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)

Manganese superoxide dismutase (MnSOD) is essential for life as dramatically illustrated by the neonatal lethality of mice that are deficient in MnSOD. In addition, mice expressing only 50% of the normal compliment of MnSOD demonstrate increased susceptibility to oxidative stress and severe mitochondrial dysfunction resulting from elevation of reactive oxygen species. Thus, it is important to know the status of both MnSOD protein levels and activity in order to assess its role as an important regulator of cell biology. Numerous studies have shown that MnSOD can be induced to protect against pro-oxidant insults resulting from cytokine treatment, ultraviolet light, irradiation, certain tumors, amyotrophic lateral sclerosis, and ischemia/reperfusion. In addition, overexpression of MnSOD has been shown to protect against pro-apoptotic stimuli as well as ischemic damage. Conversely, several studies have reported declines in MnSOD activity during diseases including cancer, aging, progeria, asthma, and transplant rejection. The precise biochemical/molecular mechanisms involved with this loss in activity are not well understood. Certainly, MnSOD gene expression or other defects could play a role in such inactivation. However, based on recent findings regarding the susceptibility of MnSOD to oxidative inactivation, it is equally likely that post-translational modification of MnSOD may account for the loss of activity. Our laboratory has recently demonstrated that MnSOD is tyrosine nitrated and inactivated during human kidney allograft rejection and human pancreatic ductal adenocarcinoma. We have determined that peroxynitrite (ONOO- ) is the only known biological oxidant competent to inactivate enzymatic activity, to nitrate critical tyrosine residues, and to induce dityrosine formation in MnSOD. Tyrosine nitration and inactivation of MnSOD would lead to increased levels of superoxide and concomitant increases in ONOO- within the mitochondria which, could lead to tyrosine nitration/oxidation of key mitochondrial proteins and ultimately mitochondrial dysfunction and cell death. This article assesses the important role of MnSOD activity in various pathological states in light of this potentially lethal positive feedback cycle involving oxidative inactivation.
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PMID:Invited review: manganese superoxide dismutase in disease. 1132 70

Observations of the effects of carbon monoxide (CO) on mammalian systems have been known for thousands of years. To be sure, CO is deadly under certain conditions and concentrations, but perhaps as the data presented here will make clear, it also possesses other diverse functional and immunomodulatory properties. This review, together with the other reviews in this issue, will detail that over the past three decades, fundamental functional role(s) for this gas molecule are beginning to emerge. This review outlines that at low concentrations, exogenously administered CO is a molecule involved in the regulation of the inflammatory response in a variety of disease models. CO has been shown to modulate such cellular functions as cytokine production, cell proliferation and apoptosis, protecting the lungs and hearts of rodents from such stressors as endotoxin, ischemia/reperfusion injury, cardiac xenograft rejection, and asthma. Although the mechanism by which this simple diatomic gas provides this protection remains obscure, the conclusions are the same: CO at low concentrations, concentrations that are well below those that would otherwise create toxic effects, is proving beneficial in models of acute injury. CO, akin to nitric oxide, is proving to be an extraordinary signaling molecule generated by the cell that is vital in the regulation of cellular homeostasis.
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PMID:Carbon monoxide: innovative anti-inflammatory properties of an age-old gas molecule. 1200 82

The present study summarizes the biological effects elicit upon A(3) adenosine receptor (A(3)AR) activation in normal and tumor cells. Anti-inflamatory response is mediated upon A(3)AR activation in neutrophils, eosinophils and macrophages via direct effect on cell degranulation or the production of anti-inflamatory cytokines. In basophils, which highly express A(3)AR, degranulation and mediator release upon receptor activation lead to pro-inflammatory effects resulting in bronchospasm and asthma. In other normal cells such as cardiomyocytes, neuronal cells and bone marrow cells A(1)AR activation induces cytoprotective effects in vitro. In vivo, A(3)AR agonists act as cardio- and neuroprotective agents and attenuate ischemic damage. Furthermore, agonists to A(3)AR induce granulocyte colony stimulating factor (G-CSF) production and myeloprotective effect in chemotherapy treated mice. Interestingly, A(3)AR agonists inhibit tumor cell growth both in vitro and in vivo through a cytostatic effect mediated via the de-regulation of the Wnt signaling pathway. The variety of activities elicit by A(3)AR agonists suggest their potential use as therapeutic agents in inflammation, brain/cardiac ischemia and cancer. Antagonists to A(3)AR may be implemented to the therapy of asthma and additional allergic conditions.
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PMID:Pharmacology and therapeutic applications of A3 receptor subtype. 1257 Jul 62

