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1.
Diabetes Metab ; 41(4): 272-281, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26323666

ABSTRACT

Diabetes-associated micro- and macrovascular complications contribute to the increased morbidity and mortality observed in diabetes. Diabetes leads to accelerated generation of advanced glycation end products (AGEs) and activation of their receptor, RAGE, as well as activation of NAD(P)H oxidase (Nox), an enzyme dedicated to the production of reactive oxygen species, which ultimately leads to a pro-inflammatory environment characterised by oxidative stress. This review outlines the current evidence about the contribution of and interaction between the AGE-RAGE axis and Nox derived ROS formation in the development and progression of micro- and macrovascular diabetic complications (especially in atherosclerosis and nephropathy), and the mechanisms by which this occurs. We also outline novel treatments targeting the AGE-RAGE axis and specific Nox isoforms, which hold great promise in attenuating the development of diabetes-associated atherosclerosis and diabetic nephropathy.


Subject(s)
Diabetic Angiopathies/genetics , NADPH Oxidases/physiology , Receptor for Advanced Glycation End Products/physiology , Animals , Atherosclerosis/etiology , Atherosclerosis/genetics , Atherosclerosis/metabolism , Diabetic Angiopathies/metabolism , Diabetic Nephropathies/genetics , Diabetic Nephropathies/metabolism , Glycation End Products, Advanced/metabolism , Glycation End Products, Advanced/physiology , Humans , NADPH Oxidase 1 , Oxidative Stress/physiology , Reactive Oxygen Species/adverse effects , Reactive Oxygen Species/metabolism
2.
Diabetologia ; 57(3): 633-42, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24292634

ABSTRACT

AIMS/HYPOTHESIS: Enhanced vascular inflammation, immune cell infiltration and elevated production of reactive oxygen species (ROS) contribute significantly to pro-atherogenic responses in diabetes. We assessed the immunomodulatory role of NADPH oxidase (NOX)-derived ROS in diabetes-accelerated atherosclerosis. METHODS: Diabetes was induced in male Apoe(-/-) mice with five daily doses of streptozotocin (55 mg kg(-1) day(-1)). Atherosclerotic plaque size, markers of ROS and immune cell accumulation were assessed in addition to flow cytometric analyses of cells isolated from the adjacent mediastinal lymph nodes (meLNs). The role of NOX-derived ROS was investigated using the NOX inhibitor, GKT137831 (60 mg/kg per day; gavage) administered to diabetic and non-diabetic Apoe(-/-) mice for 10 weeks. RESULTS: Diabetes increased atherosclerotic plaque development in the aortic sinus and this correlated with increased lesional accumulation of T cells and CD11c(+) cells and altered T cell activation in the adjacent meLNs. Diabetic Apoe(-/-) mice demonstrated an elevation in vascular ROS production and expression of the proinflammatory markers monocyte chemoattractant protein 1, vascular adhesion molecule 1 and IFNγ. Blockade of NOX-derived ROS using GKT137831 prevented the diabetes-mediated increase in atherosclerotic plaque area and associated vascular T cell infiltration and also significantly reduced vascular ROS as well as markers of inflammation and plaque necrotic core area. CONCLUSIONS/INTERPRETATION: Diabetes promotes pro-inflammatory immune responses in the aortic sinus and its associated lymphoid tissue. These changes are associated with increased ROS production by NOX. Blockade of NOX-derived ROS using the NOX inhibitor GKT137831 is associated with attenuation of these changes in the immune response and reduces the diabetes-accelerated development of atherosclerotic plaques in Apoe(-/-) mice.


Subject(s)
Aorta, Thoracic/pathology , Diabetes Mellitus, Experimental/drug therapy , Diabetic Angiopathies/drug therapy , Inflammation/drug therapy , NADPH Oxidases/drug effects , Plaque, Atherosclerotic/drug therapy , Pyrazoles/pharmacology , Pyridines/pharmacology , Reactive Oxygen Species/metabolism , Animals , Aorta, Thoracic/drug effects , Apolipoproteins E/deficiency , Atherosclerosis , Diabetes Mellitus, Experimental/immunology , Diabetes Mellitus, Experimental/pathology , Diabetic Angiopathies/immunology , Diabetic Angiopathies/pathology , Immunohistochemistry , Inflammation/immunology , Inflammation/pathology , Male , Mice , NADPH Oxidases/biosynthesis , Oxidation-Reduction , Plaque, Atherosclerotic/immunology , Plaque, Atherosclerotic/pathology , Pyrazolones , Pyridones
3.
Diabetologia ; 56(5): 1155-65, 2013 May.
Article in English | MEDLINE | ID: mdl-23344731

