| Part One Screening of anti-echinococcosis drugsEchinococcosis, a kind of zoonotic infection caused by cestode species of the genus Echinococcus, has long been neglected as a parasitic disease. The clinical drug, Albendazole(ABZ), is the preferred drug used as anti-echinococcosis agent. But, there are cases where ABZ has been proven ineffective in use, and toxicity has also been reported, and resistance formation has occurred due to several decades using. Thus, searching for novel drug candidates with more effective treatment and mild side effects is of great significance for effective treatment and control of echinococcosis infection.In this work, the molecular docking was applied to drug screening of echinococcosis for the first time. Considering GAPDH of Echinococcus as a drug target, traditional Chinese medicines of hexahydrocurcumin and eupafolin with high docking scores, were selected by using virtual screening technology from Zinc TCM Database. Clinical drugs imipenem, masoprocol, dobutamine and fenoldopan were also selected from FDA-approved Drug Library by using virtual screening technology with the same target. In addition, we confirmed that tiliroside, anacardic acid, osthole and esculetin, traditional Chinese medicine inhibitors of Trypanosoma GAPDH, had high docking scores of interaction with the GAPDH of Echinococcus.On the basis of the above, we used experiments to validate the result of virtual screening. In order to evaluate the anti-echinococcosis activity of the molecular docking screening drugs, In vitro efficacy of these drugs against E. granulosus was used in this study, we discovered that the masoprocol and two traditional Chinese medicine, anacardic acid and osthole, exhibited significant effective effect against E.granulosus. And the in vivo efficacy of masoprocol and osthole was investigated in E.multilocularis infection mice in this study, both of which resulting in a significant reduction in parasite burden compared with untreated group.To explore the mechanism of these drugs, we expressed and purified the GAPDH of Echinococcus successfully, and studied the inhibition rate of Eg GAPDH of masoprocol, anacardic acid and osthole. The results showed that the IC50 of these drugs were far greater than its effective anti-echinococcosis concentration, indicating that the enzyme activity inhibition of GAPDH was only one mechanism of these drugs treatment for echinococcosis. Fortunately, we discovered that the inhibition of metacestode growth and blood vessel formation were one of potentially important mechanisms of osthole and masoprocol anti-echinococcosis, with the study of efficacy and toxicology of drugs.In this study, we also studied the toxicity of these drugs. We used the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-te(MTT) assay, the cytotoxicity of masoprocol, anacardic acid and osthole was studied. The results indicated that all of these drugs display low toxicity on cells at the effective anti-echinococcosis concentration. Our studies had also investigated the influence of morphological observation and function indexes detection of liver and kidney in vivo, with effective anti-echinococcosis concentration of masoprocol and osthole, the results indicated that osthole and masoprocol were low toxicity drugs, which opened up a way for clinical application in future.Taken together, masoprocol and two traditional Chinese medicine, anacardic acid and osthole, could be used as new drug candidates against echinococcosis.Part Two Study on power system of implantable medical devicesImplantable medical devices(IMDs) have been widely used for therapies and diagnosis. Among all factors affecting the performance of an IMD, a power source is indispensable for its operation, which is now becoming a major technological difficulty for sustainable and stable operation of the IMDs. Piezoelectric nanogenerator(NG) exhibit profound potential for IMDs power supply, but, as for the application of powering IMDs, the in vivo biocompatibility and in vivo output of NG are big concern. Thus, developing a kind of biocompatible NG with high performance is critically important for clinical applications. Besides, exploration of high performance IMDs based on biosensor will contribute to study the diagnosis, therapies and prognosis for diseases.In order to develop a biocompatible NG, a new kind of nanogenerator is developed based on electrospun 0.5Ba(Zr0.2Ti0.8)O3-0.5(Ba0.7Ca0.3)Ti O3(BZT-BCT) nanowires. In our study, MTT assay is used to study the cytotoxicity of BZT-BCT NWs, the cells’ morphology and the distribution of mitochondria in the cells are obeserved via LSCM, and the detailed structure of the interface between the cells and BZT-BCT NWs is studied by SEM, and all of them indicate that the BZT-BCT NWs are biocompatible. Besides, we study the influence on cells in vitro and tissue in rabbit of nanogenerator, all of them comfirm that the NG has a good biocompatibility and biosafety. We developed a biocompatible NG for the first time, and this new NG has a great potential for in vivo applications such as powering the IMDs.In order to improve the output of nanogenerator, the BZT-BCT NWs are mixed with iron powder and polydimethylsiloxane(PDMS). A wireless piezoelectric nanogenerator with good performance is fabricated base on the composite film, and the open-circuit voltages of this nanogenerator reaches up to 3.6 V in vitro and 1.2 V in vivo. This power-free nanosystem supplies a new general technical solution of wireless, power-free and all time mode for in-vivo resistance-based biodetections by connecting it with a resistance-based biosensor, which further exhibited a potential for powering the IMDs.In this study, fabrication of novel IMDs of biosensor was studied. By using chemical vapor deposition(CVD) method, the silicon nanowires are synthesized by us, facilitating the fabrication of biosensor with high performance, which shows a good response for p H in solution environment and open up a way for diagnosis therapies and prognosis for diseases. |
PDF Full Text Request