Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Microencapsulation of cell spheroids in an immunoselective, highly biocompatible, biomembrane offers a way to create viable implantation options in the treatment of insulin-dependent diabetes mellitus (IDDM). Traditionally the encapsulation process has been achieved through the injection/extrusion of alginate/cell mixtures into a calcium chloride solution to produce calcium alginate capsules around the cells. A novel alternative is explored here through a procedure using an emulsion process to produce thin adherent calcium alginate membranes around cell spheroids. In this study, a thorough investigation has been used to establish the emulsion process parameters that are critical to the formation of a coherent alginate coat both on a model spheroid system and subsequently on cell spheroids. Optical and fluorescence microscopy are used to assess the morphology and coherence of the calcium alginate/poly-L-ornithine/alginate (APA) capsules produced.
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PMID:Emulsion strategies in the microencapsulation of cells: pathways to thin coherent membranes. 1598 91

Neonatal porcine cell clusters (NPCCs) might replace human for transplant in patients with type 1 diabetes mellitus (T1DM). However, these islets are not immediately functional, due to their incomplete maturation/ differentiation. We then have addressed: 1) to assess whether in vitro coculture of islets with homologous Sertoli cells (SC) would shorten NPCCs' functional time lag, by accelerating the beta-cell biological maturation/differentiation; 2) to evaluate metabolic outcome of the SC preincubated, and microencapsulated NPCCs, upon graft into spontaneously diabetic NOD mice. The islets, isolated from < 3 day piglets, were examined in terms of morphology/viability/function and final yield. SC effects on the islet maturation pathways, both in vitro and in vivo, upon microencapsulation in alginate/poly-L-ornithine, and intraperitoneal graft into spontaneously diabetic NOD mice were determined. Double fluorescence immunolabeling showed increase in beta-cell mass for SC+ neonatal porcine islets versus islets alone. In vitro insulin release in response to glucose, as well as mRNA insulin expression, were significantly higher for SC+ neonatal porcine islets compared with control, thereby confirming SC-induced increase in viable and functional beta-cell mass. Graft of microencapsulated SC+ neonatal porcine islets versus encapsulated islets alone resulted in significantly longer remission of hyperglycemia in NOD mice. We have preliminarily shown that the in vitro NPCCs' maturation time lag can dramatically be curtailed by coincubating these islets with SC. Graft of microencapsulated neonatal porcine islets, precultured in Sertoli cells, has been proven successful in correcting hyperglycemia in stringent animal model of spontaneous diabetes.
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PMID:Accelerated functional maturation of isolated neonatal porcine cell clusters: in vitro and in vivo results in NOD mice. 1605 7

Cell encapsulation technology raises hopes in medicine and biotechnology. Encapsulated pancreatic islets is a promising approach for the final solution of Type 1 diabetes. Unfortunately, evidence of long-term encapsulated islet graft survival and functional competence lies behind expectancy. Failure was often ascribed to the lack of biocompatibility generating inflammatory response, or limited immunobarrier competence or hypoxia or finally, low beta-cell replication. In order to prevent severe inflammation at early stages after implantation, composite microcapsules were designed. Biodegradable microspheres containing ketoprofen were enveloped into the well established alginate/poly-L-ornithine/alginate capsules. Polyester microspheres were prepared, by solvent evaporation, and characterized for encapsulation efficiency, particle size and in vitro release. Biocompatibility and efficacy to prevent the inflammatory response were studied in vivo. Good encapsulation efficiency and the desired particle size were achieved. In vitro release studies evidenced a high burst effect probably due to a plasticizing effect of both water and ketoprofen. The composite systems showed good biocompatibility and capacity to completely avoid the inflammatory response and the pericapsular cell overgrowth. In conclusion, the inflammatory response in the immediate post-transplant period can be circumvented using multicompartment microcapsules releasing non-steroidal anti inflammatory drugs.
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PMID:Ketoprofen controlled release from composite microcapsules for cell encapsulation: effect on post-transplant acute inflammation. 1612 7

Activity of tubular lysosomic (N-acetyl-beta-D-glucosaminidase--NAG, its thermostable isoenzyme NAG B and B-galactosidase--beta-GAL) and mitochondrial (L-canavanine: ornithine amidinetransferase--COAT) enzymes were measured in urine of 30 patients with diabetes complicated by diabetic nephropathy (DN). It was shown that activity of NAG, especially its thermostable isoenzyme NAG B and also beta-GAL in urine of DN patients was higher compare to those in healthy subject. Moreover COAT activity was registered in urine of DN patients while it is not presented in healthy persons. The precise dependence of NAG, NAG B, beta-GAL levels and COAT activity on the functional state of renal parenchyma in particular on tubular nephron nephrocytes was found that allows us to consider the given parameters as markers of diabetic process progressing in kidneys in patients with diabetes.
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PMID:[Urinary enzymes as markers of functional state of kidneys with diabetic lesions]. 1655 3

