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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bearing in mind that the pathological process in keratoconus starts with anterior corneal layers and is gradually progressing into inner corneal parts we put a question whether a pathological process can be stopped by affecting the anterior layers of the cornea. This paper presents the results of 5-year experience excimer laser surgery, a combination of photorefractive and phototherapeutic keratectomy (PRK + PTK) in the treatment of the initial keratoconus. The diagnosis of early keratoconus was based upon computed tomographic data, pachymetry in 5 points, and biomicroscopy of the cornea. The "firework" symptom a stromal ramification area that corresponds to the future apex of the keratoconus is described. PRK was performed with an ablation zone of 6 mm, and the transitional zone of 7 mm. The ablation zone in PhTk was dislocated towards the most ectasia--conical apex, topography and the apex site were predetermined of computed tomography. The PTK was performed with ablation zone of 8.00 mm and transitional zone of 9 mm. The described method allowed the authors to increase average uncorrected acuity of vision from 0.07 +/- 0.003 to 0.76 +/- 0.03. At the same time the acuity of vision was 1.0 in 69.2% of the eyes to enhance the mean corrected acuity of vision from 0.70 +/- 0.03 to 0.83 +/- 0.04. 2 by gradually progressing significantly to decline the degree of ametropia. The spherical component of refraction--myopia--decreased from 5.32 +/- 0.62 to 1.55 +/- 0.3 D. The cylindrical component of refraction myopic astigmatism reduced from 3.25 +/- 0.53 to 1.75 +/- 0.25 D. 3 to stop the progression of keratoconus in 91.3% of cases at a follow-up of 40.8 +/- 1.5 months (3 years 4 months) and at the maximal follow-up of 5.5 years. Thus, PRK + PTK with pathogenetically based, effective method in the treatment of the patients with initial keratoconus.
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PMID:[Pathogenetic basis for treatment of primary keratoconus by a combined method of excimer laser surgery (combination of photorefraction and phototherapeutic keratectomy)]. 1253 40

The work focuses on the present of the medical treatment of relapsing erosions of a cornea. It monitors the frequency of the occurrence of relapsing erosions of a cornea in our workplace in the ophthalmology department in Prague and possibilities of the usage of the therapeutic methods. The most frequent cause of the origin of relapsing erosion within our patients has been traumatic etiology of the cornea. From the results of our work complies that the most successful solution of this problem is the abrasion of the epithelium with the puncturation of the anterior stroma of a cornea and the phototherapeutic method "excime laser" (PTK).
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PMID:[Recurrent corneal erosion--current therapy]. 1262 53

We wished to evaluate the potential of iontophoresis to promote the delivery of antisense oligonucleotides (ODN) directed at the vascular endothelial growth factor (VEGF)-R2 receptor (KDR/Flk) to the cornea of the rat eye. Fluorescence (CY5)-labeled ODNs in phosphate-buffered saline (PBS) (20 microM) were locally administered to rat eyes, and their fate within the anterior segment was studied. Thirty-four male, 5-week-old Wistar rats were used for all experiments. The rats were divided in four groups. In group I (12 rats, 12 eyes), the ODNs (20 microM) were delivered by iontophoresis (300 microA for 5 minutes) using a specially designed corneal applicator. In group II (12 rats, 12 eyes), the ODNs (20 microM) were delivered using the same applicator, but no electrical current was applied. In group III (6 rats, 6 eyes), a corneal neovascular reaction was induced prior to the application of ODNs (20 microM), and iontophoresis electrical current was delivered as for group I rats. Group IV (4 rats, 4 eyes) received ODN (60 microM) iontophoresis application (300 microA for 5 minutes) and were used for ODN integrity studies. The animals were killed 5 minutes, 90 minutes, and 24 hours after a single ODN application and studied. Topically applied ODNs using the same iontophoresis applicator but without current do not penetrate the cornea and remain confined to the superficial epithelial layer. ODNs delivered with transcorneoscleral iontophoresis penetrate into all corneal layers and are also detected in the iris. In corneas with neovascularization, ODNs were particularly localized within the vascular endothelial cells of the stroma. ODNs extracted from eye tissues 24 hours after iontophoresis remained unaltered. The iontophoresis current did not cause any detectable ocular damage under these conditions. Iontophoresis promotes the delivery of ODNs to the anterior segment of the eye, including all corneal layers. Iontophoresis of ODNs directed at VEGF-R2 may be used for the design of specific antiangiogenic strategy in diseases of the cornea.
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PMID:Delivery of antisense oligonucleotide to the cornea by iontophoresis. 1280 37

