Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

LEC rats show spontaneous hepatitis and hepatocarcinoma development related to oxidative stress due to abnormal copper accumulation in the liver. We used DNA microarrays bearing 22,012 genes to investigate at the transcriptomic level the progression of the hepatitis in LEC rats in comparison to a control obtained from LEC rats treated with D-penicillamine, a copper chelating agent known to block hepatitis development. Multivariate statistical analyses as partial least square (PLS) regression between transcriptomic data and hepatitis markers in plasma led us to select 483 genes related to hepatitis development in these rats. After a complementary discriminant analysis (PLS-DA), 239 important genes for the separation between the different rat groups were selected. Gene ontology classification revealed an overrepresentation of genes involved in protein metabolism-related functions. More importantly, some genes implicated in proteasome pathway were upregulated. However, analysis of 20S proteasome activity showed that trypsin-like and peptidylglutamyl peptide hydrolase activities were diminished during hepatitis. Because oxidative stress is known to promote the inactivation of the proteasome complex, we propose the deregulation of the proteasome genes expression as a result of oxidative inactivation of proteasome activity during hepatitis in LEC rats. These results bring new insights in the hepatitis and the hepatocarcinogenesis development.
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PMID:Proteasome activity deregulation in LEC rat hepatitis: following the insights of transcriptomic analysis. 1809 9

The ubiquitin-proteasome system is involved in various cellular processes, including transcription, apoptosis, and cell cycle. In vitro, in vivo, and clinical studies suggest the potential use of proteasome inhibitors as anticancer drugs. Cadmium (Cd) is a widespread environmental pollutant that has been classified as a human carcinogen. Recent study in our laboratory suggested that the clinically used anti-alcoholism drug disulfiram (DSF) could form a complex with tumor cellular copper, resulting in inhibition of the proteasomal chymotrypsin-like activity and induction of cancer cell apoptosis. In the current study, we report, for the first time, that DSF is able to convert the carcinogen Cd to a proteasome-inhibitor and cancer cell apoptosis inducer. Although the DSF-Cd complex inhibited the chymotrypsin-like activity of a purified 20S proteasome with an IC(50) value of 32 micromol/L, this complex was much more potent in inhibiting the chymotrypsin-like activity of prostate cancer cellular 26S proteasome. Inhibition of cellular proteasome activity by the DSF-Cd complex resulted in the accumulation of ubiquitinated proteins and the natural proteasome substrate p27, which was followed by activation of calpain and induction of apoptosis. Importantly, human breast cancer MCF10DCIS cells were much more sensitive to the DSF-Cd treatment than immortalized but non-tumorigenic human breast MCF-10A cells, demonstrating that the DSF-Cd complex could selectively induce proteasome inhibition and apoptosis in human tumor cells. Our work suggests the potential use of DSF for treatment of cells with accumulated levels of carcinogen Cd.
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PMID:Disulfiram promotes the conversion of carcinogenic cadmium to a proteasome inhibitor with pro-apoptotic activity in human cancer cells. 1830 98

Zinc and copper are trace elements essential for proper folding, stabilization and catalytic activity of many metalloenzymes in living organisms. However, disturbed zinc and copper homeostasis is reported in many types of cancer. We have previously demonstrated that copper complexes induced proteasome inhibition and apoptosis in cultured human cancer cells. In the current study we hypothesized that zinc complexes could also inhibit the proteasomal chymotrypsin-like activity responsible for subsequent apoptosis induction. We first showed that zinc(II) chloride was able to inhibit the chymotrypsin-like activity of a purified 20S proteasome with an IC(50) value of 13.8 microM, which was less potent than copper(II) chloride (IC(50) 5.3 microM). We then compared the potencies of a pyrrolidine dithiocarbamate (PyDT)-zinc(II) complex and a PyDT-copper(II) complex to inhibit cellular proteasomal activity, suppress proliferation and induce apoptosis in various human breast and prostate cancer cell lines. Consistently, zinc complex was less potent than copper complex in inhibiting the proteasome and inducing apoptosis. Additionally, zinc and copper complexes appear to use somewhat different mechanisms to kill tumor cells. Zinc complexes were able to activate calpain-, but not caspase-3-dependent pathway, while copper complexes were able to induce activation of both proteases. Furthermore, the potencies of these PyDT-metal complexes depend on the nature of metals and also on the ratio of PyDT to the metal ion within the complex, which probably affects their stability and availability for interacting with and inhibiting the proteasome in tumor cells.
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PMID:Pyrrolidine dithiocarbamate-zinc(II) and -copper(II) complexes induce apoptosis in tumor cells by inhibiting the proteasomal activity. 1850 97

