Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.2.1.13 (glyceraldehyde-3-phosphate dehydrogenase)
6,511 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Iron overload is associated with long-term cardiac iron accumulation and tissue changes such as fibrosis. To determine short-term iron-dependent changes in expression of genes associated with iron homeostasis and fibrosis we measured mRNA on Northern blots prepared from cultured rat neonatal cardiomyocytes and non-myocytes (fibroblasts) as a function of iron loading and chelation. Transferrin receptor mRNA was reduced in myocytes exposed to various concentrations of iron for 3 days and this decline was associated with a 63% decline in iron-response element (IRE) binding of iron regulatory protein-1, indicating that myocytes utilize IRE-dependent mechanisms to modulate gene expression. In myocytes iron caused a dose-dependent decline in mRNAs coding for transforming growth factor- beta(1)(TGF- beta(1)), biglycan, and collagen type I while plasminogen activator inhibitor-1 mRNA was unaffected by iron loading and decorin mRNA doubled. Total TGF- beta bioactivity was also decreased by iron loading. Thus, the effects of iron loading on genes related to cardiac fibrosis are gene-specific. Addition of deferoxamine for 1 day did not have any significant effect on any of these genes. Parallel changes in gene expression were exhibited by non-myocytes (fibroblasts), where chelation also decreased TGF- beta(1)mRNA and activity, and mRNA for collagen type I and biglycan, and collagen synthesis. In addition to these changes in transcripts associated with matrix formation the mRNA of the metabolic enzyme glyceraldehyde-3-phosphate dehydrogenase was unaffected by iron loading but doubled in both cell types upon treatment with deferoxamine. These findings suggest that in both cardiac myocytes and non-myocyte fibroblasts gene expression is coupled to intracellular iron pools by gene-specific and IRE-dependent and idependent mechanisms. This linkage may influence matrix deposition, a significant component of cardiac injury.
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PMID:Changes in gene expression with iron loading and chelation in cardiac myocytes and non-myocytic fibroblasts. 1072

We examined the cartilaginous gene expression in the inner layer of the pseudo-tendon sheath formed by an silicon rod. While cartilaginous gene expression was not detected in the outer layer of the tissue, gene expressions of aggrecan and type II collagen were detected in the inner layer of the the newly formed pseudo-tendon sheath around the silicon rod. Relative expression of aggrecan and Type II collagen were 0.15 and 0.28, respectively, compared to that of GAPDH. The expression of type II collagen was 0.57-folds of that of type I collagen. In these tissues, a sliding surface was formed by a silicon rod and the surrounding tissues, and its mechanical stress may induce cartilaginous gene expression. Mechanical stress together with various growth factors and cytokines may be critically important for the formation of more physiological tendon sheath structures. Therefore, we will further examine the changes detected in the tissues and evaluate mechanical stress for formation of the tendon sheath.
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PMID:Expression of differentiated phenotype in the pseudo-tendon sheath formed by a silicon rod. 1098 63

In the patients with dislocated hip arthropathy, cartilage gene expression was confirmed in weight-bearing inner layer tissues of the joint capsule. Because these inner layer tissues of the joint capsule formed joint-like structures with the femoral head for a long period, cartilaginous genes may have been expressed in the weight-bearing inner surface of the joint capsule. There was a difference in expression of the genes between weight-bearing and non-weight-bearing parts. From a quantitative comparison between GAPDH and aggrecan gene expression, aggrecan gene expression was 30-fold higher in the weight-bearing part than in the non-weight-bearing part. Aggrecan gene expression was not detected in outer layer tissues of the joint capsule. Type II collagen and TGF-beta genes were also detected, and both genes showed differences in expression between the weight-bearing and non-weight-bearing parts like the aggrecan gene. This may have been because mechanical stress caused cartilaginous differentiation in undifferentiated mesenchymal tissues in the inner layer of the joint capsule. Cell differentiation and proliferation caused by mechanical stress are indicate key role to osteoarticular tissues, and it is considered important for orthopedic treatment to evaluate the process in detail.
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PMID:Effects of mechanical stress on expression of differentiated phenotypes of chondrocytes. 1098 64

