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Structural and Biochemical Studies of the Dynein ATPase
Published in Claude Gagnon, Controls of Sperm Motility, 2020
Silvio P. Marchese-Ragona, Kenneth A. Johnson
Despite the extensive use of ATP analogs for probing the mechanochemistry of dynein, there can be no substitute for establishing the sequence of reactions following the binding of the natural substrate to determine whether ATP binding or hydrolysis is required for the dissociation of the dynein-microtubule complex. Porter and Johnson33 measured the rate of ATP binding to the dynein-microtubule complex using stopped-flow light scattering methods. The results of this study established that dynein dissociation occurred very rapidly following the addition of ATP to the dynein-microtubule complex. The rate of dissociation increased linearly with increasing ATP concentration, and at high ATP concentrations, the reaction was faster than the temporal resolution of the stopped-flow apparatus (1.6 x.10−3 sec). Thus, the rate of dissociation provided a direct measurement of the rate of ATP binding and the dissociation of dynein from the dynein-microtubule complex. From this information, the second order rate constant for ATP binding was determined to be 4.7 × 106M/sec. The rates of ATP binding and hydrolysis were then measured directly by chemical-quench-flow methods. In brief, the hydrolysis of ATP by dynein leads to an dynein-ADP-Pi intermediate and to a presteady state phosphate burst. The addition of acid stops the reaction and liberates the phosphate. The amplitude of the phosphate burst is less than or equal to the concentration of ATPase sites and can be used to determine the rate of ATP hydrolysis at the active site of the enzyme. The chemical-quench-flow data determined unequivocally that ATP was hydrolyzed at a slower rate than ATP-induced dissociation and consequently occurred after dissociation. It is important to note that although the data proves ATP hydrolysis occurs after dissociation, it does not suggest that dissociation is a prerequisite for hydrolysis.
Mechanochemical prepared ibuprofen-Polygonatum sibiricum polysaccharide drug delivery system for enhanced bioactivity with reduced renal injury induced by NSAIDs
Published in Drug Delivery, 2022
Wenhao Xu, Jinli Yang, Xiangyang Gu, Wenjing Su, Faxiang Pu, Zhangfu Xie, Kongliang Jin, Weike Su, Lichan Mao
Nevertheless, PSP is dampened easily and unstable in high temperatures; PSP drug delivery by traditional methods will face inhomogeneous and agglomerate problems. It would be highly affected drug release. Recently, mechanochemistry was successfully applied to prepare highly efficient drug delivery systems based on polysaccharides. Chistyachenko et al. (2015) prepared a drug delivery system of aspirin via mechanochemical solid-phase technology. By using highly branched natural polysaccharide as the carrier, the solubility of aspirin increased 1.2-fold, and its anticoagulant effect increased twofold. Xu et al. (2021) used a planetary ball mill to prepare solid dispersion of 5-aminosalicylic acid with chitosan and sodium alginate as carriers, which formed a hydrogel in aqueous solution and could realize localized release in the colon, thereby achieving the purpose of treating ulcerative colitis. Kong et al. (2017) used mechanical ball milling technology to prepare a variety of compounds with different natural polysaccharides as carriers to solve the problems of poor water solubility and low oral bioavailability of Statins. The results showed that the three systems improved the water solubility and bioavailability of drugs and significantly reduced blood lipid than the original drugs. Hence, applying mechanochemistry to drug delivery will provide a new approach for preparing PSP drug deliveries.
Mechanochemical preparation of triptolide-loaded self-micelle solid dispersion with enhanced oral bioavailability and improved anti-tumor activity
Published in Drug Delivery, 2022
Dabu Zhu, Qiuqin Zhang, Yifang Chen, Minghua Xie, Jianbo Li, Shen Yao, Ming Li, Zhao Lou, Yue Cai, Xuanrong Sun
Because of the superiority of environment friendliness, easy operation and higher cost performance, more and more attention has been focused on mechanochemistry, such as the development of green synthesis (Bahri et al., 2016; Wei et al., 2018), cocrystal synthesis, and amorphous solid dispersion (W Xu et al., 2018; X Sun et al., 2019). When solid molecular gets high-energy grinding, their particle sizes, crystal forms and physicochemical stability will vary greatly (Boldyrev, 2005). In addition to the above advantages, all the changes may be possible to enhance the solubility and bioavailability (Descamps & Willart, 2016).