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)

Insulin-like growth factor 1 and insulin, considered primarily as metabolic and growth modulatory hormones, were found to inhibit the replication of HIV-1 in cultured cord blood mononuclear cells and chronically HIV-infected U937 cells. The effect of IGF-1 was seen at physiological concentrations or lower (1.7 x 10(-10) M) while that of insulin was observed at supraphysiological concentrations (8 x 10(-7) M). The EC50 for IGF-1 was found to be in the physiological range (2.5-4.5 x 10(-9) M) while that for insulin was considerably higher (1.1-3.3 x 10(-6) M). Insulin-like growth factor 1 and insulin at the concentrations employed exhibited no toxicity on the cells used in these studies. Furthermore, neither IGF-1 nor insulin exhibited any inhibitory activity on purified reverse transcriptase in vitro. Epidermal growth factor from 1.6 x 10(-10) to 1.6 x 10(-8) M demonstrated no inhibition of HIV-1 replication, while IGF-1 inhibited p24 antigen production 49 and 42% at 1.3 x 10(-9) and 1.3 x 10(-8) M IGF-1, respectively. These results suggest that IGF-1 under certain conditions has significant inhibitory effects on HIV-1 replication at physiological concentrations. This may prove to be of therapeutic value in patients infected with HIV-1.
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PMID:Insulin-like growth factor 1 and insulin inhibit HIV type 1 replication in cultured cells. 757 11

Development of a high capacity multiplex reverse transcriptase-polymerase chain reaction protocol has allowed us to screen lineage related rat islet tumors classified as alpha-, beta-, and delta-like as judged by their hormone profile for differential expression of more than 50 selected genes. We find that in addition to insulin the insulinoma express the normal beta-cell markers Pdx-1, IAPP, and Glut-2, and that these markers are absent from the glucagonoma: a reflection of the normal alpha-cell. Furthermore, this study suggests that the GLP-1, glucagon, GIP, IGF-1, and insulin receptors as well as E-cadherin, R-cadherin, Id-1, and Id-2 are differentially expressed within the islet of Langerhans. Importantly, insulinoma-specific expression of the recently cloned homeodomain protein Nkx 6.1 predicted beta-cell-specific expression in the normal islet. Immunohistochemistry using antibodies raised against recombinant Nkx 6.1 did indeed localize Nkx 6.1 expression exclusively to the nuclei of normal islet beta-cells. Apart from pancreatic islets only the antral part of the stomach contained Nkx 6.1 mRNA. We conclude that multiplex reverse transcriptase-polymerase chain reaction-based mRNA profiling is a powerful tool to identify differentially expressed genes within phenotypically related cells and propose that Nkx 6.1 is involved in specifying the unique characteristics of the beta-cell.
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PMID:mRNA profiling of rat islet tumors reveals nkx 6.1 as a beta-cell-specific homeodomain transcription factor. 870 31

Thyroid hormone plays a major role in the regulation of bone metabolism but the mechanism by which this is accomplished is not clear. Interactions of thyroid hormone with the growth hormone/insulin-like growth factors (IGFs) axis suggest an alternate pathway of action for triiodothyronine (T(3)) on bone formation, besides direct effects. The present study investigates the influence of T(3) on IGF-1, IGF-2, IGF-1 receptor (IGF-1R), and IGF binding protein (IGFBP) transcripts, and on IGF-1 action in human osteoblastic cells (hOB) under serum-free culture conditions. No influence of T(3) on IGF-1, IGF-2, IGFBP-3, or IGFBP-4 mRNA levels in hOB was observed. However, T(3) at concentrations of 10(-8) mol/L and 10(-7) mol/L increased IGF-1R mRNA levels in a dose-dependent manner (p < 0.01) and enhanced IGFBP-5 mRNA levels at a concentration of 10(-7) mol/L (p < 0.05), as assessed by reverse transcriptase-polymerase chain reaction. Correspondingly, Scatchard analysis of [(125)I]-IGF-1 binding revealed that T(3) at 10(-7) mol/L increased the number of IGF-1 binding sites in hOB, with small changes in receptor affinity. In addition, a synergistic effect of T(3) and IGF-1 on hOB proliferation was found (p < 0.05). We conclude that IGF-1R and IGFBP-5 are thyroid hormone target genes in human osteoblasts, whereas IGF-1 mRNA expression itself appears not to be regulated by T(3) in hOB. However, T(3) stimulates IGF-1R mRNA expression as well as IGF-1 binding and IGF-1 induced cell proliferation in osteoblasts, thus suggesting thyroid hormone may potentiate the effect of IGF-1 at the receptor level. This may contribute to the positive effects of thyroid hormone on bone formation, which, in addition, may be modulated by increased IGFBP-5 expression.
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PMID:Effects of triiodothyronine on the insulin-like growth factor system in primary human osteoblastic cells in vitro. 1172 24

