Gene/Protein Disease Symptom Drug Enzyme Compound
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 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adult female Wistar rats were injected with 125 mg/kg b.w. of human methemoglobin (M-Hb) in order to induce a first episode of hemodynamically-mediated acute renal failure (HMARF). Eleven days after the injection of M-Hb, other groups of rats received another equal dose of the drug in order to induce a second episode of HMARF. Evaluation of renal function, histopathology studies, and determinations of plasma and kidney erythropoietin (Epo) titers by radioimmunoassay in normoxic and hypoxic conditions were performed 1, 2, 3, 5 and 10 days after M-Hb administration. Treatment induced transient increases in plasma urea concentration, fractional sodium excretion, and urine volume, and significant depression in urine osmolality. In every case, the maximal effect of the first injection of M-Hb on the individual parameters was always greater than that of the second injection, and observed on the 5th post-injection day. Histologic sections showed interstitial cellular infiltration, desquamation of the proximal tubular epithelium and collapse or dilation of the tubular lumen. Treatment with M-Hb depressed Epo titers in both kidney homogenates and plasma in normoxic as well as hypoxic rats. Here again, the effect of the first injection of the drug was higher than that of the second one. These observations indicate that there is a negative correlation between kidney tubule injury and Epo production in normoxic and hypoxic conditions. The findings give support to the concept that Epo production is related to proximal tubular function.
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PMID:Depressed plasma erythropoietin levels in rats with hemodynamically-mediated acute renal failure. 209 64

Adult female Wistar rats were injected with 1 mg/kg body weight of uranyl nitrate (UN). Evaluation of renal function, histopathology studies, and determination of plasma erythropoietin (Ep) titers after exposure to 456 mb for 16 h were performed at 1, 2, 7, 10, 15, and 21 days after drug injection. Plasma urea and creatinine concentrations markedly increased during the first seven days after injection, reaching maximal values on day 7 and decreasing thereafter. Significant increases in urine volume and significant depressions in urine osmolality also were observed; both alterations were most marked on day 7 after injection. A coagulative necrosis of the epithelium of proximal convoluted tubules, desquamation of the necrotic cells, and dilation or collapse of the tubular lumen were observed; the lesions were more marked on day 7. Plasma Ep levels in UN-treated rats exposed to hypobaria were markedly lower than in noninjected controls similarly exposed. Measurements were performed one, two, and seven days after UN injection, with maximal depression observed on day 7. These observations indicate that there is a correlation between the extent of both tubule damage and degree of renal dysfunction and plasma Ep production during exposure to hypoxia in UN-treated rats. This suggests that the renal Ep component is derived primarily from tubular cells.
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PMID:Relationship between severity of renal damage and erythropoietin production in uranyl nitrate-induced acute renal failure. 369 9

A 13 year old Thoroughbred gelding was presented with a history of a single episode of collapse during mild exercise. Clinical examination revealed a high packed cell volume (PCV) of 72%, a haemoglobin concentration of 24.9 g/l and 15.2 millions erythrocytes/microliters. Despite continuous intravenous infusion therapy with large volumes, the PCV never decreased to a physiological level. The animal showed a normal appetite and no signs of discomfort or syncope. Arterial blood gas values were in the normal range as well as the concentration of erythropoietin (measured by radioimmunoassay, RIA). A test for neoplasms (carcino-embryonic antigen, CEA) was negative. The liver enzymes of the animal were extremely elevated and a liver biopsy showed a severe fibrosis. Examination of sternal bone marrow aspirate revealed no abnormalities. Based on these findings, the presumptive diagnosis was "absolute polycythaemia". The animal was treated for 7 days with repeated phlebotomy. During this time, the PCV never decreased below 50%, despite no obvious signs of discomfort from the animal. Because of the poor prognosis based on the liver biopsy result, the animal was euthanized 11 days after hospitalization. Post mortem findings were: a granular cell myoblastoma with a diameter of approximately 5 cm in the lungs, severe fibrosis of the liver, mild acute tubular nephrosis in the kidneys, activation of the erythropoietic cells in the bone marrow and thrombosis of the abdominal aorta. The possibility of secondary polycythaemia due to the lung neoplasia was not entirely excluded, but considered to be unlikely. Therefore, the definite diagnosis was polycythemia vera.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Case report: polycythemia in a horse]. 756 45

