Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Propanolol and metoprolol exert adrenoceptor-independent effects including scavenging of free radicals and inhibition of protein kinase C leading to inhibition of leukocyte migration and radical release as a consequence. Whether topically used metipranolol and timolol exert such effects is unknown. Neutrophil chemotaxis was tested using modified Boyden microchemotaxis chambers. Respiratory burst activity of neutrophils was detected fluorometrically. Radical scavenging properties were tested using 2',7'-dichlorofluorescein diacetate. Metipranolol and timolol inhibited neutrophil chemotaxis at doses in the micromolar range, oxygen free radical production triggered with formyl-Met-Leu-Phe was inhibited at higher concentration. Protein kinase C involvement, suggested to trigger free radical production with phorbol myristate acetate, was antagonized. A direct radical scavenging effect of the beta-blockers was also seen. Inhibition of neutrophil chemotaxis and free radical production is a novel mode of action of metipranolol and timolol that may be relevant for beneficial effects in the topical treatment of eye disease.
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PMID:Inhibition of neutrophil migration and oxygen free radical release by metipranolol and timolol. 1283 74

Diabetic retinopathy (DR) remains a major cause of new cases of blindness onset in adults. The prevalence of diabetic eye disease is strongly related to the duration of diabetes, blood pressure and glycemic control, although a multifactorial pathogenesis is likely to be probable. Despite the effectiveness of current prevention (by tight metabolic and blood pressure control) and treatment (with laser photocoagulation) methods, and with the help of screening programs, diabetic eye disease is still a problem. Recent advances in our understanding of the pathogenesis of microvascular complications and particularly of the role of growth factors (GFs) in retinal changes have allowed significant advances in the medical management of DR. Studies of the biochemical process underlying DR have clearly demonstrated an important role for a number of aberrantly expressed GFs or their second messengers (eg, vascular endothelial growth factor, growth hormone, insulin-like growth factor-1, protein kinase C and pigment epithelium derived factor) possibly acting together in the development of structural changes characterizing early stages of vascular DR. The critical role of GF expression has led to new experimental therapeutic intervention in DR. In fact, timely pharmacological intervention in GF synthesis and activities may arrest the development of early vascular changes. As the effects of GFs become better understood, pharmacological manipulation of GF synthesis and action will be useful in the early stages of vascular change with the potential to prevent diabetes-related visual loss.
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PMID:Treating diabetic retinopathy by tackling growth factor pathways. 1589 47

Angiogenic eye disease is among the most common causes of blindness worldwide. Current treatment approaches are insufficiently effective and partially associated with significant adverse effects. From an investigational view, the eye provides an ideal setting to observe real-time and serial observations of angiogenesis in vivo in humans. The current understanding of molecular biology involved in angiogenesis has already led to the identification of a number of potential therapeutic targets, some of them being highly effective angiostatic molecules. Most experimental approaches currently favour or even require the systemic administration of the investigated substances (somatostatin analogues, PKC-inhibitors). However, the systemic administration of bioactive substances always risks significant systemic adverse effects. Due to the morphological characteristics of the eye, local therapies including intraocular injection or even local gene transfer might be feasible. They might provide a valuable opportunity of targeted and sustained delivery of therapeutic proteins to the retina. This review aims to outline the current understanding of the pathogenesis of proliferative diabetic retinopathy and will focus on some as yet experimental, but potentially effective new therapeutic possibilities of this disease.
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PMID:Novel approaches in the treatment of angiogenic eye disease. 1602 67

Vascular complications of chronic hyperglycemia including diabetic retinopathy are an increasing therapeutic and socioeconomic challenge. The epidemiology of diabetic eye disease has been well described, and there is as yet no clear indication for a reduction of incidence of blindness. Due to the complex multifactorial nature of the damage to diabetic vessels, it had been difficult to identify key targets for treatment and prevention. Novel techniques to study molecules and mechanisms involved in retinal vessel development and vascular cell interactions improved the understanding of retinal cell biology and pathobiology. A unifying concept has been proposed which links hyperglycemia-induced mitochondrial overproduction of reactive oxygen species with long-known biochemical alterations such as the formation of advanced glycation end products or the activation of the protein kinase C pathway. Specific inhibitors were identified that inhibited multiple biochemical abnormalities downstream of oxidative stress induced by high glucose.
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PMID:Incipient diabetic retinopathy--insights from an experimental model. 1757 94

Heterozygosity for the transcription factor PAX6 causes eye disease in humans, characterized by corneal opacity. The molecular aetiology of such disease was investigated using a Pax6+/- mouse model. We found that the barrier function of uninjured Pax6+/- corneas was compromised and that Ca2+-PKC/PLC-ERK/p38 signalling pathways were abnormally activated, mimicking a 'wounded' epithelial state. Using proteomic analysis and direct assay for oxidized proteins, Pax6+/- corneas were found to be susceptible to oxidative stress and they exhibited a wound-healing delay which could be rescued by providing reducing agents such as glutathione. Pax6 protein was oxidized and excluded from the nucleus of stressed corneal epithelial cells, with concomitant loss of corneal epithelial markers and expression of fibroblast/myofibroblast markers. We suggest a chronic wound model for Pax6-related corneal diseases, in which oxidative stress underlies a positive feedback mechanism by depleting nuclear Pax6, delaying wound healing, and activating cell signalling pathways that lead to metaplasia of the corneal epithelium. The study mechanistically links a relatively minor dosage deficiency of a transcription factor with potentially catastrophic degenerative corneal disease.
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PMID:Chronic wound state exacerbated by oxidative stress in Pax6+/- aniridia-related keratopathy. 1849 Dec 89

Thrombin signalling through PAR (protease-activated receptor)-1 is involved in cellular processes, such as proliferation, differentiation and cell survival. Following traumatic injury to the eye, thrombin signalling may participate in disorders, such as PVR (proliferative vitreoretinopathy), a human eye disease characterized by the uncontrolled proliferation, transdifferentiation and migration of otherwise quiescent RPE (retinal pigment epithelium) cells. PARs activate the Ras/Raf/MEK/ERK MAPK pathway (where ERK is extracellular-signal-regulated kinase, MAPK is mitogen-activated protein kinase and MEK is MAPK/ERK kinase) through the activation of G(alpha) and G(betagamma) heterotrimeric G-proteins, and the downstream stimulation of the PLC (phospholipase C)-beta/PKC (protein kinase C) and PI3K (phosphoinositide 3-kinase) signalling axis. In the present study, we examined the molecular signalling involved in thrombin-induced RPE cell proliferation, using rat RPE cells in culture as a model system for PVR pathogenesis. Our results showed that thrombin activation of PAR-1 induces RPE cell proliferation through Ras-independent activation of the Raf/MEK/ERK1/2 MAPK signalling cascade. Pharmacological analysis revealed that the activation of 'conventional' PKC isoforms is essential for proliferation, although thrombin-induced phosphorylation of ERK1/2 requires the activation of atypical PKCzeta by PI3K. Consistently, thrombin-induced ERK1/2 activation and RPE cell proliferation were prevented completely by PI3K or PKCzeta inhibition. These results suggest that thrombin induces RPE cell proliferation by joint activation of PLC-dependent and atypical PKC isoforms and the Ras-independent downstream stimulation of the Raf/MEK/ERK1/2 MAPK cascade. The present study is the first report demonstrating directly thrombin-induced ERK phosphorylation in the RPE, and the involvement of atypical PKCzeta in this process.
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PMID:PKC isoenzymes differentially modulate the effect of thrombin on MAPK-dependent RPE proliferation. 1863 65