Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Different intrinsic alterations of skeletal muscle metabolism and gene expression have been described in chronic heart failure (CHF). As proposed skeletal muscle alterations in CHF may contribute to exercise intolerance and early muscular fatigue. However the exact molecular changes occurring in the skeletal muscle are still unclear. The aim of this study was to characterize the pattern of differential gene expression in an animal model of CHF and to study the regulation of one selected gene. Rats were subjected to LAD ligation or sham operation. mRNA was isolated from musculus quadriceps of both groups and differential gene expression was determined by subtractive hybridization. Quantitative RT-PCR and cell culture experiments were performed to further characterize the changed expression of protein phosphatase 2A (PP2A) in human skeletal muscle biopsies as well as the cytokine dependent regulation of PP2A expression. Out of 800 picked clones differential expression of 24 distinct genes could be identified by sequencing and reverse Northern blotting. PP2A expression demonstrated a significant upregulation in skeletal muscle biopsies from patients with CHF as compared to healthy controls (9.7 +/- 1.9 vs. 4.2 +/- 0.7 arbitrary units; p<0.05). Incubation of rat skeletal muscle myoblasts with a combination of TNF-alpha, IL-1beta, and gamma-IFN caused a 3-fold upregulation of PP2A expression vs. untreated cells. These results suggest that CHF is accompanied by changes in expression of genes involved in energy metabolism, contractility, and apoptosis in the skeletal muscle. The upregulation of PP2A, an important regulator in intracellular signaling and apoptosis, may be due to an increase of inflammatory cytokines.
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PMID:Differential gene expression in skeletal muscle after induction of heart failure: impact of cytokines on protein phosphatase 2A expression. 1456 76

Treatment of acute myeloid leukaemia (AML) is challenging and emerging treatment options include protein phosphatase 2A (PP2A) activators. Fingolimod is a known PP2A activator that inhibits multiple signalling pathways and has been used extensively in patients with multiple sclerosis and other indications. The initial positive results of PP2A activators in vitro and mouse models of AML are promising; however, its safety for use in AML has not been assessed. From human studies of fingolimod in other indications, it is possible to evaluate whether the safety and toxicity profile of the PP2A activators will allow their use in treating AML. A literature review was carried out to assess safety before the commencement of Phase I trials of the PP2A activator Fingolimod in AML. From human studies of fingolimod in other indications, it is possible to evaluate whether the safety and toxicity profile of the PP2A activators will allow their use in treating AML. A systematic review of published literature in Medline, EMBASE and the Cochrane Library of critical reviews was carried out. International standards for the design and reporting of search strategies were followed. Search terms and medical subject headings used in trials involving PP2A activators as well as a specific search were performed for 'adverse events', 'serious adverse events', 'delays in treatment', ' side effects' and 'toxicity' for primary objectives. Database searches were limited to papers published in the last 12 years and available in English. The search yielded 677 articles. A total of 69 journal articles were identified as relevant and included 30 clinical trials, 24 review articles and 15 case reports. The most frequently reported adverse events were nausea, diarrhoea, fatigue, back pain, influenza viral infections, nasopharyngitis and bronchitis. Specific safety concerns include monitoring of the heart rate and conduction at commencement of treatment as cardiotoxicity has been reported. There is little evidence to suggest specific bone marrow toxicity. Lymophopenia is a desired effect in the management of multiple sclerosis, but may have implications in patients with acute leukaemia as it may potentially increase susceptibility to viral infections such as influenza. Fingolimod is a potential treatment option for AML with an acceptable risk to benefit ratio, given its lack of bone marrow toxicity and the relatively low rate of serious side effects. As most patients with AML are elderly, specific monitoring for cardiac toxicity as well as infection would be required.
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PMID:A systematic evaluation of the safety and toxicity of fingolimod for its potential use in the treatment of acute myeloid leukaemia. 2696 15