Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dermagraft is three-dimensional, allogeneic, human neonatal dermal fibroblast culture grown on a degradable scaffold and cryopreserved. Clinical trials for treatment of diabetic foot ulcers showed optimal healing within a therapeutic range of metabolic activity, determined by 3[4,5-dimethylthiazol-2-yl]2,5-diphenyltetrazolium bromide (MTT) reduction. Actions of Dermagraft in wound repair include colonization by cells and provision of growth factors and cytokines, both activities dependent on living cells. Cells in the cryopreserved culture showed 60% viability by dye exclusion and, when isolated, were able to proliferate in monolayer culture. Protein synthesis by Dermagraft was inhibited 70-98% by cryopreservation, but, if within the therapeutic range, recovered to 45-85% of the prefreeze value over 48 h. Subtherapeutic Dermagraft showed variable, low recovery. Expression of mRNA for vascular endothelial growth factor (VEGF), platelet-derived growth factor A chain, and insulin-like growth factor-1 was reduced >83% in subtherapeutic compared with therapeutic Dermagraft. Granulocyte colony-stimulating factor and VEGF protein secretion, determined by enzyme-linked immunosorbent assay (ELISA), and angiogenic activity also depended on therapeutic range. VEGF secretion dropped sharply with MTT reductase in subtherapeutic tissue. The data demonstrate the critical dependence of the therapeutic properties of this living dermal implant on recovery of protein synthesis, growth factor expression, and angiogenesis, determined by metabolic activity.
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PMID:Three-dimensional fibroblast culture implant for the treatment of diabetic foot ulcers: metabolic activity and therapeutic range. 991 72

The known role of steroids on the hair follicle leads us to investigate their effects on hair follicle cell angiogenic responses in vitro. We verified, using the immunohistochemical technique, whether human occipital scalp follicle cells express steroid receptors in vitro. We showed that androgen and estrogen receptors were expressed by dermal papilla cells (DPC) and keratinocytes from the outer root sheath in vitro. With regard to steroidal enzymes (type I and II 5alpha-reductases and Cytochrome-p-450-aromatase), the type I 5alpha-reductase gene is much more expressed in DPC than in dermal fibroblasts; however, the type II 5a-reductase gene is transcribed more in dermal fibroblasts than in DPC. The transcription of the two 5alpha-reductase isoform genes in cultured DPC is regulated by a 5alpha-reductase inhibitor. We also demonstrated that DPC, dermal fibroblasts, and outer root shealth keratinocytes expressed cytochrome-p-450-aromatase. Using ELISA and reverse transcriptase-polymerase chain reaction, we investigated the role played by some steroids (estrogens, androgens, antiandrogens) in the modulation of vascular endothelial growth factor (VEGF) expression by DPC. The association of different treatments of DPC (5alpha-reductase inhibitor and androgen receptor antagonist) shows a great stimulation of VEGF and aromatase expression. Strong stimulation of VEGF protein and gene expression is observed in the presence of 17beta-estradiol. Also, the concentration-dependent inhibition of VEGF expression by DPC using the cytochrome-p-450-aromatase inhibitor, confirms the involvement of this estrogenic pathway in the regulation of VEGF expression in vitro.
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PMID:In vitro main pathways of steroid action in cultured hair follicle cells: vascular approach. 1067 84

