Project description:Purpose: The transcriptional alterations underlying physiological changes in fetal alcohol spectrum disorder are largely unidentified. Here we perform RNA sequencing on 0% and 1% EtOH (12 hpf - 5 dpf) zebrafish at 7dpf stages in order to identify significant transcriptional alterations.
Project description:Corosolic acid (CA) and its derivatives constitute a prominent class of drug candidates; however, their anticancer efficacy against resistant cancer types has been infrequently documented. Organelle-targeted drug delivery is a promising strategy to maximize anti-cancer effects and minimize adverse reactions. Herein, we report a mitochondria-targeted prodrug (CA-TPP) via an esterase-responsive phenolic ester bond to in situ release enough original drug (corosolic acid, CA) in mitochondria, and enhance the therapeutic efficacy. This mitochondria in situ releasing original drug theragnosis significantly reduced the treatment dose of CA to 25% both in vivo and in vitro. CA-TPP induces cell death in DU145 cells through mitochondrial-apoptosis pathway. RNA sequencing analysis further revealed that CA-TPP activated apoptosis through PINK1/Parkin-mediated mitophagy. Inhibition of mitophagy by PINK1 shRNA resulted in an alleviation in CA-TPP induced cytotoxicity in DU145 cells. Further mechanistic study indicates that ROS production in CA-TPP-treated cells causes mitochondrial apoptosis and mitophagy. Together, this prodrug design strategy obviously improved the specificity and anti-tumor activities, which provides a novel opportunity for cancer therapeutic development and broaden the targeted therapy options.
Project description:The deregulation of complex diseases often spans multiple molecular processes. A multimodal functional characterization of these processes can shed light on the disease mechanisms and the effect of drugs. Thermal Proteome Profiling (TPP) is a mass-spectrometry based technique assessing changes in thermal protein stability that can serve as proxies of functional changes of the proteome. These unique insights of TPP can complement those obtained by other omics technologies. Here, we show how TPP can be integrated with phosphoproteomics and transcriptomics in a network-based approach using COSMOS, a framework for causal integration of multi-omics, to provide an integrated view of transcription factors, kinases and proteins with altered thermal stability. This allowed us to recover known mechanistic consequences of PARP inhibition in ovarian cancer cells on cell cycle and DNA damage response in detail and to uncover new insights into drug response mechanisms related to interferon and hippo signaling. We found that TPP complements the other omics data and allowed us to obtain a network model with higher coverage of the main underlying mechanisms. These results illustrate the added value of TPP, and more generally the power of network models to integrate the information provided by different omics technologies. We anticipate that this strategy can be used to broadly integrate functional proteomics with other omics to study complex molecular processes.
Project description:In this study, we investigate how mitochondrial thiamine pyrophosphate (TPP) transporter SLC25A19 regulates mitochondrial function and cell metabolism.
Project description:In this study, we used triphenylphosphonium-conjugated ceria nanoparticles (Ceria-TPP) to target mitochondrial ROS in APOEε4 iPSC-derived neurons, and analyzed transcriptional changes using bulk RNA sequencing.
Project description:To study the consequences of transcription factor pp-1 deletion during vegetative cell fusion, we sequenced mRNA of WT and M-NM-^Tpp-1 conidia during a period of intense germling fusion activity . The,WT,(FGSC2489),and,M-NM-^Tpp1,strains,were,analyzed
Project description:In this study, we used triphenylphosphonium-conjugated ceria nanoparticles (Ceria-TPP) to target mitochondrial ROS in APOEε4 human iPSC-derived brain organoid, and profiled transcriptional changes via single-cell RNA-seq.
Project description:U251 gliolbastoma cells were treated with vehicle (DMSO) or G-TPP, a mitochondrial targeted version of 17-AAG. 6 hours after treatment RNA was harvested and subjected to microarray analysis on Human Gene 1.0 ST Array.
Project description:U251 gliolbastoma cells were treated with vehicle (DMSO) or G-TPP, a mitochondrial targeted version of 17-AAG. 6 hours after treatment RNA was harvested and subjected to microarray analysis on Human Gene 1.0 ST Array. We sought to determine a mitochdondrial gene response after targeting inhibition of mitochondrial chaperones, Hsp90.