) positive and DCX/BrdU-positive cells in the ipsilateral corpus of the white matter but no increase in BrdU-positive cells in the subventricular zone, suggesting a selective effect on neuroblast migration. Neurogenesis indicated by neuronal nuclear protein and BrdU double staining was also enhanced by whisker stimulation in the penumbra at 30 days after stroke. Local cerebral blood flow was better recovered in mice that received whisker stimulation. It is suggested that the enriched microenvironment created by specific peripheral stimulation increases regenerative responses in the postischemic brain and may benefit long-term functional recovery from ischemic stroke.
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PMID:Enhanced neurogenesis and cell migration following focal ischemia and peripheral stimulation in mice. 1877 65

Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear protein best known to facilitate DNA base excision repair. Recent work has expanded the physiologic functions of PARP-1, and it is clear that the full range of biologic actions of this important protein are not yet fully understood. Regulation of the product of PARP-1, poly(ADP-ribose) (PAR), is a dynamic process with PAR glycohydrolase playing the major role in the degradation of the polymer. Under pathophysiologic situations overactivation of PARP-1 results in unregulated PAR synthesis and widespread neuronal cell death. Once thought to be necrotic cell death resulting from energy failure, we have found that PARP-1-dependent cell death is dependent on the generation of PAR, which triggers the nuclear translocation of apoptosis-inducing factor resulting in caspase-independent cell death. This form of cell death is distinct from apoptosis, necrosis, or autophagy and is termed parthanatos. PARP-1-dependent cell death has been implicated in tissues throughout the body and in diseases afflicting hundreds of millions worldwide, including stroke, Parkinson's disease, heart attack, diabetes, and ischemia reperfusion injury in numerous tissues. The breadth of indications for PARP-1 injury make parthanatos a clinically important form of cell death to understand and control.
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PMID:Mitochondrial and nuclear cross talk in cell death: parthanatos. 1907 45

Neonatal hypoxic-ischemic brain injury (HIE) remains a major cause of neurologic disabilities. However, many experimental therapies have shown limited successes. We assessed whether human mesenchymal stem cells (MSCs) could be transplanted in the HIE rat brain to improve neurologic disabilities. P7 SD rats were either subjected to left carotid artery ligation and hypoxic exposure [hypoxia-ischemia (HI)] or sham operation and normoxic exposure (sham). On P10, rat pubs received either PKH26-labeled MSCs or buffer via intracardial injection, resulting in four experimental groups: sham-buffer, sham-MSC, HI-buffer, and HI-MSC. Cylinder test and accelerating rotarod test were performed 14, 20, 30, and 40 d after injection. Six weeks after injection, cresyl violet and double immunofluorescence staining were performed. MSCs were transplanted to the whole brain mainly after HI. Glial fibrillary acidic protein and OX42 were more abundantly colocalized with MSC than neuronal specific nuclear protein or myelin basic protein. There were no significant differences in the total amounts and cell types between the lesioned and nonlesioned hemisphere. The lesioned hemispheric volume was decreased after HI (p = 0.012) but not restored by MSC. Neurologic performance was significantly impaired only on the cylinder test after HI (p = 0.034), and MSC transplants improved it (p = 0.010). These suggest MSC can be a candidate for the treatment of neonatal HIE.
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PMID:Mesenchymal stem-cell transplantation for hypoxic-ischemic brain injury in neonatal rat model. 1974 81

High mobility group box 1 (HMGB1) is a nuclear protein released from stressed or damaged cells that activates inflammatory cascades involved in the pathogenesis of liver ischemia reperfusion (I/R) injury. In efforts to develop strategies aimed at preventing its release from ischemic cells following I/R, we studied the use of cisplatin, a member of the platinating chemotherapeutic agents capable of inducing DNA lesions that have high binding affinities for high mobility group proteins inside the nucleus of cells. In addition to demonstrating that cisplatin prevents liver damage associated with liver I/R by sequestering HMGB1 inside the nucleus of ischemic cells, cisplatin also alters cell survival signaling through autophagy. Our results provide a potential approach involving the use of platinating agents and their effects on autophagy in mitigating the deleterious effects of ischemia reperfusion-mediated disease processes.
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PMID:Protective role of cisplatin in ischemic liver injury through induction of autophagy. 1978 28

The aim of this study was to define the effects of glutamate release on cell death in an eleven vessel rat occlusion model. Male Sprague-Dawley rats (250-350g) were used for the 11 vessel occlusion ischemic model, which was induced by a 5- and 10-min transient occlusion. During the surgical procedure, the extracellular glutamate concentration was measured in real-time using a microdialysis amperometirc biosensor with cerebral blood flow. In order to confirm neuronal cell death, brains were removed 72h after ischemia for the detection of the neuron-specific nuclear protein and cleaved caspase-3 levels, using double-immunofluorescence. A significant decrease in % cerebral blood flow was observed in both the 5- and 10-min 11 vessel occlusion models, while an increase in glutamate release was detected after the onset of ischemia that continued to rise during the ischemic period. However, a significantly higher level of glutamate release was observed in the 10-min ischemia group compared to the 5-min group. Unlike the small amount of brain damage in the 5-min group, the increased glutamate levels in the 10-min group resulted in ischemic cell death in the hippocampal region with the activation of cleaved caspase-3 and the inhibition of neuron-specific nuclear protein expression. This study suggests that the increased level of glutamate release induces apoptotic cell death in the 11 vessel occlusion ischemic model.
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PMID:Correlation between extracellular glutamate release and neuronal cell death in an eleven vessel occlusion model in rat. 2042 14

Following stroke or traumatic damage, neuronal death via both necrosis and apoptosis causes loss of functions, including memory, sensory perception, and motor skills. As necrosis has the nature to expand, while apoptosis stops the cell death cascade in the brain, necrosis is considered to be a promising target for rapid treatment for stroke. We identified the nuclear protein, prothymosin alpha (ProTalpha) from the conditioned medium of serum-free culture of cortical neurons as a key protein-inhibiting necrosis. In the culture of cortical neurons in the serum-free condition without any supplements, ProTalpha inhibited the necrosis, but caused apoptosis. In the ischemic brain or retina, ProTalpha showed a potent inhibition of both necrosis and apoptosis. By use of anti-brain-derived neurotrophic factor or anti-erythropoietin IgG, we found that ProTalpha inhibits necrosis, but causes apoptosis, which is in turn inhibited by ProTalpha-induced neurotrophins under the condition of ischemia. From the experiment using anti-ProTalpha IgG or antisense oligonucleotide for ProTalpha, it was revealed that ProTalpha has a pathophysiological role in protecting neurons in stroke.
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PMID:Prothymosin alpha as robustness molecule against ischemic stress to brain and retina. 2053 46


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