The Experts below are selected from a list of 57 Experts worldwide ranked by ideXlab platform
P Varalakshmi - One of the best experts on this subject based on the ideXlab platform.
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the cytoprotective role of a low molecular weight Heparin Fragment studied in an experimental model of glomerulotoxicity
European Journal of Pharmacology, 2003Co-Authors: Perinkulam Ravi Deepa, P VaralakshmiAbstract:Abstract Abnormal glomerular glycosaminoglycan metabolism is involved in the onset of the morphological and functional aberrations of glomerulopathies. In the present study, a Heparin derivative, low-molecular-weight Heparin, was tested for its ability to afford renoprotection in an established model of experimental glomerulopathy. Two groups of male albino rats of the Wistar strain (140±10 g) received a single intravenous injection of adriamycin (7.5 mg/kg) to induce glomerulopathy, and one of them received low-molecular-weight Heparin (Certoparin Sodium, Troparin®; 300 μg/day/rat s.c.) treatment, commencing on day 8, for a week. Urinary protein/creatinine ratio, serum albumin, urea, uric acid and creatinine clearance were evaluated. Renal cell injury was assessed in terms of renal tissue lactate dehydrogenase, aminotransferases (aspartate and alanine transaminases) and alkaline phosphatase activities, as well as renal antioxidant status (superoxide dismutase, catalase and glutathione peroxidase, reduced glutathione, vitamins E and C). The kidney tissue was subjected to histopathologic examination. Low-molecular-weight Heparin significantly reduced proteinuria and improved creatinine clearance and serum albumin levels in the rats with glomerulopathy. The significant rise in serum uric acid in the rats with glomerulopathy was reversed by low-molecular-weight Heparin. Altered tissue enzyme activities in response to injury, oxidative stress challenged renal antioxidant system and abnormal renal histology were observed in the untreated nephrotic rats, while low-molecular-weight Heparin treatment protected the nephrotic rats against these changes. Thus, in this study, low-molecular-weight Heparin was evaluated for its role in combating glomerular injury, on the basis of some salient biochemical parameters, oxidative injury indices and histologic picture. The ability of low-molecular-weight Heparin to restore glomerular anatamo-functional features in this nephrotoxic condition illuminates its multi-faceted renoprotective role.
Robert J Linhardt - One of the best experts on this subject based on the ideXlab platform.
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binding between the integrin αxβ2 cd11c cd18 and Heparin
Journal of Biological Chemistry, 2007Co-Authors: Thomas Vorupjensen, Robert J Linhardt, Lianli Chi, Louise C Gjelstrup, Uffe Birk Jensen, Craig A Jewett, Can Xie, Motomu Shimaoka, Timothy A SpringerAbstract:Abstract The interactions between cell surface receptors and sulfated glucosamineglycans serve ubiquitous roles in cell adhesion and receptor signaling. Heparin, a highly sulfated polymer of uronic acids and glucosamine, binds strongly to the integrin receptor αXβ2 (p150,95, CD11c/CD18). Here, we analyze the structural motifs within Heparin that constitute high affinity binding sites for the I domain of integrin αXβ2. Heparin oligomers with chain lengths of 10 saccharide residues or higher provide strong inhibition of the binding by the αX I domain to the complement Fragment iC3b. By contrast, smaller oligomers or the synthetic Heparinoid fondaparinux were not able to block the binding. Semipurified Heparin oligomers with 12 saccharide residues identified the fully sulfated species as the most potent antagonist of iC3b, with a 1.3 μm affinity for the αX I domain. In studies of direct binding by the αX I domain to immobilized Heparin, we found that the interaction is conformationally regulated and requires Mg2+. Furthermore, the fully sulfated Heparin Fragment induced conformational change in the ectodomain of the αXβ2 receptor, also demonstrating allosteric linkage between Heparin binding and integrin conformation.
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increase in the growth inhibition of bovine pulmonary artery smooth muscle cells by an o hexanoyl low molecular weight Heparin derivative
Carbohydrate Research, 2006Co-Authors: Hari G Garg, Charles A Hales, Melissa Butler, Tasneem Islam, Jin Xie, Robert J LinhardtAbstract:Proliferation of pulmonary artery smooth muscle cells (PASMCs) appears to play a significant role in chronic pulmonary hypertension. The proliferation of PASMCs is strongly inhibited by some commercial Heparin preparations. Heparin Fragments were prepared by periodate treatment, followed by sodium borohydride reduction, to enhance potency. The tributylammonium salt of this Fragmented Heparin was O-acylated with hexanoic anhydride. Gradient polyacrylamide gel electrophoresis showed that the major Heparin Fragment contained eight disaccharide units. NMR analysis showed that approximately one hexanoyl group per disaccharide residue was present. The O-hexanoyl Heparin Fragments were assayed for growth inhibitory effect on bovine PASMCs in culture. This derivative was found to be more effective in growth inhibition of bovine PASMCs in culture than the Heparin from which it was derived. In the future, it is envisioned that this or similar derivatives may be an effective treatment for pulmonary hypertension.
