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)

Awareness of the importance of carbohydrates in living systems and medicine is growing due to the increasing understanding of their biological and pharmacological relevance. Carbohydrates are ubiquitous and perform a wide array of biological roles. Carbohydrate-based or -modified therapeutics are used extensively in cardiovascular and hematological treatments ranging from inflammatory diseases and anti-thrombotic treatments to wound healing. Heparin is a well-known and widely used example of a carbohydrate-based drug but will not be discussed as it has been extensively reviewed. We will detail carbohydrate-based and -modified therapeutics, both those that are currently marketed or in various stages of clinical trials and those that are potential therapeutics based on promising preclinical investigations. Carbohydrate-based therapeutics include polysaccharide and oligosaccharide anti-inflammatory, anti-coagulant and anti-thrombotic agents from natural and synthetic sources, some as an alternative to heparin and others which were designed based on known structure-functional relationships. Some of these compounds have multiple biological effects, showing anti-adhesive, anti-HIV and anti-arthrithic activities. Small molecules, derivatives or mimetics of complement inhibitors, are detailed for use in limiting ischemia/ reperfusion injuries. Monosaccharides, both natural and synthetic, have been investigated for their in vivo anti-inflammatory and cardioprotective properties. Modification by glycosylation of natural products, or glycosylation-mimicking modification, has a significant effect on the parent molecule including increased plasma half-life and refining or increasing desired functions. It is hoped that this review will highlight the vast therapeutic potential of these natural bioactive molecules.
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PMID:Carbohydrates in therapeutics. 1763 Sep 44

Heat shock protein 27 (HSP27) is an intracellular stress protein with the cytoprotective effect for a variety of noxious stresses. In this study, using a protein delivery system, we demonstrated the potential cytoprotective effect of HSP27 as a therapeutic protein in cardiac cells and ischemia/reperfusion animal model. We constructed a recombinant HSP27 fused to the protein transduction domain (PTD) derived from HIV-1 TAT protein. Purified recombinant TAT-HSP27 protein was efficiently delivered to H9c2 cells, and its transduction showed cytoprotective effect against the hypoxic stress. Moreover, transduction of TAT-HSP27 also attenuated hypoxia-induced apoptosis, which was accompanied by reduced caspase-3 activity. In addition, intraperitoneal injection of TAT-HSP27 into rat resulted in efficient protein transduction in heart tissues, decreased infarcted myocardium (control vs TAT-HSP27, 39.1% vs 29.5%, P<0.05) and preserved heart function (fractional shortening, 15.6% vs 33.4%, P<0.05), as determined at 7 d after I/R. These results suggest that the PTD-mediated delivery of HSP27 protein may represent a potential therapeutic strategy as protein drug for ischemic heart diseases.
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PMID:Protective effect of heat shock protein 27 using protein transduction domain-mediated delivery on ischemia/reperfusion heart injury. 1786 18

The blood-brain barrier (BBB) is the specialized system of brain microvascular endothelial cells (BMVEC) that shields the brain from toxic substances in the blood, supplies brain tissues with nutrients, and filters harmful compounds from the brain back to the bloodstream. The close interaction between BMVEC and other components of the neurovascular unit (astrocytes, pericytes, neurons, and basement membrane) ensures proper function of the central nervous system (CNS). Transport across the BBB is strictly limited through both physical (tight junctions) and metabolic barriers (enzymes, diverse transport systems). A functional polarity exists between the luminal and abluminal membrane surfaces of the BMVEC. As a result of restricted permeability, the BBB is a limiting factor for the delivery of therapeutic agents into the CNS. BBB breakdown or alterations in transport systems play an important role in the pathogenesis of many CNS diseases (HIV-1 encephalitis, Alzheimer's disease, ischemia, tumors, multiple sclerosis, and Parkinson's disease). Proinflammatory substances and specific disease-associated proteins often mediate such BBB dysfunction. Despite seemingly diverse underlying causes of BBB dysfunction, common intracellular pathways emerge for the regulation of the BBB structural and functional integrity. Better understanding of tight junction regulation and factors affecting transport systems will allow the development of therapeutics to improve the BBB function in health and disease.
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PMID:Blood-brain barrier: structural components and function under physiologic and pathologic conditions. 1804 Aug

Proinflammatory cytokines and chemokines have been implicated in the pathogenesis of several neurological and neurodegenerative disorders. Prominent among such factors is the pleiotropic cytokine, tumor necrosis factor (TNF)-alpha. Under normal physiological conditions, TNF-alpha orchestrates a diverse array of functions involved in immune surveillance and defense, cellular homeostasis, and protection against certain neurological insults. However, paradoxical effects of this cytokine have been observed. TNF-alpha is elicited in the brain following injury (ischemia, trauma), infection (HIV, meningitis), neurodegeneration (Alzheimer's, Parkinson's), and chemically induced neurotoxicity. The multifarious identity for this cytokine appears to be influenced by several mechanisms. Among the most prominent are the regulation of TNFalpha-induced NF-kappaB activation by adapter proteins such as TRADD and TRAF, and second, the heterogeneity of microglia and their distribution pattern across brain regions. Here, we review the differential role of TNF-alpha in response to brain injury, with emphasis on neurodegeneration, and discuss the possible mechanisms for such diverse and region-specific effects.
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PMID:Divergent roles for tumor necrosis factor-alpha in the brain. 1804 Aug 39