In this study, we investigated the effects of migration inhibitory factor (rhMIF) on angiogenesis-related signaling cascades and apoptosis in human endothelial cells (ECs). We show that in vitro rhMIF induces migration and tube formation in Matrigel of human dermal microvascular endothelial cells (HMVECs), with potency comparable to that of basic fibroblast growth factor. In vivo, rhMIF induces angiogenesis in Matrigel plugs and in the corneal bioassay. Using panels of relatively specific kinase inhibitors, antisense oligonucleotides, and dominant-negative mutants, we show that mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) are critical for MIF-dependent HMVEC migration, whereas Src and p38 kinases are nonessential. Moreover, we demonstrate that rhMIF induces time-dependent increases in phosphorylation levels of MEK1/2, Erk1/2, and Elk-1, as well as PI3K, and its effector kinase, Akt, in HMVECs. Studies with dominant-negative mutants and antisense oligonucleotides corroborate these effects in HMVECs. Furthermore, we demonstrate that rhMIF-induced angiogenesis in the rat cornea in vivo and in the ex vivo endothelial cell morphogenesis assay is also MAPK- and PI3K-dependent. Our findings support a role for MIF as an angiogenic factor and provide a rationale for the use of MIF as a therapeutic inducer of neovascularization in the development of collateral circulation in coronary artery disease.
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PMID:Migration inhibitory factor mediates angiogenesis via mitogen-activated protein kinase and phosphatidylinositol kinase. 1288 77

This article reviews the results of the basic research about epidermal growth factor and its receptor, and the development of the novel drug, EGF eyedrop, that containing chemically synthesized EGF gene, the construction of EGF expression vector, the transformation of the host cells, the purification of the recombinant protein EGF, the preparation of three batches of the EGF product and identification, the preclinical and clinical trials. Relevant studies show that recombinant EGF consisting of 51 amino acids can be secreted into the medium under the control of the alpha factor leading sequence in the yeast cells. The EGF can accelerate the growth of corneal-limbal epithelial cells and the healing of an alkali burned corneal. The EGF can be used in curing oral cavity ulcer and skin burned wound. And it has the preventive effects on experimental duodenal ulcer of rat. The antiserum was made for test of the concentration of blood EGF and urine EGF by RIA. Data from studies demonstrate the inhibition effect of EGF on the growth of tumor cells, such as A431 and BT325 cells in the presence of high EGF concentration (> 10 ng/ml). The expression of EGFR and DNA ploidy in renal carcinoma has clinical significance. Crystallization and preliminary x-ray diffraction studies of the EGF has been made. The MW of the EGF product is 6000, and the pI is about 4.6 and it has correct N-terminal amino acids sequences, immunogenicity and biological activity. There is no vestige of the DNA of the yeast cells. Animal experiments reveal that there is no cumulation of the EGF in the body, and EGF can promote corneal epithelial healing. There is no toxicological effect during cornea wound healing of rabbit. A randomized, double-blind, placebo-controlled, multi-center clinical trial was conducted in four hospitals to assess safety, ocular tolerance and efficacy of an ophthalmic solution of EGF for 200 cases of cornea transplantation and 247 cases of nebulae. Unequivocal results were obtained as the eyedrop really accelerate the wounded cornea healing. So, the EGF eyedrop as a novel drug of class I is approved by the National Drug Administration, and this is the first gene engineering drug that come from yeast expression system in China.
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PMID:[The basic and applied study on the epidermal growth factor]. 1290 98

The article describes the methods for the correction of hypermetropia, i.e. micro-lamellar keratotomy (MLK) and MLK plus thermokeratocoagulation (MLKTKC). The experiment was made on 6 rabbits (12 eyes). Lamellar corneal incisions were implemented by ALK ACS system (USA) to a depth of 73-75% of the corneal thickness. Simultaneously, thermokeratocoagulation (TKC) to 80% of the corneal thickness was made in a part of animals in meridians 6, 8, 10 and 12 (an 8 mm optic zone and 3 to 4 coagulates in each meridian). Postoperatively, the keratometric data were evaluated in 1, 3 and 6 months. The corneal optic power went up, postoperatively, in the center by around 4.0 diopters in cases, when the common surgical technique was used, and it went up to 5.0-9.0 diopters, when the common technique was combined with TKC. A clinical approbation of the MLK and MLKTKC methods in adults with hypermetropia (44 operations, mean age 29.3 years) showed their efficiency and safety. The corneal refraction improvement ranged from 3.5 diopters to 7.5 diopters (mean 4.49 +/- 0.89 diopters). The developed method of the above surgeries (the diameter of the modeled optic zone is 5 mm, the lamellar depth incision is 73%) prevents the complications, which lead to irreversible changes of the cornea; besides, it makes it possible to preserve a sufficiently wide central optic zone with a present refraction. This study provided a foundation for the clinical use of the method in pediatric practice.
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PMID:[Experimental-clinical substantiation of the use of micro-lamellar keratotomy combined with kerato-thermocoagulation in the correction of hypermetropia]. 1367 7

