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)

Multiple lines of evidence, mostly from population-based studies, suggest that green tea consumption is associated with reduced risk of several human malignancies such as cancer and diabetes. Epigallocatechin-3-gallate (EGCG), a major polyphenol found in green tea, is a widely studied chemopreventive agent with potential anticancer activity. Green tea polyphenols inhibit angiogenesis and metastasis, and induce growth arrest and apoptosis through regulation of multiple signaling pathways. Specifically, EGCG regulates expression of VEGF, matrix metalloproteinases, uPA, IGF-1, EGFR, cell cycle regulatory proteins and inhibits NFk B, PI3-K/Akt, Ras/Raf/MAPK and AP-1 signaling pathways, thereby causing strong cancer chemopreventive effects. This review discusses the molecular mechanisms of green tea polyphenols and their therapeutic implications in cancer.
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PMID:Green tea polyphenols: biology and therapeutic implications in cancer. 1756 17

Between January 2000 and June 2003, 70 patients (63 men and 7 women) with acute-on-chronic lower limb vascular occlusion underwent thrombolysis with 1 million units of urokinase. Forty-eight patients had unilateral and 22 had bilateral involvement; 9 had gangrenous changes. The mean age was 47 +/- 9 years, 73% were smokers, and 13% had diabetes. The definition of a good response was either return of distal pulses or a warm limb and relief of pain at rest. Fifty-three (76%) patients (including 5 with gangrenous changes) had symptomatic improvement with thrombolysis (group 1), and 17 (24%) did not respond (group 2). All 70 patients (including 7 who later required amputation) underwent surgical intervention with a polytetrafluoroethylene interposition graft or arterioplasty. A good response to surgical treatment was found in significantly more patients (49/53, 92%) in group 1 compared to group 2 (7/17, 41%). Claudication distance after 6 months of follow-up improved in a significantly higher percentage of patients in group 1 (85%) than group 2 (38%). Preoperative thrombolysis improved the outcome and predicted the result of arterial surgery.
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PMID:Urokinase thrombolysis in acute-on-chronic vascular occlusion of lower limb. 1791 Oct 68

This study aimed to characterize matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in relation to changes in left ventricle (LV) geometry and function in a porcine model with streptozotocin (STZ)-induced diabetes. In 15 Chinese Guizhou minipigs with STZ-induced diabetes (diabetic group) and 15 age-matched normal controls (control group), Doppler tissue imaging was performed at 6 months of diabetes. Serum MMP-2, -9, TIMP-1, -4 and B-type natriuretic peptide (BNP) were determined. Expression of MMPs, TIMPs, urokinase type-plasminogen activator (uPA), its receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1) in aortic intima and LV myocardium was evaluated, with gelatinolytic activities of tissue MMP-2, -9 accessed by zymography. Left ventricle end-diastolic septum thickness (P < 0.05) and mass (P < 0.05) were increased, whereas peak systolic mitral annulus velocity (Sm, P < 0.001), LV systolic (P = 0.01) and diastolic strain (P < 0.001) were significantly decreased in diabetic group than in controls. Diabetic group showed higher expression of TIMP-1, -4 in aortic intima and LV myocardium (P < 0.01 or P < 0.05), with increased collagen content and elevated serum BNP level (P = 0.004) and lower gelatinolytic activities of tissue MMP-2, -9 (all P < 0.05). Semi-quantitative RT-PCR of those diabetic tissues revealed elevated mRNA levels of major TIMPs, uPA, uPAR and PAI-1. Reduction of serum MMP-2 and -9 levels was observed in diabetic group vs. control group (both P < 0.05). This study features elevated levels of TIMP-1, -4, uPA, uPAR and PAI-1, and decreased activities of MMP-2, -9 in aorta and myocardium in STZ-induced diabetic minipigs, indicating that MMP-TIMP dysregulation is associated with LV hypertrophy, cardiac dysfunction and increased cardiovascular fibrosis in diabetes.
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PMID:Dysregulation of matrix metalloproteinases and their tissue inhibitors is related to abnormality of left ventricular geometry and function in streptozotocin-induced diabetic minipigs. 1833 30