ABSTRACT

AIMS/HYPOTHESIS: The small, highly conserved vasoactive peptide urotensin II (UII) is upregulated in atherosclerosis. However, its effects in diabetes-associated atherosclerosis have not been assessed. METHODS: Endothelial cells were grown in normal- and high-glucose (5 and 25 mmol/l) media with and without UII (10⁻8 mol/l) and/or the UII receptor antagonist, SB-657510 (10⁻8 mol/l). Apoe knockout (KO) mice with or without streptozotocin-induced diabetes were treated with or without SB-657510 (30 mg kg⁻¹ day⁻¹; n = 20 per group) and followed for 20 weeks. Carotid endarterectomy specimens from diabetic and non-diabetic humans were also evaluated. RESULTS: In high (but not normal) glucose medium, UII significantly increased CCL2 (encodes macrophage chemoattractant protein 1 [MCP-1]) gene expression (human aortic endothelial cells) and increased monocyte adhesion (HUVECs). UII receptor antagonism in diabetic Apoe KO mice significantly attenuated diabetes-associated atherosclerosis and aortic staining for MCP-1, F4/80 (macrophage marker), cyclooxygenase-2, nitrotyrosine and UII. UII staining was significantly increased in carotid endarterectomies from diabetic compared with non-diabetic individuals, as was staining for MCP-1. CONCLUSIONS/INTERPRETATION: This is the first report to demonstrate that UII is increased in diabetes-associated atherosclerosis in humans and rodents. Diabetes-associated plaque development was attenuated by UII receptor antagonism in the experimental setting. Thus UII may represent a novel therapeutic target in the treatment of diabetes-associated atherosclerosis.


Subject(s)
Atherosclerosis/prevention & control , Diabetes Mellitus, Type 1/complications , Diabetic Angiopathies/prevention & control , Endothelium, Vascular/drug effects , Protective Agents/therapeutic use , Receptors, G-Protein-Coupled/antagonists & inhibitors , Urotensins/antagonists & inhibitors , Animals , Aorta/drug effects , Aorta/immunology , Aorta/metabolism , Aorta/pathology , Atherosclerosis/complications , Atherosclerosis/metabolism , Atherosclerosis/pathology , Cell Adhesion/drug effects , Cells, Cultured , Crosses, Genetic , Diabetic Angiopathies/immunology , Diabetic Angiopathies/metabolism , Diabetic Angiopathies/pathology , Endothelium, Vascular/immunology , Endothelium, Vascular/metabolism , Endothelium, Vascular/pathology , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/immunology , Human Umbilical Vein Endothelial Cells/metabolism , Human Umbilical Vein Endothelial Cells/pathology , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/drug effects , Monocytes/immunology , Pilot Projects , Protective Agents/pharmacology , Receptors, G-Protein-Coupled/metabolism , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Urotensins/biosynthesis , Urotensins/metabolism
4.
J Forensic Sci ; 46(4): 822-9, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11451062

ABSTRACT

Comparing the infrared transmission spectrum of cocaine HCl to its attenuated total reflection (ATR) spectrum has raised questions about the use of ATR spectra for forensic drug analysis. Whenever infrared spectra are collected using different modes or sample preparation methods, small variations in peak intensity ratios or peak positions are possible. These variations in infrared spectra are small and do not interfere with qualitative analysis, but they can cause confusion when unrecognized as normal effects of the different spectroscopic techniques. Comparison of the absorption and ATR spectra of cocaine hydrochloride illustrates the type of differences that can be expected. These differences are explained by the fundamental differences in the collection techniques. For the best quantitative results, only spectra collected by the same technique should be compared.

5.
J Forensic Sci ; 45(4): 876-81, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10914588

ABSTRACT

An infrared spectral library containing 455 controlled and noncontrolled solid drug standards was generated using internal reflection spectroscopy. All attenuated total reflection (ATR) spectra were obtained with small diamond internal reflection elements. ATR spectra will have minor variations from transmission spectra commonly found in commercial infrared libraries.


Subject(s)
Pharmaceutical Preparations/chemistry , Spectrum Analysis , Databases, Factual , Forensic Medicine , Humans
6.
Emerg Med Clin North Am ; 11(3): 739-53, 1993 Aug.
Article in English | MEDLINE | ID: mdl-8359140

ABSTRACT

Essential aspects of emergency department assessment and initial treatment of patients with traumatic amputations are outlined. Pitfalls of early treatment and indications for replantation are discussed. The dogmatic approach is avoided.


Subject(s)
Amputation, Traumatic/surgery , Hand Injuries/surgery , Replantation , Age Factors , Contraindications , Finger Injuries/surgery , Humans , Vascular Surgical Procedures
7.
Handchir Mikrochir Plast Chir ; 25(2): 66-71, 1993 Mar.
Article in English | MEDLINE | ID: mdl-8325553

ABSTRACT

450 wrists in 362 patients underwent release of carpal tunnel compression combined with synovialectomy and reconstruction of the retinaculum flexorum between 1981 and 1989. To reconstruct the retinaculum flexorum, a "flap" of the antebrachial fascia continuous with the retinaculum flexorum, based radially and distally, was elevated and sutured to the hook of the hamate. This technique provides for carpal tunnel decompression while preserving the biomechanical role of the retinaculum flexorum and the normal anatomic relationship between the flexor tendons and the axial skeleton. The patients in this study appeared to recover function faster and more completely than those undergoing division of the retinaculum flexorum alone. No secondary procedures for recurrent carpal tunnel compression were necessary.


Subject(s)
Carpal Tunnel Syndrome/surgery , Synovectomy , Tendons/surgery , Adolescent , Adult , Aged , Aged, 80 and over , Carpal Tunnel Syndrome/pathology , Female , Follow-Up Studies , Humans , Ligaments, Articular/pathology , Ligaments, Articular/surgery , Male , Middle Aged , Synovial Membrane/pathology , Tendons/pathology
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