Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.49 (reverse transcriptase)
 31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to test the selectivity, in-vivo effectiveness, and potential mechanism of action of a linomide analogue (N-phenyl-1,2-dihydro-4-hydroxyl-2-oxo-quinoline-3-carboxamide, Lin05) for inhibition of choroidal neovascularization. The selectivity of Lin05 was tested in cell proliferation assays with human umbilical vein endothelial cells (HUVEC) and a retinal pigmented epithelial cell line(ARPE-19). In-vivo anti-angiogenic effect of Lin05 was investigated utilizing an experimental laser-induced choroidal neovascularization (ECNV) model in adult Brown Norway rats. Western blot and/or reverse transcriptase-PCR was used to test the effect of Lin05 on potential targets. Our results indicate that Lin05 is at least an 8-fold more selective inhibitor of endothelial cell proliferation compared to RPE cells. Systemic administration of Lin05 in an ECNV model was associated with a significant decrease in both vascular leakage on fluorescein angiography and lesion size by histopathology (p = 0.02). No systemic toxicity was detected for Lin05 in major organs such as the liver, lung and kidneys. Lin05 did not inhibit VEGF-induced VEGFR2 (KDR) phosphorylation in HUVEC nor was associated with decreased VEGF gene expression. Also it did not inhibit insulin-like growth factor (IGF-1) and Epidermal Growth Factor (EGF) induced activation of p42/p44 MAPK activation. It inhibited both PDGF- and bFGF-induced p42/p44 MAPK phosphorylation. However, the effect on PDGF was variable in different HUVEC cells. In conclusion, Lin05 is a potential anti-angiogenic agent for the treatment of eye diseases associated with pathological neovascularization. The anti-angiogenic effect of Lin05 is likely through inhibition of bFGF but not through inhibition of the VEGF/KDR pathway.
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PMID:Investigation of the potential utility of a linomide analogue for treatment of choroidal neovascularization. 2105

NKX3.1, which is a prostate-specific homeobox gene, plays an important role in prostate cancer and usually functions as a tumour suppressor gene. In this study, we investigated the inhibitory effect of NKX3.1 on insulin-like growth factor (IGF)-1R expression and its downstream signalling pathway in PC3 cells. PC3 cells were stably transfected with NKX3.1 expression plasmid (pcDNA3.1-NKX3.1) or vector plasmid (pcDNA3.1+). The IGF-IR mRNA and protein expression levels were assessed in PC3-NKX3.1 transfectants by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting. The expression and activation of IGF-1/IGF-1R downstream signalling targets were examined by Western blotting and luciferase reporter assay. The cells were subsequently treated with relevant concentrations of IGF-1. The effect of IGF-1 on cell growth was examined by 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-diphenytetrazoliumromide (MTT) assay and flow cytometry analysis. A significant suppression of IGF-1R mRNA and protein expression was observed after forced expression of NKX3.1 in PC3 cells. Correspondingly, the forced expression of NKX3.1 decreased IGF-1-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (AKT) and activation of the Elk-1 transcription factor and downregulated the expression of the downstream target genes c-fos and cyclin D1. Furthermore, the forced expression of NKX3.1 inhibited IGF-1-induced cell growth. In conclusion, NKX3.1 could downregulate IGF-1R expression and could inhibit IGF-1R-mediated mitogen-activated protein kinase (MAPK)/ERK and AKT signalling pathways, which might partially leads to the inhibition of IGF-1-induced cell growth. This study provides new insights into the molecular mechanisms that NKX3.1 exerts against prostate cancer and ultimately expands the scope of alternative approaches in advanced prostate cancer therapy.
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PMID:The inhibitory effects of NKX3.1 on IGF-1R expression and its signalling pathway in human prostatic carcinoma PC3 cells. 2217 13