Neovascularization stimulated by IGF-1 mediated induction of vascular endothelial growth factor (VEGF) is one of the leading causes of blindness in humans. It plays a central role in the pathogenesis of proliferative diabetic retinopathy (DR), neovascular glaucoma, exudative age-related macular degeneration (AMD) and retinopathy of prematurity. Neovascularization is a multi-step process that involves complex interactions of a variety of mitogenic factors such as VEGF and IGF-I which are produced locally in the human eye by a variety of cells including retinal pigment epithelial (RPE) cells, retinal capillary pericytes, endothelial cells, Mueller cells and ganglion cells. We hypothesized that somatostatin would inhibit the IGF-1 signal transduction pathway in RPE cells, resulting in decreased VEGF production. We have observed expression of somatostatin receptor protein in retinal pigment epithelial (RPE) cells of the human eye using immunohistochemistry and have confirmed expression of somatostatin receptors in cultured human RPE cells using reverse transcriptase-PCR. IGF-1 induced a dose dependent increase in IGF-1R phosphorylation and in VEGF mRNA levels in cultured human RPE cells. Somatostatin and octreotide, a somatostatin analogue, inhibited IGF-1 receptor (IGF-1R) phosphorylation and decreased VEGF production. Both IGF-1R phosphorylation and accumulation of VEGF mRNA were inhibited by physiological levels of somatostatin and octreotide (1 nM). These results demonstrate somatostatin and octreotide mediated attenuation of both IGF-1R signal transduction and VEGF mRNA accumulation via somatostatin receptor type 2 (sst2). Furthermore, these data suggest a rationale for the use of octreotide as a prophylactic and therapeutic option in disease states that cause ocular neovascularization.
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PMID:Somatostatin inhibits IGF-1 mediated induction of VEGF in human retinal pigment epithelial cells. 1538 Oct 31

IGF-1, IGF-2, and type 1 IGF receptor (IGF-R1) mRNA expression and immunolocalization and cell proliferation index were studied in human adrenals from early infancy to late puberty. Adrenals were obtained from transplantation donors or from necropsies of endocrinologically normal subjects. Subjects were divided into three age groups: group 1, <3 mo of age, involution of fetal adrenals; group 2, 3 mo to 6 y of age, preadrenarche; and group 3, older than 6 y up to 20 y of age, postadrenarche. Cell proliferation index (Ki-67) in the outer, subcapsular, zona glomerulosa was significantly higher than in zona fasciculata of all groups and in zona reticularis or fetal zone. IGF-1 mRNA (semiquantitative reverse transcriptase-PCR and Northern blot) in group 2 was significantly higher than in group 1 and group 3 (p < 0.05). IGF2 mRNA in group 1 was significantly higher than in the other groups. IGF-R1 mRNA in group 3 was significantly higher than in group 2 but not different from group 1. Strong IGF-1, IGF-2, and IGF-R1 immunostaining signal was observed in the outer, subcapsular, zona glomerulosa and in zona fasciculata in the three groups, whereas a very weak IGF-1 and IGF-R1 immunostaining signal was found in fetal zone cells of group 1 and in zona reticularis of group 3. We propose that IGF-1 could be a factor involved in the postnatal mechanism of progenitor adrenal cell proliferation and migration. Our data also suggest that IGF-1 is not a direct regulatory factor of adrenal androgen production by zona reticularis cells.
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PMID:Expression of the IGF system in human adrenal tissues from early infancy to late puberty: implications for the development of adrenarche. 1614 56

