glucuronyl-glucosamine-glycan-sulfate and Inflammation

Coronavirus disease 2019 (COVID-19), currently a worldwide pandemic, is a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The suspected contribution of thrombotic events to morbidity and mortality in COVID-19 patients has prompted a search for novel potential options for preventing COVID-19-associated thrombotic disease. In this article by the Global COVID-19 Thrombosis Collaborative Group, we describe novel dosing approaches for commonly used antithrombotic agents (especially heparin-based regimens) and the potential use of less widely used antithrombotic drugs in the absence of confirmed thrombosis. Although these therapies may have direct antithrombotic effects, other mechanisms of action, including anti-inflammatory or antiviral effects, have been postulated. Based on survey results from this group of authors, we suggest research priorities for specific agents and subgroups of patients with COVID-19. Further, we review other agents, including immunomodulators, that may have antithrombotic properties. It is our hope that the present document will encourage and stimulate future prospective studies and randomized trials to study the safety, efficacy, and optimal use of these agents for prevention or management of thrombosis in COVID-19.

Topics: Animals; Anti-Inflammatory Agents; Anticoagulants; Antiviral Agents; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Fibrinolytic Agents; Glycosaminoglycans; Hemostasis; Humans; Inflammation; Pandemics; Platelet Aggregation Inhibitors; Pneumonia, Viral; SARS-CoV-2; Thrombosis

Oxidative stress may promote chronic inflammation and contribute to accelerated atherogenesis in patients with coronary artery disease (CAD). Sulodexide, a glycosaminoglycan consisting primarily of heparin, has been shown to affect oxidative stress in experimental settings. The purpose of this pilot study was to determine the effect of sulodexide administration on oxidative stress, inflammation and plasma lipids in patients with proven stable CAD.. Fifty-six optimally treated male CAD patients (pts), mean age 57+/-6 yrs, were randomized to either 8 weeks of sulodexide treatment (SUL, n=28), or to a control group (n=28). At baseline and at the end of the study, all pts underwent full clinical and standard laboratory plasma level assessment of lipids, markers of inflammation, and 8-isoprostane, as a sensitive index of oxidative stress.. At entry the 2 groups did not differ significantly in terms of age, coronary risk factors, clinical status and concomitant medication. SUL treatment appeared to be safe and caused a significant decrease in the level of plasma 8-isoprostane (77.4 vs 44.5 pg/ml, p<0.0001) compared with controls (75.7 vs 68.3 pg/ml, p=NS). In contrast, neither LDL cholesterol (2.71 vs 2.72 mmol/l) and triglycerides (1.38 vs 1.43 mmol/l), nor markers of inflammation - fibrinogen (3.7 vs 3.6 g/l), C-reactive protein (0.14 vs 0.13 mg/l), leukocyte count (6.33 vs 6.32x10(9)/l) - were affected by SUL treatment.. Sulodexide administration resulted in significant reduction in oxidative stress in stable CAD patients, and neither the changes in cholesterol metabolism nor in systemic inflammation underlay this effect.

Topics: Antioxidants; Biomarkers; C-Reactive Protein; Coronary Artery Disease; Dinoprost; Fibrinogen; Glycosaminoglycans; Humans; Inflammation; Leukocyte Count; Lipids; Male; Middle Aged; Oxidative Stress; Pilot Projects

Although the number of vascular surgeries performed is increasing, the incidence of complications associated with this surgery has not improved and re-operations are frequently required. Thrombosis in a vessel is the most hazardous postoperative complication.. The aim of this study was to evaluate the anti-thrombotic and anti-inflammatory effects of sulodexide compared to aspirin in a rat model.. We divided the animals into three groups (sham (saline), aspirin, and sulodexide). The abdominal aorta was surgically opened and closed, primarily with 8/0 Prolene sutures. Postoperatively, saline, aspirin, or sulodexide was administered by oral gavage for 14 days to the rats. The degree of neovascularization, thrombus, calcification, inflammatory infiltrates, and fibrosis were analyzed histopathologically by hematoxylin and eosin staining.. There was no significant difference in the incidence of postoperative thrombogenesis, but less calcification and inflammatory infiltrates were observed in the sulodexide group compared to the aspirin group. Histopathologic score revealed less infiltration of inflammatory cells and mild calcification for the sulodexide group (0.17±0.41 and 1.33±0.52, respectively) compared to the aspirin group (0.67±0.52 and 1.67±0.52, respectively) at days 14.. This study offers the possibility that sulodexide could be used as an aspirin substitute for the postoperative management of vascular patients, with low gastrointestinal discomfort. In addition, it may also offer reduced postoperative calcification and inflammation.