In Alzheimer's disease (AD) Abeta accumulates because of imbalance between the production of Abeta and its removal from the brain. There is increasing evidence that in most sporadic forms of AD, the accumulation of Abeta is partly, if not in some cases solely, because of defects in its removal--mediated through a combination of diffusion along perivascular extracellular matrix, transport across vessel walls into the blood stream and enzymatic degradation. Multiple enzymes within the central nervous system (CNS) are capable of degrading Abeta. Most are produced by neurons or glia, but some are expressed in the cerebral vasculature, where reduced Abeta-degrading activity may contribute to the development of cerebral amyloid angiopathy (CAA). Neprilysin and insulin-degrading enzyme (IDE), which have been most extensively studied, are expressed both neuronally and within the vasculature. The levels of both of these enzymes are reduced in AD although the correlation with enzyme activity is still not entirely clear. Other enzymes shown capable of degrading Abetain vitro or in animal studies include plasmin; endothelin-converting enzymes ECE-1 and -2; matrix metalloproteinases MMP-2, -3 and -9; and angiotensin-converting enzyme (ACE). The levels of plasmin and plasminogen activators (uPA and tPA) and ECE-2 are reported to be reduced in AD. Reductions in neprilysin, IDE and plasmin in AD have been associated with possession of APOEepsilon4. We found no change in the level or activity of MMP-2, -3 or -9 in AD. The level and activity of ACE are increased, the level being directly related to Abeta plaque load. Up-regulation of some Abeta-degrading enzymes may initially compensate for declining activity of others, but as age, genetic factors and diseases such as hypertension and diabetes diminish the effectiveness of other Abeta-clearance pathways, reductions in the activity of particular Abeta-degrading enzymes may become critical, leading to the development of AD and CAA.
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PMID:Abeta-degrading enzymes in Alzheimer's disease. 1836 35

Several gene array studies have suggested that osteopontin (Opn) expression strongly correlates with albuminuria and glomerular disease. Urinary Opn concentration and kidney Opn immunoreactivity were found to be increased in patients with steroid-sensitive nephrotic syndrome. In addition, renal Opn mRNA was increased in the Ins2(Akita) mouse model of type 1 diabetic nephropathy, in the LPS-induced albuminuria model, and in glomeruli of puromycin aminonucleotide-induced nephrotic rats. Opn knockout mice did not develop albuminuria in response to LPS injection, and Opn knockout mice were protected from diabetes-induced albuminuria and mesangial expansion. In the glomerulus, Opn immunostaining was increased specifically in podocytes. Treatment of podocytes with recombinant Opn activated the NF-kappaB pathway, increased expression of urokinase plasminogen activator and matrix metalloproteinases 2 and 9, and increased podocyte motility. Taken together, these results indicate that Opn plays an important role in the development of albuminuria, possibly by modulating podocyte signaling and motility.
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PMID:The role of osteopontin in the development of albuminuria. 1844 55

Transplantation of islets of Langerhans (islets) is a promising technique for treating insulin-dependent diabetes mellitus (type I). One unresolved issue is early graft loss due to inflammation triggered by blood coagulating on the surface of islets after transplantation into the portal vein. Here, we describe a versatile method for modifying the surface of islets with an ultrathin membrane carrying the fibrinolytic enzyme urokinase or the anticoagulant heparin. The surface of islets was modified with a poly(ethylene glycol)--phospholipid conjugate bearing a biotin group (biotin-PEG-lipids, PEG MW: 5000). Biotin-PEG-lipids were anchored to the cell membranes of islets, and the PEG-lipid layer on the islets was further covered by streptavidin and biotin-bovine serum albumin conjugate using a layer-by-layer method. The surface was further activated with oxidized dextran. Urokinase was anchored to the islets through Schiff base formation. Heparin was anchored to the islets through polyion complex formation between anionic heparin and a cationic protamine coating on the islets. No practical islet volume increase was observed after surface modification, and the modifications did not impair insulin release in response to glucose stimulation. The anchored urokinase retained high fibrinolytic activity, which could help to improve graft survival by preventing thrombosis on the islet surface.
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PMID:Islets surface modification prevents blood-mediated inflammatory responses. 1853 7

One of the major complications of diabetes is the alteration of the blood-retinal barrier, leading to retinal edema and consequent vision loss. The aim of this study was to evaluate the role of the urokinase plasminogen activator (uPA)/uPA receptor (uPAR) system in the regulation of retinal vascular permeability. Biochemical, molecular, and histological techniques were used to examine the role of uPA and uPAR in the regulation of retinal vascular permeability in diabetic rats and cultured retinal endothelial cells. The increased retinal vascular permeability in diabetic rats was associated with a decrease in vascular endothelial (VE) -cadherin expression in retinal vessels. Treatment with the uPA/uPAR-inhibiting peptide (A6) was shown to reduce diabetes-induced permeability and the loss of VE-cadherin. The increased permeability of cultured cells in response to advanced glycation end products (AGEs) was significantly inhibited with A6. Treatment of endothelial cells with specific matrix metalloproteinases or AGEs resulted in loss of VE-cadherin from the cell surface, which could be inhibited by A6. uPA/uPAR physically interacts with AGEs/receptor for advanced glycation end products on the cell surface and regulates its activity. uPA and its receptor uPAR play important roles in the alteration of the blood-retinal barrier through proteolytic degradation of VE-cadherin. The ability of A6 to block retinal vascular permeability in diabetes suggests a potential therapeutic approach for the treatment of diabetic macular edema.
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PMID:A peptide inhibitor of the urokinase/urokinase receptor system inhibits alteration of the blood-retinal barrier in diabetes. 1855 77