Our objective was to assess the complications of laparoscopic fundoplication in 77 patients older than 70 years of age. The indications for surgery were (1) complications of reflux esophagitis (n = 17), (2) large hiatal hernia (n = 10), (3) asthma and bronchitis (n = 7), (4) the need for other surgery (n = 13), and (5) a patient's desire to discontinue medical treatment that was controlling reflux esophagitis (n = 30). Operative time varied from 34 to 250 minutes (mean [standard deviation], 116 +/- 20). Hospital stay varied from 12 hours to 19 days (mean, 1.2). No patient needed conversion to open operation. Intraoperative complications were observed in 4 patients (5.2%): left pneumothorax in 2, major operative bleeding in 1, and minor spleen lesion in 1. The most common postoperative complications were gas-bloating syndrome and dysphagia. Gastric ulcer was diagnosed in two. Other postoperative complications included acute delirium, acute urinary retention, and acute ischemia of the lower extremity. One patient died of congestive heart failure. It is concluded that laparoscopic fundoplication is an effective procedure for treating geriatric patients with reflux esophagitis and may be performed with low morbidity and mortality rates.
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PMID:Complications of laparoscopic fundoplication in the elderly. 1259 50

The ubiquitin-proteasome pathway has a central role in the selective degradation of intracellular proteins. Among the key proteins modulated by the proteasome are those involved in the control of inflammatory processes, cell cycle regulation, and gene expression. Consequently proteasome inhibition is a potential treatment option for cancer and inflammatory conditions. Thus far, proof of principle has been obtained from studies in numerous animal models for a variety of human diseases including cancer, reperfusion injury, and inflammatory conditions such as rheumatoid arthritis, asthma, multiple sclerosis, and psoriasis. Two proteasome inhibitors, each representing a unique chemical class, are currently under clinical evaluation. Velcade (PS-341) is currently being evaluated in multiple phase II clinical trials for several solid tumor indications and has just entered a phase III trial for multiple myeloma. PS-519, representing another class of inhibitors, focuses on the inflammatory events following ischemia and reperfusion injury. Since proteasome inhibitors exhibit anti-inflammatory and antiproliferative effects, diseases characterized by both of these processes simultaneously, as is the case in rheumatoid arthritis or psoriasis, might also represent clinical opportunities for such drugs.
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PMID:Proteasome inhibition: a new anti-inflammatory strategy. 1270 Aug 91

Adenosine is a ubiquitous autacoid that acts on four defined receptors, named A(1), A(2A), A(2B) and A(3). Although the biological activity of adenosine has been known for more than 70 years and the existence of specific receptors for more than 25 years, it is only now that the full potential for drug development is becoming clear. Among some of the conditions for which adenosine receptor-based therapy might be used are Parkinson's disease, hypoxia/ischemia, epilepsy, kidney disease and asthma.
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PMID:Adenosine receptors as targets for drug development. 1294 59