Topics: Animals; Anti-Inflammatory Agents; Anticoagulants; Aspirin; Disease Models, Animal; Glycosaminoglycans; Humans; Inflammation; Male; Rats; Rats, Sprague-Dawley; Thrombosis

Amounts of macrophages were infiltrated in glomeruli in diabetic nephropathy. Heparanase has been thought to be closely related to proteinuria. Our aims were to determine the effect of heparanase on the inflammation in AGEs-stimulated macrophages and its role on the functions of glomerular endothelial cells (GEnCs).. The expression of inflammation cytokines in macrophages were assayed by q-RT PCR, western, and ELISA. Then western was used to measure the expression of RAGE and key proteins in NF-κB pathway in macrophages. The expression of the adherence molecules and tight junction proteins in GEnCs were assessed by western. The adherence of mononuclear cells to GEnCs were observed by HE staining and transendothelial FITC-BSA were tested for the permeability of GEnCs.. HPA siRNA and heparanase inhibitor sulodexide could attenuate the increasing inflammatory factors (TNF-α and IL-1β) in AGEs-stimulated macrophages. NF-κB inhibitor PDTC could also decrease the augmented inflammation cytokines through inhibiting the activation of the NF-κB pathway induced by AGEs. The phosphorylation of NF-κB signaling pathway could be also attenuated by HPA siRNA and sulodexide, the same to the receptor of AGEs RAGE. When the macrophage-conditioned culture medium were added to the glomerular endothelial cells, we found HPA siRNA and sulodexide groups could decrease the increasing adherence and permeability of GEnCs induced by AGEs.. Heparanase increases the inflammation in AGEs-stimulated macrophages through activating the RAGE-NF-κB pathway. Heparanase driven inflammation from AGEs-stimulated macrophages increases the adherence of GEnCs and augments the permeability of GEnCs.

Topics: Animals; Cell Membrane Permeability; Cells, Cultured; Diabetic Nephropathies; Endothelial Cells; Glucuronidase; Glycation End Products, Advanced; Glycosaminoglycans; Inflammation; Interleukin-1beta; Kidney Glomerulus; Macrophages; Mice; NF-kappa B; RNA, Small Interfering; Signal Transduction; Tumor Necrosis Factor-alpha

According to previous studies, sulodexide suppresses intravascular inflammation when used in patients with chronic venous disease (CVD). In the current study, we tested the effect of prolonged in vitro exposure of human venous endothelial cells to the serum from patients with CVD, examining the function of these cells and how it is modified when these cells are simultaneously exposed to sulodexide.. Human umbilical venous cells (HUVEC) were cultured in standard medium (control), in medium supplemented with 5% serum pooled from CVD patients (CVD-serum) or in medium from CVD patients who were treated with sulodexide (CVD-serum-SUL). The synthesis of interleukin-6 (IL-6), monocyte chemoattractant protein -1(MCP-1) and soluble intercellular adhesion molecule - 1 (s-ICAM-1) were studied at the beginning of incubation and were measured after 9 and 15 days of exposure to the studied media. The concentration of IL-6 after cell stimulation by interleukin -1 (IL-1) was also measured. In a subsequent part of the experiment, the effect of the studied sera on the in vitro replicative ageing of HUVEC was evaluated. A total of 15 passages of the cell culture were performed and both the PDT (population doubling time) and the cell hypertrophy were assessed.. The concentrations of Il-6, MCP-1, and ICAM-1 gradually increased in the supernatants containing 5% CVD serum compared with the control medium. In the supernatants obtained after cell incubation with serum from sulodexide treated patients, the increase in concentrations of IL-6, MCP-1 and ICAM-1 was significantly less than the control. Release of IL-6 after stimulation with IL-1 (100 pg/mL) was the highest in the CVD-serum group: 3540±670 pg/105 cells vs. 1850±540 pg/105 cells in the control (P<0.01 vs. CVD-serum) and 2320 ±430 pg/105 cells in CVD-serum-SUL (P<0.02 vs. CVD-serum). PDT was significantly longer in the cells incubated with CVD serum compared with the control group, and PDT was reduced when serum from sulodexide treated patients was used. The cells became senescent in the presence of CVD serum, but the cells obtained from patients at the end of 8 weeks of treatment with sulodexide showed a much weaker inflammatory phenotype than the CVD group.. Chronic in vitro exposure of HUVEC to medium supplemented with CVD patient serum induces an inflammatory phenotype. Sulodexide treatment significantly reduces that effect and slows HUVEC senescence in the milieu of CVD serum.