Adaptation to hypoxia is a topic of considerable clinical relevance, as it influences the pathophysiology of anaemia, polycythaemia, tissue ischaemia and cancer. A growing number of physiologically relevant genes are regulated in response to changes in intracellular oxygen tension. These include genes encoding erythropoietin, vascular endothelial growth factor and tyrosine hydroxylase. Studies on the regulation of the erythropoietin gene have provided insights into the common mechanism of oxygen sensing and signal transduction, leading to activation of the hypoxia-inducible transcription factor 1 (HIF-1). Activation of HIF-1 by hypoxia depends on rescue of its alpha-subunit from oxygen-dependent degradation in the proteasome, allowing it to form a heterodimer with HIF-1 beta. This then translocates to the nucleus. There, HIF-1 assembles with a highly conserved orphan nuclear receptor, HNF-4, and a critical transcriptional adaptor, p300. This complex binds to a 3' enhancer on the erythropoietin gene, enabling transcription of erythropoietin. HIF-1 also activates other genes, the cis-acting elements of which contain cognate hypoxia response elements. There is growing evidence that the oxygen sensor is a flavohaem protein and that the signal transduction pathway involves changes in the level of intracellular reactive oxygen intermediates. We have recently cloned a novel fusion protein called cytochrome b5/b5 reductase, which is a cyanide-insensitive NADPH oxidase and, therefore, a candidate to be the oxygen sensor. This flavohaem protein is widely expressed in cell lines and tissues, with localization in the perinuclear space. In the presence of oxygen and iron, it may induce oxidative modifications that target HIF-1 alpha for ubiquitination and degradation.
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PMID:Detecting and responding to hypoxia. 1181 5

Hypoxia induces a group of physiologically important genes that include erythropoietin (EPO) and vascular endothelial growth factor (VEGF). Hypoxia-inducible factor 1 (HIF-1) was identified as a hypoxia-activated transcription factor; however, the molecular mechanisms that underlie hypoxia signal transduction in mammalian cells remain undefined. In this study, we found that a flavoprotein, NADPH-P450 reductase (NPR), could regulate the induction of EPO mRNA under hypoxic conditions. Hypoxic EPO mRNA induction in Hep3B cells was inhibited by diphenyleneiodonium chloride, which is an inhibitor of NADPH-dependent enzymes. NPR antisense cDNA was transfected into Hep3B cells, and NPR-deficient hepatocyte cells (NPR(-) cells) were established. NPR(-) cells lacked EPO induction under hypoxia, and HIF-1alpha in NPR(-) cells did not respond to either transcriptional activation or translocation to the nucleus based on electrophoretic mobility shift assays and reporter gene assay including hypoxia response element. In contrast, NPR overexpression in Hep3B cells enhanced the DNA binding activity of HIF-1alpha by luciferase reporter gene assay. A study with HeLa S3 cells produced the same results. Furthermore, anti-NPR IgG inhibited EPO induction. EPO induction inhibited by diphenyleneiodonium chloride was recovered by bovine serum albumin-NADPH (a covalent binding complex of bovine serum albumin and NADPH) as well as NADPH. These results suggested that NPR located at the plasma membrane regulates EPO expression in hypoxia, including HIF-1 activation and translocation. We further studied the expression of NPR and VEGF mRNAs in human tumor tissues and found that the NPR mRNA levels were correlated with the VEGF mRNA levels, suggesting that NPR might be an important factor in the hypoxic induction of genes such as VEGF in vivo.
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PMID:NADPH-cytochrome P-450 reductase in the plasma membrane modulates the activation of hypoxia-inducible factor 1. 1197 99

Angiogenesis is implicated in the pathogenesis of cancer, rheumatoid arthritis, and atherosclerosis and in the treatment of coronary artery and peripheral vascular disease. Here, cholesterol-lowering agents, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are shown to interfere with angiogenesis. In vivo, the HMG-CoA reductase inhibitor simvastatin dose-dependently inhibited capillary growth in both vascular endothelial growth factor-stimulated chick chorioallantoic membranes and basic fibroblast growth factor-stimulated mouse corneas. In vitro, the development of tubelike structures by human microvascular endothelial cells cultured on 3D collagen gels was inhibited at simvastatin concentrations similar to those found in the serum of patients on therapeutic doses of this agent. HMG-CoA reductase inhibitors interfered with angiogenesis via inhibition of the geranylgeranylation and membrane localization of RhoA. Simvastatin inhibited membrane localization of RhoA with a concentration dependence similar to that for the inhibition of tube formation, whereas geranylgeranyl pyrophosphate, the substrate for the geranylgeranylation of Rho, reversed the effect of simvastatin on tube formation and on the membrane localization of RhoA. Furthermore, tube formation was inhibited by GGTI, a specific inhibitor of the geranylgeranylation of Rho; by C3 exotoxin, which inactivates Rho; and by the adenoviral expression of a dominant-negative RhoA mutant. The expression of a dominant-activating RhoA mutant reversed the effect of simvastatin on tube formation. Finally, HMG-CoA reductase inhibitors inhibited signaling by vascular endothelial growth factor, Akt, and focal adhesion kinase, three RhoA-dependent pathways known to be involved in angiogenesis. This study demonstrates a new relationship between lipid metabolism and angiogenesis and an antiangiogenic effect of HMG-CoA reductase inhibitors with possible important therapeutic implications.
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PMID:3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors interfere with angiogenesis by inhibiting the geranylgeranylation of RhoA. 1214 47