Despite epidemiological evidence of cardiovascular complications in asthmatics, the direct contribution of asthmatic pathophysiology to cardiovascular effects is unknown. Considering parallels in underlying pathophysiology, we tested the hypothesis that presence of systemic allergy and asthma worsens the outcome of myocardial ischemia-reperfusion injury. Systemic allergy and asthma were created in rabbits by repeated intraperitoneal injections of allergen with adjuvant, followed by an airway challenge in two groups. Nonsensitized animals served as controls. In situ myocardial ischemia-reperfusion was induced in anesthetized animals by a 30-min ligation of a coronary artery, followed by 3 h of reperfusion. Ischemia-reperfusion was done at 24 h after intraperitoneal boost (1 DB) and 7 days (7 DB) after the last intraperitoneal injection and at 24 h (1DAWCH) and 7 days (7DAWCH) after airway challenge. The infarct size (determined by 2,3,5-triphenyltetrazolium chloride staining, normalized to area at risk) was significantly higher in all sensitized groups compared with control (1DB, 31 +/- 4; 7DB, 28.9 +/- 2.6; 1DAWCH, 66.1 +/- 4.1; 7DAWCH, 28.9 +/- 9.2; control, 16.7 +/- 3.2; means +/- SE; P < 0.01 by ANOVA; n = 6). The 1DAWCH group showed significantly greater infarct than all other groups (P < 0.05). Myocardial neutrophil infiltration was significantly higher in the sensitized groups compared with control (P < 0.01). Tissue neutrophil counts showed a strong positive correlation to infarct sizes (r2 = 0.9). These observations indicate that the presence of systemic allergy and asthma is associated with increased myocardial neutrophil infiltration during acute ischemia-reperfusion and increased size of the resulting infarct.
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PMID:Myocardial ischemia-reperfusion injury is enhanced in a model of systemic allergy and asthma. 1471 13

As our understanding of integrins as multifunctional adhesion and signaling molecules has grown, so has their recognition as potential therapeutic targets in human diseases. Leukocyte integrins are of particular interest in this regard, as they are key molecules in immune-mediated and inflammatory processes and are thus critically involved in diverse clinical disorders, ranging from asthma to atherosclerosis. Antagonists that interfere with integrin-dependent leukocyte trafficking and/or post-trafficking events have shown efficacy in multiple preclinical models, but these have not always predicted success in subsequent clinical trials (e.g., ischemia-reperfusion disorders and transplantation). However, recent successes of integrin antagonists in psoriasis, inflammatory bowel disease, and multiple sclerosis demonstrate the tremendous potential of antiadhesion therapy directed at leukocyte integrins. This article will review the role of the leukocyte integrins in the inflammatory process, approaches to targeting leukocyte integrins and their ligands, and the results of completed clinical trials.
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PMID:Targeting leukocyte integrins in human diseases. 1554 73

The complement system not only represents an effective innate immune mechanism of host defense to eradicate microbial pathogens, but it is also widely involved in many forms of acute and chronic inflammatory diseases including sepsis, acute lung injury, ischemia-reperfusion injury, and asthma, to give just a few examples. The complement-activated product, C5a, displays powerful biological activities that lead to inflammatory sequelae. C5a is a strong chemoattractant and is involved in the recruitment of inflammatory cells such as neutrophils, eosinophils, monocytes, and T lymphocytes, in activation of phagocytic cells and release of granule-based enzymes and generation of oxidants, all of which may contribute to innate immune functions or tissue damage. Accumulating data suggest that C5a provides a vital bridge between innate and adaptive immune functions, extending the roles of C5a in inflammation. Herein, we review human and animal data describing the cellular and molecular mechanisms of C5a in the development of inflammatory disorders, sepsis, acute lung injury, ischemia-reperfusion injury, and asthma.
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PMID:Role of C5a in inflammatory responses. 1577 87

It is well established now that beta-blockers are an important treatment of heart failure due to left ventricular systolic dysfunction. It has been shown that this drugs counteract the negative effects of sympathetic stimulation on the myocardium (myocardial hypertrophy, fibrosis and ischemia arythmogenic effect, increase of cardiac loading, apoptosis). Many big trials as CIBIS-II, MERIT-HF and CAPRICORN show that Bisoprolol, Metropolol and Carvedilol decrease the hospitalization rate due to heart failure, improve the functional status and increase the survival rate of patients in class II, Ill and IV. However, beta-blockers are not always safe and there use must be guided by some rules: respect of contra-indications (asthma, severe bradycardia, second or third atrio-ventricular block, arterial hypotension), initiation after 2 or 4 weeks of clinical stability, low initial doses with an increase every 2 or 4 weeks.
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PMID:[Beta blockers in the treatment of heart failure due to left ventricular systolic dysfunction]. 1577 41


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