5-Chloro-7-iodo-quinolin-8-ol (Clioquinol) is a halogenated 8-hydroxyquinoline that was used in 1950-1970s as an oral anti-parasitic agent for the treatment and prevention of intestinal amebiasis. However in the 1970s oral Clioquinol was withdrawn from the market due to reports of neurotoxicity in Japanese patients. Recently, reports have demonstrated that Clioquinol has activities beyond its use as an antimicrobial. For example, Clioquinol inhibits the function of the proteasome and displays preclinical efficacy in the treatment of malignancy. In addition, due to its ability to bind copper and dissolve beta-amyloid plaques in the brain, Clioquinol has been investigated for the treatment of Alzheimer's disease. As such, efforts are underway to repurpose Clioquinol. In light of the reemergence of oral Clioquinol, we review the toxicology of this compound in animals and humans with an emphasis on its neurotoxicity. Such information will aid in the design of clinical trials of oral Clioquinol for new indications such as cancer therapy.
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PMID:The toxicology of Clioquinol. 1881 16

A series of three complexes with diethyldithiocarbamate ligand and three different metals (Ni, Cu, Zn) was prepared, confirmed by X-ray crystallography, and tested in human breast cancer MDA-MB-231 cells. Zinc and copper complexes, but not nickel complex, were found to be more active against cellular 26S proteasome than against purified 20S proteasome core particle. One of the possible explanations is inhibition of JAMM domain in the 19S proteasome lid.
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PMID:Ni(II), Cu(II), and Zn(II) diethyldithiocarbamate complexes show various activities against the proteasome in breast cancer cells. 1881 9

Interest in the use of metallic compounds for cancer treatment has been increasing since the discovery of cisplatin. Clinical studies suggest the use of proteasome inhibitors as potential novel anticancer agents. L-glutamine is the most abundant free amino acid in the body, and has been shown to play a regulatory role in several cellular processes, including metabolism, degradation, redox potential and cellular integrity. Although glutamine is reported to play a role in the regulation of apoptosis, the effect of glutamine copper complex on tumor cells and the involved molecular mechanism have not been investigated. Here, for the first time, we report that a newly synthesized L-glutamine-containing copper complex has proteasome-inhibitory activity in human breast cancer and leukemia cells. The inhibition of the tumor proteasomal activity results in the accumulation of ubiquitinated proteins and ubiquitinated form of IkappaB-alpha, a natural proteasome substrate, followed by induction of apoptosis. Furthermore, this glutamine Schiff base copper complex selectively inhibits the proteasomal activity and induces cell death in cultured breast cancer cells, but not normal, immortalized breast cells. Our data suggest that glutamine Schiff base copper complexes have a potential use for to be used in cancer treatment and prevention.
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PMID:L-glutamine Schiff base copper complex as a proteasome inhibitor and an apoptosis inducer in human cancer cells. 1894 71

Schiff bases have been intensively investigated due to their antibacterial and antitumor properties. Copper is a cofactor essential for the tumor angiogenesis processes, whereas other transition metals are not. Consistently, high serum or tissue levels of copper were found in many types of human cancer including breast, prostate, colon, lung, and brain, supporting the idea that copper could be used as a novel selective target for cancer therapies. In the current study we hypothesize that a synthetic taurine Schiff base copper complex (Compound 1) could suppress tumor cell growth via the direct inhibition of proteasomal activity. Compound 1 potently inhibits the activity of purified 20S and 26S proteasome in human breast cancer MDA-MB-231 and leukemia Jurkat T cells. Inhibition of tumor cellular proteasomal activity by Compound 1 results in the accumulation of ubiquitinated protein and the proteasome target proteins p27 and Bax, followed by the induction of apoptosis. Our results strongly suggest that taurine Schiff base copper complexes, as potent proteasome inhibitors, have great potential to be developed into novel anticancer drugs.
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PMID:Induction of tumor cell apoptosis by taurine Schiff base copper complex is associated with the inhibition of proteasomal activity. 1894 90