The aging human extracellular matrix (ECM) and tissues rich in long-lived proteins undergo extensive changes with age that include increased stiffening, loss of elasticity, insolubilization, and decreased proteolytic digestibility. Most if not all these changes can be duplicated by the Maillard reaction in vitro, that is, the incubation of the proteins with reducing sugars and oxoaldehydes. These carbonyls eventually form advanced glycation end products (AGEs) and crosslinks that impair proteolytic digestibility and alter protein conformation. To date, close to 20 AGEs have been found in the human skin, of which ornithine is the single major result of damage to arginine residues, and glucosepane the single major crosslink. Although redox active metals and oxoaldehydes appear to play an important role in protein damage in experimental diabetes, their role in diabetic humans is still poorly understood. Evidence for the existence of deglycating enzymes has been found in vertebrates, bacteria, and fungi. However, only the vertebrate enzymes can deglycate larger, intracellular proteins via an ATP-dependent mechanism. Protein engineering will thus be needed to adapt Amadoriase enzymes toward deglycation of ECM proteins for purpose of probing the role of advanced glycation in animal models of diabetes and age-related diseases. The blocking of the reactivity of the glucosepane precursor using potent nucleophiles may be useful in preventing age-related changes in ECM proteins. However, there currently is no evidence in support of the proposed ability of so-called "AGE breakers" to cleave existing crosslinks of the Maillard reaction in vivo, and other mechanisms of action should be sought for this class of compounds.
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PMID:Prevention and repair of protein damage by the Maillard reaction in vivo. 1670 54

Methylglyoxal (MG) is a highly reactive alpha-oxoaldehyde formed endogenously in numerous enzymatic and nonenzymatic reactions. It modifies arginine and lysine residues in proteins forming advanced glycation end-products such as N(delta)-(5-methyl-4-imidazolon-2-yl)-L-ornithine (MG-H1), 2-amino-5-(2-amino-5-hydro-5-methyl-4-imidazolon-1-yl)pentanoic acid (MG-H2), 2-amino-5-(2-amino-4-hydro-4-methyl-5-imidazolon-1-yl)pentanoic acid (MG-H3), argpyrimidine, N(delta)-(4-carboxy-4,6-dimethyl-5,6-dihydroxy-1,4,5,6-tetrahydropyrimidine-2-yl)-L-ornithine (THP), N(epsilon)-(1-carboxyethyl)lysine (CEL), MG-derived lysine dimer (MOLD), and 2-ammonio-6-({2-[4-ammonio-5-oxido-5-oxopently)amino]-4-methyl-4,5-dihydro-1H-imidazol-5-ylidene}amino)hexanoate (MODIC), which have been identified in vivo and are associated with complications of diabetes and some neurodegenerative diseases. In foodstuffs and beverages, MG is formed during processing, cooking, and prolonged storage. Fasting and metabolic disorders and/or defects in MG detoxification processes cause accumulation of this reactive dicarbonyl in vivo. In addition, the intake of low doses of MG over a prolonged period of time can cause degenerative changes in different tissues, and can also exert anticancer activity. MG in biological samples can be quantified by HPLC or GC methods with preliminary derivatization into more stable chromophores and/or fluorophores, or derivatives suitable for determination by MS by use of diamino derivatives of benzene and naphthalene, 6-hydroxy-2,4,5-triaminopyrimidine, cysteamine, and o-(2,3,4,5,6-pentafluorobenzyl) hydroxylamine. The methods include three basic steps: deproteinization, incubation with derivatization agent, and chromatographic analysis with or without preliminary extraction of the formed products.
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PMID:Methylglyoxal in food and living organisms. 1710 72

Protein transduction domains (PTDs), both naturally occurring and synthetic, have been increasingly employed to deliver biologically active agents to a variety of cell types in vitro and in vivo. In addition to the previously characterized arginine-rich PTDs, including Tat (transactivator of transcription), Antp (Antennapedia) and PTD-5, we have demonstrated that lysine and ornithine, as well as arginine, homopolymers are able to mediate transduction of a wide variety of agents. To screen for optimal PTDs, we have used as a therapeutic cargo a peptide derived from IKK {IkappaB [inhibitor of NF-kappaB (nuclear factor kappaB)] kinase} beta, able to bind to the IKK regulatory subunit [NEMO (NF-kappaB essential modulator)], preventing formation of an active kinase complex. This peptide, termed NBD, is able to block activation of NF-kappaB, but not basal activity. We demonstrate that PTD-mediated delivery of NBD using certain PTDs, in particular 8K (octalysine), is therapeutic following systemic delivery in murine models of inflammatory bowel disease, diabetes and muscular dystrophy. In addition, we have developed a peptide phage display library screening method for novel transduction peptides able to facilitate tissue-specific internalization of marker protein complexes. Using this approach, we have identified transduction peptides that are able to facilitate internalization of large protein complexes into tumours, airway epithelia, synovial fibroblasts, cardiac tissue and HEK-293 (human embryonic kidney) cells in culture and/or in vivo.
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PMID:Protein transduction: identification, characterization and optimization. 1763 54

