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

---

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

The safety and efficacy of phacoemulsification and posterior chamber lens insertion combined with the Pearce trabeculectomy (PE/PCL/P-TRX) in patients with coexistent cataract and glaucoma was evaluated retrospectively. The Pearce trabeculectomy is a form of nonfiltration glaucoma surgery in which an inner block containing trabecular meshwork is excised under a scleral-pocket incision which is closed tightly. Thirty consecutive eyes sustained a reduction of mean intraocular pressure from 21.0 +/- 4.4 mm Hg to 16.6 +/- 3.3 mm Hg after PE/PCL/P-TRX at one year (P less than .001). The average number of glaucoma medications used was reduced from 1.9 to 0.8 postoperatively. At one year, 60% (18 of 30) of eyes treated with PE/PCL/P-TRX had intraocular pressures less than 21 mm Hg without medications.
...
PMID:Surgical outcome of phacoemulsification combined with the Pearce trabeculectomy in patients with glaucoma. 159 37

In order to increase the ocular absorption of carteolol, this antiglaucomatous drug was incorporated into either nanoparticles (NP) or nanocapsules (NC). The polymer used was poly(epsilon-caprolactone) (PCL). The dosage forms were tested on intraocular hypertensive-induced rabbits. Results are presented as the chronological variations of the intraocular pressure (IOP) in comparison with the commercial aqueous solution (Carteol eye drops). The therapeutic results (decrease in IOP) were much more pronounced with carteolol incorporated into the colloidal carriers than with the commercial eye drops. Further, NC displayed a better effect than NP because the drug was entrapped in the oily core of the carrier, thus more readily available to the eye. The incorporation of the drug into nanocapsules produced a decline in the cardiovascular side effects in comparison with aqueous eye drops, thus showing that the undesired noncorneal absorption was reduced. In conclusion, colloidal suspension made of poly(epsilon-caprolactone) could offer a good opportunity for ophthalmic delivery of drugs.
...
PMID:Poly(epsilon-caprolactone) nanocapsules in carteolol ophthalmic delivery. 846 11

5-Acetoxyacetylimino-4-methyl-delta2-1,3,4,-thiadiazoline -2-sulfonamide (compound (1)) is an ester prodrug that lowered intraocular pressure (IOP) in albino New Zealand rabbits, but was found to be inactive in pigmented Dutch Belt rabbits. In order to explain the differences in pharmacological activity for the two rabbit species, metabolism and melanin binding were studied. Depending on the initial concentration, the binding of compound (1) to natural melanin (Sepia officinalis) was 20-60%. The binding constant, K, at 37 degrees C was 4.32 x 10(5) M(-1) and the maximum moles bound to melanin, r(max), was 4.5 x 10(-7) mol/mg of melanin. From a determination of binding at temperatures between 25 degrees C and 47 degrees C, a van't Hoff plot was constructed to determine enthalpy and entropy changes accompanying the binding process, deltaH and deltaS, respectively. Values calculated from the plot were -12.7 and -15.4 kcal/(mol deg), respectively. Negative values for these parameters are consistent with charge transfer interactions and therefore suggest that this may be an operative mechanism between compound (1) and melanin. The in vitro incubation of compound (1) was also studied with various ocular tissues from both albino and pigmented rabbits which were iris-ciliary body, intact cornea, stroma/endothelium and aqueous humor. A major metabolite, MET 1, was identified and also observed from in vivo analyses of the same tissues following topical application. The metabolite was isolated and subjected to mass spectroscopy and proton nuclear magnetic resonance spectroscopy analysis. From these analyses, it was hypothesized that the formation of MET 1 involved a GSH conjugation mechanism which displaced the sufonamide (-SO2NH2) group. The metabolism was found to be less extensive in the pigmented rabbit than in the albino rabbit and suggested that the binding affinity of compound (1) for melanin was a better explanation for the lack of IOP activity in the pigmented rabbit than differences in metabolism.
...
PMID:Significance of melanin binding and metabolism in the activity of 5-acetoxyacetylimino-4-methyl-delta2-1,3,4,-thiadiazolin e-2-sulfonamide. 970 21

