Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alloimmune thrombocytopenia of the newborn (AITN) is due to the transplacental passage of maternal antibodies directed against fetal platelet antigens, most commonly PLA, (HPA-1a). Sensitization and clinical manifestations of disease can occur in the first pregnancy. It carries a mortality rate of 15%, usually due to intracranial hemorrhage (ICH). Twenty-four cases of AITN were reviewed, five of whom had radiological evidence of ICH in utero. Petechiae and/or bruising were present in 14 babies. Platelet counts at birth ranged from 5 to 206 x 10(9)/L. One infant died. The duration of follow-up for the four survivors of ICH ranged from 15 to 71 months. All had serious neurodevelopmental sequelae, including severe mental retardation, cortical blindness, seizures, and cerebral palsy. The emotional and financial cost created by the care of these children is immeasurable. Steps to identify and prevent AITN should be part of routine prenatal care if we are to reduce the morbidity and mortality caused by this disorder.
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PMID:Alloimmune thrombocytopenia of the newborn: neurodevelopmental sequelae. 872 21

A prototype multiple-drug delivery implant has been developed for the intraocular management of proliferative vitreoretinopathy (PVR). Because of the recurrent nature of the disease, PVR causes blindness in approximately 7% of patients who have undergone retinal re-attachment surgery. The poly(dl-lactide-co-glycolide) 50/50 (PLGA) implant consists of three cylindrical segments, each of which contains one of the following drugs: 5-fluorouridine (5FUrd, an antimetabolite), triamcinolone (Triam, a corticosteroid), and human recombinant tissue plasminogen activator (t-PA, a thrombolytic agent). The device can be inserted through a 20-gauge syringe needle into the vitreous body of the eye. The implant also possesses a PLGA coating over the t-PA-containing terminal segment, which creates a lag-time to deliver t-PA when most needed and to decrease the risk of postoperative bleeding. Two methods of cylinder fabrication were investigated: heat and solvent extrusion. The release behavior of several drugs was examined as a function of the processing variables including: extrusion method, drug loading, polymer molecular weight, and drug particle size. The presence of either the organic solvent (acetone) during processing or a highly water-soluble drug (5FUrd) in the formulation increased the polymer porosity, which in turn, increased the drug release-rate. Drug loading effects were consistent with percolation concepts, and a low-molecular-weight PLGA (e.g., Mw=42000 for inherent viscosity=0.58 dl/g) was desirable to produce controlled release close to one month. Based on pharmacological and pharmacokinetic data of these compounds and our clinical experience with this disease, several design criteria for a combined implant were devised. Optimal cylindrical segments from the formulation studies were selected and combined in series to form a contiguous implant. After successful combination and coating procedures were developed, prototype implants were prepared. From the 3-drug prototype, 5FUrd and Triam were released approximately 1 microgram/day for over 4 weeks and 10-190 microgram/day over 2 weeks, respectively. The solvent-extrusion procedure did not significantly alter the stability of the encapsulated t-PA (>94+/-5% serine protease activity after preparation). After a lag-time of approximately 2 days, t-PA was released active at a rate of approximately 0.2-0.5 microgram/day in approximately 2 weeks. The release characteristics from the combined implant largely met our initial design criteria. Hence, controlled-release implants of this kind may have potential use for intraocular treatment of PVR.
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PMID:Development of a multiple-drug delivery implant for intraocular management of proliferative vitreoretinopathy. 979 83

Pathologies affecting the posterior segment of the eye are one of the major causes of blindness in developed countries and are becoming more prevalent due to the increase in society longevity. Successful therapy of diseases affecting the back of the eye requires effective concentrations of the active substance maintained during a long period of time in the intraocular target site. Treatment of vitreoretinal diseases often include repeated intravitreous injections that are associated with adverse effects. Local administration of biodegradable microspheres offers an excellent alternative to multiple administrations, as they are able to deliver the therapeutic molecule in a controlled fashion. Furthermore, injection of microparticles is performed without the need for surgical procedures. As most of the retinal diseases are multifactorial, microspheres result especially promising because they can be loaded with more than one active substance and complemented with the inclusion of additives with pharmacological properties. Personalized therapy can be easily achieved by changing the amount of administered microspheres. Contrary to non-biodegradable devices, biodegradable PLA and PLGA microspheres disappear from the site of administration after delivering the drug. Furthermore, microspheres prepared from these mentioned biomaterials are well tolerated after periocular and intravitreal injections in animals and humans. After injection, PLA and PLGA microspheres suffer aggregation behaving like an implant. Biodegradable microspheres are potential tools in regenerative medicine for retinal repair. According to the reported results, presumably a variety of microparticulate formulations for different ophthalmic therapeutic uses will be available in the clinical practice in the near future.
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PMID:The potential of using biodegradable microspheres in retinal diseases and other intraocular pathologies. 2481 36