Topics: Aged; Cells, Cultured; Chemokine CCL2; Chronic Disease; Endothelial Cells; Glycosaminoglycans; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-6; Middle Aged; Vascular Diseases

Sulodexide is a powerful antithrombin agent with reno-protective property. However, whether it has beneficial effects on Contrast-Induced Nephropathy (CIN) remained elusive. In the current study, we evaluated the therapeutic effects of Sulodexide on CIN and investigated the potential mechanisms.. CIN model was induced by intravenous injection of indomethacin, followed by Ioversol and L-NAME. Sprague-Dawley rats were divided into 4 groups: control group, CIN group, CIN+vehicle group (CIN rats pretreated with vehicle) and CIN+ Sulodexide (CIN rats pretreated with Sulodexide). Sulodexide or an equivalent volume of vehicle was intravenously delivered 30 min before the induction of CIN. All the animals were sacrificed at 24h after CIN and tissues were harvested to evaluate renal injury, kidney oxidative stress and apoptosis levels. Plasma antithrombin III (ATIII) activities were also measured.. Compared to the untreated CIN group, improved renal function, reduced tubular injury, decreased levels of oxidative stress and apoptosis were observed in CIN rats receiving Sulodexide injection. In addition, we also found that ATIII activity was significantly higher in Sulodexide-administered group than that in vehicle-injected CIN rats. For in vitro studies, HK2 cells were exposed to Ioversol and the cyto-protective effects of Sulodexide were also determined. Sulodexide pretreatment protected HK2 cells against the cytotoxicity of Ioversol via inhibiting caspase-3 activity. Preincubation with Sulodexide could also attenuate H2O2-induced increases in ROS, apoptosis and caspase-3 levels.. Taken together, Sulodexide could protect against CIN through activating ATIII, and inhibiting oxidative stress, inflammation and apoptosis.

Topics: Animals; Antithrombin III; Apoptosis; Blood Urea Nitrogen; Caspase 3; Cell Line; Contrast Media; Creatinine; Glycosaminoglycans; Humans; Hydrogen Peroxide; Inflammation; Kidney Diseases; Macrophages; Male; Oxidative Stress; Protective Agents; Rats, Sprague-Dawley; Triiodobenzoic Acids

Dysfunction of the arterial endothelial cells promotes the progression of atherosclerosis. We studied how exposure of human arterial endothelial cells to atherosclerotic serum from patients with peripheral artery disease changes the secretory activity of these cells, and whether that reaction is modified by sulodexide.. Endothelial cells in in vitro culture were exposed to standard culture medium ± 100pg/mL Interleukin-1(IL-1) or to medium supplemented with 20% atherosclerotic serum. Afterwards, the expression of genes responsible for the synthesis of Interleukin-6 (IL-6), Vascular Cell Adhesion Protein-1 (VCAM-1) and Von Willebrand Factor (VWF) was evaluated, together with the secretion of these compounds. Additionally, the effect of sulodexide on these processes was studied.. Atherosclerotic serum stimulated the expression of IL6, VCAM-1 and VWF genes in endothelial cells, which was followed by increased secretion of these compounds by 179%, 121% and 116%, respectively. Sulodexide (0.5 LRU/mL) reduced atherosclerotic serum-induced increased expression of genes for IL-6 (-32%), VCAM-1 (-20%) and VWF (-42%), and lowered secretion of these molecules: IL-6 (-27%), VCAM-1(-27%), VWF (-25%). Sulodexide also reduced, in a dose- dependent manner, secretion of IL6 from unstimulated and stimulated with IL-1 endothelial cells.. Atherosclerotic serum induces proinflammatory and prothrombotic phenotype in arterial endothelium, which is partially reduced by sulodexide, via inhibition of genes expression, and in consequence lower secretory activity.

