Visualizing Photodynamic Therapy in Transgenic Zebrafish Using Organic Nanoparticles with Aggregation-Induced Emission

Photodynamic therapy(PDT) employs accumulation of photosensitizers(PSs) in malignant tumor tissue followed by the light-induced generation of cytotoxic reactive oxygen species to kill the tumor cells. The success of PDT depends on optimal PS dosage that is matched with the ideal power of light. This in turn depends on PS accumulation in target tissue and light administration time and period.As theranostic nanomedicine is driven by multifunctional therapeutics that aim to achieve targeted tissue delivery and image-guided therapy, fluorescent PS nanoparticle(NP)accumulation in target tissues can be ascertained through fluorescence imaging to optimize the light dose and administration parameters. In this regard, zebrafish larvae provide a unique transparent in vivo platform to monitor fluorescent PS bio-distribution and their therapeutic efficiency. Using fluorescent PS NPs with unique aggregation-induced emission characteristics, we demonstrate for the first time the real-time visualization of polymeric NP accumulation in tumor tissue and, more importantly, the best time to conduct PDT using transgenic zebrafish larvae with inducible liver hyperplasia as an example.

Highly efficient genome editing using oocyte-specific zcas9 transgenic zebrafish

Since its first application to induce mutations in mammalian cells （Cong et al., 2013： Mall et al., 2013）, CRISPR/Cas9 has rapidly become a routine technique to perform genome editing in a variety of biological systems due to its facile, robust, and multiplexable fea- tures （Hwang et al, 2013; Wang et al., 2013; Guo et al., 2014; Liu, 2017）.

Targeting lactate dehydrogenase A (LDHA) exerts antileukemic effects on T-cell acute lymphoblastic leukemia

Background:T-cell acute lymphoblastic leukemia(T-ALL)is an uncommon and aggressive subtype of acute lymphoblastic leukemia(ALL).In the serum of T-ALL patients,the activity of lactate dehydrogenase A(LDHA)is increased.We proposed that targeting LDHA may be a potential strategy to improve T-ALL outcomes.The current study was conducted to investigate the antileukemic effect of LDHA gene-targeting treatment on T-ALL and the underlying molecular mechanism.Methods:Primary T-ALL cell lines Jurkat and DU528 were treated with the LDH inhibitor oxamate.MTT,colony formation,apoptosis,and cell cycle assays were performed to investigate the effects of oxamate on T-ALL cells.Quantitative real-time PCR(qPCR)and Western blotting analyses were applied to determine the related signaling pathways.A mitochondrial reactive oxygen species(ROS)assay was performed to evaluate ROS production after T-ALL cells were treated with oxamate.A T-ALL transgenic zebrafish model with LDHA gene knockdown was established using CRISPR/Cas9 gene-editing technology,and then TUNEL,Western blotting,and T-ALL tumor progression analyses were conducted to investigate the effects of LDHA gene knockdown on T-ALL transgenic zebrafish.Results:Oxamate significantly inhibited proliferation and induced apoptosis of Jurkat and DU528 cells.It also arrested Jurkat and DU528 cells in G0/G1 phase and stimulated ROS production(all P<0.001).Blocking LDHA significantly decreased the gene and protein expression of c-Myc,as well as the levels of phosphorylated serine/threonine kinase(AKT)and glycogen synthase kinase 3 beta(GSK-3β)in the phosphatidylinositol 3′-kinase(PI3K)signaling pathway.LDHA gene knockdown delayed disease progression and down-regulated c-Myc mRNA and protein expression in T-ALL transgenic zebrafish.Conclusion:Targeting LDHA exerted an antileukemic effect on T-ALL,representing a potential strategy for T-ALL treatment.

Animal models of T-cell acute lymphoblastic leukemia: mimicking the human disease

T-cell acute lymphoblastic leukemia(T-ALL)is a heterogeneous group of hematological tumors composed of distinct subtypes that vary in their genetic abnormalities.In the past decade,large-scale genomic analysis has shed new light on providing potentially important oncogenic or tumor suppressive candidates involved in the disease progression.Following in silico analysis,functional studies are usually performed to vigorously investigate the biological roles of candidate genes.For this purpose,animal models faithfully recapitulating the human disease are widely applied to decipher the mechanism underlying T-cell transformation.Conversely,an increased understanding of T-ALL biology,including identification of oncogene NOTCH1,TAL1 and MYC as well as tumor suppressor phosphatase and tensin homolog(PTEN),has significantly improved the development of T-ALL animal models.These progresses have opened opportunities for development of new therapeutic strategy to benefit T-ALL patients.In this review,we particularly summarize the mouse and zebrafish models used in T-ALL research and also the most recent advances from these in vivo studies.