Access of recombinant proteins to the retina following intravitreal administration is poorly understood. A study was conducted in male Rhesus monkeys (15 to 28 mo of age; 2.8-3.3 kg) in order to compare the intraocular tissue distribution, pharmacokinetics, and safety of 125Iodine (I)-labeled full-length humanized rhuMAb HER2 antibody (148 kD) and of 125I-labeled humanized rhuMAb vascular endothelial growth factor Fab antibody (48.3 kD) following bilateral bolus intravitreal injection on day 0 (5 animals/group). The dose administered to each eye was 25 microg (9-10 microCi) in 50 microl. Animals were euthanatized on day 0 (1 hr postdose) and on days 1, 4, 7, and 14. Safety assessment included direct ophthalmoscopy, intraocular pressure measurements, clinical observations, body weight, and hematology and clinical chemistry panels. Blood and vitreous samples were collected daily (blood only) and at necropsy for pharmacokinetics and analysis for antibodies to the test materials; the ocular tissue distribution of the test material was evaluated by microautoradiography. All animals completed the study. Microautoradiography demonstrated that the full-length antibody did not penetrate the inner limiting membrane of the retina at any of the time points examined. In contrast, the Fab antibody fragment diffused through the neural retina to the retinal pigment epithelial layer at the 1-hr time point and persisted in this location for up to 7 days. Systemic exposure to test material was low but variable: the highest plasma concentration of the full-length antibody was 20.3 ng/ml, whereas plasma concentrations for the Fab antibody remained below the limit of quantitation (i.e., <7.8 ng/ml). An immune response to the test material was not evident in either treatment group. The half-life in vitreous was 5.6 days for the full-length antibody and 3.2 days for the Fab antibody. The shorter intravitreal half-life of the Fab antibody is related to its smaller size and its significant diffusion through the retinal layers. The differences in pharmacokinetics and tissue distribution that are noted between the full-length and Fab antibodies in this study identify potential therapeutic approaches that may be exploited in specific disease conditions.
...
PMID:Comparisons of the intraocular tissue distribution, pharmacokinetics, and safety of 125I-labeled full-length and Fab antibodies in rhesus monkeys following intravitreal administration. 1052 33

This study investigates whether the immediate early gene (IEG) products c-Fos and c-Jun are activated in vivo in monkeys with experimental glaucoma, and in vitro in cultured human ONH astrocytes exposed to hydrostatic pressure (HP). Three Rhesus monkeys with mild glaucomatous damage (mean intraocular pressure (IOP) 27 +/- 1.3 mm Hg approximately 42 weeks) and three with moderate glaucomatous damage (mean IOP 44 +/- 6.7% mm Hg approximately 11 weeks) were used for this study; the contralateral eye served as normal control (mean IOP 18.6 +/- 1.7 mm Hg). ONH tissues were stained with GFAP, DAPI, and c-Jun or c-Fos, and transcription factor positive and negative nuclei were counted to determine nuclear localization. Cultured human normal and glaucomatous ONH astrocytes exposed to elevated HP served as the in vitro model of elevated pressure. Activation and nuclear localization of c-Fos and c-Jun increased significantly in the monkeys with elevated IOP. These data correlated with axonal loss, reactive astrocytes, and remodeling of the optic disc. Cultured human ONH astrocytes showed increased nuclear localization of c-Fos and c-Jun under exposure to HP. Immunohistochemistry demonstrated that the upstream regulators of c-Fos and c-Jun, ERK-MAPK and MAPKp38 localized to the nuclei of ONH astrocytes in monkeys with experimental glaucoma. Taken together, these results demonstrate c-Fos and c-Jun activation in ONH astrocytes in vivo and in vitro, and that activation of both transcription factors is associated with ERK and MAPKp38 activation in experimental glaucoma, suggesting that activation of transcription factors may participate in the induction and maintenance of the reactive astrocyte phenotype in glaucomatous optic neuropathy.
...
PMID:Long-term activation of c-Fos and c-Jun in optic nerve head astrocytes in experimental ocular hypertension in monkeys and after exposure to elevated pressure in vitro. 1608 Oct 55