The study of drug metabolism in cultured rat hepatocytes is hampered by the rapid loss of the expression of cytochrome P450 enzymes. Nevertheless, the activity of cytochrome P450 3A (CYP3A), one of the most important isoenzymes for drug metabolism, can be elevated by chemical inducers. In the present study, we investigated in cultured rat hepatocytes the induction of all four currently identified CYP3A isoforms by dexamethasone, and compared the results obtained in vitro with the induction profile of dexamethasone in vivo. To this end, CYP3A mRNA levels were quantified with a novel, radioactive reverse transcriptase-polymerase chain reaction (RT-PCR) assay, and CYP3A enzymatic activity was measured by a testosterone hydroxylation assay. In the RT-PCR assay, CYP3A isoforms were co-amplified with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the presence of radioactively labeled nucleotides. This resulted in an extremely sensitive and accurate determination of CYP3A expression levels, relative to those of GAPDH. Using this RT-PCR assay, it was found that the expression of all CYP3A isoforms in rat hepatocytes, cultured on a collagen matrix, was decreased by 80-90% within one day of cultivation. After addition of dexamethasone, at one day after isolation, CYP3A1 mRNA levels were elevated to levels comparable to those in freshly isolated hepatocytes within two days. In contrast, CYP3A2, CYP3A9, and CYP3A18 mRNA levels were not affected by dexamethasone treatment, and were hardly detectable after three days of cultivation. CYP3A enzymatic activity was also induced in cultured hepatocytes (approximately 6-fold) after addition of dexamethasone. In vivo, CYP3A1 mRNA levels increased 45-fold after dexamethasone administration. However, in contrast to the situation in cultured hepatocytes, CYP3A2 and CYP3A18 were also induced, albeit to a lesser extent (4- and 7-fold elevated mRNA levels, respectively). We conclude that the selective induction of CYP3A1 in dexamethasone-treated rat hepatocytes allows the study of biotransformation reactions by CYP3A1, without interference by any of the other CYP3A isoenzymes.
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PMID:Selective induction of cytochrome P450 3A1 by dexamethasone in cultured rat hepatocytes: analysis with a novel reverse transcriptase-polymerase chain reaction assay section sign. 1102 Apr 54

To test the hypothesis that loading conditions can be used to engineer early ligament scar behaviors, we used an in vitro system to examine the effect that cyclic hydrostatic compression and cyclic tension applied to 6-week rabbit medial collateral ligament scars had on mRNA levels for matrix molecules, collagenase, and the proto-oncogenes c-fos and c-jun. Our specific hypothesis was that tensile stress would promote more normal mRNA expression in ligament whereas compression would lead to higher levels of mRNA for cartilage-like molecules. Femur (injured medial collateral ligament)-tibia complexes were subjected to a hydrostatic pressure of 1 MPa or a tensile stress of 1 MPa of 0.5 Hz for 1 minute followed by 14 minutes of rest. On the basis of a preliminary optimization experiment, this 15-minute testing cycle was repeated for 4 hours. Semiquantitative reverse transcription-polymerase chain reaction analysis was performed for mechanically treated medial collateral ligament scars with use of rabbit specific primer sets for types I, II, and III collagen, decorin, biglycan, fibromodulin, versican, aggrecan, collagenase, c-fos, c-jun, and a housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase. Cyclic hydrostatic compression resulted in a statistically significant increase in mRNA levels of type-II collagen (171% of nonloaded values) and aggrecan (313% of nonloaded values) but statistically significant decreases in collagenase mRNA levels (35% of nonloaded values). Cyclic tension also resulted in a statistically significant decrease in collagenase mRNA levels (66% of nonloaded values) and an increase in aggrecan mRNA levels (458% of nonloaded values) but no significant change in the mRNA levels for the other molecules. The results show that it is possible to alter mRNA levels for a subset of genes in scar tissue by supplying unique mechanical stimuli in vitro and thus that further investigation of scar engineering for potential reimplantation appears feasible.
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PMID:Compressive compared with tensile loading of medial collateral ligament scar in vitro uniquely influences mRNA levels for aggrecan, collagen type II, and collagenase. 1105 87