Androgenetic alopecia (AGA) is hereditary and androgen-dependent, progressive thinning of the scalp hair that follows a defined pattern. While the genetic involvement is pronounced but poorly understood, major advances have been achieved in understanding principal elements of the androgen metabolism involved: androgen-dependent processes are predominantly due to the binding of dihydrotestosterone (DHT) to the androgen receptor (AR). DHT-dependent cell functions depend on the availability of weak androgens, their conversion to more potent androgens via the action of 5 alpha-reductase, low enzymatic activity of androgen inactivating enzymes, and functionally active AR present in high numbers. The predisposed scalp exhibits high levels of DHT, and increased expression of the AR. Conversion of testosterone to DHT within the dermal papilla plays a central role, while androgen-regulated factors deriving from dermal papilla cells are believed to influence growth of other components of the hair follicle. Current available treatment modalities with proven efficacy are oral finasteride, a competitive inhibitor of type 2 5 alpha-reductase, and topical minoxidil, an adenosine-triphosphate-sensitive potassium channel opener which has been reported to stimulate the production of vascular endothelial growth factor in cultured dermal papilla cells. Since the clinical success rate of treatment of AGA with modulators of androgen metabolism or hair growth promoters is limited, sustained microscopic follicular inflammation with connective tissue remodeling, eventually resulting in permanent hair loss, is considered a possible cofactor in the complex etiology of AGA.
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PMID:Molecular mechanisms of androgenetic alopecia. 1221 48

Androgenetic alopecia (AGA) is the combined result of an androgen-dependent process and genetic transmission. These characteristics have mainly, if not exclusively, been demonstrated in men and perhaps improperly extended to women. When considering the androgen-dependent process, AGA must only be limited to the androgen receptor areas. In the scalp, these receptors have only been detected in the frontal and vertex areas but never in the temporal or the occipital areas. Male AGA exhibits these clinical features, whereas in women hair loss is rarely limited to this localization, even when large areas of hair loss often appear with age. It is now commonly accepted that male AGA is associated with an increase in 5 alpha reductase activity leading to an increase in local production of dihydrotestosterone. The mechanism by which the local dihydrotestosterone increase leads to hair follicle loss is not clearly demonstrated. Inhibition of cell proliferation in the dermal papilla and a vascular process based on the inhibition in local production of vascular endothelial growth factor (VEGF) have been proposed. The increase in 5 alpha reductase activity is genetic and depends on androgen receptor polymorphism, characterized by a decrease in the number of CAG sequences on the exon 1. Male AGA is associated with an insulin-resistant process and to a higher risk of polycystic ovary in the lineage. Therapeutically, this hormone-dependent process explains the well demonstrated efficacy of 5 alpha reductase inhibitors. In women, except in some rare cases, alopecia is diffuse and the mechanisms are different. Their origin is unknown, and probably ambiguous. Based on an association with Hashimoto's thyroiditis, an auto-immune origin could be suggested in some cases. Alopecia is unaffected by thyroid substitution. Pharmacological doses of oestrogens (pregnancy, contraception) have a beneficial effect on such alopecia, probably through different mechanisms: anti-androgen effect, increased VEGF, proliferative effect of dermal papilla cells. However, it is important to mention that the dermal papilla has an aromatase, particularly in the occipital area, the activity of which has not been assessed in female alopecia. In practice 5 alpha reductase inhibitors are ineffective in women. It is likely that the predominance observed in the frontal and vertex areas, occasionally in elderly women, is a result of the two combined disorders, the almost physiological androgen-dependent hair loss combined with diffuse loss. Pharmacological doses of oestrogens associated with anti-androgen progesterone-like agents are widely used with positive results, but not demonstrated by clinical trials.
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PMID:[Androgenetic alopecia]. 1222 62

