Sulodexide counteracts endothelial dysfunction induced by metabolic or non-metabolic stresses through activation of the autophagic program

OBJECTIVE: Endothelial dysfunction (ED) predisposes to venous thrombosis (VT) and post-thrombotic syndrome (PTS), a long-term VT-related complication. Sulodexide (SDX) is a highly purified glycosaminoglycan with antithrombotic, pro-fibrinolytic and anti-inflammatory activity used in the treatment of chronic venous disease (CVD), including patients with PTS. SDX has recently obtained clinical evidence in the “extension therapy” after initial-standard anticoagulant treatment for the secondary prevention of recurrent deep vein thrombosis (DVT). Herein, we investigated how SDX counteracts ED. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVEC) were used. Metabolic and non metabolic-induced ED was induced by treating with methylglyoxal (MGO) or irradiation (IR), respectively. Bafilomycin A1 was used to inhibit autophagy. The production of reactive oxygen species (ROS), tetrazolium bromide (MTT) assay for cell viability, terminal de-oxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay for cell apoptosis, Real-time PCR and Western blot analysis for gene and protein expression were used. RESULTS: SDX protected HUVEC from MGO- or IR-induced apoptosis by counteracting the activation of the intrinsic and extrinsic caspase cascades. The cytoprotective effects of SDX resulted from a reduction in a) ROS production, b) neo-synthesis and release of pro-inflammatory cytokines (TNFα, IL1, IL6, IL8), c) DNA damage induced by MGO or IR. These effects were reduced when autophagy was inhibited. CONCLUSIONS: Data herein collected indicate the ability of SDX to counteract ED induced by metabolic or non-metabolic stresses by involving the intracellular autophagy pathway. Our experience significantly increases the knowledge of the mechanisms of action of SDX against ED and supports the use of SDX in the treatment of CVD, PTS and in the secondary prevention of recurrent DVT

The potential for circular dichroism as an additional facile and sensitive method of monitoring low-molecular-weight heparins and heparinoids

The ultraviolet circular dichroism (CD) spectra of commercial low-molecular-weight heparins, heparinoids and other anticoagulant preparations have been recorded between 180 and 260 nm. Principal component analysis of the spectra allowed their differentiation into a number of groups related to the means of their production reflecting the structural changes introduced by each process. The findings suggest that CD provides a complementary technique for the rapid analysis of heparin preparations

Endothelotropic activity of 4-hydroxy-3,5-di-tret-butylcinnamic acid in the conditions of experimental cerebral ischemia

The aim of the study was to evaluate the endothelioprotective activity of 4-hydroxy-3,5-di-tret-butylcinnamic acid in conditions of experimental cerebral ischemia. The brain ischemia was reproduced by the method of irreversible right-sided thermocoagulation of the middle cerebral artery. As comparative drugs, mexidol (30 mg/kg) and sulodexide (30 U/kg) were use

Leg ulcer and osteomyelitis due to methicillin-susceptible Staphylococcus aureus infection after fracture repair treatment: a case highlighting the potential role of prostaglandin E₁ vasodilator

Prostaglandins appear to reduce biofilm formation and chronicization of infections, and stimulate a rapid and effective clearance of infecting micro-organisms. We report a case of recovery from methicillin-susceptible Staphylococcus aureus (MSSA) osteomyelitis after multidisciplinary management with antibiotics, anti-thrombotics and prostaglandin E1 (PGE1) vasodilator, in a patient with tibial plateau fracture repaired with internal fixation devices. A 47-year-old HIV-negative male with chronic ulcer on the proximal third of the left leg was admitted to the Orthopaedic Unit of the Orestano Clinic in Palermo, Italy, for suspected osteomyelitis. A biopsy of the skin ulcer and blood cultures were performed and resulted positive for MSSA. Labelled leukocyte scintigraphy confirmed osteomyelitis. No clinical improvement was observed after combined antibiotic treatment with rifampicin plus trimethoprim-sulfamethoxazole. The patient underwent a 4-day therapeutic cycle: PGE1 (alprostadil 60 mg/day IV) combined with nadroparin calcium plus gentamicin, followed by treatment with aminaftone plus sulodexide plus levofloxacin. At discharge, the patient's painful symptoms had completely resolved and the ulcer had cicatrized; recovery from osteomyelitis was confirmed by scintigraphy. This treatment protocol including PGE1 may result in a significant improvement in quality of life and functional status of patients with a reduction in direct and indirect costs and economic benefit for the National Health Service

Estudio prospectivo de profilaxis ambulatoria con sulodexida después de una artroplastia total de cadera o rodilla