Topics: Arteries; Endothelial Cells; Gene Expression Regulation; Glycosaminoglycans; Humans; Inflammation; Interleukin-6; Peripheral Arterial Disease; Vascular Cell Adhesion Molecule-1; von Willebrand Factor

According to previously performed studies, inflammation plays a crucial role in vein wall and leg tissue injury related to chronic venous insufficiency (CVI) development. Sulodexide (SUL) is a balanced mix of glycosaminoglycans with potential anticoagulant and profibrinolytic activity, also protecting endothelial cells and suppressing inflammatory reactions in various vascular disease-related conditions. The goal of the present study was to evaluate the anti-inflammatory action of SUL in patients with CVI.. The study was performed on a group of 11 patients with chronic venous disease (stage C5 according to CEAP classification). The mean age of the patients was 58.4±7.7 years, and none of them were diabetic. The patients were treated for 8 weeks with orally-administered SUL (2 x 500 LSU/day). Blood samples were collected at the start and at the end of the study for measurement of MMP-9, IL-6 and monocyte chemoattractant protein-1 (MCP-1). Additionally, the effect of the obtained serum samples on the function of human venous endothelial cells (HVEC) in in-vitro culture was evaluated.. After treatment with SUL, the serum concentration of MMP-9 (ng/mL) decreased from 6.50±3.48 to 5.41±1.36, P<0.05, and the concentration of IL-6 (pg/mL) decreased from 11.5±3.4 to 10.1±2.3, P<0.005. There was also a trend of decreased serum MCP-1 (pg/mL) from 31.3±23.0 before treatment to 27.1±10.7 at the end. Intracellular generation of oxygen-derived free radicals in HVEC maintained in in-vitro culture was lower in the serum samples collected after treatment with SUL: 3.09±0.35 abs/μg protein vs. 3.63±0.32 abs/μg protein, at the start, P<0.05. Synthesis of IL-6 was lower in HVEC exposed in vitro to serum collected at the end of SUL treatment: 1.02±0.31 ng/μg cell protein vs. 1.32±0.41 ng/μg cell protein before SUL treatment. The proliferation rate of HVEC was similar in serum collected at the beginning and at the end of SUL treatment.. We conclude that treatment with SUL in patients with CVI reduces intravascular inflammation and is protective for the endothelial cells and for the extracellular matrix changes related to metalloproteinase expression.

Topics: Aged; Anti-Inflammatory Agents; Anticoagulants; Chemokine CCL2; Chronic Disease; Endothelial Cells; Female; Glycosaminoglycans; Humans; Inflammation; Interleukin-6; Male; Matrix Metalloproteinase 9; Middle Aged; Treatment Outcome; Venous Insufficiency

Patients with HIV are at an increased risk of cardiovascular disease. In this study we investigated the effect of Nef, a secreted HIV protein responsible for the impairment of cholesterol efflux, on the development of atherosclerosis in two animal models. ApoE(-/-) mice fed a high-fat diet and C57BL/6 mice fed a high-fat, high-cholesterol diet were injected with recombinant Nef (40 ng/injection) or vehicle, and the effects of Nef on development of atherosclerosis, inflammation, and dyslipidemia were assessed. In apoE(-/-) mice, Nef significantly increased the size of atherosclerotic lesions and caused vessel remodeling. Nef caused elevation of total cholesterol and triglyceride levels in the plasma while reducing high-density lipoprotein cholesterol levels. These changes were accompanied by a reduction of ABCA1 abundance in the liver, but not in the vessels. In C57BL/6 mice, Nef caused a significant number of lipid-laden macrophages presented in adventitia of the vessels; these cells were absent from the vessels of control mice. Nef caused sharp elevations of plasma triglyceride levels and body weight. Taken together, our findings suggest that Nef causes dyslipidemia and accumulation of cholesterol in macrophages within the vessel wall, supporting the role of Nef in pathogenesis of atherosclerosis in HIV-infected patients.-Cui, H. L., Ditiatkovski, M., Kesani, R., Bobryshev, Y. V., Liu, Y., Geyer, M., Mukhamedova, N., Bukrinsky, M., Sviridov, D. HIV protein Nef causes dyslipidemia and formation of foam cells in mouse models of atherosclerosis.