1. Arginase is the focal enzyme of the urea cycle hydrolysing L-arginine to urea and L-ornithine. Emerging studies have identified arginase in the vasculature and have implicated this enzyme in the regulation of nitric oxide (NO) synthesis and the development of vascular disease. 2. Arginase inhibits the production of NO via several potential mechanisms, including competition with NO synthase (NOS) for the substrate L-arginine, uncoupling of NOS resulting in the generation of the NO scavenger, superoxide and peroxynitrite, repression of the translation and stability of inducible NOS protein, inhibition of inducible NOS activity via the generation of urea and by sensitization of NOS to its endogenous inhibitor asymmetric dimethyl-L-arginine. 3. Upregulation of arginase inhibits endothelial NOS-mediated NO synthesis and may contribute to endothelial dysfunction in hypertension, ageing, ischaemia-reperfusion and diabetes. 4. Arginase also redirects the metabolism of L-arginine to L-ornithine and the formation of polyamines and L-proline, which are essential for smooth muscle cell growth and collagen synthesis. Therefore, the induction of arginase may also promote aberrant vessel wall remodelling and neointima formation. 5. Arginase represents a promising novel therapeutic target that may reverse endothelial and smooth muscle cell dysfunction and prevent vascular disease.
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PMID:Arginase: a critical regulator of nitric oxide synthesis and vascular function. 1764 39

Nitric oxide (NO) is a potent regulator of both vascular tone and oxygen utilization. Diabetes is commonly associated with both NO deficiency and reduced renomedullary oxygen availability. Arginine availability as regulator of NO production has gained growing interest. We hypothesized that arginine limitation causes diabetes-induced renomedullary NO deficiency, which directly influences renomedullary oxygen tension (P(o2)). Medullary NO, P(o2), and blood flow were measured in control and streptozotocin-induced diabetic rats, which were treated or not treated with alpha-tocopherol, and administered l-arginine followed by N(omega)-nitro-l-arginine methyl ester. Major components of arginine metabolism were also investigated. Diabetic rats had reduced renomedullary NO levels compared with controls. Arginine selectively increased NO levels in diabetic rats and totally restored NO levels in alpha-tocopherol-treated animals. Tocopherol prevented the reduction in medullary P(o2) in the diabetic animals. Although blood flow increased equally in all groups, arginine increased P(o2) exclusively in the diabetic groups. Diabetes decreased plasma arginine and asymmetric dimethylarginine concentrations, but increased hepatic CAT-2A and plasma ornithine independently of alpha-tocopherol treatment. In conclusion, diabetic rats had reduced renomedullary NO due to decreased plasma arginine following increased hepatic arginine uptake and degradation. This was unrelated to oxidative stress. The diabetes-induced reduction in renomedullary P(o2) was restored by either acute arginine administration, which also restored NO levels, or long-term antioxidant treatment. Arginine increased medullary NO and P(o2) independently of altered hemodynamics in the diabetic groups. This reveals a direct regulatory function of NO for renomedullary P(o2) especially during situations of elevated oxidative stress.
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PMID:Reduced nitric oxide in diabetic kidneys due to increased hepatic arginine metabolism: implications for renomedullary oxygen availability. 1800 55

Several diseases concomitant with L-arginine deficiency (diabetes, chronic kidney failure, psoriasis) are significantly associated with dry eye syndrome. One important factor that has so far been neglected is the y(+) transporter. In humans, y(+) accounts for nearly 80% of arginine transport, exclusively carrying the cationic amino acids L-arginine, L-lysine and L-ornithine. y(+) is represented by CAT(cationic amino acid transporter) proteins. L-arginine is a precursor of the moisturizer urea, which has been used in the treatment of dry skin diseases. Although urea has also been shown to be part of the tear film, little attention has been paid to it in this role. Moreover, L-arginine and L-lysine are major components contributing to synthesis of the antimicrobially active beta-defensins induced under dry eye conditions. The first results have demonstrated that transport of L-arginine and L-lysine into epithelial cells is limited by the y(+) transporter at the ocular surface.
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PMID:Cationic amino acid transporters and beta-defensins in dry eye syndrome. 2050 22


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