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)

Recent studies of ischemia-reperfusion (I/R) injury have focused on the function of neutrophils, the action mechanism of inflammatory cytokines. However, few reports have addressed peroxisome proliferator-activated receptor (PPAR)-gamma. PPAR-gamma is a ligand-activated transcriptional factor belonging to the steroid receptor superfamily. It plays a role in both adipocyte differentiation and tumorigenesis. We researched the expression of PPAR-gamma in renal I/R injury of the rat. Male Lewis rats were used. The right kidney was harvested and the left renal artery and vein were clamped at 90 minutes of ischemic time. Rats were killed at 0, 1.5, 3, 5, and 12 hours after reperfusion. PPAR-gamma expression was studied by immunohistostaining. PPAR-gamma expression was observed only on mesangial and endothelial cells of normal kidney. From 1.5 to 3 hours after reperfusion, PPAR-gamma expression gradually became stronger on mesangial and endothelial cells. PPAR-gamma expression was most intense on mesangial cells and endothelial cells at 3 hours after reperfusion. Twelve hours after reperfusion, necrosis extended throughout the ischemic kidney and nearly all the tubular epithelial cells were destroyed, but 12 hours after reperfusion PPAR-gamma expression gradually became weaker on mesangial and endothelial cells. PPAR-gamma was expressed in the rat model having renal I/R injury. Several hours after maximal of PPAR-gamma expression, maximal renal I/R injury was observed. These results may indicate a relationship between PPAR-gamma expression and renal I/R injury.
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PMID:Study of peroxisome proliferator-activated receptor (PPAR)-gamma in renal ischemia-reperfusion injury. 1551 7

Hypoxia, an insufficient level of oxygen in the cell, occurs during normal activity and also in pathological conditions such as ischemia and tumorigenesis. Although many hypoxia-response genes have been identified, an understanding of the functional role for these genes in the living animal is lacking. Here we present a genome-wide study of gene expression changes during hypoxia and then functionally test a subset of these genes for roles in survival and recovery from hypoxia. We found 79 genes with increased mRNA levels when adult flies were treated with 0.5% O2 for 6 h. A subset of these genes had detectably increased levels in as short as 1 h of low-oxygen treatment. Mild hypoxia levels resulted in an increase in transcription levels for only 20 genes. Viability during hypoxia and recovery time from hypoxia-induced paralysis was examined in flies with a reduction in activity in hypoxia-response genes. The observed decreased viability and increased recovery time from paralysis in many of the lines demonstrate that the increased transcript levels seen after hypoxia are important for the response to low oxygen.
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PMID:Identification and function of hypoxia-response genes in Drosophila melanogaster. 1640 41

The transcription factor hypoxia-inducible factor-1 (HIF-1) regulates the expression of more than 70 genes involved in cellular adaptation and survival under hypoxic stress. Activation of HIF-1 is associated with numerous physiological and pathological processes that include tumorigenesis, vascular remodeling, inflammation, and hypoxia/ischemia-related tissue damage. Clinical studies suggested that HIF-1 activation correlates directly with advanced disease stages and treatment resistance among cancer patients. Preclinical studies support the inhibition of HIF-1 as a major molecular target for antitumor drug discovery. Considerable effort is underway, in government laboratories, industry and academia, to identify therapeutically useful small molecule HIF-1 inhibitors. Natural products (low molecular weight organic compounds produced by plants, microbes, and animals) continue to play a major role in modern antitumor drug discovery. Most of the compounds discovered to inhibit HIF-1 are natural products or synthetic compounds with structures that are based on natural product leads. Natural products have also served a vital role as molecular probes to elucidate the pathways that regulate HIF-1 activity. Natural products and natural product-derived compounds that inhibit HIF-1 are summarized in light of their biological source, chemical class, and effect on HIF-1 and HIF-mediated gene regulation. When known, the mechanism(s) of action of HIF-1 inhibitors are described. Many of the substances found to inhibit HIF-1 are non-druggable compounds that are too cytotoxic to serve as drug leads. The application of high-throughput screening methods, complementary molecular-targeted assays, and structurally diverse chemical libraries hold promise for the discovery of therapeutically useful HIF-1 inhibitors.
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PMID:Natural product-based inhibitors of hypoxia-inducible factor-1 (HIF-1). 1651 32