An unexpected case of nonocclusive mesenteric infarction in a patient on continuous ambulatory peritoneal dialysis is described. The common clinical finding in this entity is a low cardiac output state or even circulatory collapse. Nonocclusive mesenteric infarction has been reported very rarely during continuous ambulatory peritoneal dialysis, and only in the setting of cardiac dysfunction or prolonged hypotension. The current patient had none of the typical features commonly described in the clinical setting of nonocclusive mesenteric infarction; potential mechanisms, including the role of erythropoietin, in the genesis of this disorder are discussed.
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PMID:Unexpected nonocclusive mesenteric infarction during continuous ambulatory peritoneal dialysis. 797 88

Push/pull hemodiafiltration (HDF) is characterized by alternate repetition of filtration and backfiltration during hemodialysis with high-flux membrane. In the pressure-controlled push/pull (PC P/P) HDF system, which is the newest push/pull HDF system, there are about 25 repetitions of dilution and concentration of the blood while it passes through the hemodiafilter. Hence, the PC P/P is functionally close to the predilution mode of on-line HDF. In the PC P/P, body fluid is replaced usually by more than 120 L of dialysate during the 4 h treatment. In selecting a hemodiafilter for PC P/P, one must be certain that the blood flow channels in the hemodiafilter do not collapse by the positive pressure on the dialysate side in the backfiltration phase. Thus, the polyacrylonitrile hollow-fiber hemodiafilter and polysulfon hollow-fiber hemodiafilter are suitable for PC P/P. In the short term, PC P/P has been reported to be effective against joint pain, itchiness, insomnia, irritability, and restless leg syndrome experienced by hemodialysis patients. Midterm clinical effectiveness of PC P/P includes the requisite lowering of the erythropoietin dose and improvement in skin pigmentation. The albumin loss per treatment with the PC P/P was significantly lower than that with the conventional HDF approach when a protein-permeable membrane is used. In terms of the removal rate of prolactin, no significant difference was found between PC P/P and conventional HDF. On the other hand, the removal rates of myoglobin and beta2M, where molecular size was smaller than prolactin, was significantly greater with the PC P/P than with conventional HDF.
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PMID:Push/pull hemodiafiltration: technical aspects and clinical effectiveness. 1061 32

The erythropoietin-producing hepatocellular (Eph) family of receptor tyrosine kinases regulates a multitude of physiological and pathological processes. Despite the numerous possible research and therapeutic applications of agents capable of modulating Eph receptor function, no small molecule inhibitors targeting the extracellular domain of these receptors have been identified. We have performed a high throughput screen to search for small molecules that inhibit ligand binding to the extracellular domain of the EphA4 receptor. This yielded a 2,5-dimethylpyrrolyl benzoic acid derivative able to inhibit the interaction of EphA4 with a peptide ligand as well as the natural ephrin ligands. Evaluation of a series of analogs identified an isomer with similar inhibitory properties and other less potent compounds. The two isomeric compounds act as competitive inhibitors, suggesting that they target the high affinity ligand-binding pocket of EphA4 and inhibit ephrin-A5 binding to EphA4 with K(i) values of 7 and 9 mum in enzyme-linked immunosorbent assays. Interestingly, despite the ability of each ephrin ligand to promiscuously bind many Eph receptors, the two compounds selectively target EphA4 and the closely related EphA2 receptor. The compounds also inhibit ephrin-induced phosphorylation of EphA4 and EphA2 in cells, without affecting cell viability or the phosphorylation of other receptor tyrosine kinases. Furthermore, the compounds inhibit EphA4-mediated growth cone collapse in retinal explants and EphA2-dependent retraction of the cell periphery in prostate cancer cells. These data demonstrate that the Eph receptor-ephrin interface can be targeted by inhibitory small molecules and suggest that the two compounds identified will be useful to discriminate the activities of EphA4 and EphA2 from those of other co-expressed Eph receptors that are activated by the same ephrin ligands. Furthermore, the newly identified inhibitors represent possible leads for the development of therapies to treat pathologies in which EphA4 and EphA2 are involved, including nerve injuries and cancer.
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PMID:Small molecules can selectively inhibit ephrin binding to the EphA4 and EphA2 receptors. 1872 10

The authors present the case of a 15-year-old female patient (Jehova's Witness) who was operated at the age of two on account of a Wilms' tumour of the kidney and irradiated with subsequent postirra-diation scoliosis. In 1990-1993 she was six times subjected to anaesthesia for distraction with a Harrington rod and repeated redistractions. All anaesthesias were of the general type, with artificial pulmonary ventilation in the prone position and without complications. Anaesthesiological methods and procedures were used which made it possible to avoid administration of blood or blood derivatives. In March 1993 the patient was prepared with erythropoietin for the final treatment of the deformed spine. During general anaesthesia suddenly artificial pulmonary ventilation in a prone position became impossible due to complete collapse of the trachea closely behind the end of the armed tracheal tube. After postponing the procedure, bronchoscopic and CT examination in a supine position during spontaneous respiration confirmed stenosis of the distal portion of the trachea to one third of the lumen. The authors assume that the cause are altered anatomical relations of the mediastinum caused by distraction and repeated redistractions in a field affected by irradiation. Key words: deformity of the spine, stenosis of the trachea, Jehova's Witnesses.
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PMID:[Impossibility of artificial ventilation in a prone position in a patient with deformity of the spine (case-history).]. 2044 89

