An engineered abcb4 expression model reveals the central role of NF-κB in the regulation of drug resistance in zebrafish.

Multi-drug resistance (MDR) is a phenomenon that tumor cells are exposed to a chemotherapeutic drug for a long time and then develop resistance to a variety of other anticancer drugs with different structures and different mechanisms. The in vitro studies of tumor cell lines cannot systematically reflect the role of MDR gene in vivo, and the cost of in vivo studies of transgenic mice as animal models is high. Given the myriad merits of zebrafish relative to other animal models, we aimed to establish a screening system using zebrafish stably expressing ATP-binding cassette (ATP-cassette) superfamily transporters and unveil the potential regulatory mechanism. We first used the Tol2-mediated approach to construct a Tg (abcb4:EGFP) transgenic zebrafish line with ATP-binding cassette (ABC) subfamily B member 4 (abcb4) gene promoter to drive EGFP expression. The expression levels of abcb4 and EGFP were significantly increased when Tg(abcb4:EGFP) transgenic zebrafish embryos were exposed to doxorubicin (DOX) or vincristine (VCR), and the increases were accompanied by a marked decreased accumulation of rhodamine B (RhB) in embryos, indicating a remarkable increase in DOX or VCR efflux. Mechanistically, Akt and Erk signalings were activated upon the treatment with DOX or VCR. With the application of Akt and Erk inhibitors, drug resistance was reversed with differing responsive effects. Notably, downstream NF-κB played a central role in the regulation of abcb4-mediated drug resistance. Taken together, the data indicate that the engineered Tg(abcb4:EGFP) transgenic zebrafish model is a new platform for screening drug resistance in vivo, which may facilitate and accelerate the process of drug development.

A natural acylphloroglucinol triggered antiproliferative possessions in HEL cells by impeding STAT3 signaling and attenuating angiogenesis in transgenic zebrafish model.

Leukemia is responsible for a reason of death, globally. Even though there are several treatment regimens available in the clinics against this disease, a perfect chemotherapeutic agent for the same is still under investigation. Natural plant-derived secondary metabolites are used in clinics to treat leukemia for better benefits with reduced side-effects. Likely, several bioactive compounds from Callistemon sp. were reported for their bioactive benefits. Furthermore, acylphloroglucinol derivatives from Callistemon salignus, showed both antimicrobial and cytotoxic activities in various adherent human cancer cell lines. Thus, in the present study, a natural acylphloroglucinol (2,6-dihydroxy-4-methoxyisobutyrophenone, L72) was tested for its antiproliferative efficacy in HEL cells. The MTT and the cell cycle analysis study revealed that L72 treatment can offer antiproliferative effects, both time and dose-dependent manner, causing G2/M cell cycle arrest. The western blot analysis revealed that L72 treatment triggered intrinsic apoptotic machinery and activated p21. Likewise, L72 could downregulate the gene expressions of XIAP, FLT3, IDH2, and SOD2, which was demonstrated by qPCR analysis, thus promoting its antiproliferative action. The L72 could impede STAT3 expression, which was evidenced by insilico autodock analysis and western blot analysis using STAT3 inhibitor, Pimozide. The treatment of transgenic (Flk-1+/egfr+) zebrafish embryos resulted in the STAT3 gene inhibition, proving its anti-angiogenic effect, as well. Thus, the study revealed that L72 could act as an antiproliferative agent, by triggering caspase-dependent intrinsic apoptosis, reducing cell proliferation by attenuating STAT3, and activating an anti-angiogenic pathway via Flk-1inhibition.

Application study of medical robots in vascular intervention.

BACKGROUND: Based on the background of minimally invasive surgery and applications of medical robots, a vascular interventional robotic system has been developed that can be used in the field of vascular intervention. METHODS: The robotic system comprises a propulsion system, an image navigation system and a virtual surgery training system. Integration of the three systems constitutes a vascular intervention prototype robotic system used to carry out in vitro vascular intervention and animal experiments. RESULTS: On a transparent glass vascular model, a catheter was shown to enter an arbitrary branch of the vascular model with catheter motion meeting the requirements of clinical vascular intervention surgery (VIS); i.e. error band of catheter motion < 0.5 mm. In the animal experiments, 1.33-2.00 mm (4F-6F) diameter catheters were selectively inserted successfully into predefined targets in the animal, such as the renal, cardiovascular and cerebrovascular artery. Compared with conventional manual surgery, the time for robotic surgery is a little longer. There were no operative complications in the animal experiments. CONCLUSIONS: These simulation and animal study results demonstrate that this vascular interventional robotic system allows doctors to perform angiography remotely and prevents them from radiation exposure. The system may be the basis for further clinical applications of vascular intervention.