The maintenance of pH homeostasis in the CNS is of key importance for proper execution and regulation of neurotransmission, and deviations from this homeostasis are a crucial factor in the mechanism underlying a spectrum of pathological conditions. The first few sections of the review are devoted to the brain operating under normal conditions. The article commences with an overview of how extrinsic factors modelling the brain at work: neurotransmitters, depolarising stimuli (potassium and voltage changes) and cyclic nucleotides as major signal transducing vehicles affect pH in the CNS. Further, consequences of pH alterations on the major aspects of CNS function and metabolism are outlined. Next, the major cellular events involved in the transport, sequestration, metabolic production and buffering of protons that are common to all the mammalian cells, including the CNS cells. Since CNS function reflects tight interaction between astrocytes and neurons, the pH regulatory events pertinent to either cell type are discussed: overwhelming evidence implicates astrocytes as a key player in pH homeostasis in the brain. The different classes of membrane proteins involved in proton shuttling are listed and their mechanisms of action are given. These include: the Na+/H+ exchanger, different classes of bicarbonate transporters acting in a sodium-dependent- or -independent mode, monocarboxylic acid transporters and the vacuolar-type proton ATPase. A separate section is devoted to carbonic anhydrase, which is represented by multiple isoenzymes capable of pH buffering both in the cell interior and in the extracellular space. Next, impairment of pH regulation and compensatory responses occurring in brain affected by different pathologies: hypoxia/ischemia, epilepsy, hyperammonemic encephalopathies, cerebral tumours and HIV will be described. The review is limited to facts and plausible hypotheses pertaining to phenomena directly involved in pH regulation: changes in pH that accompany metabolic stress but have no distinct implications for the pH regulatory mechanisms are not dealt with. In most cases, the vast body of knowledge derived from in vitro studies remains to be verified in in vivo settings.
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PMID:Regulation of pH in the mammalian central nervous system under normal and pathological conditions: facts and hypotheses. 1806 8

In contrast to many years of important research and clinical attention to the pathological effects of alcohol (ethanol) abuse, the past several decades have seen the publication of a number of peer-reviewed studies indicating the beneficial effects of light-moderate, nonbinge consumption of varied alcoholic beverages, as well as experimental demonstrations that moderate alcohol exposure can initiate typically cytoprotective mechanisms. A considerable body of epidemiology associates moderate alcohol consumption with significantly reduced risks of coronary heart disease and, albeit currently a less robust relationship, cerebrovascular (ischemic) stroke. Experimental studies with experimental rodent models and cultures (cardiac myocytes, endothelial cells) indicate that moderate alcohol exposure can promote anti-inflammatory processes involving adenosine receptors, protein kinase C (PKC), nitric oxide synthase, heat shock proteins, and others which could underlie cardioprotection. Also, brain functional comparisons between older moderate alcohol consumers and nondrinkers have received more recent epidemiological study. In over half of nearly 45 reports since the early 1990s, significantly reduced risks of cognitive loss or dementia in moderate, nonbinge consumers of alcohol (wine, beer, liquor) have been observed, whereas increased risk has been seen only in a few studies. Physiological explanations for the apparent CNS benefits of moderate consumption have invoked alcohol's cardiovascular and/or hematological effects, but there is also experimental evidence that moderate alcohol levels can exert direct "neuroprotective" actions-pertinent are several studies in vivo and rat brain organotypic cultures, in which antecedent or preconditioning exposure to moderate alcohol neuroprotects against ischemia, endotoxin, beta-amyloid, a toxic protein intimately associated with Alzheimer's, or gp120, the neuroinflammatory HIV-1 envelope protein. The alcohol-dependent neuroprotected state appears linked to activation of signal transduction processes potentially involving reactive oxygen species, several key protein kinases, and increased heat shock proteins. Thus to a certain extent, moderate alcohol exposure appears to trigger analogous mild stress-associated, anti-inflammatory mechanisms in the heart, vasculature, and brain that tend to promote cellular survival pathways.
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PMID:Alcohol in moderation, cardioprotection, and neuroprotection: epidemiological considerations and mechanistic studies. 1903 83

Patients with HIV or AIDS frequently present with GI symptoms, sometimes due to early and diffuse atherosclerosis. We report 3 cases of HIV patients with abdominal pain due to severe splanchnic arterial stenosis. Only one patient presented typical clinical findings of mesenteric ischemic. Endovascular treatment was performed in all three cases. Good clinical outcome was immediate in 2 cases. In the third case, subsequent bowel resection was required due to irreversible ischemic injury in spite of local thrombolysis and endovascular revascularization in a patient presenting with acute severe mesenteric ischemia. In all three cases, vascular patency was demonstrated at follow-up. Mesenteric ischemia is a severe complication requiring early diagnosis in HIV patients, especially those with vascular risk factors, especially since endovascular treatment is a valid therapeutic option.
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PMID:[Role of endovascular treatment of symptomatic splanchnic artery stenoses in HIV patients: report of three cases]. 1930 7