The precise role of insulin-like growth factor (IGF)-1 in gastric ulcer healing is unknown. In experimental rat gastric ulcers, we examined expression of IGF-1 mRNA and protein by reverse transcriptase-polymerase chain reaction or enzyme-linked immunosorbent assay and immunostaining, respectively. In cultured rat gastric epithelial RGM1 cells, we examined effects of exogenous IGF-1 on cell migration, re-epithelialization, and proliferation-essential components of ulcer healing. We also examined whether IGF-1 induces cyclooxygenase (COX)-2 expression and determined the role of phosphatidylinositol 3-kinase and mitogen-activated protein kinase signaling pathways in mediating IGF-1 actions. Gastric ulceration triggered an approximately threefold increase in IGF-1 expression in epithelial cells of the ulcer margins (P < 0.001 versus control), especially in cells re-epithelizing granulation tissue and in mucosa in proximity to the ulcer margin. Treatment of RGM1 cells with IGF-1 caused a dramatic increase in actin polymerization, an eightfold increase in cell migration (P < 0.001), a 195% increase in cell proliferation (P < 0.05), and a sixfold increase in COX-2 expression (P < 0.01). Inhibitor of phosphatidylinositol 3-kinase abolished IGF-1-induced RGM1 cell migration and proliferation, actin polymerization, and COX-2 expression. The up-regulation of IGF-1 in gastric ulcer margin accelerates gastric ulcer healing by promoting cell re-epithelization, proliferation, and COX-2 expression via the phosphatidylinositol 3-kinase pathway.
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PMID:Novel roles of local insulin-like growth factor-1 activation in gastric ulcer healing: promotes actin polymerization, cell proliferation, re-epithelialization, and induces cyclooxygenase-2 in a phosphatidylinositol 3-kinase-dependent manner. 1739 62

We have previously shown that transforming growth factor-beta1 (TGF-beta1) stimulates transdifferentiation of fibroblasts into smooth muscle alpha-actin (alpha-SMA) positive myofibroblasts. However, TGF-beta, as such, is unsuitable for effective population of a heart valve matrix, because it dose-dependently inhibits growth of fibroblasts. The aim of this study was to investigate combinations of other growth factors with TGF-beta to stimulate the proliferation of suitably differentiated cells and to enhance their invasion into aortic valve matrices. Human dermal mesenchymal cells (hDMC1.1) were treated with combinations of growth factors to stimulate these cells to trans-differentiate into myofibroblasts, to proliferate, and to invade. Growth factors were chosen after expression of their respective receptors was confirmed in hDMC1.1 using reverse transcriptase polymerase chain reaction. We combined TGF-beta with several growth factors such as insulin-like growth factor (IGF-1, IGF-2), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF-AA, PDGF-BB, and PDGFAB). Nuclear Ki67 staining, MTT assay, and cell counting revealed that only EGF and bFGF were capable of overcoming TGF-beta-induced growth inhibition. However, bFGF but not EGF inhibited TGF-beta-induced alpha-SMA expression, as evidenced by immuno-cytochemistry and Western blotting. A growth factor cocktail (TGF-beta, EGF, bFGF) has been established that maintains TGF-beta-induced trans-differentiation but overcomes TGF-beta-induced growth inhibition while stimulating fibroblast proliferation and invasion.
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PMID:Growth factor modulation of fibroblast proliferation, differentiation, and invasion: implications for tissue valve engineering. 1751 40

In this study, we delineate the sequential expression of selected growth factors associated with bone formation in vitro. Mineralization, osteocalcin, and alkaline phosphatase (ALP-2) were measured to monitor the differentiation and maturation of osteoprogenitor cells collected from C57BL mice. Bone-related growth factors, including transforming growth factor beta (TGF-beta), fibroblast growth factor 2 (FGF-2), platelet-derived growth factor (PDGF), insulinlike growth factor (IGF)-1, vascular endothelial growth factor (VEGF), bone morphogenetic protein (BMP)-2, and BMP-7, were selected. Enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase polymerase chain reaction (RT-PCR) were used to measure growth factors at the protein and messenger ribonucleic acid (mRNA) level, respectively. The results found that ALP-2 expression increased progressively over time, whereas mineralization and osteocalcin did not become evident until culture day 14. VEGF and IGF-1 were upregulated early during proliferation. PDGF and TGF-beta mRNA expression was bimodal. FGF-2 and BMP-2 mRNAs were expressed only later in differentiation. FGF-2 mRNA signal levels were highest at day 14 and remained prominent through day 28 of culture. BMP-2 showed a similar profile as FGF-2. BMP-7 was not detectable using RT-PCR or ELISA. Strong correlations existed for the expression patterns between several early-response growth factors (VEGF, TGF-beta, and IGF-1) and were also evident for several late-response growth factors (BMP-2, PDGF, and FGF-2). Differential expression for grouped sets of growth factors occurs during the temporal acquisition of bone-specific markers as osteoprogenitor cell maturation proceeds in vitro.
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PMID:The sequential expression profiles of growth factors from osteoprogenitors [correction of osteroprogenitors] to osteoblasts in vitro. 1752 79