Copper toxicity is associated with formation of reactive oxygen species, which are capable to oxidize proteins. The selective removal of the latter by the 20S proteasome is considered an essential part of the cell antioxidant defense system. The aim of the present study was to investigate whether peptidase activities of rat liver proteasomes were affected by chronic (40 mg CuSO(4)/rat/daily with the drinking water for 2 weeks) and acute (20 mg/kg CuSO(4), s.c.) copper treatment. To evaluate the role of proteasome, its inhibitor MG132 was also used. The degree of copper-induced oxidative stress (OS), established by measuring lipid peroxidation, protein oxidation, and cellular glutathione level, as well as activities of antioxidant enzymes--catalase, superoxide dismutase, and gultathionine peroxidase, depended on the mode of copper administration. Chronic copper administration (mild oxidative stress) did not affect proteasome activities, whereas acute copper treatment (severe oxidative stress) caused a decline in chymotryptic- and tryptic-like activities. The treatment of copper-loaded animals with MG132 did not change copper-induced alterations in the tested indices, except an additional increase in protein oxidation and inhibition of glutathionine peroxidase activity. The results suggested that the in vivo copper-induced oxidative stress was associated with changes in the catalytic activity of proteasome.
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PMID:Effect of copper intoxication on rat liver proteasome activity: relationship with oxidative stress. 1897

While physiological changes associated with copper toxicity have been studied in adult fathead minnow, Pimephales promelas, little is known about the effect of copper on newly hatched larvae. As a result we initiated an investigation on the mechanism of copper toxicity in 24 h post-hatch larvae using gene expression changes to identify responsive genes. Fish were exposed to copper concentrations of 0, 50, 125 and 200 mug/L in a 48 h toxicity test. Total RNA from survivors was used in a differential display assay to screen for differentially expressed gene products. Altogether, 654 copper-responsive differentially expressed bands were collected. Database searches found homology for 261 sequences. One hundred and sixty-one bands were homologous to NCBI genes of known function, of which 69 were individual genes. The most abundant categories of functional genes responding to copper were involved in protein synthesis/translational machinery and contractile proteins. Twenty-one dose-responsive genes were measured for expression changes using real-time quantitative PCR. Differential gene expression was validated for 11 of 13 genes, when a 1.2 times qPCR difference between the copper and control samples was observed. Transcripts identified as titin, cytochrome b, fast muscle specific heavy myosin chain 4, fast muscle troponin I, proteasome 26S subunit and troponin T3a were induced over twofold. Differential display bands identified as 60S ribosomal proteins L27 and L12 were repressed approximately threefold. We conclude that copper exposure affects several cellular pathways in larval fathead minnows with protein synthesis, ribosome structure, and muscle contractile proteins being the most sensitive to this stress.
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PMID:Identification of copper-responsive genes in an early life stage of the fathead minnow Pimephales promelas. 1902 Sep 76

The achievements of burn metabolism and nutrition in China are briefly presented. Advance a new theory "Enterogenous Hypermetabolism". Develop a formula to calculate calorie needs in Chinese burn adults. Put forward new ideas on glucose absorption, neo glycogenesis, insulin resistance, and the use of hypoglycemic agent after burn injury. Observe the variation of plasma level of free aminoacids, investigate the changes and mechanisms of 26S proteasome and 19S regulator in skeletal muscle of burn trauma, and the clinical application and its mechanism of glutamine and arginine. Introduce the approach of (13)C NMR spectroscopy to investigate the alterations of hepatic anabolism functions in severely burned rats. Offer supplying the suitable dosage of vitamin A, C, E and microelement of zinc, copper, ferrum for burn patients. Carry out serial studies of early enteral and parenteral nutrition, and compare enteral nutrition with parenteral nutrition. Early enteral nutrition with synbiotics might be beneficial to the controlling of burn infection. Both glucagon like peptide-2 (GLP-2) and intestinal trefoil factor (ITF) exhibit protective effect on intestinal mucosa in minimizing injury and protecting barrier function. The choice of suitable opportunity to use rhGH (growth hormone) is investigated. In addition, advance the view points of ischemia and anoxia in metabolism, anti-inflammatory immune and nutrition.
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PMID:[Progress of burn research in metabolism and nutrition in China]. 1910 30


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