thromboplastin and ruscogenin

Ruscogenin (RUS) has anti-inflammatory and antithrombotic effects, while its potential effects on deep venous thrombosis (DVT) and pulmonary embolism (PE) remain unclear.. We aimed to elucidate the effects of RUS on DVT and PE induced by the inferior vena cava stenosis (IVCS) model and investigate the underlying mechanism.. Male C57/BL6 mice were used to explore whether IVCS model could be complicated with deep venous thrombosis and pulmonary embolism. Then, effects of RUS on DVT and PE related inflammatory factors and coagulation were examined using H&E staining, ELISA, and real-time PCR. Western blot analysis was used to examine the effects of RUS on MEK/ERK/Egr-1/TF signaling pathway in PE.. IVCS model induced DVT and complied with PE 48 h after surgery. Administration of RUS (0.01, 0.1, 1 mg/kg) inhibited DVT, decreased biomarker D-Dimer, cardiac troponin I, N-Terminal probrain natriuretic peptide in plasma to ameliorate PE induced by IVCS model. Meanwhile, RUS reduced tissue factor and fibrinogen content of lung tissue, inhibited P-selectin and C-reactive protein activity in plasma, and suppressed the expressions of interleukin-6 and interleukin-1β in mice. Furthermore, RUS suppressed the phosphorylation of ERK1/2 and MEK1/2, decreasing the expressions of Egr-1 and TF in the lung.. IVCS model contributed to the development of DVT and PE in mice and was associated with increased inflammation. RUS showed therapeutic effects by inhibiting inflammation as well as suppressing the activation of MEK/ERK/Egr-1/TF signaling pathway.

Topics: Animals; Constriction, Pathologic; Inflammation; Male; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase Kinases; Pulmonary Embolism; Signal Transduction; Spirostans; Thromboplastin; Vena Cava, Inferior; Venous Thrombosis

Inflammation, endothelial dysfunction, and thrombosis contribute to the pathogenesis and development of human pulmonary arterial hypertension (PAH). The aim of this study was to investigate the effects of ruscogenin, a natural anti-inflammatory and anti-thrombotic agent, on the development of monocrotaline (MCT)-induced PAH in rats. Our results revealed that ruscogenin had favorable effects on hemodynamics and pulmonary vascular remodeling, preventing the development of PAH 3 weeks after MCT. In addition, ruscogenin resulted in markedly reduced expression of inflammatory cytokine and leukocyte infiltration via the inhibition of nuclear factor (NF)-κB activity in rat lungs. Ruscogenin also attenuated MCT-induced endothelial cell apoptosis in the remodeled pulmonary arterioles and rescued destruction of endothelial cell membrane proteins such as eNOS, caveolin-1, and CD31. Our findings suggest that ruscogenin might have therapeutic benefits for PAH patients.

Topics: Animals; Anti-Inflammatory Agents; Antihypertensive Agents; Arterial Pressure; Caveolin 1; Endothelium, Vascular; Familial Primary Pulmonary Hypertension; Hypertension, Pulmonary; Interleukin-1beta; Male; Monocrotaline; NF-kappa B; Nitric Oxide Synthase Type III; Platelet Endothelial Cell Adhesion Molecule-1; Rats; Rats, Sprague-Dawley; Spirostans; Thromboplastin

Acute lung injury is still a significant clinical problem with a high mortality rate and there are few effective therapies in clinic. Here, we studied the inhibitory effect of ruscogenin, an anti-inflammatory and anti-thrombotic natural product, on lipopolysaccharide (LPS)-induced acute lung injury in mice basing on our previous studies. The results showed that a single oral administration of ruscogenin significantly decreased lung wet to dry weight (W/D) ratio at doses of 0.3, 1.0 and 3.0 mg/kg 1 h prior to LPS challenge (30 mg/kg, intravenous injection). Histopathological changes such as pulmonary edema, coagulation and infiltration of inflammatory cells were also attenuated by ruscogenin. In addition, ruscogenin markedly decreased LPS-induced myeloperoxidase (MPO) activity and nitrate/nitrite content, and also downregulated expression of tissue factor (TF), inducible NO synthase (iNOS) and nuclear factor (NF)-κB p-p65 (Ser 536) in the lung tissue at three doses. Furthermore, ruscogenin reduced plasma TF procoagulant activity and nitrate/nitrite content in LPS-induced ALI mice. These findings confirmed that ruscogenin significantly attenuate LPS-induced acute lung injury via inhibiting expressions of TF and iNOS and NF-κB p65 activation, indicating it as a potential therapeutic agent for ALI or sepsis.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Lipopolysaccharides; Male; Mice; Mice, Inbred ICR; NF-kappa B; Nitrates; Nitric Oxide Synthase Type II; Nitrites; Peroxidase; Spirostans; Thromboplastin

With the aim to obtain more effective tissue factor (TF) inhibitors, the microbial transformation of three steroidal sapogenins, ruscogenin (1), diosgenin (2) and sarsasapogenin (3), was carried out and only ruscogenin was selectivity converted to 1-hydroxy-spirost-4-en-3-one (4) by Phytophthora cactorum ATCC 32134. The in vitro anti-TF procoagulant activity of this metabolite was enhanced almost 10 times to an IC(50) value of 0.29 microM. The chemical assignments of compound 4 were made unambiguously using ESI-MS, IR and 2D NMR spectroscopy.

Topics: Biotransformation; Magnetic Resonance Spectroscopy; Molecular Structure; Phytophthora; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Infrared; Spirostans; Steroids; Thromboplastin