Topics: Animals; Apolipoproteins E; Atherosclerosis; ATP Binding Cassette Transporter 1; Cholesterol; Dyslipidemias; Foam Cells; Glycosaminoglycans; HIV; HIV Infections; Human Immunodeficiency Virus Proteins; Inflammation; Lipoproteins, HDL; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; nef Gene Products, Human Immunodeficiency Virus; Triglycerides

Sulodexide is a mixture of heparin and dermatan sulfate with antithrombotic and profibrynolytic activity. Individual reports suggest the anti-inflammatory action of sulodexin. The goal of this study was to evaluate the effect of sulodexide on the release of the inflammatory mediators from endothelium in normal conditions and in cells chronically exposed to glucose. The experiments were performed on in vitro cultured human umbilical endothelial cells kept for 7 days in standard medium or in the same medium but supplemented with glucose 30 mmol/L. Sulodexide was added to the culture medium in concentrations of 0.125 lipase releasing unit (LRU)/mL, 0.25 LRU/mL, and 0.5 LRU/mL Spontaneous generation of oxygen-derived free radicals and the release of monocyte chemotactic protein-1 (MCP-1) and interleukin-6 (IL-6) from the studied cells was evaluated. Additionally, the healing of the injured mesothelium was studied in the presence of sulodexide and glucose. Sulodexide caused the inhibition of the intracellular generation of free radicals in a dose-dependent manner (maximally by 32%, P < 0.01), as well as the inhibition of MCP-1 (maximally by 60%, P < 0.001) and IL-6 (maximally by 69%, P < 0.01). Cells cultured in a medium with glucose 30 mmol/L generated more free radicals (+20%, P < 0.05) and released more MCP-1 (+113%, P < 0.001) and IL-6 (+26%, P < 0.05). Cell monolayers treated with glucose had a decreased ability to heal after mechanical injury (-28%, P < 0.001). All these glucose effects were reversed when cells were exposed to sulodexide simultaneously. The results of our study demonstrate a significant anti-inflammatory action of sulodexide in the endothelial cells and a protective effect of that drug against glucose cytotoxicity.

Topics: Cell Death; Cells, Cultured; Chemokine CCL2; Endothelial Cells; Free Radicals; Glucose; Glycosaminoglycans; Humans; Inflammation; Interleukin-6; Intracellular Space; Wound Healing

Peritonitis is one of the complications of peritoneal dialysis. We demonstrate the systemic and intraperitoneal anti-inflammatory action of sulodexide given systemically.. Dialysis was performed in male Wistar rats with acute peritonitis induced by addition of endotoxin to the fluid. Sulodexide (10 mg/kg b.w.) was used acutely as supplement to the dialysis fluid or chronically, during 7 days preceding the study by intramuscular (i.m.) injection.. In rats given i.m. sulodexide the dialysate cell count was lower by 45% (p < 0.001) versus untreated rats with peritonitis. Dialysate elastase activity in i.m. sulodexide-treated rats was lower by 22% (p < 0.05) compared to peritonitis. In rats treated with i.m. sulodexide the increase of plasma tumor necrosis factor-alpha was reduced by 53% (p < 0.002). Pretreatment with i.m. sulodexide reduced transperitoneal loss of total protein and albumin during peritonitis by 26% (p < 0.002) and by 16% (p < 0.05), respectively.. Sulodexide given systemically reduces the intraperitoneal and vascular inflammatory response during acute peritonitis in rats.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Glycosaminoglycans; Inflammation; Male; Peritoneal Dialysis; Peritonitis; Rats; Rats, Wistar; Treatment Outcome