In recent decades, a large body of research has focused on the role of nitric oxide (NO) in the development of cerebral vasospasm (CV) following subarachnoid hemorrhage (SAH). Literature searches were therefore conducted regarding the role of NO in cerebral vasospasm, specifically focusing on NO donors, reactive nitrogen species, and peroxynitrite in manifestation of vasospasm. Based off the assessment of available evidence, two competing theories are reviewed regarding the role of NO in vasospasm. One school of thought describes a deficiency in NO due to scavenging by hemoglobin in the cisternal space, leading to an NO signaling deficit and vasospastic collapse. A second hypothesis focuses on the dysfunction of nitric oxide synthase, an enzyme that synthesizes NO, and subsequent generation of reactive nitrogen species. Both theories have strong experimental evidence behind them and hold promise for translation into clinical practice. Furthermore, NO donors show definitive promise for preventing vasospasm at the angiographic and clinical level. However, NO augmentation may also cause systemic hypotension and worsen vasospasm due to oxidative distress. Recent evidence indicates that targeting NOS dysfunction, for example, through erythropoietin or statin administration, also shows promise at preventing vasospasm and neurotoxicity. Ultimately, the role of NO in neurovascular disease is complex. Neither of these theories is mutually exclusive, and both should be considered for future research directions and treatment strategies.
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PMID:Nitric oxide in cerebral vasospasm: theories, measurement, and treatment. 2387 35

Trans interactions of erythropoietin-producing human hepatocellular (Eph) receptors with their membrane-bound ephrin ligands generate higher-order clusters that can form extended signaling arrays. The functional relevance of the cluster size for repulsive signaling is not understood. We used chemical dimerizers and fluorescence anisotropy to generate and visualize specific EphB2 cluster species in living cells. We find that cell collapse responses are induced by small-sized EphB2 clusters, suggesting that extended EphB2 arrays are dispensable and that EphB2 activation follows an ON-OFF switch with EphB2 dimers being inactive and trimers and tetramers being fully functional. Moreover, the strength of the collapse response is determined by the abundance of multimers over dimers within a cluster population: the more dimers are present, the weaker the response. Finally, we show that the C-terminal modules of EphB2 have negative regulatory effects on ephrin-induced clustering. These results shed new light on the mechanism and regulation of EphB2 activation and provide a model on how Eph signaling translates into graded cellular responses.
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PMID:The composition of EphB2 clusters determines the strength in the cellular repulsion response. 2446 34

The receptor tyrosine kinase, erythropoietin-producing hepatocellular A4 (EphA4), was recently identified as a molecular target for Alzheimer's disease (AD). We found that blockade of the interaction of the receptor and its ligands, ephrins, alleviates the disease phenotype in an AD transgenic mouse model, suggesting that targeting EphA4 is a potential approach for developing AD interventions. In this study, we identified five FDA-approved drugs-ergoloid, cyproheptadine, nilotinib, abiraterone, and retapamulin-as potential inhibitors of EphA4 by using an integrated approach combining virtual screening with biochemical and cellular assays. We initially screened a database of FDA-approved drugs using molecular docking against the ligand-binding domain of EphA4. Then, we selected 22 candidate drugs and examined their inhibitory activity towards EphA4. Among them, five drugs inhibited EphA4 clustering induced by ephrin-A in cultured primary neurons. Specifically, nilotinib, a kinase inhibitor, inhibited the binding of EphA4 and ephrin-A at micromolar scale in a dosage-dependent manner. Furthermore, nilotinib inhibited the activation of EphA4 and EphA4-dependent growth cone collapse in cultured hippocampal neurons, demonstrating that the drug exhibits EphA4 inhibitory activity in cellular context. As demonstrated in our combined computational and experimental approaches, repurposing of FDA-approved drugs to inhibit EphA4 may provide an alternative fast-track approach for identifying and developing new treatments for AD.
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PMID:Identification of new EphA4 inhibitors by virtual screening of FDA-approved drugs. 2974 17


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