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differential interactions of Heparin and heparan sulfate glycosaminoglycans with the selectins implications for the use of unfractionated and low molecular weight Heparins as therapeutic agents
Journal of Clinical Investigation, 1998Co-Authors: Andrea Koenig, Robert J Linhardt, Karin Norgardsumnicht, Ajit VarkiAbstract:The selectins are calcium-dependent C-type lectins that bind certain sialylated, fucosylated, sulfated glycoprotein ligands. L-selectin also recognizes endothelial proteoglycans in a calcium-dependent manner, via heparan sulfate (HS) glycosaminoglycan chains enriched in unsubstituted glucosamine units. We now show that these HS chains can also bind P-selectin, but not E-selectin. However, while L-selectin binding requires micromolar levels of free calcium, P-selectin recognition is largely divalent cation-independent. Despite this, HS chains bound to P-selectin are eluted by ethylenediamine tetraacetic acid (EDTA), but only at high concentrations. Porcine intestinal mucosal (mast cell-derived) Heparin (PIM-Heparin) shows similar properties, with no binding to E-selectin, calcium-dependent binding of a subfraction to L-selectin and to P-selectin, and calcium-independent binding of a larger fraction to P-selectin, the latter being disrupted by high EDTA concentrations. Analysis of defined Heparin Fragment pools shows a size dependence for interaction, with tetradecasaccharides showing easily detectable binding to L- and P-selectin affinity columns. L-selectin binding Fragments include more heavily sulfated and epimerized regions and, as with the endothelial HS chains, they are enriched in free amino groups. The P-selectin binding component includes this fraction as well as some less highly modified regions. Thus, endothelium-derived HS chains and mast cell-derived Heparins could play a role in modulating the biology of selectins in vivo. Notably, P- and L-selectin binding to sialyl-Lewisx and to HL-60 cells (which are known to carry the native ligand PSGL-1) is inhibited by unfractionated pharmaceutical Heparin preparations at concentrations 12-50-fold lower than those recommended for effective anticoagulation in vivo. In contrast, two low molecular weight Heparins currently considered as clinical replacements for unfractionated Heparin are much poorer inhibitors. Thus, patients undergoing Heparin therapy for other reasons may be experiencing clinically significant inhibition of L- and P-selectin function, and the current switchover to low-molecular weight Heparins may come at some loss of this effect. Low-dose unfractionated Heparin should be investigated as a treatment option for acute and chronic diseases in which P- and L-selectin play pathological roles.
J Bourgouin - One of the best experts on this subject based on the ideXlab platform.
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prevention of deep vein thrombosis after major knee surgery a randomized double blind trial comparing a low molecular weight Heparin Fragment enoxaparin to placebo
Thrombosis and Haemostasis, 1992Co-Authors: J R Leclerc, William H Geerts, Louis Desjardins, F Jobin, F Laroche, F Delorme, S Haviernick, S Atkinson, J BourgouinAbstract:Consecutive patients undergoing knee arthroplasty or tibial osteotomy at four participating hospitals received either enoxaparin, 30 mg subcutaneously every 12 h (n = 66) or an identical-appearing placebo (n = 65). All study medications started the morning after the operation and were continued up to a maximum of 14 days. Patients underwent surveillance with 125I-fibrinogen leg scanning and impedance plethysmography. Bilateral contrast venography was performed routinely at Day 14 or at time of discharge, if sooner. Deep vein thrombosis was detected by venography in 35 of 54 patients (65%) in the placebo group and in 8 of 41 patients in the enoxaparin group (19%), a risk reduction of 71%, P less than 0.0001. For the entire study group, deep vein thrombosis was detected by either venography of non-invasive tests in 37 of 64 patients (58%) in the placebo group and in 11 of 65 patients (17%) in the enoxaparin group, a risk reduction of 71%, P less than 0.0001. Proximal vein thrombosis was found in 19% of the placebo patients and in none of the enoxaparin patients, a risk reduction of 100%, P less than 0.001. Bleeding complications occurred in 5 of 65 patients (8%) in the placebo group and in 4 of 66 patients (6%) in the enoxaparin group, P = 0.71. There were no differences in the amount of blood loss, minimum hemoglobin levels and number of units of packed red cells given between the two treatment groups. We conclude that a fixed dose regimen of enoxaparin, started post-operatively, is an effective and safe regimen for reducing the frequency of deep vein thrombosis after major knee surgery.