The biologic actions of insulin-like growth factor-1(IGF-1) are associated with cell growth, differentiation, migration, and survival. IGF-1 constitutes the pathogenic factor in formation of nasal polyps and the regulatory factor in expression of mucins. However, the effect of IGF-1 on MUC8 and MUC5B expression has not been reported. Therefore, in this study, the effect and brief signaling pathway of IGF-1 on MUC8 and MUC5B expression were investigated in human airway epithelial cells. In mucin-producing human NCI-H292 airway epithelial cells and the primary cultures of normal human nasal epithelial cells, the effect and signaling pathway of IGF-1 on MUC8 and MUC5B expression were investigated using reverse transcriptase-polymerase chain reaction (RT-PCR), real-time PCR, enzyme immunoassay, and immunoblot analysis with specific inhibitors and small interfering RNA (siRNA) for mitogen-activated protein kinase (MAPK). IGF-1 induced MUC8 and MUC5B expression, and activated phosphorylation of ERK1/2 and p38 MAPK. U0126 (ERK1/2 inhibitor) and SB203580 (p38 MAPK inhibitor) inhibited IGF-1 induced MUC8 and MUC5B mRNA expression. In addition, the knockdown of ERK1 and p38 MAPK by siRNA significantly blocked IGF-1 induced MUC8 and MUC5B mRNA expression; the knockdown of ERK2 MAPK by siRNA did not. These results demonstrate for the first time that IGF-1 induced MUC8 and MUC5B expression is regulated by activation of the ERK1 and p38 MAPK signaling pathway in human airway epithelial cells.
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PMID:Insulin-like growth factor-1 induces MUC8 and MUC5B expression via ERK1 and p38 MAPK in human airway epithelial cells. 2321 93

The purpose of this study was to examine whether insulin-like growth factor (IGF-1) and Akt/mTOR/p70S6K pathway activity is altered by chronic eccentric exercise in rat medial gastrocnemius muscle. Male Wistar rats (n = 24) were randomly assigned to 1 of the 2 groups: eccentric exercise (ECC) group or sham-operated control (CON) group. Rats in the ECC group were trained every second day for 10 days (5 sessions in total) or 20 days (10 sessions in total). After either 5 or 10 exercise sessions, muscle specimens were dissected and weighed. The mRNA expression of IGF-1 and its variant, mechano growth factor (MGF), was evaluated using real time reverse transcriptase-polymerase chain reaction (RT-PCR). Tissue concentrations of Akt (P), mTOR (P), and p70S6K (P) were measured by using western blot analysis. The medial gastrocnemius muscle mass of the ECC group did not show any significant difference after 5 exercise sessions, whereas the muscle mass increased significantly after 10 exercise sessions with a concomitant increase in the cross-sectional area of muscle fibers (p < 0.05). The expression of IGF-1 mRNA and the tissue concentrations of Akt (P) and p70S6K (P) after 10 exercise sessions was significantly higher than those of the age-matched controls and the rats that received 5 exercise sessions. The expression of MGF mRNA in both ECC5S and ECC10S were significantly higher than that in each period-matched control (p < 0.01). The tissue concentration of mTOR (P) after 10 sessions showed a significant increase when compared with period-matched controls (p < 0.01). These results suggest that activation of the IGF-1/Akt/mTOR/p70S6K signaling pathway becomes dominant in the later phase of chronic exercise, when significant muscular hypertrophy is observed. Key pointsWe confirmed that the rat muscular exercise model using originally-developed equipment increased the wet mass of the medial gastrocnemius muscle and cross-sectional areas of muscle fibres in 10 sessions (20 days) but not in 5 sessions (10days).We clarified that the increases of muscle mass and CSA of muscle fibers were accompanied by IGF-1 mRNA expression, the phosphorylated Akt, mTOR, and p70S6K.These results suggest that muscular hypertrophy in our model was achieved after 10 sessions of exercise and associated with the activation of IGF-1/Akt/mTOR/p70S6K signal pathway.
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PMID:Time Course Change of IGF1/Akt/mTOR/p70s6k Pathway Activation in Rat Gastrocnemius Muscle During Repeated Bouts of Eccentric Exercise. 2414 82


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