Hypoxia inducible factors (HIFs) regulate adaptive responses to changes in oxygen (O(2)) tension during embryogenesis, tissue ischemia, and tumorigenesis. Because HIF-deficient embryos exhibit a number of developmental defects, the precise role of HIF in early vascular morphogenesis has been uncertain. Using para-aortic splanchnopleural (P-Sp) explant cultures, we show that deletion of the HIF-beta subunit (ARNT) results in defective hematopoiesis and the inhibition of both vasculogenesis and angiogenesis. These defects are rescued upon the addition of wild-type Sca-1(+) hematopoietic cells or recombinant VEGF. Arnt(-/-) embryos exhibit reduced levels of VEGF protein and increased numbers of apoptotic hematopoietic cells. These results suggest that HIF coordinates early endothelial cell emergence and vessel development by promoting hematopoietic cell survival and paracrine growth factor production.
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PMID:HIF-dependent hematopoietic factors regulate the development of the embryonic vasculature. 1682 55

Connexins had been considered to be the only class of the vertebrate proteins capable of gap junction formation; however, new candidates for this function with no homology to connexins, termed pannexins were discovered. So far three pannexins were described in rodent and human genomes: Panx1, Panx2 and Panx3. Expressions of pannexins can be detected in numerous brain structures, and now found both in neuronal and glial cells. Hypothetical roles of pannexins in the nervous system include participating in sensory processing, hippocampal plasticity, synchronization between hippocampus and cortex, and propagation of the calcium waves supported by glial cells, which help maintain and modulate neuronal metabolism. Pannexin also may participate in pathological reactions of the neural cells, including their damage after ischemia and subsequent cell death. Recent study revealed non-gap junction function of Panx1 hemichannels in erythrocytes, where they serve as the conduits for the ATP release in response to the osmotic stress. High-throughput studies produced some evidences of the pannexin involvement in the process of tumorigenesis. According to brain cancer gene expression database REMBRANDT, PANX2 expression levels can predict post diagnosis survival for patients with glial tumors. Further investigations are needed to verify or reject hypotheses listed.
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PMID:What is hidden in the pannexin treasure trove: the sneak peek and the guesswork. 1698 24

Cyclooxygenase is an enzyme that catalyzes the first two steps in the biosynthesis of prostanoids. The constitutively expressed isoform COX-1 is regarded as a housekeeping enzyme that is responsible for the normal production of prostanoids. The inducible isoform COX-2, on the other hand, is transiently induced during inflammation by various stimuli. Increasing evidence has shown that COX-2 is not only implicated in inflammation but also in oncogenesis. Overexpression of COX-2 has been observed in a variety of tumors. Prostaglandins produced by COX-2 affect important processes in carcinogenesis, including angiogenesis, tissue invasion, metastasis and apoptosis. Several studies indicate that COX-2 is also involved in neurological disorders, like Alzheimer's disease, Parkinson's disease and ischemia, where COX-2 overexpression leads to neurotoxicity. Many aspects of the role of COX-2 in (patho)physiology, however, remain unclear. At present, COX-2 expression is determined by ex vivo laboratory analysis, but the results could be greatly affected by the instability of COX-2 mRNA and protein and by sampling errors. A noninvasive imaging method to monitor COX-2 expression, like positron emission tomography (PET) or single photon emission computed tomography (SPECT), could overcome this complication and may provide novel insights in the role of COX-2, especially in neurological disorders where repetitive sampling is not possible. Such a technique could also be applied to the in vivo evaluation of novel selective COX-2 inhibitors and in dose-escalation studies. This review will present an overview of the developments in the recently emerging field of COX-2 imaging.
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PMID:Imaging of cyclooxygenase-2 (COX-2) expression: potential use in diagnosis and drug evaluation. 1707 83

The transcription factor hypoxia-inducible factor-1 (HIF-1) regulates the expression of more than 100 genes involved in cellular adaptation and survival under hypoxic stress. Activation of HIF-1 is associated with numerous physiological and pathological processes that include tumorigenesis, vascular remodelling, inflammation, and hypoxia/ischemia-related tissue damage. Experimental data support the concept that modulation of Reactive Oxygen Species (ROS) levels have an important impact on the hypoxic response mediated by HIF-1 alpha. However, ROS generation, the exact kinetics and conditions of ROS production and their specific relevance to HIF-l alpha activation are issue still to be clarified. Clinical studies suggested that HIF-1 activation correlates directly with advanced disease stages and treatment resistance among cancer patients. Preclinical studies support the inhibition of HIF-1 as a major molecular target for anti-tumour drug discovery. Considerable effort is underway to identify therapeutically useful molecule HIF-1 inhibitors. Most of the compounds discovered to inhibit HIF-1 are natural products or synthetic compounds with structures that are based on natural product leads. Natural products have also served a vital role as molecular probes to elucidate the pathways that regulate HIF-1 activity. Many of the substances found to inhibit HIF-I are non-druggable compounds that are too cytotoxic to serve as drug leads. The application of high-throughput screening methods, complementary molecular-targeted assays, and structurally diverse chemical libraries hold promise for the discovery of therapeutically useful HIF-1 inhibitors.
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PMID:Cellular redox status regulates hypoxia inducible factor-1 activity. Role in tumour development. 1755 Jan 31

