Abstract
Traditional Chinese medicine has been used to treat a variety of human diseases for many centuries. Zanthoxylum nitidum var. tomentosum is used as an adjuvant to promote blood circulation and remove stasis. However, the mechanisms of improving circulation and other biological activities of Z. nitidum var. tomentosum are still unclear. Plasminogen activator inhibitor-1 (PAI-1) regulates the plasminogen activation system through inhibition of tissue-type and urokinase-type plasminogen activators (tPA and uPA). PAI-1 has been linked to fibrin deposition that evolves into organ fibrosis and atherosclerosis. In the present study, we showed that ethanol extract prepared from Z. nitidum var. tomentosum exhibited PAI-1 inhibitory activity, and identified toddalolactone as the main active component that inhibited the activity of recombinant human PAI-1 with IC50 value of 37.31 ± 3.23 μM, as determined by chromogenic assay, and the effect was further confirmed by clot lysis assay. In vitro study showed that toddalolactone inhibited the binding between PAI-1 and uPA, and therefore prevented the formation of the PAI-1/uPA complex. Intraperitoneal injection of toddalolactone in mice significantly prolonged tail bleeding and reduced arterial thrombus weight in a FeCl3-induced thrombosis model. In addition, the hydroxyproline level in the plasma and the degree of liver fibrosis in mice were decreased after intraperitoneal injection of toddalolactone in CCl4-induced mouse liver fibrosis model. Taken together, PAI-1 inhibition exerted by toddalolactone may represent a novel molecular mechanism by which Z. nitidum var. tomentosum manifests its effect in the treatment of thrombosis and fibrosis.
Highlights
Thromboembolism is a disease that can seriously affect people’s health
By using a chromogenic substrate-based assay, we found many fractions of these extracts with inhibitory activity against Plasminogen activator inhibitor-1 (PAI-1), including one fraction from Zanthoxylum nitidum var. tomentosum, which is a variant of Rutaceae Zanthoxylum, mainly produced in the bushes of Pingnan area in Guangxi Province of China
Subsequent assay of the different HPLC fractions for plasminogen activator inhibitors (PAIs)-1 inhibitory activity, which was detected by a lack of PAI-1 inhibition of urokinase activity in the presence of the extract, showed that only #25 to #29 were active, with #27 being the most active, capable of reducing the activity of PAI-1 by more than 70% (Figure 1B)
Summary
Cardiovascular thrombosis can result in morbidity and mortality. Thrombosis is triggered by abnormal formation of blood clots in the blood stream. Fibrinolysis is a process characterized by the decomposition and liquidation of fibrin mesh formed from blood coagulation, and it involves two stages: activation of fibrinolytic enzyme and degradation of fibrin (Kivirikko et al, 1967; Morishima et al, 1997; Goto et al, 2004; Horio et al, 2007). Prothrombin is converted to thrombin by prothrombin activator when the coagulation system is activated. Thrombin cleaves fibrinogen and converts it into fibrin monomer, which can polymerize and form insoluble and cross-linked fibrin mesh. The anticoagulant and fibrinolytic system will be activated along with the activation of coagulation to promote the release of plasminogen activator and fibrinolysis. Coagulation, anticoagulation, and fibrinolysis together maintain a dynamic equilibrium that ensures normal blood flow
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