Objective: To investigate the different inhibition effects of different sequential usages of microtubule depolymerization drug and polymerization drug on tumor cells. Methods: Three tumor cell lines including MCF-7, S...Objective: To investigate the different inhibition effects of different sequential usages of microtubule depolymerization drug and polymerization drug on tumor cells. Methods: Three tumor cell lines including MCF-7, SK-OV3, A549 were incubated with paclitaxel (PTX) and/or vinorelbine (NVB) of different concentrations. The cyto-toxicity was exam- ined by MTT test after incubating 72 h. According to different drugs and different sequences added to 96-well tissue culture plates, 5 groups were divided: PTX group (Group 1), NVB group (Group 2), PTX plus NVB group (Group 3), PTX first and NVB 4-h-later group (Group 4), and NVB first and PTX 4-h-later group (Group 5). Drug concentrations were 100% peak plasma concentration (PPC), 50% PPC, 25% PPC, 12.5% PPC, and 6. 25% PPC. Results: The inhibition effects on the three tumor cell lines in Group 5 were stronger than those in the other four groups (P < 0.01). And the inhibition effects in Group 4 were not stronger than those in Groups 1, 2 or 3 (P > 0.1). Conclusion: Using microtubule depolymerization drug first and then using microtubule polymerization drug has synergic inhibition effect on tumor cells.展开更多
Kinesin-8 motors can move with a high processivity on microtubule lattices toward the plus end.After reaching the plus end,the kinesin-8 motors can pause for a long time and promote the microtubule depolymerization.He...Kinesin-8 motors can move with a high processivity on microtubule lattices toward the plus end.After reaching the plus end,the kinesin-8 motors can pause for a long time and promote the microtubule depolymerization.Here,using atomistic molecular dynamics simulations we studied the structural changes of the kinesin-8 head in different nucleotide states bound to the straight and curved tubulins and the corresponding interactions between them.We found that the kinesin-8 head in ATP and/or ADP–Pi state has the similar strong affinity while in ADP state has the similar weak affinity to both the straight and curved tubulins,which is strongly implicated in the mechanism of the long but very different residence times of the kinesin-8 motor on the microtubule lattice and at the end.Moreover,we found that loop-2 of the kinesin-8 head bound strongly to the curved tubulin in the stable state has a large interference with its neck linker pulled in the minusended orientation.This is contrary to the case of the head bound strongly to the straight tubulin,where loop-2 has little interference with its neck linker pulled in the minus-ended orientation.The large interference can induce a larger internal force between the two heads and thus can induce the two curved tubulins bound strongly by the two heads to be more curved relative to each other.This is strongly implicated in the mechanism of the depolymerase activity of the kinesin-8motors and explains the origin of loop-2 playing a facilitating role in the depolymerase activity.展开更多
Even though many studies have identified roles of proteasomes in axonal degeneration, the mo- lecular mechanisms by which axonal injury regulates proteasome activity are still unclear. In the present study, we found e...Even though many studies have identified roles of proteasomes in axonal degeneration, the mo- lecular mechanisms by which axonal injury regulates proteasome activity are still unclear. In the present study, we found evidence indicating that extracellular calcium influx is an upstream regulator of proteasome activity during axonal degeneration in injured peripheral nerves. In degenerating axons, the increase in proteasome activity and the degradation of ubiquitinated proteins were sig- nificantly suppressed by extracellular calcium chelation. In addition, electron microscopic findings revealed selective inhibition of neurofilament degradation, but not microtubule depolymerization or mitochondrial swelling, by the inhibition of calpain and proteasomes. Taken together, our findings suggest that calcium increase and subsequent proteasome activation are an essential initiator of neurofilament degradation in Wallerian degeneration.展开更多
文摘Objective: To investigate the different inhibition effects of different sequential usages of microtubule depolymerization drug and polymerization drug on tumor cells. Methods: Three tumor cell lines including MCF-7, SK-OV3, A549 were incubated with paclitaxel (PTX) and/or vinorelbine (NVB) of different concentrations. The cyto-toxicity was exam- ined by MTT test after incubating 72 h. According to different drugs and different sequences added to 96-well tissue culture plates, 5 groups were divided: PTX group (Group 1), NVB group (Group 2), PTX plus NVB group (Group 3), PTX first and NVB 4-h-later group (Group 4), and NVB first and PTX 4-h-later group (Group 5). Drug concentrations were 100% peak plasma concentration (PPC), 50% PPC, 25% PPC, 12.5% PPC, and 6. 25% PPC. Results: The inhibition effects on the three tumor cell lines in Group 5 were stronger than those in the other four groups (P < 0.01). And the inhibition effects in Group 4 were not stronger than those in Groups 1, 2 or 3 (P > 0.1). Conclusion: Using microtubule depolymerization drug first and then using microtubule polymerization drug has synergic inhibition effect on tumor cells.
基金Project supported by the Science and Technology Research Program of Chongqing Municipal Education Commission(Grant No.KJQN202504529)the General Program of Chongqing Natural Science Foundation(Grant No.CSTB2025NSCQ-GPX0833)。
文摘Kinesin-8 motors can move with a high processivity on microtubule lattices toward the plus end.After reaching the plus end,the kinesin-8 motors can pause for a long time and promote the microtubule depolymerization.Here,using atomistic molecular dynamics simulations we studied the structural changes of the kinesin-8 head in different nucleotide states bound to the straight and curved tubulins and the corresponding interactions between them.We found that the kinesin-8 head in ATP and/or ADP–Pi state has the similar strong affinity while in ADP state has the similar weak affinity to both the straight and curved tubulins,which is strongly implicated in the mechanism of the long but very different residence times of the kinesin-8 motor on the microtubule lattice and at the end.Moreover,we found that loop-2 of the kinesin-8 head bound strongly to the curved tubulin in the stable state has a large interference with its neck linker pulled in the minusended orientation.This is contrary to the case of the head bound strongly to the straight tubulin,where loop-2 has little interference with its neck linker pulled in the minus-ended orientation.The large interference can induce a larger internal force between the two heads and thus can induce the two curved tubulins bound strongly by the two heads to be more curved relative to each other.This is strongly implicated in the mechanism of the depolymerase activity of the kinesin-8motors and explains the origin of loop-2 playing a facilitating role in the depolymerase activity.
基金supported by research funds from Dong-A University,South Korea
文摘Even though many studies have identified roles of proteasomes in axonal degeneration, the mo- lecular mechanisms by which axonal injury regulates proteasome activity are still unclear. In the present study, we found evidence indicating that extracellular calcium influx is an upstream regulator of proteasome activity during axonal degeneration in injured peripheral nerves. In degenerating axons, the increase in proteasome activity and the degradation of ubiquitinated proteins were sig- nificantly suppressed by extracellular calcium chelation. In addition, electron microscopic findings revealed selective inhibition of neurofilament degradation, but not microtubule depolymerization or mitochondrial swelling, by the inhibition of calpain and proteasomes. Taken together, our findings suggest that calcium increase and subsequent proteasome activation are an essential initiator of neurofilament degradation in Wallerian degeneration.