The focus of this study was a new adult pluripotent cell derived from human peripheral blood monocytes identified as a "programmable cell of monocytic origin" (PCMO). In contrast to bone marrow-derived stem cells, these cells can be harvested from peripheral venous blood without aspiration of the bone marrow and have multilineage potential comparable to that of mesenchymal stem cells (MSC). The aim of this study was to evaluate the potential of PCMOs to differentiate into collagen type II-producing chondrocytes using various extrinsic cues (TGFbeta-1, IGF-1, BMP-2, and BMP-7). Collagen type I and II proteins were localized using immunohistochemistry and quantified by enzyme-linked immunosorbent assays (ELISA). The shape of the differentiating PCMOs was monitored with electron microscopy. Collagen type I and II messenger RNA expression was analyzed using real-time reverse transcriptase-polymerase chain reaction (RT PCR) and regular RT PCR. Immunohistochemistry revealed a strong accumulation of collagen type II after a 6-week incubation period with BMP-2, BMP-7, TGF-beta, IGF-I, and TGF-beta, and IGF-1. Collagen type I was only mildly induced by the applied stimulants. Electron microscopy findings showed a shift from a monocyte-like structure to a chondrocyte-like structure after 2 weeks of stimulation. Stimulation of PCMOs with BMP-2, BMP-7, TGF-beta, IGF-I, and TGF-beta, and IGF-1 induced a chondrogenic differentiation with continuous expression of collagen type II mRNA and protein over several weeks time. Collagen type I and II expression in undifferentiated PCMOs or in control cells incubated without any stimulant was not detected. PCMOs have the potential to differentiate into collagen type II synthesizing chondrocytes. The ability to reprogram and differentiate PCMOs from peripheral blood into sizable quantities might enable their clinical application in cartilage repair after mechanical injury or in cases of osteoarthritis.
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PMID:Programmable cells of monocytic origin (PCMO): a source of peripheral blood stem cells that generate collagen type II-producing chondrocytes. 1796 14

The underlying mechanism for electroacupuncture (EA) associated functional improvement in patients suffering from spinal cord injury (SCI) is largely unknown. Collateral sprouting is one plausible factor, where the cord microenvironment may contribute greatly. The present study evaluated the effects of EA on collateral sprouting from spared dorsal root ganglion (DRG), sensory functional restorations, and differential gene expressions in spinal cord after partial DRG removal in the rat. Following EA, N1 waveform latencies for cortical somatosensory evoked potential significantly shortened. The densities of terminal sprouting from the spared DRG significantly increased on the EA versus the non-EA side. Microarray analysis revealed that several genes were upregulated on the acupunctured side at different time points; they were ciliary neurotrophic factor (CNTF) at 1 day postoperation (dpo), fibroblast growth factor (FGF)-1, insulin-like growth factor (IGF) 1 receptor, neuropeptide Y, and FGF-13 at 7 dpo, and CNTF and calcitonin gene-related polypeptide-alpha at 14 dpo, respectively. Meanwhile, five genes (CNTF, p75-like apoptosis-inducing death domain protein, IGF-1, transforming growth factor-beta 2, and FGF-4) were downregulated at 7 dpo. Furthermore, reverse transcriptase polymerase chain reaction results supported the gene chip analysis. It was concluded that the EA induced sensory functional restorations following partial DRG ganglionectomies could be brought about by intraspinal sprouting from the spared DRG, as well as multiple differential gene expressions in the spinal cord. The results could have clinical application in EA treatment of patients after spinal injury.
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PMID:Electroacupuncture induced spinal plasticity is linked to multiple gene expressions in dorsal root deafferented rats. 1858 Dec 69


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