Hypoxia-inducible factors (HIFs) are key transcriptional regulators of genes involved in cellular adaptation to reduced oxygen availability through effects on anaerobic metabolism, oxygen delivery, angiogenesis, and cellular survival and proliferation. As such, HIFs contribute to the pathogenesis of diseases in which oxygen availability is compromised, notably ischemia and tumorigenesis. Though tremendous progress has been made in elucidating the mechanisms underlying O(2)-dependent regulation of HIF by Fe(II)- and 2-oxoglutarate-dependent dioxygenases, HIF induction can be uncoupled from these modes of regulation in diseases such as cancer. Consequently, renewed interest has developed in understanding the structure/function relationships of individual P(er)/ARNT/S(im) (PAS) domains that are important for maintaining transcriptionally active HIF complexes, regardless of the manner by which HIF is induced. This review highlights strategies for the biophysical and biochemical characterization of the PAS domains found within both HIF subunits and provides a platform for future efforts to exploit these domains in therapeutic settings.
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PMID:Hypoxia-inducible factors Per/ARNT/Sim domains: structure and function. 1799 46

Decreases in oxygen levels are observed in physiological processes, such as development, and pathological situations, such as tumorigenesis and ischemia. In the complete absence of oxygen (anoxia), mammalian cells are unable to generate sufficient energy for survival, so a mechanism for sensing a decrease in the oxygen level (hypoxia) before it reaches a critical point is crucial for the survival of the organism. In response to decreased oxygen levels, cells activate the transcription factors hypoxia-inducible factors (HIFs), which lead to metabolic adaptation to hypoxia, as well as to generate new vasculature to increase oxygen supply. How cells sense decreases in oxygen levels to regulate HIF activation has been hotly debated. Emerging evidence indicates that reactive oxygen species (ROS) generated by mitochondrial complex III are required for hypoxic activation of HIF. This review examines the current knowledge about the role of mitochondrial ROS in HIF activation, as well as implications of ROS-level regulation in pathological processes such as cancer.
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PMID:Mitochondrial complex III regulates hypoxic activation of HIF. 1821 20

HIF-1alpha is originally identified as a transcription factor that activates gene expression in response to hypoxia. In metazoans, HIF-1alpha functions as a master regulator of oxygen homeostasis and regulates adaptive responses to change in oxygen tension during embryogenesis, tissue ischemia, and tumorigenesis. Because Hif-1alpha-deficient mice exhibit a number of developmental defects, the precise role of HIF-1alpha in early cardiac morphogenesis has been uncertain. Therefore, to clarify the role of HIF-1alpha in heart development, we investigated the effect of knockdown of HIF-1alpha in Xenopus embryos using antisense morpholino oligonucleotide microinjection techniques. Knockdown of HIF-1alpha resulted in defects of cardiogenesis. Whole mount in situ hybridization for cardiac troponin I (cTnI) showed the two separated populations of cardiomyocytes, which is indicative of cardia bifida, in HIF-1alpha-depleted embryos. Furthermore, the depletion of HIF-1alpha led to the reduction in cTnI expression, suggesting the correlation between HIF-1alpha and cardiac differentiation. We further examined the expression of several heart markers, nkx2.5, gata4, tbx5, bmp4, hand1, and hand2 in HIF-1alpha-depleted embryos. Among them, the expression of nkx2.5 was significantly reduced. Luciferase reporter assay using the Nkx2.5 promoter showed that knockdown of HIF-1alpha decreased its promoter activity. The cardiac abnormality in the HIF-1alpha-depleted embryo was restored with co-injection of nkx2.5 mRNA. Collectively, these findings reveal that HIF-1alpha-regulated nkx2.5 expression is required for heart development in Xenopus.
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PMID:HIF-1alpha signaling upstream of NKX2.5 is required for cardiac development in Xenopus. 1830 27


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