tgf-mediated-endothelial-to-mesenchymal-transition-endmt-functional

TGF-&#946;-mediated Endothelial to Mesenchymal Transition (EndMT) and the Functional Assessment of EndMT Effectors using CRISPR/Cas9 Gene Editing

In response to specific external cues and the activation of certain transcription factors, endothelial cells can differentiate into a mesenchymal-like ...

Leiden University Medical Center

In this work, we presented ternary nanoparticles [poly(carboxybetaine methacrylate) (pCBMA)(peptide dendrimer-modified carbon dots (CD-D)/doxorubicin (DOX))] based on peptide dendritic carbon dots (CDs) to realize tumor-specific drug delivery and highly efficient cancer therapy. The versatile nanoparticles could achieve "stealth" delivery in blood due to the antifouling zwitterion coating. Meanwhile, charge changes of the zwitterions could be moderated during their transportation toward/inside tumor cells, where subtle environmental pH variations acted as potent stimuli to actualize desired functions. In particular, the detachment of the zwitterionic "coat" at the tumor site resulted in the exposure of abundant peripheral guanidine groups on peptide dendritic carbon dots (CD-D/DOX) owing to the extracellular pH environment (pH 6.8)-induced charge conversion. Consequently, the positively charged CD-D/DOX (+7.02 mV) interacted with the negatively charged cancer cell membrane to enhance cellular uptake. After endocytosis, tumor intracellular microenvironments (acidic conditions and high glutathione (GSH) levels) could lead to effective disintegration of the CD-D/DOX entities due to acid-induced protonation of guanidine groups and glutathione-induced cleavage of peptide dendritic components on CDs, and then effective endosomal escape and fast doxorubicin hydrochloride (DOX·HCl) release (73.2% accumulative release within 4 h) were achieved successively. This strategy enabled a 9.19-fold drug release rate at tumor sites in comparison with the one in the physiological environment. Moreover, the excellent fluorescence properties of CDs endowed the pCBMA(CD-D/DOX) with fluorescence bioimaging function. In view of the above-mentioned advantages, pCBMA(CD-D/DOX) exhibited outstanding antitumor activities both in vitro and in vivo, demonstrating much higher antitumor efficacy and less side effects than the free DOX·HCl.

Detachable Polyzwitterion-Coated Ternary Nanoparticles Based on Peptide Dendritic Carbon Dots for Efficient Drug Delivery in Cancer Therapy.

Endothelial to mesenchymal transition (EndMT) is a complex biological process that gives rise to cells with multipotent potential. EndMT is essential for the formation of the cardiovascular system during embryonic development. Emerging results link EndMT to the postnatal onset and progression of fibrotic diseases and cancer. Moreover, recent reports have emphasized the potential for EndMT in tissue engineering and regenerative applications by regulating the differentiation status of cells. Transforming growth factor β (TGF-β) engages in many important physiological processes and is a potent inducer of EndMT. In this review, we first summarize the mechanisms of the TGF-β signaling pathway as it relates to EndMT. Thereafter, we discuss the pivotal role of TGF-β-induced EndMT in the development of cardiovascular diseases, fibrosis, and cancer, as well as the potential application of TGF-β-induced EndMT in tissue engineering.

TGF-β-Induced Endothelial to Mesenchymal Transition in Disease and Tissue Engineering.

Frequent activation of the co-transcriptional factor YAP is observed in a large number of solid tumors. Activated YAP associates with enhancer loci via TEAD4-DNA-binding protein and stimulates cancer aggressiveness. Although thousands of YAP/TEAD4 binding-sites are annotated, their functional importance is unknown. Here, we aim at further identification of enhancer elements that are required for YAP functions.

Article	Year
Detachable Polyzwitterion-Coated Ternary Nanoparticles Based on Peptide Dendritic Carbon Dots for Efficient Drug Delivery in Cancer Therapy. ACS applied materials & interfaces\| PubMed ID: 30474366	2018
TGF-β-Induced Endothelial to Mesenchymal Transition in Disease and Tissue Engineering. Frontiers in cell and developmental biology\| PubMed ID: 32373613	2020
A comprehensive enhancer screen identifies TRAM2 as a key and novel mediator of YAP oncogenesis. Genome biology\| PubMed ID: 33514403	2021

Jin Ma

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