Paclitaxel （PTX） is one of the most efficient anticancer drugs for the treatment of cancers through β-tubulin-binding. Our previous work indicated that a PTX-derivative hydrogelator Fmoc-Phe-Phe-Lys（paclitaxel）-...Paclitaxel （PTX） is one of the most efficient anticancer drugs for the treatment of cancers through β-tubulin-binding. Our previous work indicated that a PTX-derivative hydrogelator Fmoc-Phe-Phe-Lys（paclitaxel）-Tyr（H2PO3）-OH （1）could promote neuron branching but the underlying mechanism remains unclear. Using tubulin assembly-disassembly assay, in this work, we found that compound 1 obviously delayed more microtubule aggregation than PTX did. Under the catalysis of alkaline phosphatase, Fmoc-Phe-Phe-Lys（paclitaxel）- Tyr（H2PO3）-OH could self-assemble into nanofiber Fmoc-Phe-Phe-Lys（paclitaxel）-Tyr-OH with width comparable to the size of αβ-tubulin dimer. Therefore, we proposed in this work that nanofiber Fmoc-Phe-Phe-Lys（paclitaxel）-Tyr-OH not only inhibits the αβ-tubulin dimer binding to each other but also interferes with the plus end aggregation of microtubule. This work provides a new mechanism of the inhibition of microtubule formation by a PTX- derivative hydrogelator.展开更多
The antithrombotic and antiplatelet effects of two fucoidan fractions with low molecular weight and different sulfate content from Laminaria japonica were compared in order to examine the influence of chemical charact...The antithrombotic and antiplatelet effects of two fucoidan fractions with low molecular weight and different sulfate content from Laminaria japonica were compared in order to examine the influence of chemical character on their antithrombotic activity and the possible mechanism. Both LMW fucoidan fractions exhibited favorable antithrombotic activity in an Fecl3-induced arterial thrombosis. The antithrombotic activity of LMW fucoidan was related with decrease of TXB2 and whole blood viscosity and hematocrit. LMW fucoidan showed a correlation between anticoagulant, antiaggregant and antithrombotic effects in vivo. For LMW fucoidan, antithrombotic activity required high dose of 5-10 nmol kg-1, concomitantly with increase in anticoagulant activity and inhibition of platelet aggregation. Administration of LMW fucoidan significantly promoted the 6-keto-PGF1α content and decreased the TXB2 content, indicating its inhibition of tissue factor pathway and regulation of metabolism of arachidonic acid. By comparison, highly sulfated fucoidan LF2 with Mw 3900 seemed to be a more suitable choice for antithrombotic drug for its antithrombotic activity accompanied with specific inhibitory activity on platelet aggregation, low anticoagulant activity and low hemorrhagic risk in vivo.展开更多
基金This work was supported by the Ministry of Science and Technology of China （No.2016YFA0400904） and the National Natural Science Foundation of China （No.U1532144 and No.21675145）.
文摘Paclitaxel （PTX） is one of the most efficient anticancer drugs for the treatment of cancers through β-tubulin-binding. Our previous work indicated that a PTX-derivative hydrogelator Fmoc-Phe-Phe-Lys（paclitaxel）-Tyr（H2PO3）-OH （1）could promote neuron branching but the underlying mechanism remains unclear. Using tubulin assembly-disassembly assay, in this work, we found that compound 1 obviously delayed more microtubule aggregation than PTX did. Under the catalysis of alkaline phosphatase, Fmoc-Phe-Phe-Lys（paclitaxel）- Tyr（H2PO3）-OH could self-assemble into nanofiber Fmoc-Phe-Phe-Lys（paclitaxel）-Tyr-OH with width comparable to the size of αβ-tubulin dimer. Therefore, we proposed in this work that nanofiber Fmoc-Phe-Phe-Lys（paclitaxel）-Tyr-OH not only inhibits the αβ-tubulin dimer binding to each other but also interferes with the plus end aggregation of microtubule. This work provides a new mechanism of the inhibition of microtubule formation by a PTX- derivative hydrogelator.
基金supported in part by the Notional Natural Science Foundation of China (No.30800858)the Shandong Natural Science Foundation (No.ZR2010 CQ020)
文摘The antithrombotic and antiplatelet effects of two fucoidan fractions with low molecular weight and different sulfate content from Laminaria japonica were compared in order to examine the influence of chemical character on their antithrombotic activity and the possible mechanism. Both LMW fucoidan fractions exhibited favorable antithrombotic activity in an Fecl3-induced arterial thrombosis. The antithrombotic activity of LMW fucoidan was related with decrease of TXB2 and whole blood viscosity and hematocrit. LMW fucoidan showed a correlation between anticoagulant, antiaggregant and antithrombotic effects in vivo. For LMW fucoidan, antithrombotic activity required high dose of 5-10 nmol kg-1, concomitantly with increase in anticoagulant activity and inhibition of platelet aggregation. Administration of LMW fucoidan significantly promoted the 6-keto-PGF1α content and decreased the TXB2 content, indicating its inhibition of tissue factor pathway and regulation of metabolism of arachidonic acid. By comparison, highly sulfated fucoidan LF2 with Mw 3900 seemed to be a more suitable choice for antithrombotic drug for its antithrombotic activity accompanied with specific inhibitory activity on platelet aggregation, low anticoagulant activity and low hemorrhagic risk in vivo.