La falta de continuidad en el tratamiento profiláctico ambulatorio se muestra como una de las causas determinantes en la aparición de complicaciones tromboembólicas en el primer mes tras el alta hospitalaria. La dificultad de administración por parte del paciente de las heparinas de bajo peso molecular y la diferencia de preocupación entre los médicos de Atención Primaria y los Servicios especializados por el problema tromboembólico son algunas de las causas de esta discontinuidad. Se realiza un estudio prospectivo sobre 221 pacientes intervenidos de prótesis total de cadera y rodilla con la finalidad de estudiar los resultados obtenidos con el tratamiento profiláctico mediante Sulodexida, un fármaco que une a sus propiedades antitrombóticas la comodidad de la administración vía oral. Se encontró una respuesta satisfactoria sin aparición de complicaciones tromboembólicas en el 98,8% del grupo que completó el tratamiento (n=164), frente al 21% de complicaciones que presentó el grupo que no completó el estudio.The discontinous thromboprophylaxis is a determinant cause in the presence of thromboembolic complications in the first month after hospital discharge. The difficult administration of the low -molecular- weight heparin by the patient and the different preoccupation for this problem between the Primary Care and the orthopedics specialists are the causes that incite to discontinous thromboprophylaxis. A prospective study was made of 221 patients who undergoing a total hip arthroplasty or a total knee arthroplasty and the objective was to investigate the incidence of venous thrombosis in the patients who were treated with oral sulodexide in the first month after hospital discharge. We analized the efficacy and the secondary effects of sulodexide. There were satisfactory results in 98,8% of patients who were treated with sulodexide (1,2% of venous complications), and 21% of venous complications in the group of patients who did not continue the thromboprophylactic treatment

Sulodexide decreases albuminuria and regulates matrix protein accumulation in C57BL/6 mice with streptozotocin-induced type I diabetic nephropathy

OBJECTIVE: Sulodexide is a mixture of glycosaminoglycans that may reduce proteinuria in diabetic nephropathy (DN), but its mechanism of action and effect on renal histology is not known. We investigated the effect of sulodexide on disease manifestations in a murine model of type I DN. METHODS: Male C57BL/6 mice were rendered diabetic with streptozotocin. After the onset of proteinuria, mice were randomized to receive sulodexide (1 mg/kg/day) or saline for up to 12 weeks and renal function, histology and fibrosis were examined. The effect of sulodexide on fibrogenesis in murine mesangial cells (MMC) was also investigated. RESULTS: Mice with DN showed progressive albuminuria and renal deterioration over time, accompanied by mesangial expansion, PKC and ERK activation, increased renal expression of TGF-β1, fibronectin and collagen type I, III and IV, but decreased glomerular perlecan expression. Sulodexide treatment significantly reduced albuminuria, improved renal function, increased glomerular perlecan expression and reduced collagen type I and IV expression and ERK activation. Intra-glomerular PKC-α activation was not affected by sulodexide treatment whereas glomerular expression of fibronectin and collagen type III was increased. MMC stimulated with 30 mM D-glucose showed increased PKC and ERK mediated fibronectin and collagen type III synthesis. Sulodexide alone significantly increased fibronectin and collagen type III synthesis in a dose-dependent manner in MMC and this increase was further enhanced in the presence of 30 mM D-glucose. Sulodexide showed a dose-dependent inhibition of 30 mM D-glucose-induced PKC-βII and ERK phosphorylation, but had no effect on PKC-α or PKC-βI phosphorylation. CONCLUSIONS: Our data demonstrated that while sulodexide treatment reduced proteinuria and improved renal function, it had differential effects on signaling pathways and matrix protein synthesis in the kidney of C57BL/6 mice with DN.published_or_final_versio

Влияние флавоноидов: гесперидина и патулетина на вазодилатирующую функцию эндотелия сосудов головного мозга экспериментальных животных на фоне его фокальной ишемии

Проведено исследование о влиянии гесперидина и патулетина на вазодилатирующую функцию эндотелия мозговых сосудов на фоне фокальной ишемии головного мозга животных во время эксперимент

Endothelial glycocalyx: Role in body fluid homeostasis and fluid management

Endothelial glycocalyx layer (EGL) coating the luminal surface of vascular endothelium plays an essential role in maintaining the normal fluid homeostasis of the body. This highly fragile layer can be damaged by a number of pathophysiological conditions and interventions. Disease state management should be directed to maintain EGL integrity to improve patient's outcome. When intravenous (IV) fluids are used, appropriate type, rate and amount of fluid should be determined by the pathophysiology of the condition and measures to maintain the integrity of the EGL. This review depicts the structure and function of the EGL, its alteration in common pathological states and the rationale of IV fluid management to preserve EGL in such conditions