To test the hypothesis that loading conditions can be used to "engineer" ligament autograft behaviors, the effect of cyclic tension on the mRNA levels of matrix molecules and collagenase in in-vivo immobilized and mobilized 6-week rabbit medial collateral ligament (MCL) autografts was examined using an in-vitro system. Femur-[autograft MCL]-tibia complexes were subjected to a tensile stress of 4 MPa at 0.5 Hz for 1 min, followed by 14 min of rest. This 15-min testing cycle was repeated for 4 h. Semi-quantitative reverse transcrip-tase polymerase chain reaction (RT-PCR) was performed on RNA from mechanically treated MCL autografts, using rabbit-specific primer sets for types I and III collagen, biglycan, decorin, fibromodulin, lumican, versican, matrix metalloproteinase-1 (MMP-1, collagenase-1), MMP-13 (collagenase-3), and a housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Interestingly, 4 h of culture of normal control MCLs led to increased mRNA levels for MMP-1 (P < 0.05), but there were no significant changes in MMP-13 mRNA levels. Total RNA levels in that normal MCL tissue were, however, decreased after culture (P < 0.05). In-vitro tensile loading of in-vivo mobilized autografts resulted in a significant increase in total RNA (185% of in-vitro non-loaded autografts). On the other hand, in-vitro tensile loading of in-vivo immobilized autografts resulted in no significant changes in total RNA levels compared with levels in non-loaded control grafts. MMP-1 mRNA levels in both the in-vivo mobilized (47% of non-loaded autograft) and in-vivo immobilized (38% of non-loaded autograft) MCL autografts were significantly lower than those in non-loaded control tissue following in-vitro tensile loading, but there were no significant changes in the mRNA levels for the seven other matrix molecules assessed. These results show that it is possible to selectively inhibit MMP-1 mRNA levels in autograft ligaments by supplying mechanical stimuli in vitro. The results also demonstrate that in-vivo immobilization leads to a decrease in the effects of subsequent in-vitro mechanical loading in such autografts with respect to total RNA levels. Collectively, these results demonstrate that both in-vivo and in-vitro loading have implications in the engineering of an ideal ligament graft.
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PMID:In-vitro cyclic tensile loading of an immobilized and mobilized ligament autograft selectively inhibits mRNA levels for collagenase (MMP-1). 1118 Sep 9

Smokers look older than non-smokers of the same age. We have compared the concentrations of mRNA for matrix metalloproteinase 1 (MMP-1) in the buttock skin of smokers and non-smokers with quantitative real-time polymerase chain reactions. MMP-1 degrades collagen, which accounts for at least 70% of the dry weight of dermis. We report significantly more MMP-1 mRNA in the skin of smokers than non-smokers whereas no difference was seen for the tissue inhibitor of metalloproteinases 1 (TIMP-1) or the housekeeping gene GAPDH (glyceraldehyde-3-phosphate dehydrogenase). We suggest that smoking-induced MMP-1 might be important in the skin-ageing effects of tobacco smoking.
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PMID:Matrix metalloproteinase-1 and skin ageing in smokers. 1150 31

Collagen alpha1(I) mRNA is posttranscriptionally regulated in hepatic stellate cells (HSCs). Binding of protein factors to the evolutionary conserved stem-loop in the 5'-untranslated region (5' stem-loop) is required for a high level of expression in activated HSCs. The 5' stem-loop is also found in alpha2(I) and alpha1(III) mRNAs. Titration of the 5' stem-loop binding factors by a stably expressed RNA containing the 5' stem-loop (molecular decoy) may decrease the expression of these collagen mRNAs. We designed a 108-nt RNA that is transcribed from the optimized mouse U7 small nuclear RNA gene and contains the 5' stem-loop (p74WT decoy). This decoy accumulates in the nucleus and in the cytoplasm. When expressed in NIH 3T3 fibroblasts, the p74WT decoy decreased collagen alpha1(I) mRNA level by 60% and decreased collagen type I secreted into the cellular medium by 50%. We also expressed this decoy in quiescent rat HSCs by adenoviral gene transfer. Quiescent HSCs undergo activation in culture, resulting in a 60-70-fold increase in collagen alpha1(I) mRNA. The decoy decreases collagen alpha1(I) mRNA expression by 50-60% during activation of HSCs. It also decreases collagen alpha2(I) mRNA expression and collagen alpha1(III) mRNA expression. The cellular levels of collagen alpha1(I) propeptide and of disulfide-bonded collagen type I trimer are reduced by 70%. However, the p74WT decoy did not decrease alpha smooth muscle actin protein or the mRNA levels of glyceraldehyde-3-phosphate dehydrogenase and interleukin-6. The p74WT decoy was also introduced into activated human HSCs. In these cells, the decoy decreased collagen alpha1(I) propeptide and disulfide-bonded collagen trimer by 50-60%. These results indicate that the 5' stem-loop specifically regulates fibrillar collagen synthesis and represents a novel target for antifibrotic therapy. The molecular decoys provide a generalized method of assessing the functional significance of blocking the interactions of mRNA and proteins.
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PMID:Inhibition of collagen alpha 1(I) expression by the 5' stem-loop as a molecular decoy. 1188 20