Diabetes mellitus is associated with a number of prothrombotic abnormalities, and correction of these abnormalities might translate into the reduction of cardiovascular risk. Glitazones improve endothelial function and reduce inflammation, but much less is known about their effect on thrombogenic factors. We have therefore studied the effect of rosiglitazone on leukocyte and soluble thrombogenic markers in patients with type 2 diabetes mellitus. Thirty-three subjects with type 2 diabetes and 32 normal controls were included; patients were examined at baseline and after 5 months of rosiglitazone treatment (4 mg/day). We measured leukocyte-platelet aggregates and leukocyte expression of either P-selectin glycoprotein ligand 1 (PSGL-1) or receptor for urokinase-type plasminogen activator (uPAR) using flow cytometry, as well as several circulating soluble thrombogenic markers by ELISA method. Leukocyte expression of uPAR and PSGL-1 was significantly higher in patients than in controls. Leukocyte-platelet aggregates and leukocyte expression of uPAR and PSGL-1 significantly decreased after rosiglitazone. There was also significant decrease in CRP and fibrinogen levels, but there was no effect of diabetes and/or rosiglitazone on other circulating molecules. In conclusions, we observed a substantial improvement in the expression of thrombogenic markers on leukocytes after rosiglitazone treatment, suggesting the novel antithrombotic effects of rosiglitazone.
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PMID:The effect of rosiglitazone on the expression of thrombogenic markers on leukocytes in type 2 diabetes mellitus. 1909 19

Plasminogen activator inhibitor-1 (PAI-1) controls the regulation of the fibrinolytic system in blood by inhibiting both urokinase-type and tissue-type plasminogen activators. Enhanced levels of PAI-1 are found in patients with type 2 diabetes mellitus which is associated with a dysbalance in glucose and lipid homeostasis. Especially a defective insulin response in the liver contributes to the development of hyperglycemia, dyslipidemia and peripheral insulin resistance and may contribute to hepatic over-expression of PAI-1 in diabetes type 2. Furthermore, a substantial upregulation of PAI-1 expression has also been shown in a variety of liver injury models. Thus, the liver appears to be not only a major site of PAI-1 synthesis in response to hormonal changes, but also in response to a variety of other pathological events. PAI-1 expression in liver largely depends on activation of signalling pathways and transcriptional regulators which may be the basis for a new level of cross-talk between different signalling pathways and thus may represent attractive therapeutic candidates. This article will primarily focus on the regulation of PAI-1 expression in liver cells and discuss potential cross-talks between metabolic, hormonal and environmental signals.
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PMID:Metabolic, hormonal and environmental regulation of plasminogen activator inhibitor-1 (PAI-1) expression: lessons from the liver. 1913 22

Diaryl esters of alpha-aminophosphonates are a group of low molecular weight inhibitors of serine proteases. For over 30 years these molecules have captured the attention of biochemists and medicinal chemists due to their similarity to the transition state of peptide bond cleavage observed in enzymatic reactions (transition state analogs) as well as their high potency of action. High reactivity toward serine proteases and complete lack of activity against cysteine or threonine proteases give alpha-aminophosphonates great advantage over other classes of inhibitors such as chloromethyl ketones or peptidyl derivatives of ketoesters and ketoamides, which are known to react with serine and cysteine proteases. Moreover, the selectivity of alpha-aminophosphonates' action can be easily adjusted - even for serine proteases with similar specificity a small modification in the inhibitor structure could lead to absolute selectivity towards a particular enzyme. Furthermore alpha-aminophosphonate derivatives are successfully used as the activity based probes (ABP) for serine protease-like activity screening and as covalently reactive antigens for the development of catalytic antibodies (CAbs). The design of alpha-aminophosphonate diaryl ester inhibitors focuses on enzymes involved in the development and progression of pathophysiological states in living organisms. Examples include cancer growth and metastasis (urokinase-type plasminogen activator, uPA), diabetes or transplant rejection (dipeptidyl peptidase IV, DPPIV), osteoarthritis and lung injury (elastase) or heart failure (mast cell chymase). This review article focuses on the design of new alpha-aminophosphonic inhibitors as well as on in vivo studies performed previously using this class of inhibitors and includes recently published research data.
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PMID:Irreversible inhibition of serine proteases - design and in vivo activity of diaryl alpha-aminophosphonate derivatives. 1944 39


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