The aim of this study was to examine the effects of timolol in an experimental model of elevated intraocular pressure (IOP). Three episcleral veins of rats with normal IOP were cauterized. Three months later we examined the effects on anterograde axonal transport from the retinal ganglion cells (RGCs) to the superior colliculus (SC) as well as on the number of neurons in the retinal ganglion layer (RGL). These parameters were also studied in a group of rats submitted to treatment with timolol after confirming that their IOP was still raised after two weeks. After the surgical procedure, the mean IOP of the experimental eyes increased to 33.5+/-1.06 mmHg (1.25 fold compared to the control group) and three months later the IOP remained significantly elevated; however, after a long period of treatment with timolol the IOP was 14.05+/-0.81 mmHg, similar to that of the control group. In the group with normal IOP, labelling with horseradish rabbit peroxidase (HRP) at 120 minutes and 24 hours postinjection showed continuous staining from the retina to the SC. In the experimental group the optic nerve head (ONH) was completely negative, although in the group treated with timolol there was partial block of axonal transport in the ONH, in which the staining was slightly more intense. The number of neurons in the RGL, counted by immunohistochemical labelling with Neu-N, showed that in eyes with normal and elevated IOP there were 423+/-11 neurons/mm(2) and 283+/-10 neurons/mm(2), respectively. After treatment with timolol the number of neurons (331+/-10 cells/mm(2) increased compared with elevated IOP eyes, although the number did not reach that of the control group. These results indicate that treatment with timolol, started two weeks after the surgical procedure, was partially neuroprotective because the loss of neurons in the RGL was lower than in untreated animals, though not sufficient to re-establish normal axonal transport.
...
PMID:Effects of a non-selective beta-blocker on adult rat anterograde axonal transport and retinal ganglion layer after increased intraocular pressure. 1613 90

This study investigates cell death and survival pathways in experimental glaucoma using the translimbal photocoagulation laser model. Glaucoma was induced unilaterally in 79 Wistar rats and all eyes developed elevated intraocular pressure. The involvement of caspase-3, p-AKT and members of the MAP kinase pathway was evaluated by immunohistochemistry and Western blotting. We found that protein levels of caspase-3 were elevated from day 15 to day 30 (p<0.05). All investigated members of the MAP kinase pathway were significantly activated. P-SAPK/JNK activation began on day 2, reaching a 6-fold elevation by day 30 (p<0.05). The p-P38 level was elevated on days 2 and 8 (p<0.05), followed by a decrease to baseline on day 15. The level of p-ATF-2, the substrate of P38, was significantly elevated at all time points tested, up to day 30 (p<0.05). P-ERK was detected early (p<0.05) on day 1, returning to normal on day 15. The pro-survival protein p-Akt, a member of the PI3-kinase survival pathway, was also detected early on day 1 (p<0.05) returning to baseline on day 8 and remaining unchanged up to 64days. We conclude that retinal ganglion cell death in glaucoma involves activation, at different time points, of multiple pro-apoptotic pathways (the MAP kinase pathway and the caspase family) and pro-survival (PI-3 Kinase/ Akt and p-ERK).
...
PMID:Regulation of cell death and survival pathways in experimental glaucoma. 1758 94

Optic nerve head astrocytes become abnormal in eyes that have elevated intraocular pressure, and cultured astrocytes display altered protein expression after being subjected for > or = 1 days to elevated hydrostatic pressure. Here we show that 2-h elevated hydrostatic pressure (15 or 30 mmHg) causes phosphorylation of ERK1/2, ribosomal S6 protein kinase (p90(RSK)), and Na/H exchanger (NHE)1 in cultured rat optic nerve head astrocytes as judged by Western blot analysis. The MEK/ERK inhibitor U0126 abolished phosphorylation of NHE1 and p90(RSK) as well as ERK1/2. To examine NHE1 activity, cytoplasmic pH (pH(i)) was measured with BCECF and, in some experiments, cells were acidified by 5-min exposure to 20 mM ammonium chloride. Although baseline pH(i) was unaltered, the rate of pH(i) recovery from acidification was fourfold higher in pressure-treated astrocytes. In the presence of either U0126 or dimethylamiloride (DMA), an NHE inhibitor, hydrostatic pressure did not change the rate of pH(i) recovery. The findings are consistent with NHE1 activation due to phosphorylation of ERK1/2, p90(RSK), and NHE1 that occurs in response to hydrostatic pressure. These responses may precede long-term changes of protein expression known to occur in pressure-stressed astrocytes.
...
PMID:Elevated hydrostatic pressure activates sodium/hydrogen exchanger-1 in rat optic nerve head astrocytes. 1941 99