To assess the mRNA expression of extracellular matrix genes which might correlate with or contribute to mechanically weaker medial collateral ligament (MCL) scars in the ACL-deficient rabbit knee joint compared to those in anterior cruciate ligament (ACL) intact knee joints, a bilateral MCL injury was induced in 10 skeletally mature female NZW rabbits. As part of the same surgical procedure, the ACL was transected in one of the knees while the contralateral knee had a sham procedure. The side having the combined MCL and ACL injury was randomly assigned. After six weeks, the rabbits were euthanized. Histological assessments were performed on samples of the MCL scars from each operated knee (n = 3 animals) and mRNA levels for collagen type I, III, V, decorin, biglycan, lumican, fibromodulin, TGF-beta, IL-1, TNF-alpha, MMP-1, MMP-13, and a housekeeping gene (GAPDH) were assessed using semiquantitative RT-PCR on RNA isolated from the MCL scar tissue of the remaining animals (n = 7 animals). Levels of mRNA for each gene were normalized using the corresponding GAPDH value. Results showed that the total RNA yield (per mg wet weight) in the MCL scar of the ACL-deficient knee was significantly greater than that in the MCL scar from the ACL-intact knee. Collagen type I mRNA levels were significantly lower and mRNA levels for TNF-alpha were significantly greater in the scars of ACL-deficient knees compared to scars from ACL-intact joints. There were no significant differences between ACL-deficient and ACL-intact knees with respect to MCL scar mRNA levels for the remaining genes assessed. Histologically, the "flaw" area, which has been shown to correlate with mechanical properties in previous studies, was significantly greater in MCL scars from ACL-deficient knees than in the ACL-intact MCL scars. The mean number of cells/mm2 in MCL scars from ACL-deficient knees was significantly greater than in MCL scars from ACL-intact knees. The present study suggests that MCL scar cell metabolism is differentially influenced by the combined injury environment.
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PMID:ACL transection influences mRNA levels for collagen type I and TNF-alpha in MCL scar. 1203 26

Free radicals are reactive chemical species that differ from other compounds in that they have unpaired electrons in their outer orbitals. They are capable of damaging cellular components, and accumulating evidence suggests that they may contribute to various disease entities including inflammatory joint disease. Reactive oxygen species (ROS) as well as reactive nitrogen species (RNS) can directly or indirectly damage basic articular constituents and lead to the clinical expression of the inflammatory arthritis. Hydroxyl radicals degrade isolated proteoglycans, and HOCl fragments collagen. Hydrogen peroxide, which is very diffusible, readily inhibits cartilage proteoglycan synthesis, e.g. by interfering with ATP synthesis, in part by inhibiting the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase in chondrocytes, aggravating the effects of proteolytic and free-radical-mediated cartilage degradation. Peroxynitrite and HOCl may facilitate cartilage damages by inactivating TIMPs. TIMP-1 inhibits stromelysins, collagenases and gelatinases and this ability is lost after ONOO(-) or HOCl treatment. HOCl can also activate latent forms of neutrophil collagenases and gelatinase with obvious consequences. Hypochlorous acid, ONOO(-) and O(2)(*-) react with ascorbate, which is essential for cartilage function, leading to low levels of ascorbate in synovial fluid. Low concentrations of H2O(2), O(2)(*-) or both, accelerate bone resorption by osteoclasts, whereas NO. inhibits it. NO. promotes chondrocyte apoptosis, inhibits proteoglycan synthesis and activates latent metalloproteinases and cyclooxygenase. ROS, produced by activated phagocytes, could alter the antigenic behaviour of immunoglobulin G, producing fluorescent protein aggregates that can further activate phagocytic cells. Radical-exposed IgG is able to bind rheumatoid factor and results in the generation of C3alpha. This reaction may be self-perpetuating within the rheumatoid joint, suggesting that free radicals play a role in the chronicity of the inflammatory reaction which is a key question regarding to which extent free radicals contribute to the consequences of inflammation, such as the cartilage and bone destruction. Reactive oxygen intermediates can also function as signaling messengers to activate transcription factors, like NFkB and AP-1, and induce gene expression. All this knowledge might serve to apply a rational selection of antioxidants for possible therapeutic purposes, enforcing combination therapy of the inflammatory joint disease.
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PMID:The role of free radicals in the pathogenesis of rheumatoid arthritis. 1268 16


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