Diabetic retinopathy is one of the most important causes of blindness. The underlying mechanisms of this disease include inflammatory changes and remodeling processes of the extracellular-matrix (ECM) leading to pericyte and vascular endothelial cell damage that affects the retinal circulation. In turn, this causes hypoxia leading to release of vascular endothelial growth factor (VEGF) to induce the angiogenesis process. Alpha-1 antitrypsin (AAT) is the most important circulating inhibitor of serine proteases (SERPIN). Its targets include elastase, plasmin, thrombin, trypsin, chymotrypsin, proteinase 3 (PR-3) and plasminogen activator (PAI). AAT modulates the effect of protease-activated receptors (PARs) during inflammatory responses. Plasma levels of AAT can increase 4-fold during acute inflammation then is so-called acute phase protein (APPs). Individuals with low serum levels of AAT could develop disease in lung, liver and pancreas. AAT is involved in extracellular matrix remodeling and inflammation, particularly migration and chemotaxis of neutrophils. It can also suppress nitric oxide (NO) by nitric oxide sintase (NOS) inhibition. AAT binds their targets in an irreversible way resulting in product degradation. The aim of this review is to focus on the points of contact between multiple factors involved in diabetic retinopathy and AAT resembling pleiotropic effects that might be beneficial.
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PMID:Diabetic retinopathy: could the alpha-1 antitrypsin be a therapeutic option? 2572 58

Purpose: Type 2 Diabetes mellitus (DM) is a major health problem and its ocular complications like orbital infections, cataract and diabetic retinopathy cause blindness. Meibomian gland (MG) dysfunction and dry eye disease are also important ocular complications of type 2 DM but not enough research has been conducted on these complications. Our hypothesis suggests type 2 DM can alter significant gene expressions of MG. In our study, MGs of leptin-deficient spontaneous diabetic and non-diabetic mice were extracted, and gene expression profiles were analyzed with microarray technology.Methods: Mice were divided into two groups; nine Lep b/ob spontaneous diabetic mice as type 2 DM group and nine non-diabetic Balb/c mice as controls. Blood glucose levels, tearfilm break-up time and fluorescein scores were measured in both two groups for 12 weeks. MGs were dissected and RNAs were isolated for microarray gene expression analysis. We filtered probes with standard deviation of more than 0.1 and we used 40452 of 45281 probes for processing. We performed fold change analysis and identified which genes are affected, and we analyzed the impact of genes on proteins, pathways and gene ontologies by using various databases.Results: We observed 172 up-regulated and 118 down-regulated genes in type 2 diabetic mice when compared to non-diabetic mice. Interestingly, expression of collagen type I, integrin beta-I binding protein-I, pyruvate dehydrogenase kinase, TNF receptor genes up-regulated with DM; on the other hand, IL-33, cholecystokinin, plasminogen activator, IL-1 and serine peptidase inhibitor genes down-regulated significantly. Also, we have seen a significant decrease in WNT signaling and pentose phosphate pathways-related genes.Conclusion: Our data show these changes in gene expression caused by endocrine and immune mechanisms of type 2 DM which result disrupted homeostasis of epithelial cells of MG. Increased expressions of apoptosis and inflammation-related genes and their effects on related pathways have proven that MGs were negatively affected by type-2 DM.
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PMID:Effects of Type 2 Diabetes Mellitus on Gene Expressions of Mouse Meibomian Glands. 3142 65

Retinal neovascularization is a hallmark pathological process of numerous ocular diseases which comprise the most common causes of blindness and affect millions of people from infants to the elderly. Compared to large proteins, small peptides have advantages for therapeutic application in ocular diseases, especially for retinal diseases. In this study, we investigated a small peptide derived from human tissue-type plasminogen kringle 2 (t-PA kringle 2), named TKII-12, and investigated the effect of TKII-12 on various aspects of vascular endothelial growth factor (VEGF)-induced angiogenesis in vitro and in vivo. Our results showed that TKII-12 effectively inhibited VEGF-induced human retinal microvascular endothelial cell proliferation, migration and tube formation on Matrigel dose-dependently as well as sequence-dependently. TKII-12 inhibited VEGF-induced formation of actin stress fibers and focal adhesions in vascular endothelial cells. Moreover, TKII-12 effectively inhibited retinal neovascularization in a mouse oxygen-induced retinopathy (OIR) model. Our study demonstrated that TKII-12 could effectively inhibit retinal angiogenesis in vitro and in vivo by eliminating the formation of focal adhesion complexes and the organization of actin stress fibers. TKII-12 can serve as a prototype for retinal angiogenesis inhibitory drug development.
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PMID:Inhibition of Pathological Retinal Neovascularization by a Small Peptide Derived from Human Tissue-Type Plasminogen Kringle 2. 3206 54

Corneal and conjunctival infections are common ocular diseases, sometimes, causing severe and refractory drug-resistant bacteria infections. Fungal keratitis is a leading cause for blindness and traditional medical treatment is unsatisfactory. Thus, there is an urge to develop a new therapy to deal with these cases. In this study, we developed surface modified poly(lactic acid) (PLA) electrospun nanofibrous membranes (EFMs) with silver nanoparticles (AgNPs) and cellulose nanofibrils (CNF) as scaffolds for cell proliferation and antimicrobial application. The AgNPs with a very low content (below 0.1%) were easily anchored on the surface of PLA EFMs by CNF, which endowed the scaffold with hydrophilicity and antibacterial ability. The in-vitro cell co-culture experiments showed that the scaffold had great biocompatibility to ocular epithelial cells, especially the scaffolds coated by CNF, which significantly proliferated cells. Furthermore, the antibacterial activity could reach >95% inhibiting Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) due to the implantation of AgNPs, and the antifungal activity was also outstanding with most of the Fusarium spp. inhibited. Hence, the developed PLA EFMs with CNF and AgNPs are promising ocular bandages to promote cell proliferation and kill infectious pathogens, exhibiting potential applications in ocular wound healing in the future.
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PMID:Surface modified electrospun poly(lactic acid) fibrous scaffold with cellulose nanofibrils and Ag nanoparticles for ocular cell proliferation and antimicrobial application. 3227 89