NIR-II fluorophores have shown great promise for biomedical applications with superior in vivo optical properties. To date, few small-molecule NIR-II fluorophores have been discovered with donor-acceptor-donor (D-A-D) or symmetrical structures, and upconversion-mitochondria-targeted NIR-II dyes have not been reported. Herein, we report development of D-A type thiopyrylium-based NIR-II fluorophores with frequency upconversion luminescence (FUCL) at ~580 nm upon excitation at ~850 nm. H4-PEG-PT can not only quickly and effectively image mitochondria in live or fixed osteosarcoma cells with subcellular resolution at 1 nM, but also efficiently convert optical energy into heat, achieving mitochondria-targeted photothermal cancer therapy without ROS effects. H4-PEG-PT has been further evaluated in vivo and exhibited strong tumor uptake, specific NIR-II signals with high spatial and temporal resolution, and remarkable NIR-II image-guided photothermal therapy. This report presents the first D-A type thiopyrylium NIR-II theranostics for synchronous upconversion-mitochondria-targeted cell imaging, in vivo NIR-II osteosarcoma imaging and excellent photothermal efficiency.
The present study was designed to test the hypothesis that hypoxia inducible factor (HIF)-1α mediates profibrotic effects of angiotensin (ANG) II and to determine whether HIF prolyl-hydroxylase, the enzyme that promotes the degradation of HIF-1α, is involved in the profibrotic action of ANG II. In cultured renal medullary interstitial cells, ANG II (10−6 M) treatment for 20 hours remarkably increased HIF-1α levels, which was accompanied by the significant upregulation of collagen I/III and tissue inhibitor of metalloproteinases (TIMP)-1. HIF-1α siRNA decreased HIF-1α levels and completely blocked the effects of ANG II on collagen I/III and TIMP-1. HIF-1α siRNA also abolished ANG II-induced elevation of proliferating cell nuclear antigen, a marker of cell proliferation, and vimentin, a marker of cell transdifferentiation. HIF-2α siRNA did not affect the action of ANG II on collagen I/III and TIMP-1. Overexpression of PHD2 transgene, the predominant renal HIF prolyl-hydroxylase, attenuated ANG II-induced profibrotic action and silencing of PHD2 gene enhanced ANG II-induced profibrotic action. Removal of H2O2 eliminated ANG II-induced profibrotic effects. Two week ANG II infusion (150 ng/Kg/min) increased the expression of HIF-1α and α-smooth muscle actin in the renal medullary interstitial cells in vivo. Our data suggest that HIF-1α mediates ANG II-induced profibrotic effects through activation of cell transdifferentiation and that redox regulation of PHD plays a critical role in ANG II-induced activation of HIF-1α and consequent cell proliferation, transdifferentiation and abnormal extracellular matrix metabolism in renal cells.
Breast cancers have been increasingly recognized as malignancies displaying frequent inter- and intra-tumor heterogeneity. This heterogeneity is represented by diverse subtypes and complexity within tumors, and impinges on response to therapy, metastasis, and prognosis. Cancer stem cells (CSCs), a subpopulation of cancer cells endowed with self-renewal and differentiation capacity, have been suggested to contribute to tumor heterogeneity. The CSC concept posits a hierarchical organization of tumors, at the apex of which are stem cells that drive tumor initiation, progression, and recurrence. In breast cancer, CSCs have been proposed to contribute to malignant progression, suggesting that targeting breast cancer stem cells (BCSCs) may improve treatment efficacy. Currently, several markers have been reported to identify BCSCs. However, there is objective variability with respect to the frequency and phenotype of BCSCs among different breast cancer cell lines and patients, and the regulatory mechanisms of BCSCs remain unclear. In this review, we summarize current literature about the diversity of BCSC markers, the roles of BCSCs in tumor development, and the regulatory mechanisms of BCSCs. We also highlight the most recent advances in BCSC targeting therapies and the challenges in translating the knowledge into clinical practice.
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