The aim of this study was to characterize the capillary density, progression and persistence of new capillaries induced by different isoforms of vascular endothelial growth factor (VEGF)-A. They were produced and purified using the same protocol and assessed in the same experimental model, the rabbit cornea assay. Monogenic homodimers for VEGF121 and VEGF165 together with the heterodimer VEGF121/165 were tested as slow release polymer pellets implanted into the avascular rabbit cornea and examined up to 18 days post-implantation. The implants consistently stimulated angiogenesis in the absence of inflammation. The VEGF121 isoform produced the strongest increase of new capillary vessels which rapidly and persistently progressed into the corneal stroma. VEGF165 promoted the growth of a smaller number of capillaries which ten-ded to regress over time. Heterodimers of VEGF121/165 produced intermediate in vivo activities between the two homodimers. In vitro endothelial cell proliferation, mobilization and adhesion were promoted by all VEGF isoforms under serum-free or serum-reduced conditions with the same order of potency. Anti-soluble KDR (sKDR) antibody completely inhibited the effects of all the isoforms. These results indicate that monogenic homodimer preparations of VEGF121 and VEGF165 can display distinct biological effects which are functionally retained after the heterodimeric assembly of VEGF121 and VEGF165. The observed different biological behavior of the VEGF isoforms reveals the possibility that in vivo the assembly of dimers derived from splicing of a single gene may yield molecules with either different matrix or receptor interaction, stability or diffusion rate according to specific needs.
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PMID:Distinct capillary density and progression promoted by vascular endothelial growth factor-A homodimers and heterodimers. 1451 98

Lymphangiogenesis, an important initial step in tumor metastasis and transplant sensitization, is mediated by the action of VEGF-C and -D on VEGFR3. In contrast, VEGF-A binds VEGFR1 and VEGFR2 and is an essential hemangiogenic factor. We re-evaluated the potential role of VEGF-A in lymphangiogenesis using a novel model in which both lymphangiogenesis and hemangiogenesis are induced in the normally avascular cornea. Administration of VEGF Trap, a receptor-based fusion protein that binds and neutralizes VEGF-A but not VEGF-C or -D, completely inhibited both hemangiogenesis and the outgrowth of LYVE-1(+) lymphatic vessels following injury. Furthermore, both lymphangiogenesis and hemangiogenesis were significantly reduced in mice transgenic for VEGF-A(164/164) or VEGF-A(188/188) (each of which expresses only one of the three principle VEGF-A isoforms). Because VEGF-A is chemotactic for macrophages and we demonstrate here that macrophages in inflamed corneas release lymphangiogenic VEGF-C/VEGF-D, we evaluated the possibility that macrophage recruitment plays a role in VEGF-A-mediated lymphangiogenesis. Either systemic depletion of all bone marrow-derived cells (by irradiation) or local depletion of macrophages in the cornea (using clodronate liposomes) prior to injury significantly inhibited both hemangiogenesis and lymphangiogenesis. We conclude that VEGF-A recruitment of monocytes/macrophages plays a crucial role in inducing inflammatory neovascularization by supplying/amplifying signals essential for pathological hemangiogenesis and lymphangiogenesis.
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PMID:VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. 1505 11

The development of gefitinib ('Iressa', ZD1839) by targeting the EGFR tyrosine kinase is a recent therapeutic highlight. We have reported that gefitinib is antiangiogenic in vitro, as well as in vivo. In this study, we asked if the anti-angiogenic action of gefitinib is due to a direct effect on activation of vascular endothelial cells by EGF. EGF, as well as VEGF, caused pronounced angiogenesis in an avascular area of the mouse cornea, and i.p. administration of gefitinib almost completely blocked the response to EGF, but not to VEGF. Immunohistochemical analysis demonstrated phosphorylation of EGFR by EGF in the neovasculature, and gefitinib markedly reduced this effect. Gefitinib also inhibited downstream activation of ERK 1/2 via EGFR in cultured microvascular endothelial (HMVE) cells. These findings suggest that the anti-angiogenic effect of gefitinib in the vascular endothelial cells of neo-vasculature is partly attributable to direct inhibition of EGFR activation, and that endothelial cells in malignant tumors play a critical role in the cancer therapeutic efficacy of gefitinib.
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PMID:Direct inhibition of EGF receptor activation in vascular endothelial cells by gefitinib ('Iressa', ZD1839). 1524

Lymphangiogenesis, the formation of new lymphatic vessels, is important for tumor metastasis and induction of immunity to peripheral antigens including organ transplants. We herein describe a novel mouse model of spontaneous, secondary lymphangiogenesis in the normally avascular cornea. corn1 mice, which suffer from a deletion in the gene encoding the cytoskeletal protein destrin, develop hemangiogenesis as well as spontaneous outgrowth of LYVE-1+++/CD31+ lymphatic vessels into the cornea starting at age 4 weeks. Corneal lymphangiogenesis is delayed in onset, is less intense, and regresses earlier compared with hemangiogenesis. Moreover, the lymphangiogenesis is preceded only by a mild recruitment of CD45+ inflammatory cells into the cornea. In contrast to mice with inflammation-induced hem- and lymphangiogenesis, corn1 mice do not develop breakdown of the blood-aqueous barrier. Finally, in this novel mouse model, a blocking anti-VEGFR3 antibody significantly inhibited not only lymph- but also hemangiogenesis. In summary, destrin deletion has differential effects on spontaneous hem- and lymphangiogenesis in the normally avascular cornea and represents a novel mouse model to study the mechanisms of lymphangiogenesis and to test the antihem- and antilymphangiogenic properties of known or new antiangiogenic agents.
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PMID:Spontaneous corneal hem- and lymphangiogenesis in mice with destrin-mutation depend on VEGFR3 signaling. 1585 38


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