It has been shown that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) modulate vascular smooth muscle cell functions. In the present study, we investigated the effect of simvastatin on vascular endothelial growth factor (VEGF) release, and the underlying mechanism, in a rat aortic smooth muscle cell line, A10 cells. Administration of simvastatin increased the VEGF level in rat plasma in vivo. In cultured cells, simvastatin significantly stimulated VEGF release in a dose-dependent manner. Simvastatin induced the phosphorylation of p44/p42 MAP kinase but not p38 MAP kinase or SAPK (stress-activated protein kinase)/JNK (c-Jun N-terminal kinase). PD98059 and U-0126, inhibitors of the upstream kinase that activates p44/p42 MAP kinase, significantly reduced the simvastatin-induced VEGF release in a dose-dependent manner. The phosphorylation of p44/p42 MAP kinase induced by simvastatin was reduced by PD98059 or U-0126. Moreover, a bolus injection of PD98059 truly suppressed the simvastatin-increased VEGF level in rat plasma in vivo. These results strongly suggest that p44/p42 MAP kinase plays a role at least partly in the simvastatin-stimulated VEGF release in vascular smooth muscle cells.
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PMID:Simvastatin stimulates VEGF release via p44/p42 MAP kinase in vascular smooth muscle cells. 1253 62

We demonstrate that the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors atorvastatin and simvastatin enhance functional outcome and induce brain plasticity when administered after stroke to rats. With atorvastatin treatment initiated 1 day after stroke, animals exhibited significant increases in vascular endothelial growth factor, cyclic guanosine monophosphate, angiogenesis, endogenous cell proliferation and neurogenesis, and an increase in the synaptic protein, synaptophysin. Atorvastatin-induced angiogenesis in a tube formation assay was reduced by an antibody against the vascular endothelial growth factor receptor 2 (FIK-1) and by the nitric oxide synthase inhibitor, N-mono-methyl-L-arginine (L-NAME). Atorvastatin also induced phosphorylation of Akt and Erk in cultured primary cortical neurons. These data indicate that atorvastatin induced brain plasticity and has neurorestorative activity after experimental stroke.
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PMID:Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. 1278 20

Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which catalyzes conversion of HMG-CoA to mevalonate, a rate-limiting step in cholesterol synthesis. The present study was undertaken to understand the events of osteoblast differentiation induced by statins. Simvastatin at 10(-7) M markedly increased mRNA expression for bone morphogenetic protein-2 (BMP-2), vascular endothelial growth factor (VEGF), alkaline phosphatase, type I collagen, bone sialoprotein, and osteocalcin (OCN) in nontransformed osteoblastic cells (MC3T3-E1), while suppressing gene expression for collagenase-1, and collagenase-3. Extracellular accumulation of proteins such as VEGF, OCN, collagenase-digestive proteins, and noncollagenous proteins was increased in the cells treated with 10(-7) M simvastatin, or 10(-8) M cerivastatin. In the culture of MC3T3-E1 cells, statins stimulated mineralization; pretreating MC3T3-E1 cells with mevalonate, or geranylgeranyl pyrophosphate (a mevalonate metabolite) abolished statin-induced mineralization. Statins stimulate osteoblast differentiation in vitro, and may hold promise drugs for the treatment of osteoporosis in the future.
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PMID:Induction of osteoblast differentiation indices by statins in MC3T3-E1 cells. 1515 58


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