Alfio Bertolini - One of the best experts on this subject based on the ideXlab platform.
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Antithrombotic Activity of a 2‐kDa Heparin Fragment in an Experimental Model of Carotid Artery Thrombosis in Rats
Journal of Pharmacy and Pharmacology, 1996Co-Authors: Salvatore Guarini, Carla Bazzani, Annibale R. Botticelli, A Balugani, Alfio BertoliniAbstract:The antithrombotic activity of a 2-kDa Heparin Fragment was studied in a rat model of common carotid artery thrombosis that causes a completely occlusive thrombus with cessation of the blood flow within 10–15 min. The compound reduced thrombus formation in a dose-dependent manner, starting from an intravenous dose of 5 mg kg−1. A dose of 20 mg kg−1 completely prevented thrombus formation and apparently induced the almost complete lysis of the already formed occlusive thrombus. At none of the doses used did the compound cause increased bleeding or the formation of haematomas. The present results indicate that low molecular weight Heparins, which have an established, highly beneficial effect in venous thromboembolism, are also highly effective in an animal model of arterial thrombosis.
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reperfusion induced arrhythmias and lethality are reduced by a 2kda Heparin Fragment
Life Sciences, 1995Co-Authors: Salvatore Guarini, Maria Cristina Martini, Alfio BertoliniAbstract:Abstract The influence of a low molecular weight Heparin (Oligo-H, m.w. 2KDa) on ventricular arrhythmias and lethality induced by heart reperfusion following a 5 min coronary occlusion was studied in anesthetized rats. Both intravenous (i.v.) and subcutaneous (s.c.) injection of the compound doseand time-dependently prevented the reperfusion syndrome: in all salinepretreated animals post-ischemic reperfusion induced ventricular tachycardia (VT), which degenerated into ventricular fibrillation (VF) in 25 out of 30 rats, with a mortality rate of 73%; on the other hand, in rats I.V. Or s.c. pretreated with Oligo-H (20 mg/kg, 30 and 90 min, respectively, before coronary occlusion), VT occurred in 4 out of 10–11 animals and degenerated into VF in 2–3 out of 10–11 animals, with a mortality rate of 18–20%. Even more effective was a low molecular weight dermatan sulfate (Oligo-Ds, M.w. 2.1KDa). In rats treated with lidocaine, used as reference compound, at the dose of 5 mg/kg i.v. 10 min before coronary occlusion, VT occurred in 2 out of 10 animals and degenerated into VF in 1 out of 10 animals, with a mortality rate of 10%. It is concluded that low molecular weight glycosaminoglycans significantly reduce the consequences of heart reperfusion.
Perinkulam Ravi Deepa - One of the best experts on this subject based on the ideXlab platform.
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the cytoprotective role of a low molecular weight Heparin Fragment studied in an experimental model of glomerulotoxicity
European Journal of Pharmacology, 2003Co-Authors: Perinkulam Ravi Deepa, P VaralakshmiAbstract:Abstract Abnormal glomerular glycosaminoglycan metabolism is involved in the onset of the morphological and functional aberrations of glomerulopathies. In the present study, a Heparin derivative, low-molecular-weight Heparin, was tested for its ability to afford renoprotection in an established model of experimental glomerulopathy. Two groups of male albino rats of the Wistar strain (140±10 g) received a single intravenous injection of adriamycin (7.5 mg/kg) to induce glomerulopathy, and one of them received low-molecular-weight Heparin (Certoparin Sodium, Troparin®; 300 μg/day/rat s.c.) treatment, commencing on day 8, for a week. Urinary protein/creatinine ratio, serum albumin, urea, uric acid and creatinine clearance were evaluated. Renal cell injury was assessed in terms of renal tissue lactate dehydrogenase, aminotransferases (aspartate and alanine transaminases) and alkaline phosphatase activities, as well as renal antioxidant status (superoxide dismutase, catalase and glutathione peroxidase, reduced glutathione, vitamins E and C). The kidney tissue was subjected to histopathologic examination. Low-molecular-weight Heparin significantly reduced proteinuria and improved creatinine clearance and serum albumin levels in the rats with glomerulopathy. The significant rise in serum uric acid in the rats with glomerulopathy was reversed by low-molecular-weight Heparin. Altered tissue enzyme activities in response to injury, oxidative stress challenged renal antioxidant system and abnormal renal histology were observed in the untreated nephrotic rats, while low-molecular-weight Heparin treatment protected the nephrotic rats against these changes. Thus, in this study, low-molecular-weight Heparin was evaluated for its role in combating glomerular injury, on the basis of some salient biochemical parameters, oxidative injury indices and histologic picture. The ability of low-molecular-weight Heparin to restore glomerular anatamo-functional features in this nephrotoxic condition illuminates its multi-faceted renoprotective role.