Many cellular events are involved in ischemic neuronal death, and it has been difficult to identify those that play a critical role in the cascade triggered by lack of oxygen and glucose, although it has been widely recognized that overactivation of glutamate receptors represents one of the initiating factors. Different glutamate receptor antagonists, especially those for N-methyl-D-aspartate (NMDA) receptors, have achieved significant success in animal models of hypoxia/ischemia; however, these antagonists have failed in clinical trials. We previously reported that calpain-mediated truncation of metabotropic glutamate receptor 1alpha (mGluR1alpha) played a critical role in excitotoxicity, and that a TAT-mGluR1 peptide consisting of a peptide surrounding the calpain cleavage site of mGluR1alpha and the peptide transduction domain of the transactivating regulatory protein (TAT) of HIV was neuroprotective against excitotoxicity. In the present study we tested the effect of this peptide in in vitro and in vivo models of neonatal hypoxia/ischemia. TAT-mGluR1 peptide prevented oxygen/glucose deprivation- (OGD) and hypoxia/ischemia- (H/I) induced neuronal death in cultured hippocampal slices and neonatal rats, respectively. TAT-mGluR1 blocked H/I-induced mGluR1alpha degradation but had no effect on H/I-induced spectrin degradation, suggesting that neuroprotection was due to prevention of calpain-mediated mGluR1alpha truncation and not to calpain inhibition. Our results therefore suggest that mGluR1alpha truncation plays a critical role in neonatal hypoxia/ischemia and that blockade of this event may prevent the activation of many downstream cytotoxic cascades. Compared to glutamate receptor antagonists and general calpain inhibitors, TAT-mGluR1 may have limited side effects.
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PMID:Neuroprotection against neonatal hypoxia/ischemia-induced cerebral cell death by prevention of calpain-mediated mGluR1alpha truncation. 1937 98

This review is based on the honor of receiving the Discovery Award from the Society of Free Radical Biology and Medicine. The review is reflective and presents our thinking that led to experiments that yielded novel observations. Critical questioning of our understanding of oxygen free radicals in biomedical problems led us to use and develop more direct and extremely sensitive methods. This included nitrone free radical spin trapping and HPLC-electrochemical detection. This technology led to the pioneering use of salicylate to trap hydroxyl free radicals and show increased flux in ischemia/reperfused brain regions and also to first sensitively detect 8-hydroxyl-2-deoxyguanosine in oxidatively damaged DNA and help assess its role in cancer development. We demonstrated that methylene blue (MB) photoinduces formation of 8-hydroxyguanine in DNA and RNA and discovered that MB sensitively photoinactivates RNA viruses, including HIV and the West Nile virus. Studies in experimental stroke led us serendipitously to discover that alpha-phenyl-tert-butylnitrone (PBN) was neuroprotective if given after the stroke. This led to extensive commercial development of NXY-059, a PBN derivative, for the treatment of stroke. More recently we discovered that PBN nitrones have potent anti-cancer activity and are active in preventing hearing loss caused by acute acoustical trauma.
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PMID:Serendipitous findings while researching oxygen free radicals. 1943 10

The chemokine stromal cell-derived factor-1 (SDF-1/CXCL12) directs leukocyte migration, stem cell homing, and cancer metastasis through activation of CXCR4, which is also a coreceptor for T-tropic HIV-1. Recently, SDF-1 was shown to play a protective role after myocardial infarction, and the protein is a candidate for development of new anti-ischemic compounds. SDF-1 is monomeric at nanomolar concentrations but binding partners promote self-association at higher concentrations to form a typical CXC chemokine homodimer. Two NMR structures have been reported for the SDF-1 monomer, but only one matches the conformation observed in a series of dimeric crystal structures. In the other model, the C-terminal helix is tilted at an angle incompatible with SDF-1 dimerization. Using a rat heart explant model for ischemia/reperfusion injury, we found that dimeric SDF-1 exerts no cardioprotective effect, suggesting that the active species is monomeric. To resolve the discrepancy between existing models, we solved the NMR structure of the SDF-1 monomer in different solution conditions. Irrespective of pH and buffer composition, the C-terminal helix remains tilted at an angle with no evidence for the perpendicular arrangement. Furthermore, we find that phospholipid bicelles promote dimerization that necessarily shifts the helix to the perpendicular orientation, yielding dipolar couplings that are incompatible with the NOE distance constraints. We conclude that interactions with the alignment medium biased the previous structure, masking flexibility in the helix position that may be essential for the distinct functional properties of the SDF-1 monomer.
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PMID:Monomeric structure of the cardioprotective chemokine SDF-1/CXCL12. 1955 79


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