Reduced retrograde transport of neurotrophins (NT) and their receptors has been hypothesized to contribute directly to retinal ganglion cell (RGC) loss in glaucoma. However, strategies of supplementing NT and NT receptors have failed to avert ultimate RGC death in experimental glaucoma. This study examines the response of major components of the NT system and their interacting proteins in a rat glaucoma model. Unilateral chronic intraocular pressure (IOP) elevation was produced by episcleral vein injection of hypertonic saline (N = 99). Retinas were collected and grouped by extent of optic nerve injury. Quantitative reverse transcription PCR, western blot analysis and immunohistochemistry were used to determine mRNA and protein levels and protein localization. Out of three RGC-specific Brn3 proteins (Brn3a, b, and c), only Brn3a was significantly downregulated at the message level to 35 +/- 4% of fellow values with the severest nerve injury. With IOP elevation, no significant alterations were found in retinal mRNA levels for BDNF, NGF, NT-4/5 or NT-3. The abundance of mature retinal BDNF protein was not significantly affected by elevated IOP, while proBDNF protein decreased linearly with increasing injury grade (r(2) = 0.50). In retinas with the severest nerve injury, TrkB and TrkC receptor mRNA levels significantly declined to 67 +/- 9% and 44 +/- 5% of fellow values, respectively. However, the levels of TRKB protein and its phosphorylated form were unchanged. Message level for p75(NTR) was linearly upregulated up to 219 +/- 26% with increasing injury (r(2) = 0.46), but no alteration was detected at protein level. The mRNA expression of p75(NTR) apoptosis adaptor proteins NADE, NRIF, and Lingo1 were significantly downregulated in retinas with the greatest nerve injury. A positive correlation was found between injury extent and message levels for Jun (r(2) = 0.23) as well as Junb (r(2) = 0.27), and RGC labeling of activated JUN protein increased. Atf3 mRNA levels demonstrated a positive linear correlation to the extent of injury (r(2) = 0.53), resulting in a nearly five-fold increase (482 +/- 76%) in eyes with the greatest nerve damage. Among downstream pro-survival signaling components, Erk5 mRNA expression was linearly upregulated (r(2) = 0.32) up to 157 +/- 15% of fellow values in retinas with the severest nerve injury (p < 0.01). A slight positive correlation was found between NF-kappaB message levels and injury extent (r(2) = 0.12). Bcl-xl mRNA levels in the most severely injured retinas were significantly reduced to 83 +/- 7% by elevated IOP exposure. Message levels for Erk1/2, Akt1-3 or Bcl2 appeared unaffected. Elevated IOP did not alter mRNA levels of pro-apoptotic Bim, Bax, or p53. This study demonstrates that elevated IOP exposure does not result in a dramatic decrease in retinal levels of either BDNF or its receptor, TrkB. It shows that the responses of NT pathways to elevated IOP are complex, particularly with regard to the role of p75(NTR) and Atf3. A better understanding of the roles of these proteins in IOP-induced injury is likely to suggest informed strategies for neuroprotection in glaucoma.
...
PMID:Does elevated intraocular pressure reduce retinal TRKB-mediated survival signaling in experimental glaucoma? 1968 84

In this work, a biodegradable poly(ethylene glycol)-poly(epsilon-caprolactone)-poly (ethylene glycol) (PEG-PCL-PEG, PECE) triblock copolymer was successfully synthesized, which was flowing sol at low temperature and turned to nonflowing gel at body temperature. The toxicity evaluation of PECE hydrogel as a potential in situ sustained opthalmic drug delivery system was performed, including the biodegradability of PECE hydrogel in the eye, its effect on cultured human lens epithelia, intraocular pressure, and ocular tissues. The results indicated that the prepared PECE hydrogel was biocompatible and biodegradable despite of temporary elevated intraocular pressure and slight corneal endothelial damage at specific concentration. Therefore, PECE hydrogel may be a safe candidate for sustained ophthalmic drug delivery system.
...
PMID:Toxicity evaluation of biodegradable and thermosensitive PEG-PCL-PEG hydrogel as a potential in situ sustained ophthalmic drug delivery system. 1980 31


1 2 3 4 Next >>

---